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Neurally-mediated reflex syncope: diagnosis and treatment

Romme, J.J.C.M.

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Citation for published version (APA):Romme, J. J. C. M. (2010). Neurally-mediated reflex syncope: diagnosis and treatment.

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Neurally-mediated refl ex syncope: diagnosis and treatment

J.J.C.M. Romme

Neurally-m

ediated refl ex syncope: diagnosis and treatment

J.J.C.M

. Rom

me

Uitnodiging voor het bijwonen

van de openbare verdediging van het proefschrift van

Joost Romme

Neurally-mediated refl ex syncope: diagnosis and treatment

Op vrijdag 21 mei 2010 om 14.00u In de Agnietenkapel van de Universiteit van AmsterdamOudezijds Voorburgwal 231

Receptie ter plaatse na afl oop

van de promotie

Paranimfen:Miranda Stobbe

Edwin Kamphues

Joost Romme

Van Nijenrodeweg 4421082 HK Amsterdam

[email protected]

The printing of this thesis was financially supported by: Stichting Fysiologie en Pathofysiologie van de Circulatie and Stichting tot Bevordering van de Klinische Epidemiologie.

ISBN 978-90-5335-281-6Author J.J.C.M. RommeLay-out Simone VinkeCover design Simone VinkePrinted by Ridderprint, Ridderkerk, The Netherlands


ACADEMISCH PROEFSCHRIFT

ter verkrijging van de graad van doctoraan de Universiteit van Amsterdamop gezag van de Rector Magnificus

prof. dr. D.C. van den Boomten overstaan van een door het college voor

promoties ingestelde commissie, in het openbaar te verdedigen in de Agnietenkapel

op vrijdag 21 mei 2010, te 14:00 uur

door

Jacobus Johannes Christianus Maria Romme

geboren te Hooge Zwaluwe

Promotor: Prof. dr. P.M.M. Bossuyt

Co-promotores: Dr. N. van Dijk Dr. J.B. Reitsma Dr. W. Wieling

Overige leden: Prof. dr. J. Stam Dr. R.D. Thijs Prof. dr. P.W. de Leeuw Prof. dr. A.W. Hoes Prof. dr. R.J. de Haan Prof. dr. M.A.G. Sprangers

Faculteit der Geneeskunde

The research for this paper was financially supported by the Netherlands Heart Foundation (NHS 99/181 and 2003B156).

Financial support by the Netherlands Heart Foundation for the publication of this thesis is gratefully acknowledged.

Aan Mijn Vader

Contents

Chapter 1 Introduction and outline 9

Part I Diagnosis Chapter 2 Influence of age and gender on the occurrence and presentation of reflex syncope 23 Chapter 3 Diagnosing vasovagal syncope based on quantitative history-taking: validation of the Calgary Syncope Symptom Score 41

Part II Treatment Chapter 4 Prospective evaluation of non-pharmacological treatment in vasovagal syncope 63 Chapter 5 Association between general psychological complaints at baseline and syncopal recurrence during non- pharmacological treatment for vasovagal syncope 83

Chapter 6 Drugs and pacemakers for vasovagal syncope, carotid sinus syncope and situational syncope 103 Chapter 7 Effectiveness of midodrine treatment in patients with recurrent vasovagal syncope not responding to non- pharmacological treatment (STAND-trial) 151 Chapter 8 Summary of findings 169 Nederlandse samenvatting 177 List of co-authors 187 Dankwoord 189

Curriculum vitae 193

Chapter 1

Introduction and outline

Introduction and outline 9


Transient loss of consciousness (T-LOC) can be caused by various traumatic and non-traumatic clinical disorders, ranging from potentially lethal to relatively benign.1, 2 Non-traumatic episodes of T-LOC caused by a reduction of blood flow to the brain are called ‘syncope’.1, 3-5 Syncope is characterized by a rapid onset, short duration and spontaneous complete recovery.1, 3, 4 Syncopal causes of T-LOC are often categorized into three major subgroups: (neurally mediated) reflex syncope, syncope due to orthostatic hypotension and cardiac syncope (Figure 1).1, 4

Reflex syncope is the most common cause of T-LOC.2 A diagnosis of reflex syncope is obtained in 30-45% of patients presenting with T-LOC at the emergency department.6, 7 Reflex syncope is caused by reflex vasodilatation and/or bradycardia, resulting in systemic arterial hypotension and cerebral hypoperfusion.1 Although the exact pathophysiological mechanisms leading to an episode of reflex syncope are poorly understood,8 a significant number of predisposing factors or triggers have been identified.9 Based on these predisposing factors, reflex syncope can be further classified into different subtypes: vasovagal syncope (VVS), situational syncope, carotid sinus syncope, and atypical forms (Figure 1).1, 4 VVS, the common faint, is by far the most common form of reflex syncope.2, 4, 6, 7, 10, 11 VVS is mediated by acute pain, fear, or prolonged standing.9, 12 Ttriggers can differ between episodes of VVS in one person.4, 9, 12 Most patients with VVS experience their first syncope before 30 years of age.13, 14

Chapter 1 Introduction and outline12 Introduction and outline

Figure 1. Overview of different causes of transient loss of consciousness (T-LOC).

Reflex syncope associated with swallowing, coughing, micturition, or defecation is called ‘situational syncope.’1, 4, 9, while reflex syncope occurring upon mechanical manipulation of the carotid sinuses in the neck is called ‘carotid sinus syncope.’1,

15 The classic, but rare, examples of a spontaneous carotid sinus syndrome include fainting while shaving the neck, turning the neck, or wearing a tight collar4. In laboratory circumstances, carotid sinus massage will induce abnormal slowing of heart rate and hypotension in these patients.1 Based on the predominant response to carotid sinus massage, carotid sinus hypersensitivity can be further classified into vasodepressor, cardio-inhibitory and mixed suptypes.15 Reflex syncope occurring upon uncertain or even apparently absent triggers is called ‘atypical.’1 In these cases, the diagnosis is usually based on tilt-table testing or a positive response during carotid sinus massage and the exclusion of other causes of T-LOC.1

Patients diagnosed with reflex syncope have a mortality similar to that of people who have not experienced T-LOC.2 Mortality is increased in patients with cardiac and neurological causes of T-LOC.2 Since treatment options and mortality differ depending on the likely cause of T-LOC, it is of vital importance to make a clear distinction between reflex syncope and other causes of T-LOC. This is not straightforward as there can be considerable overlap in symptoms and in triggers between various causes of T-LOC. Below, a number of relevant issues in the diagnosis and treatment of patients with T-LOC are discussed.

Transient loss of

consciousnesss (T-LOC)

Non-traumatic causes Traumatic causes

Syncope Epileptic seizures Functional T-LOC

Neurally mediated

reflex syncope

Syncope due to

orthostatic hypotension

Cardiac syncope

Miscellaneous causes

Vasovagal

syncope

Situational

syncope

Carotid sinus

syncope

Atypical reflex

syncope

Introduction and outlineIntroduction and outline 13

Diagnosing patients presenting with T-LOC

The medical history, in combination with the physical examination and an ECG, plays a key role in diagnosing patients presenting with T-LOC.9, 11, 16-18 Based on this initial evaluation, attending physicians can make a diagnosis in 63% of patients, with a diagnostic accuracy of 91%.18 For this evaluation, attending physicians rely on information pertaining to personal characteristics, signs, symptoms and triggers of different causes of T-LOC as well as on their respective prevalence.

In patients with syncope so-called ‘prodromal’ or ‘pre-syncopal’ signs and symptoms occur when cerebral blood flow diminishes gradually.1, 4 Difficulty in thinking and light-headedness occur early during a typical pre-syncopal episode.4, 5 Next, loss of colour vision and blurring or darkening of vision usually occur.4 Sounds can seem to come from far away. Syncope occurs if systolic blood pressure decreases to 40 mmHg or lower at heart level for at least 6 to 8 seconds.1 Upon loss of consciousness, loss of voluntary motor control occurs and patients fall down.4 The eyes are usually open and directed upwards or straight ahead.19, 20 Additionally, if the hypotensive period is prolonged, myoclonic jerking and urinary incontinence may occur.4 Tongue biting is very rare in syncope.4, 5 If it occurs, the tip of the tongue is usually involved, rather than the side as in epilepsy.5, 21 During a syncopal episode, loss of consciousness usually lasts shorter than 20 seconds,4, 5 since the supine position usually helps to restore venous return and thereby cardiac output, leading to a rise in systemic blood pressure and cerebral perfusion.4 Restoration of consciousness occurs quickly after resumption of cerebral perfusion; patients can subsequently think clearly and remember events. Fatigue and sleepiness might however persist for some time.4

Though the clinical history is of vital importance in diagnosing patients presenting with T-LOC,9 obtaining a diagnosis can be difficult since the symptoms of the different types of syncope are often quite similar, with differences mainly caused by the rapidity of onset rather than the underlying cause.4, 5 Episodes rarely occur in a hospital setting which means that physicians have to rely on identifying presisposing factors and descriptions of symptoms and signs from patients and witnesses. An eyewitness’ account of a single episode of T-LOC should be interpreted with caution since salient features were found to be often overlooked or inaccurately recalled.22 Because of all of the factors mentioned above, properly developed and validated diagnostic tools could facilitate the diagnostic process in patients presenting with T-LOC.


The prevalence of different causes of T-LOC has been shown to depend on both age and gender.6, 12, 23, 24 In a group of medical students (median age 21 years), 39% reported to have experienced at least one episode of T-LOC in their life. In women, the percentage was almost twice that in men (47 versus 24%).12 Most of these episodes involved stresses or conditions that affect orthostatic blood pressure regulation, making reflex syncope the most likely cause of T-LOC in these young subjects. In this age-group the lifetime cumulative incidence of epilepsy (0.5%) and cardiac causes of T-LOC were much lower.18, 25 A similar pattern was found for patients aged 35 to 60 years of age, although episodes of T-LOC were less common in this age group.14 In patients of 65 years or above, episodes of T-LOC again become more common, reflex syncope was still found to be the most frequent cause of T-LOC (54%).26 However, cardiac causes of T-LOC and for instance orthostatic hypotension occur much more frequently in elderly patients compared to younger patients.6, 27-29 Since reflex syncope tends to occur more often in younger patients and women, the prevalence of prodromal signs, symptoms and triggers could also be higher in these patients. If so, information about age and gender in addition to information about prodromal signs, symptoms and triggers can be of use in diagnosing patients presenting with T-LOC.

To facilitate diagnostic decision-making upon initial evaluation, several tools have been developed.1 The Calgary Syncope Symptom Score (Calgary Score) attempts to differentiate VVS from other causes of T-LOC based on history.30 In the internal validation, the Calgary Score was reported to have a high sensitivity (89%) and specificity (91%).30

Treating patients with reflex syncope

Treatment of reflex syncope is directed at reducing the number of (pre-)syncopal recurrences and improving quality of life. The syncope management guideline of the European Society of Cardiology recommends non-pharmacological treatment as first line of treatment for patients diagnosed with reflex syncope.1 This treatment includes lifestyle measures and physical counterpressure manoeuvres, such as leg crossing and hand grip and arm tensing.1 Patients with cardio-inhibitory carotid sinus syncope and patients with other forms of reflex syncope not responding to non-pharmacological treatment are usually prescribed pharmacological and/or pacemaker treatment.1 If reflex syncope is associated with blood phobia and/or psychiatric complaints, psychological counselling might be considered.31


Non-pharmacological treatmentEducation and reassurance regarding the benign nature of the condition are key elements of the non-pharmacological management of patients with reflex syncope.1,

31 Patients are instructed to recognize warning symptoms, to avoid triggering circumstances, to increase their dietary fluid and salt intake, and to perform physical counterpressure manoeuvres.1, 32-34 Such manoeuvres have been shown to induce a significant increase in bloodpressure during the phase of impending reflex syncope, helping to prevent or delay losing consciousness in most cases.34-36

Pharmacological treatment Many pharmacological agents have been proposed for treating more resistant forms of reflex syncope.37 Midodrine is an alpha1-agonist that after absorption is rapidly metabolized to its active metabolite D-glymidodrine, which causes constriction of veins and arterioles.37, 38 In this way, venous pooling of blood is reduced, which may prevent the development of syncope.37 Other pharmacological agents to treat reflex syncope include beta-blockers, fludrocortison, serotonin re-uptake inhibitors, disopyramide and anticholinergic agents.37 Although multiple studies have been performed to assess the effectiveness of midodrine and other pharmacological agents, there are no data from large randomized, placebo controlled trials that show a long-term clinical benefit .37

Pacemaker treatmentIf significant bradycardia or asystole is detected, dual-chamber pacing is postulated to prevent reflex syncope by increasing the heart rate.39 In several non-randomized and/or non-blinded studies, syncopal recurrence was lower upon pacemaker treatment compared to no-pacemaker treatment.40 So far, these results have not been reproduced in properly blinded randomized trials.39-41 This is not surprising, if we consider that pacing may affect the cardio-inhibitory component of the reflex response, but will have no effect on the vasodepressor component, which is often dominant.1 In current syncope management guidelines, cardiac pacing is only recommended in case of spontaneous reflex syncope associated with severe bradycardia or asystole.1, 39, 41

Objectives

This thesis focuses on key issues with respect to the diagnosis and treatment of reflex syncope.


The main objectives of this thesis are:To evaluate the importance of anthropomorphic characteristics and clues derived

from history taking in diagnosing patients presenting with T-LOC.To study the short and long-term effectiveness of non-pharmacolgical treatment

in patients with frequently recurring reflex syncope.To systematically review studies examining the efficacy of different

pharmacological and pacemaker treatments for reflex syncope.To investigate the efficacy of midodrine treatment compared to placebo in

patients with reflex syncope insufficiently responding to non-pharmacological treatment measures.

As the occurrence of different causes of T-LOC appears to be influenced by both age and gender, we wondered whether the respective signs, symptoms and triggers are also influenced by age and gender. We explored this in patients with reflex syncope (Chapter 2). Using information on signs, symptoms and triggers of patients presenting with T-LOC, the Calgary Score has been designed to make a distinction between patients with vasovagal syncope and patients with other causes of T-LOC. We performed a validation study to assess the diagnostic performance of the Calgary Score in an external population. The results of this study are discussed in Chapter 3 of this thesis.42

Since the effectiveness of several treatment options for specific patient groups diagnosed with reflex syncope is still unknown, we wondered whether non-pharmacological treatment would also be beneficial for patients with frequently recurring VVS. These findings are described in Chapter 4.Several studies, mostly cross-sectional, have reported that patients with higher levels of psychological distress have more frequent syncopal recurrence,43-46 we investigated this hypothesis in the studies reported in Chapters 5 of this thesis.

A coherent evaluation of different kinds of pharmacological and pacemaker treatment for reflex syncope does not exist. To fill this gap, we systematically reviewed the available literature on this topic in Chapter 6. For most patients with reflex syncope, pharmacological and pacemaker treatment are only relevant treatment options upon failure of non-pharmacological treatment.1 We investigated the effectiveness of midodrine treatment in patients in whom non-pharmacological treatment failed in Chapter 7.

The thesis ends with a summary of the main study findings and some concluding remarks.


Reference List

1. Moya A, Sutton R, Ammirati F et al. Guidelines for the diagnosis and management of syncope (version 2009): The Task Force for the Diagnosis and Management of Syncope of the European Society of Cardiology (ESC). Eur Heart J 2009;30(21):2631-2671.

2. Soteriades ES, Evans JC, Larson MG et al. Incidence and prognosis of syncope. N Engl J Med 2002;347(12):878-885.

3. Thijs RD, Wieling W, Kaufmann H, van Dijk JG. Defining and classifying syncope. Clin Auton Res 2004;14 Suppl 1:4-8.

4. van Dijk JG, Thijs RD, Benditt DG, Wieling W. A guide to disorders causing transient loss of consciousness: focus on syncope. Nat Rev Neurol 2009;5(8):438-448.

5. Wieling W, Thijs RD, Van Dijk N, Wilde AA, Benditt DG, van Dijk JG. Symptoms and signs of syncope: a review of the link between physiology and clinical clues. Brain 2009;132(Pt 10):2630-2642.

6. Colman N, Nahm K, Ganzeboom KS et al. Epidemiology of reflex syncope. Clin Auton Res 2004;14 Suppl 1:9-17.

7. Olde Nordkamp LR, Van Dijk N, Ganzeboom KS et al. Syncope prevalence in the ED compared to general practice and population: a strong selection process. Am J Emerg Med 2009;27(3):271-279.

8. Hainsworth R. Pathophysiology of syncope. Clin Auton Res 2004;14 Suppl 1:18-24.9. Colman N, Nahm K, van Dijk JG, Reitsma JB, Wieling W, Kaufmann H. Diagnostic value of

history taking in reflex syncope. Clin Auton Res 2004;14 Suppl 1:37-44.10. Chen LY, Gersh BJ, Hodge DO, Wieling W, Hammill SC, Shen WK. Prevalence and clinical

outcomes of patients with multiple potential causes of syncope. Mayo Clin Proc 2003;78(4):414-420.

11. Linzer M, Yang EH, Estes NA, III, Wang P, Vorperian VR, Kapoor WN. Diagnosing syncope. Part 1: Value of history, physical examination, and electrocardiography. Clinical Efficacy Assessment Project of the American College of Physicians. Ann Intern Med 1997;126(12):989-996.

12. Ganzeboom KS, Colman N, Reitsma JB, Shen WK, Wieling W. Prevalence and triggers of syncope in medical students. Am J Cardiol 2003;91(8):1006-1008.

13. Sheldon RS, Sheldon AG, Connolly SJ et al. Age of first faint in patients with vasovagal syncope. J Cardiovasc Electrophysiol 2006;17(1):49-54.

14. Ganzeboom KS, Mairuhu G, Reitsma JB, Linzer M, Wieling W, Van Dijk N. Lifetime cumulative incidence of syncope in the general population: a study of 549 Dutch subjects aged 35-60 years. J Cardiovasc Electrophysiol 2006;17(11):1172-1176.

15. Healey J, Connolly SJ, Morillo CA. The management of patients with carotid sinus syndrome: is pacing the answer? Clin Auton Res 2004;14 Suppl 1:80-86.

16. Brignole M, Alboni P, Benditt DG et al. Guidelines on management (diagnosis and treatment) of syncope—update 2004. Europace 2004;6(6):467-537.

17. Grimm W, Degenhardt M, Hoffman J, Menz V, Wirths A, Maisch B. Syncope recurrence can better be predicted by history than by head-up tilt testing in untreated patients with suspected neurally mediated syncope. Eur Heart J 1997;18(9):1465-1469.

18. Van Dijk N, Boer KR, Colman N et al. High diagnostic yield and accuracy of history, physical examination, and ECG in patients with transient loss of consciousness in FAST: the Fainting Assessment study. J Cardiovasc Electrophysiol 2008;19(1):48-55.

19. Rossen R, Kabat H, Anderson JP. Acute arrest of cerebral circulation in man. Archives of Neurology and Psychiatry 1943;50:510-528.


20. Lempert T, Von Brevern M. The eye movements of syncope. Neurology 1996;46(4):1086-1088.21. Benbadis SR, Wolgamuth BR, Goren H, Brener S, Fouad-Tarazi F. Value of tongue biting in the

diagnosis of seizures. Arch Intern Med 1995;155(21):2346-2349.22. Thijs RD, Wagenaar WA, Middelkoop HA, Wieling W, van Dijk JG. Transient loss of consciousness

through the eyes of a witness. Neurology 2008;71(21):1713-1718.23. Serletis A, Rose S, Sheldon AG, Sheldon RS. Vasovagal syncope in medical students and their first-

degree relatives. Eur Heart J 2006;27(16):1965-1970.24. Wieling W, Ganzeboom KS, Krediet CT, Grundmeijer HG, Wilde AA, van Dijk JG. [Initial

diagnostic strategy in the case of transient losses of consciousness: the importance of the medical history]. Ned Tijdschr Geneeskd 2003;147(18):849-854.

25. Murdoch BD. Loss of consciousness in healthy South African men: Incidence, causes and relationship to EEG abnormality. S Afr Med J 1980;57(19):771-774.

26. Del Rosso A, Alboni P, Brignole M, Menozzi C, Raviele A. Relation of clinical presentation of syncope to the age of patients. Am J Cardiol 2005;96(10):1431-1435.

27. Kapoor W, Snustad D, Peterson J, Wieand HS, Cha R, Karpf M. Syncope in the elderly. Am J Med 1986;80(3):419-428.

28. Kapoor WN. Syncope in older persons. J Am Geriatr Soc 1994;42(4):426-436.29. Mukai S, Lipsitz LA. Orthostatic hypotension. Clin Geriatr Med 2002;18(2):253-268.30. Sheldon R, Rose S, Connolly S, Ritchie D, Koshman ML, Frenneaux M. Diagnostic criteria for

vasovagal syncope based on a quantitative history. Eur Heart J 2006;27(3):344-350.31. Wieling W, Colman N, Krediet CT, Freeman R. Nonpharmacological treatment of reflex syncope.

Clin Auton Res 2004;14 Suppl 1:62-70.32. El-Sayed H, Hainsworth R. Salt supplement increases plasma volume and orthostatic tolerance in

patients with unexplained syncope. Heart 1996;75(2):134-140.33. Claydon VE, Schroeder C, Norcliffe LJ, Jordan J, Hainsworth R. Water drinking improves

orthostatic tolerance in patients with posturally related syncope. Clin Sci (Lond) 2006;110(3):343-352.

34. Van Dijk N, Quartieri F, Blanc JJ et al. Effectiveness of physical counterpressure maneuvers in preventing vasovagal syncope: the Physical Counterpressure Manoeuvres Trial (PC-Trial). J Am Coll Cardiol 2006;48(8):1652-1657.

35. Brignole M, Croci F, Menozzi C et al. Isometric arm counter-pressure maneuvers to abort impending vasovagal syncope. J Am Coll Cardiol 2002;40(11):2053-2059.

36. Krediet CT, Van Dijk N, Linzer M, van Lieshout JJ, Wieling W. Management of vasovagal syncope: controlling or aborting faints by leg crossing and muscle tensing. Circulation 2002;106(13):1684-1689.

37. Kaufmann H, Freeman R. Pharmacological treatment of reflex syncope. Clin Auton Res 2004;14 Suppl 1:71-75.

38. McTavish D, Goa KL. Midodrine. A review of its pharmacological properties and therapeutic use in orthostatic hypotension and secondary hypotensive disorders. Drugs 1989;38(5):757-777.

39. Benditt DG, Nguyen JT. Syncope: therapeutic approaches. J Am Coll Cardiol 2009;53(19):1741-1751.

40. Sud S, Massel D, Klein GJ et al. The expectation effect and cardiac pacing for refractory vasovagal syncope. Am J Med 2007;120(1):54-62.

41. Kuriachan V, Sheldon RS, Platonov M. Evidence-based treatment for vasovagal syncope. Heart Rhythm 2008;5(11):1609-1614.


42. Romme JJCM, Van Dijk N, Boer KR, Bossuyt PM, Wieling W, Reitsma JB. Diagnosing vasovagal syncope based on quantitative history-taking: validation of the Calgary Syncope Symptom Score. Eur Heart J 2009.

43. Gracie J, Baker C, Freeston MH, Newton JL. The role of psychological factors in the aetiology and treatment of vasovagal syncope. Indian Pacing Electrophysiol J 2004;4(2):79-84.

44. Gracie J, Newton JL, Norton M, Baker C, Freeston M. The role of psychological factors in response to treatment in neurocardiogenic (vasovagal) syncope. Europace 2006;8(8):636-643.

45. Flint B, Baker C, Freeston M, Newton JL. Level of psychosocial impairment predicts early response to treatment in vasovagal syncope. Europace 2009;11(2):231-236.

46. D’Antono B, Dupuis G, St-Jean K et al. Prospective evaluation of psychological distress and psychiatric morbidity in recurrent vasovagal and unexplained syncope. J Psychosom Res 2009;67(3):213-222.

Part I

Diagnosis

Chapter 2

Infl uence of age and gender on the occurrence and presentation of refl ex syncope

Clin Auton Res 2008;18(3):127-133

Jacobus J.C.M. Romme Nynke van Dijk Kimberly R. Boer Lukas R.C. DekkerJan StamJohannes B. ReitsmaWouter Wieling

Chapter 224

Abstract

Background: The clinical history is the cornerstone of diagnosing patients with transient loss of consciousness (T-LOC). Reflex syncope is the most common cause of T-LOC in patients across all ages. Knowledge of the variation in incidence and clinical features of reflex syncope by age and gender provides important background information to acquire an accurate diagnosis.

Methods: In a cohort of 503 patients presenting with T-LOC we established a final diagnosis after systematic evaluation and two years of follow-up. The occurrence of prodromal signs, symptoms and triggers in patients with reflex syncope was analyzed by both age (< 40 yrs, 40 – 59 yrs and ≥ 60 years) and gender.

Results: Reflex syncope was the most frequently obtained diagnosis (60.2%) in patients of all ages presenting with T-LOC. Its occurrence was higher in patients under 40 years (73.4%), than above 60 years of age (45.3%). Pallor (79.9%), dizziness (73.4%) and diaphoresis (63.0%) were the most frequently reported prodromal signs and symptoms. Most triggers and prodromal signs and symptoms were more common in patients under 40 years of age and in women.

Conclusions: Reflex syncope is nearly twice as common in patients under 40 years of age than in patients aged 60 years or above. Typical signs and symptoms of reflex syncope are more common in younger patients and in women. Therefore, age and gender provide important diagnostic information and can help to decide whether additional testing is necessary.

Influence of age and gender 25

Introduction

Transient Loss of Consciousness (T-LOC) is a symptom of both benign and potentially lethal clinical disorders.1 Syncope, epilepsy, psychiatric disorders and metabolic disorders are the main causes of T-LOC.2 Syncope is characterized by a transient global cerebral hypoperfusion.3 Reflex syncope is the most prevalent cause of syncope.4 It is caused by systemic arterial hypotension resulting form reflex vasodilatation, bradycardia or both.1 The occurrence of reflex syncope is often preceded by precipitating events (triggers) such as fear, severe pain or micturition.1 Though the exact pathophysiological mechanisms by which triggers could lead to the occurrence of syncope are still unknown,5 reflex-mediated factors, physical factors, or a combination of these are thought to be involved.2

The clinical history is the cornerstone of diagnosing patients with T-LOC.2 In particular, it constitutes a powerful diagnostic tool to discriminate between seizures and syncope, and cardiac syncope and reflex syncope.6-8 Therefore, knowledge about the occurrence of triggers, signs and symptoms provides important background information for physicians to optimize and personalize their diagnostic strategy.

The age distribution of syncope in the general population is bimodal with a peak in teenagers and young adults, mainly found in females, followed by a peak in the elderly.9, 10 Despite this fact, a coherent evaluation of the respective occurrence of triggers, signs and symptoms of reflex syncope for both age and gender has not been performed. Therefore, the aim of our study is to explore differences in prodromal signs and symptoms and triggers in patients with reflex syncope by both age and gender.

Chapter 226

Methods

Study designThe data for the present study were derived from the Fainting Assessment Study (FAST), a prospective cohort study designed to assess the accuracy of diagnostic strategies for adult patients presenting with T-LOC to different departments (Cardiology, Neurology, Internal Medicine, Emergency Department or Cardiac Emergency Room) of the Academic Medical Center, Amsterdam, the Netherlands.11 Attending physicians of the different departments formulated an initial diagnosis, based on history, physical examination and a 12-lead ECG. Additional tests were performed according to an algorithm based upon the ESC-guidelines.1 After 2 years of follow-up, a final diagnosis was made using the initial diagnosis, results from additional testing and additional diagnostic information from recurrent episodes during follow-up. An expert committee reviewed the case if: a patient’s initial diagnosis was deemed incorrect and changed, the patient died during follow-up, or there was any doubt about the final diagnosis due to findings of additional tests or new episodes of T-LOC.11 The final diagnoses were classified in one of the following diagnostic categories: reflex syncope (including vasovagal syncope, situational syncope and carotid sinus syncope), orthostatic hypotension, cardiac syncope, neurological disorder, psychogenic pseudo-syncope, metabolic disorder, or no definitive diagnosis.11 This study is based on these final diagnoses.

PatientsIn the FAST-study, consecutive patients presenting with T-LOC to the Academic Medical Center Amsterdam were eligible for inclusion. T-LOC was defined as self-limiting loss of consciousness not due to head trauma, lasting not longer than 1 hour.11 Patients younger than 18 years of age were excluded. The Medical Ethical Committee of our institution approved the study. All patients gave informed consent.

Information about prodromal signs, symptoms and triggers of episodes was obtained by a physician using a structured questionnaire. Triggers were defined as those reported situations in which T-LOC occurred.1 Prodromal signs and symptoms were defined as signs and symptoms (e.g. nausea, diaphoresis and pallor) that offer warning of an impending episode of loss of consciousness.1 Patient responses to the occurrence of triggers and prodromal signs and symptoms were originally classified as: unknown, absent, sometimes present (<50% syncopal episodes) and usually present (>50% syncopal episodes).11 For analysis, these results were dichotomized (not known or absent (0) and sometimes or usually present (1)).


Statistical analysisPatients were divided into three different age groups: below 40 yrs, 40-59 yrs and 60 yrs or above. These age-groups were chosen to compare symptoms and signs separately in young adults, middle aged subjects and older adults/elderly subjects. It is known that the prevalence of episodes of T-LOC is markedly different in these patient groups.12-14 In the following sections young adults and older adults/elderly subjects will be addressed as younger and older patients.

Continuous data were expressed as mean and standard deviations or median and quartiles. The Student’s t-test, Mann-Whitney test or Kruskal-Wallis test was used to compare groups. We present categorical variables as percentages and compare between groups using the Chi-square statistic or, when appropriate, the Fisher’s exact test.

For each sign or symptom that was associated with both age and gender in univariate analysis (p < 0.1), we performed a multivariate logistic regression analysis to assess whether these effects were mainly age-related, mainly gender-related or both. The presence of a prodromal symptom or sign was used as dependent variable in these models with gender and age as categorical, independent variables. The strength of the association was expressed as an odds ratio (OR) with a 95% confidence interval (95% CI).

All data were analyzed using SPSS 14.0 (SPSS, Chicago, Illinois). P < 0.05 was considered statistically significant.

Chapter 228

Results

PopulationBetween February 2000 and May 2002, 503 patients presenting with T-LOC were included in the FAST-study (Table 1). Details of this study are presented elsewhere.11 The median age of patients was 52 years (p25-p75: 36 – 67 years) and 56% were males. Women (median age 46 years) were younger than men (median age 55; p< 0.01). T-LOC was more common in women in the youngest age group (60.8%) and in men in the oldest age group (61.2%) (p< 0.01). Patients in the youngest age group reported more presyncopal episodes than older subjects (p< 0.01).

Final diagnosesReflex syncope was the most prevalent cause of T-LOC in all age groups (Table 1). The proportion of patients with reflex syncope was highest in the youngest age group (73.4%) compared to the other age groups (62.9% and 45.3% respectively). The prevalence of cardiac syncope was much higher in patients aged 60 years or above (20.0%), compared to patients under 40 years of age (1.3%). Neurological causes of T-LOC were equally prevalent in all age groups (overall 4.2%). In 12.3% of the patients no diagnosis was made after 2 years of follow-up. This percentage was similar in all age-groups.


Table 1. Patient characteristics and final diagnoses by age in patients with transient loss of consciousness.

All ages Age groups P-value

<40 yrs 40-59 yrs

≥60 yrs

N 503 158 175 170Gender Male 56.1% 39.2% 66.3% 61.2% <0.01

Final diagnosis Reflex syncope

Vasovagal syncopeCarotid sinus syndromeSituational syncopeOther

60.2%

49.7%3.2%5.2%2.1%

73.4%

67.7%0%

3.8%1.9%

62.9%

48.6%2.9%6.9%4.5%

45.3%

34.1%6.5%4.7%

0%

<0.01

Orthostatic hypotension 9.1% 2.5% 7.4% 17.1%Cardiac syncope 3.8% 1.3% 5.7% 20.0%Neurological disorder 4.2% 4.4% 5.1% 2.9%Psychogenic pseudo syncope

4.8% 6.3% 5.7% 2.4%

Metabolic disorder 0.2% 0% 0% 0.6%No diagnosis 12.3% 12.0% 13.1% 11.8%

Syncopes last year Median (p25 – p75) 2 (1-3) 1 (1-4) 1 (1–3) 2 (1–3) 0.15Pre-syncope/month Median (p25 – p75) 0 (0-2) 1 (0-4) 0 (0-2) 0 (0-1) <0.01Duration T-LOC <1 min

57.0% 51.0% 58.5% 61.9% 0.58

Post-ictal confusion 12.4% 14.3% 12.7% 10.3% 0.60

Signs, symptoms and triggers in patients with reflex syncopeIn patients with reflex syncope (n = 303), the median number of episodes in the last year was one in patients aged 40 to 59 years of age, and two in the other age groups (Kruskal-Wallis p < 0.01; Table 2a). The median number of syncopal episodes in the last year and pre-syncopal episodes per month was highest in the youngest age group (p < 0.01 and p = 0.01 Kruskal-Wallis). The duration of the episode, according to witnesses, was < 1 minute in 39.5%, 1-5 minutes in 34.2%, > 5 minutes in 13.5% and unknown in 12.8%. The duration of the episodes was similar between age- and gender-groups.

The most frequently reported prodromal signs and symptoms by patients with reflex syncope (all episodes) were: pallor (79.9%), dizziness (73.4%) and diaphoresis (63.0%). All signs and symptoms, except ‘pallor’, were more prevalent in patients

Chapter 230

under 60 years of age, with differences reaching statistical significance for nausea, dizziness, seeing black spots, need to lie down and palpitations. The median number of different prodromal signs and symptoms that emerged over syncopal episodes was higher in patients under 60 years of age than in those above that age (5 vs. 3; p < 0.01). Additionally, young patients reported more prodromal signs and symptoms that are generally associated with neurological disorders, like muscle jerking (27.6% vs. 15.7%) and post-ictal confusion (13.1% vs. 8.5%). These difference were however not statistically significant. Post-ictal confusion was shorter than 1 minute in 12.5%, 1-5 minutes in 41.7% and > 5 minutes in 45.8% of the patients. Cyanosis was rare; only in 8 subjects (2.6%) a blue color of the face was reported.

All patients reported at least one trigger. The syncope triggers that were more frequently reported by patients under 40 years of age were prolonged standing (p = 0.01) and venepuncture (p < 0.01).

Women reported more episodes of reflex syncope in the last year (2 vs. 1; p = 0.02) and pre-syncope per month (1 vs. 0; p < 0.01) than men. Women also reported more prodromal signs and symptoms than men (Table 2b). These differences were all statistically significant, except for diaphoresis, pallor and shortness of breath. The median number of different prodromal signs and symptoms over all syncopal episodes was higher for women than men (6 vs. 4; p < 0.01). The occurrence of reflex syncope upon venepuncture and after a meal was more common in women (p = 0.03 and 0.01 respectively).

Relative contribution of age and genderLogistic regression analysis was performed for triggers, signs and symptoms which were different for both age- and gender groups in univariate analyses (Table 3). The presence of nausea, dizziness and venepuncture was mainly explained by younger age. Differences in occurrence for paraesthesias were explained by the female gender of the subjects (p = 0.02). Differences for both age and gender-groups remained present for the variables seeing black spots and needing to lie down.


Table 2a. Signs, symptoms and triggers in patients with reflex syncope by age.

All ages Age P-value< 40 years

40-59 years

≥60 years

Total 303 116 110 77

Male 53.8% 35.3% 67.3% 62.3% <0.01Syncopes last year Median (p25 – p75) 2 (1 – 3) 2 (1–4) 1 (1-3) 2 (1-4) <0.01Pre-syncopes/ month Median (p25 – p75) 1 (0 – 2) 1 (0–6) 0 (0-1) 0 (0-2) 0.01

ProdromesNausea 49.3% 58.8% 46.7 % 38.7% 0.02Diaphoresis 63.0% 68.4% 62.6 % 55.3% 0.18Pallor 79.9% 76.0% 81.5 % 83.3% 0.47Dizziness 73.4% 83.5% 75.9 % 54.1% <0.01Seeing black spots 42.9% 55.3% 42.2 % 24.7% <0.01Need lying down 56.3% 61.4% 61.3 % 41.1% 0.01Palpitations 23.5% 35.1% 25.7 % 2.7% <0.01Thoracic pain 15.5% 15.7% 17.8 % 12.0% 0.57Shortness of breath 28.2% 33.7 % 27.8 % 18.2% 0.18Shoulder pain 7.2% 5.3% 11.7 % 4.1% 0.10

Abdominal discomfort 13.2% 15.3% 11.3 % 12.7% 0.68

Paraesthesias 20.5% 23.4% 23.6 % 11.3% 0.09

Number of prodromes Median (p25 – p75) 5 (3 – 7) 5 (3–7) 5 (3–7) 3 (2-5) <0.01

Muscle jerking 23.0% 27.6% 23.8% 15.7% 0.20Tongue biting 1.7% 1.8% 2.9% 0% 0.38Urinary incontinence 19.1% 11.8% 27.6% 17.8% 0.01Post-ictal confusion 10.4% 13.1% 9.1% 8.5% 0.53 <1 min 12.5% 20.0% 12.5% 0% 1–5 min 41.7% 50.0% 25.0% 50.0% >5 min 45.8% 30.0% 62.5% 50.0%Duration syncope <1 min 39.5% 41.8% 40.0% 35.6% 0.63 1-5 min 34.2% 34.7% 35.8% 31.5% >5 min 13.5% 13.3% 9.5% 19.2% unknown 12.8% 10.2% 14.7% 13.7%

TriggersProlonged standing 73.3% 80.7% 63.6 % 76.0 % 0.01After exercise 11.2% 15.0% 11.2 % 5.4 % 0.12Change position 18.8% 19.8% 16.3 % 21.2 % 0.75Emotion/pain 24.1% 27.0% 21.1 % 24.0 % 0.59Coughing, micturition, defaecation or swallowing

20.1% 14.9% 22.9 % 24.0 % 0.21

Venepuncture 9.8% 18.6% 5.5 % 2.7 % <0.01After meal 7.8% 6.3% 5.5% 13.3% 0.11

Chapter 232

Table 2b. Signs, symptoms and triggers in patients with reflex syncope by gender.

Gender P-value

Men WomenTotal 163 140

MaleSyncopes last year Median (p25 – p75) 1 (1–3) 2 (1–4) 0.02Pre-syncopes/ month Median (p25 – p75) 0 (0–2) 1 (0–4) <0.01

ProdromesNausea 43.8% 55.9% 0.04Diaphoresis 62.1% 64.0% 0.74Pallor 78.9% 81.0% 0.69Dizziness 68.1% 79.6% 0.03Seeing black spots 33.5% 53.7% <0.01Need lying down 48.1% 65.7% <0.01Palpitations 14.8% 33.6% <0.01Thoracic pain 11.9% 19.6% 0.07Shortness of breath 23.9% 33.0% 0.15Shoulder pain 3.9% 11.1% 0.02

Abdominal discomfort 9.0% 18.0% 0.02

Paraesthesias 15.0% 26.7% 0.02

Number of prodromes Median (p25 – p75) 4 (2-5) 6 (3–7) <0.01

Muscle jerking 24.2% 21.8% 0.65Tongue biting 1.3% 2.3% 0.66Urinary incontinence 20.4% 17.6% 0.54Post-ictal confusion 10.3% 10.6% 0.94 <1 min 7.1% 20.0% 1–5 min 42.9% 40.0% >5 min 50.0% 40.0%Duration syncope <1 min 40.1% 38.7% 0.69 1-5 min 35.9% 32.3% >5 min 11.3% 16.1% unknown 12.7% 12.9%

TriggersProlonged standing 70.0% 77.2% 0.16After exercise 11.1% 11.4% 0.95Change position 16.9% 21.0% 0.45Emotion/pain 25.2% 22.7% 0.63Coughing, micturition, defaecation or swallowing

23.5% 16.2% 0.12

Venepuncture 6.3% 14.0% 0.03After meal 4.3% 12.0% 0.01


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Chapter 234

Discussion

In this study, the influence of both age and gender upon the frequency and occurrence of triggers and prodromal signs and symptoms of reflex syncope was evaluated. A unique feature of this study is that the occurrence of prodromal signs and symptoms was analyzed for both age and gender in the same patient population. In addition, we used the diagnosis after 2 years of follow-up as the final diagnosis of T-LOC. Follow-up data are also available in several studies of Sarasin et al. upon diagnostic evaluation of patients presenting with T-LOC,15, 16 unlike most other studies in which the final diagnosis was obtained after initial evaluation.17

Reflex syncope proved to be much more common in young subjects (73%) than in elderly (45%) subjects. The most common subdiagnosis of reflex syncope was vasovagal syncope (82.4% of cases). The diagnosis of carotis sinus syncope was made in 6.5% of patients aged 60 years or above, while none of the patients under 40 years of age had this diagnosis.Typical prodromal signs and symptoms of reflex syncope were about 50% more common in young patients and women than in older subjects and men. The most important triggers for reflex syncope in our study were prolonged standing, emotion/pain and increased thoracic pressure (such as coughing, micturition and defecation).

Our results confirm the high frequency of reflex syncope in patients <40 yrs (73% in our study) and the predominance of females in this young age group.9 In the general population approximately twice as many women (50%) than men (25%) are affected by T-LOC.9 Reflex syncope remained the single most frequently observed imminent cause of T-LOC in patients aged 60 years or above in our study.13 Its occurrence (45%) was, however, lower than in younger subjects, while a sharp increase in the occurrence of cardiac syncope and orthostatic hypotension was observed.13, 18 Surprisingly, the number of patients remaining undiagnosed after 2 years of follow-up was similar in all age-groups. Elderly patients are usually considered more difficult to diagnose because of co-morbid disorders.

Reflex syncope versus epilepsy: similarities and distinctionsIn our study, limb muscle jerking was present in 27.6% of the patients in the youngest age group and in 15.7% in the oldest age group. In 2001, Newman et al. also found a high number (46%) of subjects with tonic and myoclonic or twitching muscle activity after vasovagal responses during blood donation.19 Though the number of blood donations increases until 50 years of age, the number of syncopal reaction


rates was highest in patients under 40 years of age.19 Thus, limb muscle jerking is common in both reflex syncope and epileptic seizures, particularly in young patients.

Urinary incontinence was present in 19.1% of our patients with reflex syncope, confirming earlier findings that urinary incontinence provides no additional evidence for or against the diagnosis of a seizure.7 The duration of the T-LOC was <5 minutes in 73.7% of the subjects in our study. Although Hoefnagels et al.7 suggested that a duration of loss of consciousness of >5 minutes and postictal confusion are suggestive of epilepsy, 13.5% of our patients with reflex syncope suffered from prolonged loss of consciousness and postictal confusion was observed in 10% of our patients with reflex syncope. Prolonged periods of unconsciousness or postictal confusion (≥ 5 minutes) in syncope patients may be explained by continuing hypotension, for instance, when remaining in an upright position during or after the episode. Additionally, since seeing an episode of T-LOC can be very stressful to witness, the perceived duration of T-LOC could be longer than the actual duration. Thus, an eyewitness’s account about the duration of T-LOC will not always be reliable.Tongue biting was observed in 1.7% of our reflex syncope subjects. However, we did not make the distinction between lateral bites and bites at the tip of the tongue. A lateral tongue bite is highly specific (>99%) to generalized tonic-clonic seizures, while a bite at the tip of the tongue can also occur in syncope.20

Thus the distinction between convulsive syncope and true epileptic seizures can be difficult. However, previous studies indicate that a history of pre-syncope with diaphoresis, nausea and pallor as prodromal signs is strongly suggestive of reflex syncope, while tongue biting, muscle aches and cyanosis are more often associated with an epileptic seizure.7, 8, 21

Reflex syncope versus cardiac syncopePalpitations have been reported earlier as a predictor of cardiac syncope in patients without suspected or diagnosed heart disease.6 The diagnosis of cardiac syncope was obtained after further investigation in only 4 out of 146 patients without suspected heart disease after initial evaluation. Remarkably, in the same study, palpitations were no predictor of cardiac syncope in patients with suspected heart disease after initial evaluation.6 Palpitations have also been reported as features of the clinical history predictive of non-cardiac syncope,22 or as having no predictive value at all.18 Our data document that palpitations are very common and part of the normal clinical presentations of young (35%) and female (34%) subjects with reflex syncope. A likely explanation is a pronounced postural tachycardia prior to an actual faint.23

Chapter 236

Prodromal signs and symptoms and triggers of reflex syncope by ageProdromal symptoms and signs were less prevalent in older patients in our study. This effect of age can be explained by several factors. The activity of the autonomic nervous system and end-organ function decreases with age.23 When standing up, the most common trigger for all types of neurally mediated syncope,24 elderly subjects have less postural tachycardia and less diaphoresis, and thus less prodromal symptoms than younger patients.25 In these elderly subjects, standing up is commonly accompanied by straining and an instantaneous brief rise in blood pressure, followed by a fall in pressure.26, 27 In young patients a brief rise in blood pressure is absent.26,

27 It has been reported that the drop in blood pressure during a vasovagal response is more gradual in elderly subjects than in younger subjects.25 This, in combination with the observation of Lipsitz et al.,28 that for a given fall in systemic blood pressure, the fall in cerebral blood flow velocity is smaller in the elderly, might result in later awareness of the decrease in blood pressure and more time for the cardiovascular system to adapt. Given the relationship between blood pressure decrement and the occurrence of signs and symptoms in syncope,29 elderly subjects will report fewer prodromal signs and symptoms than younger subjects. Poor recollection might make it more difficult to discern specific prodromal signs and symptoms in older patients. In older adults, over one-third of fallers do not recall having fallen 3 months after a documented fall.30 These facts imply that history taking in elderly patients is not always reliable.

Prodromal signs and symptoms and triggers of reflex syncope by genderThe median number of prodromal signs and symptoms in our study was about 50% higher in women than men. Most triggers were also observed more frequently among women than men. Similar results were obtained by Ganzeboom et al..9

The reason for the observed gender differences in the occurrence of symptoms, signs and triggers is not entirely clear. Women have a greater decrease of thoracic blood volume compared to men upon standing,23 resulting in lower orthostatic tolerance associated with decreased cardiac filling.31 This explains the higher number of T-LOC episodes in women. Shoulder pain, a clinical feature known to be associated with orthostatic hypotension,32, 33 was reported in our study by 11% of women and 4% of men with reflex syncope (p = 0.02). Shoulder pain is most likely due to muscle ischaemia.33 This muscle ischaemia is thought to result from a (prolonged) impairment of blood flow in orthostatic hypotension. It is unknown whether this also occurs in patients with reflex syncope experiencing shoulder pain. Further research is therefore needed to explain the occurrence of shoulder pain in patients with reflex syncope.


Studies on pain perception have reported that women consider pain as more unpleasant and are more sensitive to it than men, because of different sociocultural, psychological and biological factors.34 Women appear to have a greater tendency to report pain to health care providers than men and are more open to discuss physical phenomena.35 It seems therefore reasonable to assume that this tendency may also lend itself to women reporting more prodromal signs and symptoms associated with their syncope than men.

Practical implicationsThe medical history is a very important tool to discern different causes of T-LOC.2 It is of utmost important to differentiate between causes with a benign prognosis (such as reflex syncope) and malign prognosis (such as cardiac syncope and neurological syncope),4 as appropriate treatment differs markedly for different causes of T-LOC. According to the ESC-guidelines, reflex syncope is diagnosed if certain triggers are associated with the occurrence of prodromal signs and symptoms.1 In this study we showed that signs and symptoms as well as triggers of reflex syncope, are more often present in women and young people. Since the occurrence of prodromal signs and symptoms is lower in cardiac syncope than in reflex syncope, and cardiac syncope is rare in young women,6, 18, 22 one can be relatively certain about the diagnosis of reflex syncope in the case of a positive history in combination with a normal physical examination and ECG.1, 6 It will then often not be necessary to perform additional tests. Because men and elderly patients report fewer prodromal sings and symptoms, there will be more uncertainty about the diagnosis. Moreover, the risk of cardiac syncope is increased in these patients. Additional tests need to be performed more often to obtain more certainty about the diagnosis. Thus, the age- and gender-related occurrence of prodromal signs and symptoms could help to decide whether additional testing is required.

Conclusion

On the basis of a 2 year follow-up we have demonstrated that the frequency and type of prodromal signs, symptoms and triggers in patients with reflex syncope depend on both age and gender, so these factors should be considered in relation to the probability of its differential diagnosis. In addition, information about age and gender could help to decide whether additional tests are needed.

Reference List


2. Colman N, Nahm K, van Dijk JG, Reitsma JB, Wieling W, Kaufmann H. Diagnostic value of history taking in reflex syncope. Clin Auton Res 2004;14 Suppl 1:37-44.



5. Hainsworth R. Pathophysiology of syncope. Clin Auton Res 2004;14 Suppl 1:18-24.6. Alboni P, Brignole M, Menozzi C et al. Diagnostic value of history in patients with syncope with or

without heart disease. J Am Coll Cardiol 2001;37(7):1921-1928.7. Hoefnagels WA, Padberg GW, Overweg J, Van der Velde EA, Roos RA. Transient loss of

consciousness: the value of the history for distinguishing seizure from syncope. J Neurol 1991;238(1):39-43.

8. Sheldon R, Rose S, Ritchie D et al. Historical criteria that distinguish syncope from seizures. J Am Coll Cardiol 2002;40(1):142-148.

9. Ganzeboom KS, Colman N, Reitsma JB, Shen WK, Wieling W. Prevalence and triggers of syncope in medical students. Am J Cardiol 2003;91(8):1006-1008.

10. Serletis A, Rose S, Sheldon AG, Sheldon RS. Vasovagal syncope in medical students and their first-degree relatives. Eur Heart J 2006;27(16):1965-1970.


12. Driscoll DJ, Jacobsen SJ, Porter CJ, Wollan PC. Syncope in children and adolescents. J Am Coll Cardiol 1997;29(5):1039-1045.

13. Ungar A, Mussi C, Del Rosso A et al. Diagnosis and characteristics of syncope in older patients referred to geriatric departments. J Am Geriatr Soc 2006;54(10):1531-1536.

14. Wieling W, Ganzeboom KS, Saul JP. Reflex syncope in children and adolescents. Heart 2004;90(9):1094-1100.

15. Sarasin FP, Louis-Simonet M, Carballo D et al. Prospective evaluation of patients with syncope: a population-based study. Am J Med 2001;111(3):177-184.

16. Sarasin FP, Pruvot E, Louis-Simonet M et al. Stepwise evaluation of syncope: A prospective population-based controlled study. Int J Cardiol 2007.

17. Morillo CA. Evidence-based common sense: the role of clinical history for the diagnosis of vasovagal syncope. Eur Heart J 2006;27(3):253-254.


19. Newman BH, Graves S. A study of 178 consecutive vasovagal syncopal reactions from the perspective of safety. Transfusion 2001;41(12):1475-1479.

20. Benbadis SR, Wolgamuth BR, Goren H, Brener S, Fouad-Tarazi F. Value of tongue biting in the diagnosis of seizures. Arch Intern Med 1995;155(21):2346-2349.

21. Lempert T. Recognizing syncope: pitfalls and surprises. J R Soc Med 1996;89(7):372-375.


22. Calkins H, Shyr Y, Frumin H, Schork A, Morady F. The value of the clinical history in the differentiation of syncope due to ventricular tachycardia, atrioventricular block, and neurocardiogenic syncope. Am J Med 1995;98(4):365-373.

23. Frey MA, Tomaselli CM, Hoffler WG. Cardiovascular responses to postural changes: differences with age for women and men. J Clin Pharmacol 1994;34(5):394-402.

24. Alboni P, Brignole M, Menozzi C et al. Clinical spectrum of neurally mediated reflex syncopes. Europace 2004;6(1):55-62.

25. Verheyden B, Gisolf J, Beckers F et al. Impact of age on the vasovagal response provoked by sublingual nitroglycerine in routine tilt testing. Clin Sci (Lond) 2007;(113):329-337.

26. Imholz BP, Dambrink JH, Karemaker JM, Wieling W. Orthostatic circulatory control in the elderly evaluated by non-invasive continuous blood pressure measurement. Clin Sci (Lond) 1990;79(1):73-79.

27. Wieling W, Veerman DP, Dambrink JH, Imholz BP. Disparities in circulatory adjustment to standing between young and elderly subjects explained by pulse contour analysis. Clin Sci (Lond) 1992;83(2):149-155.

28. Lipsitz LA, Mukai S, Hamner J, Gagnon M, Babikian V. Dynamic regulation of middle cerebral artery blood flow velocity in aging and hypertension. Stroke 2000;31(8):1897-1903.

29. Alboni P, Dinelli M, Gruppillo P et al. Haemodynamic changes early in prodromal symptoms of vasovagal syncope. Europace 2002;4(3):333-338.

30. Kenny RA, Kalaria R, Ballard C. Neurocardiovascular instability in cognitive impairment and dementia. Ann N Y Acad Sci 2002;977:183-195.

31. Fu Q, Arbab-Zadeh A, Perhonen MA, Zhang R, Zuckerman JH, Levine BD. Hemodynamics of orthostatic intolerance: implications for gender differences. Am J Physiol Heart Circ Physiol 2004;286(1):H449-H457.

32. Freeman R. Clinical practice. Neurogenic orthostatic hypotension. N Engl J Med 2008;358(6):615-624.

33. Robertson D, Kincaid DW, Haile V, Robertson RM. The head and neck discomfort of autonomic failure: an unrecognized aetiology of headache. Clin Auton Res 1994;4(3):99-103.

34. Wise EA, Price DD, Myers CD, Heft MW, Robinson ME. Gender role expectations of pain: relationship to experimental pain perception. Pain 2002;96(3):335-342.

35. Miller C, Newton SE. Pain perception and expression: the influence of gender, personal self-efficacy, and lifespan socialization. Pain Manag Nurs 2006;7(4):148-152.

Chapter 3

Diagnosing vasovagal syncope based on quantitative history-taking: validation of the Calgary Syncope Symptom Score

Eur Heart J 2009: 30(23): 2888-2896

Jacobus J.C.M. RommeNynke van DijkKimberly R. BoerPatrick M.M. BossuytWouter WielingJohannes B. Reitsma

Chapter 3 Validation of the Calgary Score42 Validation of the Calgary Score

Abstract

Background: It can be difficult to distinguish vasovagal syncope, the most common cause of transient loss of consciousness (T-LOC), from other causes of syncope by history-taking. The Calgary Syncope Symptom Score (Calgary Score) is a tool developed for this purpose. We studied its performance in a series of patients presenting with T-LOC.

Methods: We calculated the Calgary Score for 380 patients presenting with T-LOC to a number of departments of our university hospital. Diagnoses of vasovagal syncope based on the Calgary Score were then compared with the final diagnoses, obtained after additional testing and 2 years of follow-up.

Results: The sensitivity of the Calgary Score was 87% (95% CI: 82 to 91%), at a specificity of 32% (95% CI: 24 to 40%). Most items of the Calgary Score were less discriminative in our study group than in the original population. Incorrectly labelling patients with syncope as vasovagal was most common in patients with psychogenic pseudosyncope (specificity 21%) but also occurred in patients with cardiac syncope (specificity 32%).

Conclusions: The sensitivity of the Calgary Score was comparable with the one in the original study, but its specificity was much lower, limiting its value in patients presenting with T-LOC in a general hospital setting.

Validation of the Calgary ScoreValidation of the Calgary Score 43

Introduction

Transient loss of consciousness (T-LOC) is either due to syncope or non-syncope.1,

2 Syncope is a self-limited episode of T-LOC due to a transient hypoperfusion of the brain.2 It can be caused by various conditions, ranging from benign ones such as reflex syncope to more severe and potentially lethal ones such as cardiac syncope.3 Epilepsy and psychogenic pseudo-syncope are examples of non-syncopal T-LOC.1 Since prognosis and treatment differ for the various forms of T-LOC,1, 3 obtaining a correct diagnosis is essential for appropriate management of patients.

Clinical history-taking is the cornerstone of diagnosing patients presenting with T-LOC.4, 5 However, distinguishing vasovagal syncope (VVS, the most frequent cause of reflex syncope)3, 6 from other types of T-LOC by history taking can be difficult. The Calgary Syncope Symptom Score (hereafter abbreviated as Calgary Score) has been developed as a diagnostic tool to discern VVS from other types of syncope.7, 8 The Calgary Score consists of 7 diagnostic questions. Each answer is associated with points, and a total score is calculated by summing the points. Patients with a total score on or above the threshold are classified as having VVS, patients below the threshold as not having VVS.

The Calgary Score was developed in a relatively small study population, with clear syncope diagnoses, and within the specific setting of patients presenting with syncope at Cardiology departments.8 Patients with diagnoses that were less clear were excluded from the analyses used to develop the diagnostic guideline. However, in clinical practice, patients with T-LOC are being evaluated at various hospital departments. Often the precise cause of T-LOC, either syncope or non-syncope, is unclear after initial evaluation. A decision rule to diagnose patients presenting with T-LOC can therefore only be useful, if application to all patients presenting at different clinical settings with either syncopal or non-syncopal causes of T-LOC is possible. In addition, reliable evidence about the diagnostic performance of the Calgary Score is crucial, since misclassification of patients as having VVS who in reality suffer from more severe causes of T-LOC can have serious, sometimes even lethal consequences.

Thus, though the Calgary Score is currently being used in clinical practice,7, 9 it has never been validated in an external population. In this study, we have therefore determined the diagnostic performance of the Calgary Score in an independent series of patients presenting with T-LOC to various clinical departments.


Methods

Study designThe data for the present study were collected in a prospective cohort study designed to assess and compare the value of diagnostic strategies for adult patients presenting with T-LOC at a single university teaching hospital. That study is reported in detail elsewhere.10

PatientsConsecutive patients presenting with T-LOC to the Academic Medical Centre Amsterdam were eligible for inclusion.10 T-LOC was defined as a self-limiting episode of loss of consciousness not due to head trauma, lasting no longer than 1 h.10 Our study complies with the Declaration of Helsinki.11 The Medical Ethical Committee of our institution approved the research protocol. All included patients gave informed consent.

Inclusion and exclusion criteriaPatients presenting with an episode of T-LOC were included at the departments of Neurology, Cardiology, Internal Medicine, Emergency Department and Cardiac Emergency room.10 Patients could have experienced similar episodes previously, but those with a well-established earlier diagnosis for their T-LOC and patients younger than 18 years of age were excluded. As patients with epileptic seizures, cardiomyopathy and/or prior myocardial infarction were excluded from the analysis in the study in which the Calgary Score was developed,8 we also excluded these patients from our study. Patients without a final diagnosis after 2 years of follow-up were also excluded, since it is uncertain whether VVS was present or absent in these patients.

Calgary Score calculationThe Calgary Score consists of seven diagnostic questions about the medical history, triggers, circumstances and signs and symptoms of T-LOC (Table 1).8 All questions are answered as ‘yes’ or ‘no’. If a question is answered as ‘yes’, points are added or subtracted, depending on whether an answer increases the likelihood of VVS or not. The points for individual questions are then summed to obtain a total score (range: -14 to +6 points). If the total score is -2 or more positive, a Calgary Score diagnosis of VVS is made.8

The Calgary Score was originally developed in a cohort of 323 patients, of whom 235 had VVS confirmed by a positive tilt test and 88 had other forms of syncope.8 The seven diagnostic questions of the Calgary Score were selected from a potential


group of 118 historical items using a backward selection method. The additional discriminative value of each question conditional on responses to the other questions was determined in a multivariable logistic regression model, and question points were based on the magnitude of the corresponding coefficients.8

In the current study, the attending physicians took a standardized medical history, using a questionnaire similar to the guideline of the European Society of Cardiology.1 This study has been developed to determine the diagnostic yield of initial evaluation.10 The attending physicians did not know that the diagnostic accuracy of the Calgary Score would be calculated. The questionnaire used in this validation study contained questions about socio-demographic factors, a detailed T-LOC history and history of other medical conditions. This information enabled us to calculate a Calgary Score for each patient. We applied the same cut-off value to obtain a Calgary Score diagnosis of VVS.


Table 1. Individual items of the Calgary Score.8

Question Points (if yes)

1. Is there a history of at least one of bifascicular block, asystole, supraventricular tachycardia, diabetes? –52. At times have bystanders noted you to be blue during your faint? –43. Did your syncope start when you were 35 years of age or older? –34. Do you remember anything about being unconscious? –25. Do you have lightheaded spells or faint with prolonged sitting or standing? 16. Do you sweat or feel warm before a faint? 27. Do you have lightheaded spells or faint with pain or in medical settings? 3 + ___________ Total point score

The patient has vasovagal syncope if the total point score is ≥ -2.Patients with known cardiomyopathy and myocardial infarction are excluded from analysis.

Final diagnosis: further testing and additional follow-upBased upon the structured questionnaire, the findings of a physical examination and a 12-lead ECG, the attending physician formulated a working diagnosis.10 In case other diagnoses were suspected, appropriate additional diagnostic tests were performed. If the diagnosis of T-LOC remained unknown after initial evaluation, cardiac evaluation (echocardiography, 24 h Holter monitoring, and exercise ECG) and, if this revealed no diagnosis, a tilt-table test and carotid sinus massage were performed. In all patients, treatment was initiated according to the ESC-guidelines.1 After at least 2 years of follow-up, a final diagnosis was assigned based on data from the initial presentation, results from additional testing, response to treatment, and additional diagnostic information during follow-up.10 A diagnosis of VVS was made if a trigger (such as fear, pain, and long standing) was associated with prodromal signs and symptoms (such as nausea, light-headedness, and diaphoresis),1 or if a less typical history was confirmed by a positive tilt-table test and/or information from follow-up, and no other cause of T-LOC was found after additional testing and follow-up.10 Vasovagal syncope was considered not to be present in case another diagnosis of T-LOC was made.10

Psychogenic pseudosyncope is used for patients who seem unconscious with no physiologic cause present.1, 12 In our study, a final diagnosis of psychogenic pseudosyncope was made if the clinical history of the patient presenting with T-LOC was very atypical [e.g. prolonged unexplained unconsciousness in supine position (10-30 min), highly frequent episodes (up to several times a day), tight eye closure


during the episodes],4, 12 and/or T-LOC occurred during tilt-table testing or clinical observation without a drop in blood pressure and/or heart rate in patients without another cause of T-LOC. A final diagnosis of psychogenic pseudosynope was only made after consultation with a psychiatrist specialized in functional disorders. The diagnostic criteria that were used for other causes of T-LOC have been published before.1, 10 In the cases where the initial diagnosis was rejected or changed, the patient had died during follow-up or there was any doubt on the final diagnosis, an expert committee, consisting of an expert neurologist, cardiologist and internist reviewed all these cases at the end of at least 2 years of follow-up.10 The expert committee reviewed all available information summarized per patient and made a final diagnosis for each patient. At all times, patients, physicians and expert panel were unaware that a validation study would be performed.

The final diagnoses of patients obtained after additional testing, 2-years of follow-up and, if necessary, expert committee review were used as a reference standard in this study.

Statistical analysisContinuous variables were summarized as means and standard deviations, or medians and quartiles (p25-p75) if the distribution was not normal. Differences in means between groups were tested with two-sided t-test statistics, or the Mann-Whitney test statistic. We summarized dichotomous variables as proportions with 95% confidence intervals (Cis) calculated using the Wilson method13 and used Chi-square tests to compare them between groups.

Diagnostic accuracyWe determined the diagnostic accuracy of the Calgary Score by comparing diagnoses based on the score with the final diagnoses. We calculated the sensitivity, specificity, and positive and negative predictive values of the Calgary Score diagnosis of VVS. Since the relative frequency of causes and signs and symptoms of T-LOC differ between older and younger patients,14-16 we separately determined the diagnostic accuracy in patients under 50 years of age and in patients aged 50 years or above. We evaluated the specificity in a number of subgroups of patients with a final diagnosis other than VVS. We also summarized the Calgary Score distributions for patients with and without a final diagnosis of VVS in a graph.

Diagnostic value of each item of the Calgary ScoreWe counted the frequency of positive responses to each item of the Calgary Score among patients with and without final diagnosis of VVS and compared these to the


frequencies reported in the development study, to evaluate whether specific items were more or less discriminative in this validation study.

All data were analysed using SPSS 16.0 (SPSS, Chicago, IL, USA). P-values <0.05 were considered statistically significant.

Results

Study groupA total of 503 patients were included between February 2000 and May 2002 (Figure 1). Fifty-five patients with a history of cardiomyopathy or myocardial infarction and 18 patients with epileptic seizures were excluded, to match the exclusion criteria of the original publication. Also, 50 patients with an unknown cause of T-LOC were excluded. Our validation cohort, therefore, consisted of 380 patients presenting with T-LOC.

In total, 237 patients (55%) were diagnosed with VVS after additional testing and 2 years of follow-up, while 143 patients suffered from other causes of T-LOC (Figure 1). The most frequent diagnoses in the latter group were: neurally-mediated reflex syncope other than VVS (n = 43), orthostatic hypotension (n = 44), and cardiac syncope (n = 28). Compared with patients with other causes of T-LOC, patients with VVS were younger (Table 2; P < 0.001). Gender and frequency of syncopal episodes did not differ between patients with VVS and patients with other diagnoses (P = 0.08 and P = 0.81, respectively).


Figure 1. Validation cohort: patient selection and final diagnoses after 2 years of follow-up.

T-LOC, transient loss of consciousness

Patients presenting with T-LOC

n = 503

History of

cardiomyopathy or myocardial infarction

n = 55

History of epileptic seizures

n = 18

Vasovagal syncope

n = 237

Patients included in analysis

n = 380

Other forms of T-LOC

N= 143

Neurally-mediated reflex syncope,

not vasovagal syncope n = 43

Orthostatic hypotension n = 44

Cardiac syncope n = 28

Psychogenic pseudosyncope n = 24

Neurological disorder n = 3

Metabolic disorder n = 1

Unknown cause of T-LOC

n = 50


Table 2. Characteristics of patients with and without a final diagnosis of VVS in the validation cohort. a

Final diagnosis P-value

VVS Other T-LOC-diagnoses

Total (n)a 237 143

Mean follow-up time (years, SD) 2.6 (0.7) 2.5 (0.7) 0.23

Gender (n, %) Male 114 (48%) 82 (57.3%) 0.08

Age (n, %) <50 years50 years or above

146 (61.6%)91 (38.4%)

45 (31.5%)98 (68.5%)

< 0.001

Frequency of syncope in last year (n, %)

≤12–3≥4

93 (39.2%)60 (25.3%)84 (35.4%)

64 (44.8%)43 (30.1%)36 (21.6%)

0.81

Frequency of pre-syncope per month (n, %)

<11–3≥4

69 (29.1%)48 (20.3%)120 (50.6%)

66 (46.2%)14 (9.8%)81 (16.7%)

0.07

Duration T-LOC < 1 minute (n, %)

77 (32.5%) 66 (46.2%) 0.002

VVS, vasovagal syncope. T-LOC, transient loss of consciousness.a After exclusion of patients with known cardiomyopathy, myocardial infarction, epileptic seizures and no diagnosis.

Diagnostic accuracy of the Calgary Score A diagnosis of VVS based upon the Calgary Score was made in 380 patients within the validation cohort (Tables 3 - 5). The overall sensitivity of the Calgary Score diagnosis of VVS in our validation cohort was 87% (95% CI: 82 - 91%). The sensitivity was 92% (95% CI: 86 - 95%) for patients under 50 years of age, and 79% (95% CI: 70 - 86%) for patients aged 50 years or above. The overall specificity of the Calgary Score diagnosis of VVS was 32% (95% CI: 24 - 40%). The specificity was 22% (95% CI: 13 - 36%) for patients under 50 years of age and 38% (95% CI: 27 - 46%) for patients aged 50 years or above. In comparison with the original publication, the overall sensitivity was similar (87% vs. 89%), but the overall specificity in the validation cohort was much lower (32% vs. 91%).

In Figure 2, the total point scores of individual patients with and without a final diagnosis of VVS are shown. Although the distribution between the two groups is significantly different, there is a large overlap in total scores between the two groups.


Table 3. Diagnostic accuracy of the Calgary Score in the validation cohort.

Final diagnosis

VVS present VVS absent Total

Calgary Score diagnosis

VVS present 206 98 304

VVS absent 31 45 76

Total 237 143 380

Sensitivity = 206/237 = 87% (95% CI 82-91%) (Original publication: 89%)Specificity = 45/143 = 32% (95% CI 24-40%) (Original publication: 91%)Positive predictive value = 68% (95% CI 62-73%) (Original publication: 96%)Negative predictive value = 59% (95% CI 48-70%) (Original publication: 75%)

Table 4. Diagnostic accuracy of the Calgary Score in the validation cohort for patients under 50 years of age.

Final diagnosis




VVS absent 12 10 22

Total 146 45 191

Sensitivity = 134/146 = 92% (95% CI 86-95%) Specificity = 10/45 = 22% (95% CI 13-36%) Positive predictive value = 79% (95% CI 73-85%) Negative predictive value = 46% (95% CI 27-65%)

Table 5. Diagnostic accuracy of the Calgary Score in the validation cohort for patients aged 50 years or above.

Final diagnosis




VVS absent 19 35 54

Total 91 98 189

Sensitivity = 72/91 = 79% (95% CI 70-86%) Specificity = 35/98 = 38% (95% CI 27-46%) Positive predictive value = 53% (95% CI 45-62%) Negative predictive value = 65% (95% CI 52-76%)


Figure 2. Distribution of total diagnostic point scores of the Calgary Score among patients with and without a final diagnosis of vasovagal syncope (VVS).

Diagnostic value of individual items of the Calgary ScoreWe compared the discriminative value of each individual diagnostic question in the validation cohort with the corresponding value in the development cohort. Table 6 shows that the discriminative value of most diagnostic questions was lower in the validation cohort compared with the development cohort.

Performance of Calgary Score in specific subgroups of patientsWe examined whether specific types of other diagnoses than VVS were responsible for the low specificity of the Calgary Score in our validation cohort by calculating subgroup-specific specificities (Table 7). The specificities of these diagnoses were not significantly different from each other (P = 0.61). The specificity in the subgroup of patients with a cardiac cause for their syncope was 32%. In other words, 68% of these patients (n = 19) would have been incorrectly diagnosed as having VVS by the Calgary Score. In the majority of these patients, diagnostic questions 3 and 5 of the Calgary Score (Table 1) were positive (n = 16 and n = 18, respectively). Patients with psychogenic pseudosyncope had a remarkable low subgroup-specific specificity of 21% (Table 7).

VVS (n = 237) Other (n = 143)

-12

-11

-10

-9

-8

-7

-6

-5

-4

-3

-2

-1

0

1

2

3

4

5

6

7

8 P < 0.0001

Calgary

ScoreCut-off value

Calgary Score

diagnosis of VVS

Calgary Score

diagnosis different

from VVS


Tabl

e 6.

Fre

quen

cy o

f pos

itive

res

pons

es to

indi

vidu

al d

iagn

ostic

que

stio

ns o

f the

Cal

gary

Sco

re in

pat

ient

s with

and

with

out v

asov

agal

sync

ope

in th

e va

lidat

ion

coho

rt (F

AST

-stu

dy) c

ompa

red

to th

e de

velo

pmen

t coh

ort (

Cal

gary

Syn

cope

Sym

ptom

Stu

dy).

Dia

gnos

tic q

uest

ions

Cal

gary

Sco

reVa

lidat

ion

coho

rt

Odd

s ra

tioD

evel

opm

ent C

ohor

tO

dds r

atio

RO

RP-

valu

e

VV

Sn

= 23

7O

ther

T-L

OC

di

agno

ses

n =

143

VV

Sn

= 23

5O

ther

T-L

OC

di

agno

ses

n =

88

1. Is

ther

e a

hist

ory

of a

t lea

st o

ne o

f bifa

scic

ular

bl

ock,

asy

stol

e, su

prav

entri

cula

r tac

hyca

rdia

, di

abet

es?

13%

23%

0.50

3.4%

64%

0.02

24.9

1<

0.00

1

2. A

t tim

es h

ave

byst

ande

rs n

oted

you

to b

e bl

ue

durin

g yo

ur fa

int?

2.

1%4.

9%0.

421.

3%8.

0%0.

152.

800.

26

3. D

id y

our s

ynco

pe st

art w

hen

you

wer

e 35

yea

rs

of a

ge o

r old

er?

42%

78%

0.20

28%

91%

0.04

5.28

< 0.

001

4. D

o yo

u re

mem

ber a

nyth

ing

abou

t bei

ng

unco

nsci

ous?

0%0%

0a31

%53

%0.

40N

ot

calc

ulat

edN

ot

calc

ulat

ed

5. D

o yo

u ha

ve li

ghth

eade

d sp

ells

or f

aint

with

pr

olon

ged

sitti

ng o

r sta

ndin

g?

85%

83%

1.22

69%

38%

3.77

3.09

0.00

4

6. D

o yo

u sw

eat o

r fee

l war

m b

efor

e a

fain

t?

65%

43%

2.49

62%

24%

5.23

2.10

0.04

7. D

o yo

u ha

ve li

ghth

eade

d sp

ells

or f

aint

with

pa

in o

r in

med

ical

setti

ngs?

32%

15%

2.74

48%

5.7%

15.3

85.

610.

002

RO

R, r

elat

ive o

dds r

atio

indi

catin

g ho

w m

uch

mor

e or l

ess d

iscr

imin

ativ

e a d

iagn

ostic

que

stio

n is

in th

e dev

elop

men

t coh

ort c

ompa

red

with

the v

alid

atio

n co

hort

by e

xam

inin

g th

e ra

tio o

f bot

h od

ds ra

tios.

a The

ans

wer

to th

is d

iagn

ostic

que

stio

n w

as ‘n

o’ in

all

patie

nts.


Table 7. Performance of Calgary Score in subgroups of patients with a final diagnosis other than vasovagal syncope in the validation cohort.

Final diagnosis Calgary Score diagnosis not VVS

Calgary Score diagnosis VVS

Specificity diagnosis other than VVS (95% CI)

P-value

Neurally mediated reflex syncope(not vasovagal)

14 29 33% (95% CI 21-48%) 0.61

Orthostatic hypotension 15 29 34% (95% CI 22-49%)

Cardiac syncope 9 19 32% (95% CI 18-51%)

Neurological disorder 2 1 67% (95% CI 21-94%)

Psychogenic pseudosyncope 5 19 21% (95% CI 9-41%)

Metabolic syncope 0 1 a

a Not calculated because of small number. Overall specificity Calgary Score: 32%

Discussion

This is the first study evaluating the Calgary Score in a series of patients presenting with T-LOC to various departments in a large hospital. Although the sensitivity was similar in our study compared with the original publication, the specificity of the Calgary Score was much lower, implying that a large number of patients would receive an incorrect diagnosis of VVS based on the Calgary Score, while in reality they had a different cause for their T-LOC.

The methods of patient selection differed considerably between our validation study and the original study. The original study of Sheldon et al.8 only included patients with a typical manifestation (clear but strict rules) of the condition of interest (VVS) which is then contrasted with a well–defined group of patients with a different diagnosis for their T-LOC (controls). By including only well-defined cases and controls, the difference between these two groups is increased, making it easier for a test to distinguish cases and controls. There is both theoretical and empirical evidence that such an approach can lead to (severely) overoptimistic estimates of diagnostic accuracy.17-20 Therefore, we used a different approach in our validation study by including a group of consecutive patients presenting with T-LOC.


Unfortunately, there is no gold standard test to diagnose patients presenting with T-LOC.5 This implies that the final classification in any diagnostic study about T-LOC is challenging and the problem of misclassification always exists. In our study, a patient’s final diagnosis was based on three different sources of information: (i) standardized and prospectively collected information of history and physical examination; (ii) results of additional tests performed as recommended by the ESC Guidelines on syncope;1 (iii) dedicated follow-up information of at least 2 years of all patients including any additional testing, specific events, or causes of death.10 Such an approach is clinically appealing, because all these factors can provide important information, but a single factor is often not conclusive. To combine these multiple pieces of information, a team of experts reviewed and interpreted information obtained during initial evaluation and clinical follow-up and made a consensus diagnosis. The expert panel approach has been advocated in the literature for situations where a (single) gold standard does not exist.21

Other factors that could explain the observed difference in diagnostic accuracy between the original study and validation study include differences in setting and methodology. In the original study, patients were only recruited from cardiology departments and syncope units,8 whereas in our study patients were recruited from several different departments. This difference could explain the relatively high frequency of cardiac causes and relatively low frequency of non-cardiac causes in the original study. For example, orthostatic hypotension was found to be present in only one patient in the original study compared with 44 patients in our study.8 Additionally, more advanced or more typical cardiac causes seemed to be present in the original publication.

The difference in setting also helps to explain why patients in our population were older than the patients in the original cohort.8 It is known that patients aged 65 years or above experience less prodromal signs and symptoms.15, 16, 22 Because of this, it becomes more difficult with advancing age to differentiate between different causes of T-LOC based on historical criteria alone. Additionally, in older patients, the cause of their episodes is more often multifactorial, and therefore less likely to fit one diagnostic group.5 The sensitivity of the Calgary Score was therefore lower for patients aged 50 years or above (79%) compared with younger patients (92%).

A methodological issue that deserves attention is the way the Calgary Score has been developed. The Calgary Score was developed using a data-driven approach, based on multiple variables and a backward elimination strategy.8 An important drawback of such an approach is that variables can be included in the final model


due to associations based on chance in a particular dataset rather than a true, robust relationship. This is known as overfitting.23 Overfitting is more likely, if the number of potential variables considered for inclusion is large in relation to the sample size. The authors in the original publication considered 118 potential variables for inclusion on a total of 235 patients with a final diagnosis of VVS.8 If overfitting is present, the performance of the model is likely to drop considerably when applied in a new series of independent patients.24, 25 Although the authors used bootstrapping to correct for the likely overoptimism in their model, it has been shown that this method may be insufficient and may not be indicative for the model’s performance in future patients.26

Probably due to the data-driven approach, the selection and the weights of two of the seven diagnostic questions in the Calgary Score are questionable. Diagnostic question 4, whether patients remember anything about being unconscious (Table 1)8, is probably used to determine whether the patient has truly lost consciousness, since remembering anything at the moment of true loss of consciousness seems impossible.2 In our validation cohort, the answer to this question was ‘no’ in all patients. In contrast, 47% of patients in the original study reported to remember anything about being unconscious.8 This difference in reporting can almost certainly be explained by differences in data collection. In the study in which the Calgary Score was developed, data were derived from self-administered questionnaires, while in our validation study an attending physician took the history of patients.8, 10 Interviewer-administered questionnaires have been shown to be more reliable than self-administered questionnaires for medical histories.27

The other peculiarity is the large number of points that is assigned if diabetes mellitus is present in a patient (-5 points for question 1), irrespective of the presence of cardiac rhythm disturbances. If diabetes mellitus is present in a patient, it becomes more difficult to obtain a Calgary Score diagnosis of VVS (total point score ≥ - 2). Though instability of cerebral blood flow due to autonomic failure can occur in patients with diabetes,28 there is no evidence that the diagnosis of VVS is more unlikely in these patients than in patients without diabetes. Accordingly, we found that 9 of the 31 patients with a false-negative diagnosis of VVS had diabetes mellitus.

Strengths and limitationsSeveral characteristics of our study deserve attention when interpreting the results. An issue already addressed is the validity of the final diagnosis. We used all available data of history taking, physical examination and additional testing and dedicated follow-up of at least 2 years in all patients. Follow-up is useful because subsequent


events or additional testing may reveal relevant information on the accuracy of the diagnosis. However, even after 2 years of follow-up, the diagnosis was still unclear in 50 patients. This is a problematic group when evaluating the accuracy of this diagnostic tool, because it is unknown whether VVS has occurred. We excluded this group when calculating the accuracy of the Calgary Score (specificity of 32%); the specificity of the Calgary Score would drop to 30% if these patents would be included in the non-VVS group.

Another problem is that patients over time may experience T-LOC episodes with different causes. To reduce this problem, we only included patients without a previously diagnosed cause of T-LOC.

Role of quantitative history-takingIn this study, we found a high number of patients who would have received a diagnosis of vasovagal syncope according to the Calgary Score but in reality had another cause for their T-LOC (specificity of 32%). The requirements for a test (e.g minimum sensitivity and specificity) vary depending on the clinical consequences associated with false-positive or false-negative test results and the intended role of the test in clinical practice. The mortality rate and morbidity in patients with a cardiac syncope or T-LOC due to neurological disorders is much higher than in patients with VVS.3,

29-32 This implies that diagnosing patients actually suffering from a non-vasovagal cause of T-LOC as suffering from VVS (false-positives in this study) is worse than classifying patients with VVS as suffering from cardiac syncope (false negatives).

Because of its low specificity, we do not recommend to use the Calgary Score as a sole measure to diagnose individual patients presenting with T-LOC in clinical practice. Because there is no gold standard, we think the best way to obtain a diagnosis still consists of an integration of diagnostic information from medical history, physical examination, and additional testing, as recommended by the ESC Guideline on syncope.10 However, it sometimes remains quite difficult to integrate and weigh these multiple pieces of information, especially if there is a significant variation in presentation between patients, as occurs in patients with reflex syncope in general and VVS more specifically. Therefore, new, externally validated diagnostic rules could be very useful to discern malignant and benign causes of T-LOC. More targeted diagnostic rules might be necessary to discriminate between particular diagnoses, taking into account variations in presentations between patients.


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21. Rutjes AW, Reitsma JB, Coomarasamy A, Khan KS, Bossuyt PM. Evaluation of diagnostic tests when there is no gold standard. A review of methods. Health Technol Assess 2007;11(50):iii, ix-51.

22. Alboni P, Brignole M, Menozzi C et al. Diagnostic value of history in patients with syncope with or without heart disease. J Am Coll Cardiol 2001;37(7):1921-1928.

23. Moons KG, Donders AR, Steyerberg EW, Harrell FE. Penalized maximum likelihood estimation to directly adjust diagnostic and prognostic prediction models for overoptimism: a clinical example. J Clin Epidemiol 2004;57(12):1262-1270.

24. Hollander N, Schumacher M. On the problem of using ‘optimal’ cutpoints in the assessment of quantitative prognostic factors. Onkologie 2001;24(2):194-199.

25. McGinn TG, Guyatt GH, Wyer PC, Naylor CD, Stiell IG, Richardson WS. Users’ guides to the medical literature: XXII: how to use articles about clinical decision rules. Evidence-Based Medicine Working Group. JAMA 2000;284(1):79-84.

26. Bleeker SE, Moll HA, Steyerberg EW et al. External validation is necessary in prediction research: a clinical example. J Clin Epidemiol 2003;56(9):826-832.

27. Herrmann N. Retrospective information from questionnaires. II. Intrarater reliability and comparison of questionnaire types. Am J Epidemiol 1985;121(6):948-953.

28. Dandona P, James IM, Woollard ML, Newbury P, Beckett AG. Instability of cerebral blood-flow in insulin-dependent diabetics. Lancet 1979;2(8154):1203-1205.

29. Kapoor WN, Karpf M, Wieand S, Peterson JR, Levey GS. A prospective evaluation and follow-up of patients with syncope. N Engl J Med 1983;309(4):197-204.

30. Kapoor WN. Evaluation and outcome of patients with syncope. Medicine (Baltimore) 1990;69(3):160-175.

31. Day SC, Cook EF, Funkenstein H, Goldman L. Evaluation and outcome of emergency room patients with transient loss of consciousness. Am J Med 1982;73(1):15-23.

32. Dougnac A, Gonzalez R, Kychenthal A, Loyola MS, Rubio R, Rubenstein LZ. Syncope: etiology, prognosis, and relationship to age. Aging (Milano ) 1991;3(1):63-72.

Part II

Treatment

Chapter 4

Prospective evaluation of non-pharmacological treatment in vasovagal syncope

Europace: in press

Jacobus J.C.M. RommeJohannes B. ReitsmaIngeborg K. Go-SchönMark P.M. HarmsJaap H. RuiterJan S.K. LuitseJacques W.M. LendersWouter WielingNynke van Dijk

Chapter 4 Non-pharmacological treatment64 Non-pharmacological treatment

Abstract

Aims: Initial treatment of vasovagal syncope (VVS) consists of assuring an adequate fluid and salt intake, regular exercise and application of physical counterpressure manoeuvres. We examined the effects of this non-pharmacological treatment in patients with frequent recurrences.

Methods: One hundred patients with ≥3 episodes of VVS in the 2 years prior to the start of the study openly received non-pharmacological treatment. We evaluated this treatment both with respect to syncopal recurrences, factors associated with recurrence, and quality of life (QoL).

Results: The median number of syncopal recurrences was lower in the first year of non-pharmacological treatment compared with the last year before treatment (median 0 vs. 3; P < 0.001), but 49% of patients experienced at least one recurrence. In multivariable analysis, a higher syncope burden prior to inclusion was significantly associated with syncopal recurrence. Disease-specific QoL improved over time, with larger improvements for patients with more reduction in syncope burden.

Conclusion: In patients with frequent recurrences of VVS, non-pharmacological treatment has a beneficial effect on both syncopal recurrence and QoL, but nearly half of these patients still experience episodes of syncope.

Non-pharmacological treatmentNon-pharmacological treatment 65

Introduction

Syncope is a self-limited episode of transient loss of consciousness (T-LOC) due to a transient hypoperfusion of the brain.1 Reflex syncope is caused by systemic arterial hypotension resulting from reflex vasodilatation, bradycardia, or both.2 Vasovagal syncope (VVS), mediated by emotional or orthostatic stress, is the most common cause of reflex syncope.2-5

Non-pharmacological treatment, consisting of life style advice and physical counterpressure manoeuvres (i.e. muscle tensing), is recommended as the first line of treatment for VVS in current syncope management guidelines.2 Patients are educated about the benign nature of the condition and are encouraged to increase the dietary salt and fluid intake (blood volume expansion) and to perform moderate exercise training.6, 7 In a relatively mildly affected population the combination of lifestyle measures and physical counterpressure manoeuvres have been shown to decrease the syncope burden by 39%.2 However, it is yet unknown whether this combined non-pharmacological treatment is also effective in more severely affected patients.

Treatment of VVS should not only be directed at reducing the number of (pre-)syncopal recurrences, but should also aim to improve quality of life (QoL). QoL was found to be lower in patients with T-LOC compared to healthy subjects.3-7 Linzer et al.5 reported a level of impairment similar to severe rheumatoid arthritis and chronic low back pain. QoL in patients with T-LOC was found to be influenced by age, gender, co-morbidity, time of onset and frequency of syncopal recurrences as well as occurrence of pre-syncope.3, 5, 6 However, the effect of non-pharmacological treatment on QoL is still unknown.

Upon non-pharmacological treatment, we expect both a decrease in the frequency of syncopal recurrence and an improvement in quality of life. Whether both these effects occur in patients with VVS is still unknown. Therefore, we prospectively determined the effects of non-pharmacological treatment for VVS both with respect to syncopal recurrence and QoL.


Methods

This study was conducted by the Syncope Treatment and Assessment network Netherlands (STAND). Patient inclusion of this non-randomized study took place at the Emergency Departments and syncope units of 4 medical centres. All patients received non-pharmacological treatment, including life style measures, and physical counterpressure manoeuvres. This combined treatment was evaluated both with respect to syncopal recurrences and QoL.

Study populationPatients between 18 and 70 years of age with a clinical diagnosis of recurrent VVS were eligible for inclusion. The diagnosis of VVS was based on the definition of the syncope management guideline of the European Society of Cardiology.8 We defined recurrent VVS as the occurrence of at least three syncopal episodes in the last 2 years.

Both patients with a certain clinical diagnosis based on history and physical examination and patients with highly likely VVS in combination with a positive head-up tilt-table test (HUT-test) were included. The induction of either pre-syncope or syncope in the presence of hypotension (systolic blood pressure < 90 mm Hg) upon HUT-testing was defined as a positive response.8 Pre-syncope refers to a condition in which patients feel as though syncope is imminent, but actual loss of consciousness does not occur.8 Only patients with recognizable prodromal symptoms in more than 80% of syncopal episodes of VVS were included.

Patients with orthostatic hypotension, suspected or confirmed heart disease with high likelihood of cardiac syncope, steal syndrome, episodes of loss of consciousness other than VVS, pregnancy and a life expectancy < 1 year were excluded. Patients with a high likelihood of study drop-out before the ending of the study as assessed by the research physician were also excluded.

The Medical Ethical Committee of the Academic Medical Center in Amsterdam approved the study (project number 03/191). The trial was registered in the Dutch Trial Register (ISRCTN29932893) and performed according to the declaration of Helsinki.


Non-pharmacological treatment After obtaining written informed consent, study participants were given a handout with lifestyle advice. Patients were instructed to avoid - if possible - conditions in which prior episodes of (pre-)syncope occurred. An adequate fluid intake and high salt intake (accomplished by liberal addition of salt to meals) were advised; excessive alcohol intake was discouraged.9-13 All patients were also encouraged to physically exercise several times a week.9 During a biofeedback training session in physical counterpressure manoeuvres, the influence of leg-crossing, tensing of buttock and leg muscles, squatting, handgrip and arm tensing on finger arterial blood pressure was demonstrated. Details on how to perform these manoeuvres have been described elsewhere.2, 9 Finger arterial pressure was measured beat-to-beat by means of a Nexfin® (BMEYE B.V., Amsterdam, the Netherlands) or a similar device.14 Patients practiced the physical counterpressure manoeuvres with the continuous blood pressure tracing on a computer screen as feedback to gain optimal performance.

In this study, the combined effects of lifestyle measures, including assurance of an adequate fluid and salt intake, and physical counterpressure manoeuvres were determined.

Follow-up We asked patients to register date and symptoms of subsequent recurrences under non-pharmacological treatment measures in a logbook. At 1, 3, 6, 9, 12, 15, and 18 months after inclusion, we obtained information about syncopal recurrence, usage of physical counterpressure manoeuvres and also their perceived effectiveness. Patients were contacted by telephone or seen at the outpatient-clinic.

Pharmacological treatmentThe study protocol allowed patients to receive pharmacological treatment after 6 months of follow-up, if they had experienced three or more syncopal and/or severe pre-syncopal episodes during follow-up. Since we only evaluated the effects of non-pharmacological treatment in this present study, follow-up ended at the start of pharmacological treatment.

Quality of lifeQoL was measured at four time points: before treatment initiation and after 3, 12, and 18 months of follow-up. If pharmacological treatment was started, QoL was also assessed just prior to this treatment. Generic QoL was assessed using the short form-36 (SF-36) questionnaire. This self-administered questionnaire consisting of 36 items measures generic health


concepts relevant across age, disease, and treatment groups.9, 19 After completing this questionnaire, eight scale scores can be calculated: physical functioning, role functioning physical, bodily pain, general health, vitality, social functioning, role functioning emotional, and mental health. The scores can be summarized into two scales, the physical and mental component summaries. All raw scale scores are converted linearly to a scale ranging from 0 to 100 (maximum). The higher the scores within this range, the higher the level of functioning or well-being. Translation, validation and norming of the Dutch-language version have been performed previously.20

Disease-specific QoL was measured using the Syncope Functional Status Questionnaire (SFSQ). This questionnaire consists of 11 yes/no questions to assess syncope interference with a patient’s life and three 8-point Likert-scale questions assessing fear and worry with respect to syncope.15 The impairment score is calculated in two steps. Firstly, the number of areas in which syncope interfered with a patient’s life (range 0 to 11) is divided by the number of areas that were applicable to patients. Secondly, the obtained number is multiplied by 100, resulting in a score between 0 and 100, with 100 representing impairment in all areas that are applicable to patients. The three Likert-scale questions are averaged to calculate a fear/worry score scaled from 0 to 100, with 100 indicating maximum fear and worry. The Syncope Dysfunction Score (SDS) represents the averaged impairment score and fear/worry score. The higher this score, the worse syncope-related QoL. In a previous study, the validity, reliability and responsiveness of the Dutch version of the SFSQ have been determined.16

Statistical analysisWe expressed demographic and clinical data as proportions for categorical data, means (SD) for normally distributed continuous data and median with quartiles for variables with non-normal distributions.

We expressed the frequency of syncopal recurrence in several ways. The syncope burden was calculated by dividing the total number of syncopal episodes by the respective time period in years. We compared the syncope burden during the first year of treatment with the number of syncopes during the last year before the start of treatment using a Wilcoxon signed rank test. The index episode of syncope was not included in the calculation of the syncope burden before treatment as this will increase this burden in comparison to the calculation of the syncope burden after treatment which is based on a fixed period, i.e. not necessarily ending with a syncopal episode.


A Kaplan-Meier curve was used to visualize the time to first recurrence of syncope. We used univariate Cox proportional hazards models to determine the effects of gender, age, syncope burden before treatment, and co-morbidity (represented by the Charlson comorbidity index17) on syncopal recurrence. Predictors with a univariate p-value of 0.1 or lower were entered into a multivariable Cox proportional hazards model.

To analyze QoL at baseline and during follow-up, we used all available SF-36 and SFSQ questionnaires obtained at baseline and at 3, 12, and 18 months of follow-up. We calculated summary scores of the SF-36 and SFSQ questionnaires according to the guidelines of these respective questionnaires.19, 20 For each of these questionnaires separately, we analysed all available summary scores using a linear mixed effects model including time as a categorical variable and the baseline value as a continuous covariate.18 Using this model, we tested the null hypothesis that the obtained scores at baseline were equal to the scores at 3, 12, and 18 months of follow-up. We expressed any change in QoL during the study period as difference in means with a 95% confidence interval (95% CI).

To evaluate associations between clinical changes and changes in QoL we calculated a patient’s relative improvement in syncope burden and QoL. The relative improvement in syncope burden was calculated based on the amount of syncopal recurrences in the year before the start of treatment excluding the last episode that led to the health care visit (A) and the syncope burden during the first year of treatment (B) using the following formula: [(A - B) / A]*100%. If A and B were zero, we considered the relative improvement in syncope burden to be 0%. In case a patient had more episodes during treatment than before, the relative improvement could become larger than –100%, whereas in case of improvement the maximum improvement could not exceed 100%. This might lead to a distorted picture and therefore we also put a limit of –100% in case of worsening during treatment. Changes in QoL were calculated in two steps. We first calculated patients’ mean summary scores of all available SFSQ and SF-36 questionnaires during 1 year of follow-up. Secondly, we calculated the difference between the mean summary score during 1 year of follow-up and the summary score at baseline in such a way that a positive difference indicated improved QoL during treatment. Using a scatter plot, we graphically displayed the relation between the relative improvement in syncope burden and the absolute improvement in QoL during the first year of follow-up. We determined the Spearman’s rank correlation between physical symptoms and QoL.

All data were analysed using SPSS 16.0 (SPSS, Chicago, IL, USA). If not specified otherwise, we considered a P < 0.05 as statistically significant.


Results

PopulationBetween 2 January 2005 and the end of September 2008, 100 patients were included (Table 1). Mean age of the patients was 38 years and 34% were men. At inclusion, the median period since the first occurrence of syncope was 15 years [interquartile range (IQR) 6 - 26 years)]. The median number of syncopal episodes (without the index episode) in the year before study participation was three (IQR 1 - 6). Thirty-one percent of patients had experienced trauma due to VVS once or more in their lives, of which half were hematoma and/or wounds.

Follow-up was closed on 14 April 2009. Mean follow-up time was 12 months. No patients were lost to follow-up.

Table 1. Patient characteristics.

All patientsNumber 100Mean age (SD) 38 (14)Male gender (%) 34%Race (%) - Caucasian- Black- Asian- Hispanic

88%5.1%6.1%1.0%

Highest educational level (%)- No formal education- Elementary school- High school- College

1.0%5.2%46%48%

Charlson comorbidity index (%)- 0- 1- ≥ 2

86%12%2.0%

Period of complaints, years Median (p25 – p75) 15 (6 – 26)Number of syncopal episodes last 2 years Median (p25 – p75) 5 (3 - 14)Number of syncopal episodes last year Median (p25 – p75) 3 (1 - 6)

Trauma due to (pre-)syncope (%)

- Hematoma/wound- Contusion/fracture- Head injury other than skin wounds

31%

15%6.0%10%


Syncopal recurrenceWithin the first 6 months of follow-up, 42% of patients had experienced syncopal recurrence(s). This percentage increased to 49% after one year. The syncope-free survival during follow-up is represented in Figure 1. The median syncope burden during the first year of non-pharmacological treatment was lower compared with the number of syncopal episodes in the year before treatment (0 vs. 3 respectively; P < 0.001; Table 2). The median time to syncopal recurrence after start of treatment was 59 days (IQR 15 - 125). Age as well as the syncope burden before study participation were associated with syncopal recurrence in the univariate Cox analysis. In multivariate analysis, effects were significant for patients with two or more syncopal recurrences per year before study participation (hazard ratio 2.8 (95% CI 1.1 – 7.1) for two to five prior syncopal recurrences (P = 0.03); hazard ratio 3.9 (95% CI 1.6 – 9.6) for six or more prior syncopal recurrences (P = 0.004)).

Physical counterpressure manoeuvres were applied by 94% of patients within the first year (Table 2). Most (52%) of these patients reported that the manoeuvres were very beneficial to them. The most important reason for failure of physical counterpressure manoeuvres in case of syncopal recurrence was that syncope appeared too quickly to apply the manoeuvres (56% of cases). Twenty-five percent of patients reported that syncope still recurred though they managed to apply the physical counterpressure manoeuvres. Two patients (4%) were forgotten how to apply the manoeuvres to prevent syncopal recurrence.

Figure 1. Syncope-free survival.


Table 2. Number of syncopes and usage of physical counterpressure manoeuvres.

All patients P- valueNumber of syncopal episodes during the last year before treatment

Median (p25 – p75) 3 (1 – 6) < 0.001

Number of syncopes during the first year of treatment

Median (p25 – p75) 1 (0 – 3)

Days to first syncopal recurrence in case of syncopal recurrence

Median (p25 – p75) 59 (15 – 125)

Proportion of patients that used physical counterpressure manoeuvres within first year of non-pharmacological treatment

94%

Perceived benefit from physical counterpressure manoeuvres (%)

- Very much- Little- Not at all

52%36%12%

Main reason failure counterpressure manoeuvres in case of syncopal recurrence (%)

- No/too short period of prodromal symptoms

- Forgot to use manoeuvres- Manoeuvres performed, but

ineffective- Other reasons

56%

4.2%25%

15%


Quality of lifeThe Physical Component Summary scores obtained during follow-up were higher (i.e. improved QoL) than the summary score obtained at baseline (48 vs. 45; P = 0.001; Figure 2). The Mental Component Summary Scores at baseline and during follow-up were similar (P = 0.28). The estimated SDSs were lower during follow-up compared to baseline (34 vs. 22; P < 0.001), indicating an improvement in QoL.

Figure 2: Quality of life during non-pharmacological follow-up using a linear mixed effects model.

Improved quality of life is indicated by higher scores for the physical and mental component summary of the short form-36 questionnaire and lower scores with respect to the syncope dysfunction score of the syncope functional status questionnaire. The summary scores of both questionnaires can vary between 0 and 100.

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Association between improvement in syncope burden and quality of lifeThe association between relative improvement in syncope burden and absolute improvement in QoL is displayed in Figure 3. In 63% of patients the syncope burden decreased during non-pharmacological treatment (total of quadrants B and D). Forty percent of patients showed both improvements in Q0L and syncope burden. Only the correlation between absolute improvement in SDS and relative improvement in syncope-burden was statistically significant (r = 0.32; P = 0.004).

Figure 3: Relationship between improvement in quality of life and improvement in syncope burden during the first year of non-pharmacological treatment.

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PCS-score: Physical Component Summary-score of the Short Form-36 (SF-36) questionnaire. MCS-score: Mental Component Summary-score of the SF-36 questionnaire. SDS-score: Syncope Dysfunction Score of the Syncope Functional Status Questionnaire (SFSQ). For both axes in the graphs, 0 was the threshold to discern improvement and deterioration. We separated each graph in four quadrants (A, B, C, and D) by drawing straight lines through the null-values of each axis and calculated the percentage of patients in each quadrant. A.Deterioration in syncope burden and improvement in quality of life. B. Improvement in both syncope burden and quality of life. C. Deterioration in both syncope burden and quality of life. D. Improvement in syncope burden and deterioration in quality of life. Note that syncopal recurrence decreased upon non-pharmacological treatment in 63% of patients (patients in quadrants B and D). In the majority of these patients (quadrant B), a decrease in syncopal recurrence upon treatment was associated with an improvement in quality of life.


Discussion

This is the first study in which the effectiveness of non-pharmacological treatment has been determined with respect to both changes in syncopal recurrences and QoL in VVS patients with frequent syncopal recurrences. In more than 60% of patients the occurrence of syncope episodes decreased during non-pharmacological treatment. However, nearly half of patients still experienced one or more syncopal recurrences within the first year of follow-up. QoL improved during non-pharmacological treatment and there was a slight positive association between larger reductions in syncope burden and more improvement in disease-specific QoL.

After diagnosing VVS, in addition to lifestyle measures patients are given instructions to perform physical counterpressure manoeuvres. These manoeuvres have been shown to be a risk-free and effective treatment method in patients with vasovagal syncope with prodromal symptoms.2, 19 In the PC-trial, the proportion of patients with recurrence during on average 14 months of follow-up was lower in patients trained in physical counterpressure manoeuvres (32%) compared to patients that only received lifestyle advice (51%; P = 0.005).8 Compared with this previous study, the proportion of patients with a recurrence during the combination of life style measures and manoeuvres was higher in our present study (49%, after a follow-up of 12 months). This higher percentage of recurrences can be explained by the selection of more severely affected patients in our study. We only included patients with three or more true syncopal episodes, whereas in the PC-trial also patients with three pre-syncopal episodes in the last year were included.2 Accordingly, the median number of syncopal episodes in the last 2 years before study participation was nearly twice as high in this present study compared to the PC-trial (5 vs. 3).8 Since the number of syncopal episodes before presentation is the main predictor of recurrence, the selection of patients explains the higher syncopal recurrence rate in this study.20

We found that a syncope burden of two or more before study participation significantly increased the likelihood of syncopal recurrence. This confirms the earlier results by Sheldon et al.20 who found that both the number of previous syncopal episodes as well as the duration of syncopal symptoms were important to predict syncopal recurrences after diagnosis. In contrast with this previous study, the duration of symptoms was not a significant predictor of syncopal recurrence in our study.

It is well known that physical and psychosocial function are impaired in patients with T-LOC.9, 11 In previous studies, QoL has been evaluated only once after treatment initiation, in combined groups of patients with various diagnoses and treatments.10,


12, 13, 27 In contrast, we prospectively evaluated QoL at consecutive time points during follow-up in a more homogeneous group of patients. We found that both the Physical Component Summary of the SF-36 questionnaire and the SDS significantly improved during treatment including physical counterpressure manoeuvres. Of these, only the change in Physical Component Summary seems to be of clinical significance, as only the improvement in this score was larger than the minimally important difference as found in an earlier study (3 vs. 0.7).7 The improvement in both the Mental Component Summary and SDS were smaller than the minimally important difference (1.2 vs 5.6 and 12 vs. 15, respectively).7 The clinical significance of these improvements is borderline, as the changes are just above (Physical Component Summary 3 vs. 0.7) or just below (Syncope Dysfunction Score 12 vs. 15) the minimal important difference as found in an earlier study.7 Nevertheless, mainly physical aspects of QoL seem to show a clinical significant change upon non-pharmacological treatment. In our view, a prolonged period of self-experienced treatment effectiveness is needed before patients feel confident about being able to prevent impending (pre-)syncopal recurrences. We expect that all domains of QoL will increase as soon as patients feel confident about being able to prevent impending recurrences of VVS.

In most earlier studies assessing the change in QoL after treatment initiation, only the number of syncopal episodes after start of treatment, and not the change in syncope-burden was taken into account. Because of the inverse relationship between the lifetime number of syncopal episodes and QoL,9, 12, 13 we hypothesized that if syncope recurs less often during treatment than before treatment, QoL will also improve.3, 6 Therefore, in our view changes in the frequency of syncopal recurrence are as relevant as the presence or absence of recurrence alone to evaluate treatment effectiveness. In our study, the correlation between relative improvement in syncopal recurrence and improvement in QoL was significant with respect to syncope-related dysfunctioning (r = 0.32; P = 0.004), but not when assessing physical and mental functioning in general. These findings indicate that general QoL in patients with VVS is not only determined by syncopal recurrence. Other factors such as co-morbidity and psychiatric complaints are likely to be involved.3, 5

LimitationsOur study was not randomized. All included patients openly received non-pharmacological treatment for VVS. Though we had originally planned to determine the additional effect of physical counterpressure manoeuvres to lifestyle advice in a randomized fashion, results from the PC-trial revealed that treatment including physical counterpressure manoeuvres was clearly more effective.2 Because of ethical


reasons, we decided to determine the effects of combined non-pharmacological treatment only. Since we did not examine the contribution of the components of the non-pharmacological treatment, we are unable to conclude anything about the effects of these individual treatment measures. Except for counterpressure manoeuvres,2 there is only circumstantial evidence about the benefits of adequate water and salt intake and regular exercise to prevent recurrent VVS.10, 21, 22

In our single treatment study, we compared syncope burden before and after treatment, which should be interpreted with care. Sheldon et al.23 have shown that many VVS patients present themselves after a recent worsening of their syncope. Moreover, if patients present after a recent worsening of their symptoms, syncopal recurrence is likely to decrease afterwards irrespective of the treatment given. Therefore, our focus was not only a reduction of episodes, but also on the absolute value of the proportion of patients having a recurrence in this population. In addition, we evaluated which patient characteristics were associated with recurrence and whether larger reductions in syncope burden were associated with more improvement in QoL. All these questions can be adequately addressed within our single treatment study.

Both at presentation and during follow-up, patients were asked about their frequency of VVS. We suspect that patients’ memory of recurrent episodes during one to 3 months of follow-up is better than their remembrance of episodes during their whole lives, also because in the study patients had been given a diary to record episodes of VVS. If this is true, the number of episodes before presentation is probably underestimated and the real treatment effect is likely to be larger than reported in this study.

Patients were allowed to receive pharmacological treatment after six or more months of follow-up if they suffered from three or more episodes of syncope or severe pre-syncope after the start of non-pharmacological treatment. Patients with fewer recurrences were likely to have a better QoL3, 6, 7 and were followed for a longer period than more severely affected patients. If we would have excluded the highly affected, pharmacologically treated patients from the analysis after ending of their non-pharmacological study treatment, QoL determined at later moments of follow-up would be too optimistic. We therefore chose to use a linear mixed effects model, allowing estimations of QoL at times QoL was supposed to be evaluated but was however unavailable.18 Although we think that the use of a mixed effects model is best to deal with missing QoL data over time, estimations might still be too optimistic or pessimistic, and therefore need to be interpreted with caution.


Conclusion

In patients with frequent syncopal recurrences, the number of syncopal recurrences decreases after initiation of non-pharmacological treatment, while QoL improves over time. We therefore conclude that non-pharmacological treatment is also beneficial to patients that are more severely affected by VVS, but only half of patients does not experience any episode of syncope. Non-pharmacological treatment should be recommended to all patients diagnosed with VVS, but some patients may require additional treatment.


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15. Linzer M, Gold DT, Pontinen M, Divine GW, Felder A, Brooks WB. Recurrent syncope as a chronic disease: preliminary validation of a disease-specific measure of functional impairment. J Gen Intern Med 1994;9(4):181-186.

16. Van Dijk N, Boer KR, Wieling W, Linzer M, Sprangers MA. Reliability, validity and responsiveness of the syncope functional status questionnaire. J Gen Intern Med 2007;22(9):1280-1285.

17. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40(5):373-383.

18. Fitzmaurice GM, Laird NM, Ware JH. Linear Mixed Effects Models. In: Balding DJ, Cressie NAC, Fisher NI, Johnstone IM, Kadane JB, Molenberghs G et al., editors. Applied Longitudinal Analysis. 1 ed. New Jersey: John Wiley & Sons; 2004:187-236.


19. Krediet CT, Van Dijk N, Linzer M, van Lieshout JJ, Wieling W. Management of vasovagal syncope: controlling or aborting faints by leg crossing and muscle tensing. Circulation 2002;106(13):1684-1689.

20. Sheldon R, Rose S, Flanagan P, Koshman ML, Killam S. Risk factors for syncope recurrence after a positive tilt-table test in patients with syncope. Circulation 1996;93(5):973-981.

21. Claydon VE, Schroeder C, Norcliffe LJ, Jordan J, Hainsworth R. Water drinking improves orthostatic tolerance in patients with posturally related syncope. Clin Sci (Lond) 2006;110(3):343-352.

22. Gardenghi G, Rondon MU, Braga AM et al. The effects of exercise training on arterial baroreflex sensitivity in neurally mediated syncope patients. Eur Heart J 2007;28(22):2749-2755.

23. Sheldon RS, Sheldon AG, Serletis A et al. Worsening of symptoms before presentation with vasovagal syncope. J Cardiovasc Electrophysiol 2007;18(9):954-959.

Chapter 5

Association between general psychological complaints at baseline and syncopal recurrence during non-pharmacological

treatment for vasovagal syncope

Submitted

Jacobus J.C.M. RommeNynke van DijkIngeborg K. Go-SchönGerty CasteelenWouter WielingJohannes B. Reitsma

Chapter 5 Psychiatric complaints and syncopal recurrence84 Psychiatric complaints and syncopal recurrence

Abstract

Introduction: Vasovagal syncope (VVS), the most common cause of transient loss of consciousness (T-LOC), is often accompanied by higher levels of psychological distress. It is yet unknown whether psychological complaints interact with the effects of non-pharmacological treatment in patients with frequently recurring VVS.

Methods: Patients with ≥3 episodes of VVS in the 2 years prior to the start of the study openly received non-pharmacological treatment. Before treatment initiation, we determined the level of general psychological complaints by the Symptom Checklist 90-R (SCL-90-R) questionnaire. We regularly evaluated syncopal recurrence during follow-up. We compared the SCL-90-R scores of VVS patients in our study with the corresponding scores of healthy Dutch subjects (reference population). We examined whether patients with more recurrences during follow-up had higher SCL-90-R scores at baseline and whether this association changed when adjusting for other factors associated with recurrence using logistic regression.

Results: Total SCL-90-R scores were higher in our cohort of patients with frequent episodes of VVS than in the reference population (142 vs. 118; p<0.001). During the first 6 months of treatment, 42% of patients experienced syncopal recurrence(s). The SCL-90-R scores of these patients were significantly higher compared to patients without syncopal recurrence in this period (160 vs. 130; p=0.01). After adjusting for other predictors of recurrence, especially the number of episodes before inclusion, the association between SCL-90-R scores and recurrence remained intact.

Conclusion: Levels of general psychological complaints are higher in patients with syncopal recurrence during non-pharmacological treatment of VVS, even after adjusting for previous syncopal episodes.

Psychiatric complaints and syncopal recurrencePsychiatric complaints and syncopal recurrence 85

Introduction

Syncope is a self-limited episode of transient loss of consciousness (T-LOC) due to a transient hypoperfusion of the brain.1 Reflex syncope is caused by systemic arterial hypotension resulting from reflex vasodilatation, bradycardia or both.2 Vasovagal syncope (VVS), mediated by emotional or orthostatic stress,2 is the most common cause of both reflex syncope and T-LOC.3

Initial treatment of VVS consists of non-pharmacological treatment measures including reassurance regarding the benign nature of the condition, increasing the dietary salt and fluid intake, moderate exercise training and physical counterpressure manoeuvres (muscle tensing).4, 5 Physical counterpressure manoeuvres have been shown to reduce the number of syncopal episodes by almost 40% in addition to other non-pharmacological treatment measures.6 The majority of patients with occasional reflex syncope respond to the aforementioned non-pharmacological treatment measures.6 If patients do not respond to non-pharmacological treatment, pharmacological or pacemaker treatment might be considered. 2

Vasovagal syncope can have a substantial impact on a patient’s life because of its unexpected nature and fear for recurrence.7, 8 Patients diagnosed with T-LOC report poorer quality of life9-11 and more general psychological complaints compared to patients without T-LOC.8, 12 Especially anxiety, mood and somatization disorders occurred more often in patients with VVS compared to healthy control subjects.12 In addition, it has been suggested that high levels of psychological complaints at baseline could reduce the effectiveness of VVS treatment.12-15

Apart from general psychological complaints, the effectiveness of VVS treatment might also be influenced by other, possibly confounding factors. In several studies, syncopal recurrence was strongly associated with the number of previous syncopal episodes.15-17 In separate studies, syncopal recurrence was also found to be associated with age 17-19 and/or gender, 16, 17, 19 although not in all studies.12-15

Our aim of this study was to examine the risk of syncopal recurrence during non-pharmacological treatment is higher in patients with higher levels of general psychological complaints at baseline. We investigated this relationship in patients severely affected by VVS, with and without controlling for other potential predictors of syncopal recurrence.


Methods

This study was conducted by the Syncope Treatment and Assessment network Netherlands (STAND). Patients with frequent episodes of VVS were included. First, the level of general psychological complaints was determined, then non-pharmacological treatment including physical counterpressure manoeuvres was started in all patients.

Study populationPatient inclusion took place in 4 Dutch medical centers. Patients between 18 and 70 years of age with a clinical diagnosis of recurrent VVS obtained at the emergency department or syncope unit were eligible for inclusion. Recurrent VVS was defined as the occurrence of at least 3 syncopes in the last 2 years. The diagnosis of VVS was based on the definition of the ESC-guidelines2.

Syncope was defined as self-limited complete loss of consciousness with a duration of less than 5 minutes caused by a transient global cerebral hypoperfusion.2 Syncope can be triggered by several conditions, such as prolonged standing, pain, and emotional distress and is often accompanied by signs and symptoms such as pallor, sweating and nausea.20 The condition in which patients feel as though syncope is imminent but loss of consciousness does not occur is defined as pre-syncope.2

Both patients with a certain clinical diagnosis based on history and physical examination ánd patients with highly likely VVS in combination with a positive head-up tilt-table test (HUT-test) were included. The induction of either pre-syncope or syncope in the presence of hypotension (systolic blood pressure < 90 mm Hg) upon HUT-testing was defined as a positive response.2 Only patients with recognizable prodromal symptoms prior to vasovagal syncope in >80 % of the episodes and a normal physical examination and electrocardiogram (ECG) were included.

We excluded patients without a somatic explanation for their T-LOC after thorough investigation, if necessary after consulting a psychiatrist. Patients with orthostatic hypotension, suspected/certain heart disease with high likelihood of cardiac syncope, steal syndrome, episodes of loss of consciousness other than VVS, pregnancy and a life expectancy < 1 year were also excluded. Other exclusion criteria were: high likelihood of study drop-out before the ending of the study as assessed by the research physician.


The Medical Ethics Committee of the Academic Medical Center in Amsterdam approved this study as part of the STAND-trial (project number 03/191). The trial was registered in the Dutch Trial Register (ISRCTN29932893) and performed according to the declaration of Helsinki. All included patients gave written informed consent.

Evaluation of psychiatric complaints: SCL-90-R questionnaire Patients were asked to fill in the validated Dutch version of the Symptom Checklist 90-R (SCL-90-R) questionnaire before the start of non-pharmacological treatment.21 The SCL-90-R is a multidimensional questionnaire which is used to evaluate self-reported general psychological complaints21 and is sensitive to both psychiatric complaints and complaints that result from general medical illness.22 The SCL-90-R gives an indication of the severity of general psychological complaints as experienced by the patient; it is however insufficient to diagnose psychopathology.21

The SCL-90-R consists of 90 items, each with a 5-point rating scale ranging from 1 (totally not) to 5 (very much).21 The items of the SCL-90-R are grouped into 8 subscales: agoraphobia, anxiety, depression, somatization, insufficiency of thinking and acting, sensitivity, hostility, and insomnia.21 By summation of all individual subscale scores, a total score, the Global Severity Index, is obtained. The higher the subscale and total scores, the more severely patients are affected by psychiatric symptoms.

Non-pharmacological treatment and follow-upAll study participants were given a handout with lifestyle recommendations.23 Patients were instructed to avoid - if possible - conditions in which prior episodes of (pre-)syncope occurred. An adequate fluid intake and high salt intake (accomplished by liberal addition of salt to meals) were advised; excessive alcohol intake was discouraged.5 All patients were encouraged to physically exercise several times a week.5

During a training session in physical counterpressure maneuvers, the use of physical counterpressure manoeuvres such as leg-crossing, tensing of buttock and leg muscles, squatting, handgrip and arm tensing were demonstrated and explained to patients.6 Under supervision, patients practiced the manoeuvres with feedback of continuous blood pressure and heart rate recordings to gain optimal performance.

Patients were asked to register date and symptoms of subsequent (pre-)syncopal episodes in a logbook. At 1, 3 and 6 months after inclusion, the research physician contacted the patients by phone or saw them at the outpatients clinic. He collected information about the occurrence of syncopal and (pre-)syncopal episodes and general health status of patients.


Statistical analysis Demographic and clinical data were expressed as percentages for categorical data, mean (SD) for normally distributed continuous data and median with 25th and 75th percentiles (p25 – p75) for variables with non-normal distributions. In order to compare two groups on a continuous outcome we used a Student’s t-test if these variables were normally distributed and if these variables were not normally distributed a Mann-Whitney test. We used a Chi-square test to compare categorical variables.

We used the Kaplan-Meier approach to estimate the proportion of patients with syncopal recurrence during follow-up. We compared the mean subscale and total scores of the SCL-90-R questionnaire between patients recently diagnosed with VVS in our study and subjects out of the general Dutch population (reference population).21 To obtain an indication of the size of the differences in mean subscale and total scores, we calculated effect sizes (ES) as follows: Meanreference population – Meanstudy population / SDreference population 24, with 0.2 representing a small, 0.5 a moderate and 0.8 a large effect.25 We made similar calculations for the comparison of SCL-90-R subscale and total scores between patients in our study and patients at a psychiatric outpatients clinic and also for the comparison of the respective SCL-90-R scores between patients with and without syncopal recurrences during the first 6 months of follow-up.

Using univariate logistic regression analysis, we determined the strength of association between the Global Severity Index (total score SCL-90-R) at baseline and whether recurrence of syncope occurred during the first 6 months of non-pharmacological treatment. In a subsequent multivariable model, we added other predictors of recurrence of syncope to the model to examine whether the initial association between SCL-90-R score at baseline and syncope recurrence would change. The following potential predictors of recurrence were added to the model: frequency of syncope episodes in the last 2 years prior to non-pharmacological treatment, age, gender and co-morbidity (indicated by the Charlson co-morbidity index26).

In all logistical regression models, the strength of the association between included variables and syncopal recurrence within the first 6 months of non-pharmacological treatment was expressed as an odds ratio with a 95% confidence interval (95% CI).

We analyzed all data using SPSS 16.0 (SPSS, Chicago, Illinois, USA). Unless specified otherwise, a p< 0.05 was considered statistically significant.


Results

PopulationFrom February 2005 to September 2008, a total of 100 patients were included (see Table 1). Mean age of the patients was 38 years (SD=14) and 34% were men. The median period since their first occurrence of syncope was 15 years (p25-p75: 6 – 26). The median number of syncopal and pre-syncopal episodes in the last year before study participation were 4 (p25-p75: 2 - 7) and 8 (p25-p75: 2 - 48).


All patientsNumber 100Mean age (SD) 38 (14)Male gender (%) 34%Race (%)

- Caucasian- Black- Asian- Hispanic

88%5.1%6.1%1.0%

Highest educational level (%)- No formal education- Elementary school- High school- College

1.0%5.2%46%48%

Charlson comorbidity index (%)- 0- 1- ≥ 2

86%12%2.0%

Period of complaints, years Median (p25 – p75) 15 (6 – 26)Number of syncopal episodes last year Median (p25 – p75) 4 (2 - 7)Number of presyncopal episodes last year Median (p25 – p75) 8 (2 – 48)

Trauma due to any previously experienced (pre)syncopal episodes- Hematoma/wound- Contusion/fracture- Head injury other than skin wounds

31%

15%6.0%10%

SCL-90-R Scores compared to the general population and a cohort of patients visiting a psychiatric outpatients clinic


SCL-90-R Scores were available for 90 out of the 100 patients (Table 2). All subscale scores, except the subscale score sensitivity were significantly higher compared to the scores in the general reference population. The Global Severity Index (total score) was also higher compared to the general reference population (142 vs. 118; p< 0.001). In general, the effect sizes were small to moderate, except for the subscale scores of agoraphobia and somatization (both with a large effect size of 1.18). In comparison with the SCL-90-R scores of patients at a psychiatric outpatients clinic, all subscale scores of VVS patients were significantly lower (Table 2). The Global Severity Index was significantly lower for VVS patients than psychiatric outpatients (142 vs. 204; p<0.001). The effect sizes were large for the subscale scores of depression (1.18) and anxiety and sensitivity (both 0.94).


Tabl

e 2.

SC

L-90

-R sc

ores

STA

ND

-tria

l com

pare

d to

the

gene

ral p

opul

atio

n an

d a

psyc

hiat

ric

outp

atie

nts p

opul

atio

n.

Patie

nts S

TAN

D-tr

ial

Dut

ch p

opul

atio

n Ps

ychi

atric

out

patie

nts p

opul

atio

n

SCL-

90-R

subs

cale

Mea

n (S

D)

N=9

0M

ean

(SD

)N

=236

8P-

valu

e fo

r co

mpa

rison

with

ST

AN

D-tr

ial

Effe

ct si

zeM

ean

(SD

)N

=565

8P-

valu

e fo

r co

mpa

rison

with

ST

AN

D-tr

ial

Effe

ct

size

Ago

raph

obia

11 (4

.9)

7.9

(2.3

)<

0.00

11.

1814

(7.1

)<

0.00

10.

43

Anx

iety

16

(7.8

)13

(4.4

)<

0.00

10.

7525

(9.6

)<

0.00

10.

94

Dep

ress

ion

26 (1

2)22

(7.6

)<

0.00

10.

5343

(15)

< 0.

001

1.18

Som

atiz

atio

n23

(10)

17 (5

.3)

< 0.

001

1.18

26 (1

0)0.

007

0.29

Insu

ffici

ency

of t

hink

ing

and

actin

g15

(6.8

)13

(4.3

)<

0.00

10.

6622

(7.9

)<

0.00

10.

79

Sens

itivi

ty25

(9.6

)24

(7.6

)0.

370.

1038

(15)

< 0.

001

0.94

Hos

tility

8.3

(3.7

)7.

2 (2

.1)

< 0.

001

0.50

11 (5

.0)

< 0.

001

0.60

Inso

mni

a5.

7 (2

.9)

4.5

(2.2

)<

0.00

10.

567.

7 (3

.8)

< 0.

001

0.53

Glo

bal S

ever

ity In

dex

142

(56)

118

(32)

< 0.

001

0.72

204

(62)

< 0.

001

1.00


Table 3. Symptom checklist 90-R (SCL-90-R) scores. Comparison of SCL-90-R scores between patients with no and ≥ 1 syncopes during the first 6 months of non-pharmacological treatment.

SCL-90-R All patients included in

analysis N= 90

0 Syncopes during first 6 months of treatment N= 54

≥ 1 Syncope during first 6 months of treatment N= 36

Effect sizes P-value (Mann-

Whitney)Mean (SD) Mean (SD) Mean (SD)

Agoraphobia 11 (4.9) 10 (4.1) 12 (5.9) 0.40 0.28

Anxiety 16 (7.8) 14 (5.8) 19 (9.6) 0.72 0.01

Depression 26 (12) 23 (10) 29 (14) 0.55 0.01

Somatization 23 (10) 20 (8.1) 27 (12) 0.82 0.001

Insufficiency of thinking and acting

15 (6.8) 15 (6.0) 17 (7.8) 0.39 0.11

Sensitivity 25 (9.6) 23 (7.9) 28 (11) 0.59 0.02

Hostility 8.3 (3.7) 7.6 (2.3) 9.3 (5.0) 0.71 0.12

Insomnia 5.7 (2.9) 5.5 (2.9) 6.0 (2.9) 0.16 0.28

Global Severity Index 142 (56) 130 (43) 160 (68) 0.70 0.01

Figure 1. Syncope-free survival.

Survival time (months) 0 2 4 6 8 10 12

Patients at risk 100 73 62 61 59 54 51

Number of patients with syncopal recurrences within period

0 27 11 1 2 5 3

Total number of syncopal recurrences 0 27 38 39 41 46 49


Association between SCL-90-R scores and effectiveness of treatmentWithin the first 6 months of follow-up, 42% of patients had experienced syncopal recurrence(s). This percentage increased to 49% after one year. The syncope-free survival during follow-up is represented in Figure 1.23

Systolic blood pressure at rest in supine position did not differ significantly between patients with and without syncopal recurrence during the first 6 months of follow-up (mean (SD) 118 (13) vs. 123 (13); p= 0.15). We obtained similar findings with respect to the heart rate (70 vs. 71; p= 0.72). Values for all subscale and total scores of the SCL-90R were higher for patients with compared to without syncopal recurrence during the first 6 months of follow-up (Table 3). These differences were significant for the subscale scores for anxiety (p= 0.01), depression (p= 0.01), somatization (p= 0.001), sensitivity (p= 0.02) as well as the Global Severity Index (p= 0.01). The effect size for the SCL-90-R subscale score somatization was large (0.82); for other subscale scores and also for the Global Severity Index the effect sizes were either small or moderate.

The Global Severity Index of the SCL-90-R questionnaire was statistically significant associated with syncopal recurrence within the first 6 months of non-pharmacological treatment (Table 4). Other significant univariable predictors of syncopal recurrence were: frequency of syncopal episodes during the last 2 years prior to the start of non-pharmacological treatment (p< 0.001) and age per 10 years (p=0.02).The association between the Global Severity Index of the SCL-90-R questionnaire and syncopal recurrence remained significant when the other relevant predictors were added to the model. This indicates that the Global Severity Index of the SCL-90-R questionnaire has an independent effect on the likelihood of syncopal recurrence.

To enhance understanding of the absolute impact of higher SCL-90-R scores, we calculated the predicted probability of syncopal recurrence based on the multivariable model for two otherwise similar individuals but having a different Global Severity Index on the SCL-90-R questionnaire. One patient with a relatively low score (10th percentile=96), the other having a higher score (90th percentile=200). The expected probability of recurrence for women with age 38 years and 0-5 prior syncopal episodes during the last 2 years before study participation would be 13% for women with a low score and 31% for the patient with the higher score. If these women would have experienced 6 or more syncopal episodes during the last 2 years before study participation, the predicted probability of syncopal recurrence would be 47% for the low score and 72% for the high score.


Table 4. Univariate and multivariate odds ratios for predicting syncopal recurrence within the first 6 months of non-pharmacological treatment.

Univariate analysis Multivariate analysisOdds ratio (95% CI)

P-value Odds ratio (95% CI)

P-value

Age per 10 years 0.70 (0.52 – 0.95) 0.02 0.89 (0.61 – 1.30) 0.55Male gender 0.44 (0.18 – 1.07) 0.07 0.71 (0.23 – 2.18) 0.55Frequency of syncope during the last 2 years prior to treatment initiation

- 0 - 5- ≥ 6

Reference6.00 (2.42 – 14.88) < 0.001

Reference5.82 (2.10 – 16.16) 0.001

Charlson co-morbidity index 0.51 (0.15 – 1.74) 0.28 0.68 (0.16 – 2.86) 0.59Global Severity Index SCL-90-R per 10 points

1.11 (1.01 – 1.21) 0.02 1.11 (1.00 – 1.23) 0.048

Discussion

Main findingsIn this study we found that patients with VVS have a higher level of general psychological complaints (SCL-90-R) than healthy control subjects. However, the level of psychological complaints among VVS patients was, on average, lower than among outpatients at a psychiatric clinic. During the first 6 months of follow-up, syncope recurred in 42% of patients despite optimal non-pharmacological treatment. Recurrence was more likely in patients with higher levels of general psychological complaints. This association remained significant after taking into account age, gender, co-morbidity, and frequency of episodes in the last 2 years prior to treatment initiation. The number of syncopal episodes prior to the start of non-pharmacological treatment was however the strongest predictor of syncopal recurrence.

General psychological symptoms and vasovagal syncope, cause or consequence?Our and other studies find that the prevalence of general psychological complaints, as measured using various questionnaires, is higher in patients with vasovagal syncope, compared to age- and sex-matched controls without syncope.9, 12-14, 27, 28 It is however unclear whether general psychological complaints cause vasovagal syncope or vice versa. Vasovagal syncope has an important impact of physical and psychological functioning.9-11 This might result in higher levels of general psychological complaints. In support of this, it has been found that treatment of vasovagal syncope reduces the level of psychiatric morbidity.13 On the other hand, we and others find that the presence of higher levels of general


psychological complaints is associated with an increased risk of syncopal recurrence.8,

12-15, 29 In our study, the association between general psychological complaints and syncopal recurrence remained significant, also if other potential predictors of syncopal recurrence were taken into account. Treatment of general psychological complaints has been found to affect syncope-recurrence as well.28 Biofeedback assisted relaxation therapy reduces symptoms of lightheadedness and dizziness.30 In two randomized controlled trials, treatment with selective serotonin reuptake inhibitors was compared with placebo treatment.31,

32 Although no significant differences were found with respect to the syncope burden and quality of life, the occurrence of syncope during follow-up was lower during treatment with selective serotonin reuptake inhibitors than during placebo treatment.31, 32

PathophysiologyThe pathophysiological mechanisms to explain the association between general psychological complaints and syncopal recurrence are complex and at best partly understood. Several mechanisms are likely to be involved. In the absence of psychiatric disease, patients with reflex syncope were found to have a normal autonomic control of the cardiovascular system in between syncopal recurrences.33 In line with this, in our study the mean systolic blood pressure at rest without symptoms was normal34 and did not differ between patients with and without subsequent syncopal episodes. Only in patients with specific blood-injury-illness phobia, a direct relation between the psychiatric disorder and vasovagal problems has been observed. More fearful patients with blood phobia were more likely to experience syncopal recurrences than less fearful patients with blood phobia.35 In patients with blood phobia it was found that not only the sight of blood but also other triggers like head-up tilt testing could elicit VVS more easily than in control subjects.36 This specific disorder was however not studied in our, and most other, studies. The pathophysiological mechanisms for the relation between VVS and other general psychological complaints are far less clear. Although patients with higher scores on a scale assessing symptoms of depression, did have a more pronounced decrease in bloodpressure upon tilt testing 37, the pathophysiological basis for this relation is unknown. The low response to (non-pharmacological) treatment in patients with higher levels of general psychological complaints could be explained by avoidance of triggers. General psychological symptoms could impair a patients’ self-confidence about being able to combat impending episodes of VVS. Patients not feeling confident about being able to prevent episodes of VVS will avoid situations that might elicit VVS as much as possible,15 reinforcing conceptions that particular situations are dangerous.38 By not exposing themselves to situations that might elicit (pre-)


syncope, these thoughts are unlikely to disappear and patients will remain vulnerable to experience episodes of VVS.

On the other hand, the presence of syncope could enhance the occurrence of general psychological symptoms. For most patients diagnosed with VVS, the occurrence of syncope is a frightening, embarrassing experience.4 Patients will try to prevent syncopal recurrences by avoiding situations in which syncope might occur. Since many conditions could trigger VVS in daily life (e.g. crowding and prolonged standing),39 avoidance of these conditions will significantly impair participation in many different activities. This could make VVS patients feel unhappy about their lives, especially in case of frequent recurrences.9-11 These negative feelings could induce the occurrence of psychiatric symptoms, although this relation has not been studied so far.

Implications for clinical practiceAs described in the guidelines of the management of syncope,2 initial treatment of all patients diagnosed with VVS should consist of non-pharmacological treatment. Since we found that this treatment is less likely to be effective in patients who are more severely affected by general psychological complaints, psychiatric evaluation might be considered in patients not responding to this treatment in whom higher levels of general psychological complaints are suspected as a possible reinforcing factor or a consequence of their episodes. In these patients, psychological treatment besides more physical oriented treatment might be beneficial.28, 40

LimitationsIt is known that many patients with recurrent T-LOC more often seek medical care after a recent worsening of their symptoms.41 These patients could experience more psychiatric symptoms at clinical presentation than they would normally, because of fear of serious consequences of the episodes4, 28, 40 or important restrictions in daily functioning.9-11 The level of general psychological complaints found in this study might therefore be an overestimation of psychiatric symptoms upon generalization to the entire population of patients with VVS. The SCL-90-R questionnaire gives an impression about the severity of general psychological complaints, but this information is insufficient to diagnose psychopathology itself.21 For that purpose, expert judgement based on the Diagnostic and Statistical Manual of Manual Disorders (current version: DSM-IV-TR) is required after thorough psychiatric evaluation.42 This has not been done in our study.We considered treatment effective if patients experienced no or at least fewer syncopal recurrences during treatment than before treatment initiation. Though


we think that this is the best and most objective method to determine whether treatment is effective in patients, a decrease in syncopal recurrence is not the sole determinant of treatment benefit. Also if recurrences of VVS remain present after non-pharmacological treatment, patients may still feel better, since they have been reassured that their cause of T-LOC is relatively benign and since they have been given non-pharmacological treatment measures to abort impending VVS.3 Since evaluation of personal treatment benefit is quite subjective, we considered changes in syncopal recurrences during treatment as the best and most objective method to evaluate responses to treatment.

From a statistical point of view, this is still a relatively small study. This implies that the CIs around the odds ratios from the logistic regression models are still wide. Further studies are necessary to confirm our findings and to become more certain about the precise strength of the reported associations.

Conclusion

Patients with frequent episodes of VVS have higher levels of general psychological complaints than the general population. Furthermore, syncope is more likely to recur in patients with higher levels of general psychological complaints, a relationship that remains after adjusting for severity of VVS. Nonetheless, the number of syncopal episodes in the years prior to the start of treatment, is the strongest independent predictor of syncopal recurrence.


Acknowledgements

We would like to thank Prof. dr. J.W.M. Lenders (Department of Internal Medicine, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands and Department of Internal Medicine III, University Hospital Carl Gustav Carus Dresden, Dresden, Germany), Dr. M.P.M. Harms (Department of Internal Medicine, University Medical Center Groningen, Groningen, the Netherlands) and Dr. J.H. Ruiter (Department of Cardiology, Medical Center Alkmaar, Alkmaar, the Netherlands) for their cooperation with the selection, inclusion and follow-up of patients in our study.


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18. Croci F, Brignole M, Menozzi C et al. Efficacy and feasibility of isometric arm counter-pressure manoeuvres to abort impending vasovagal syncope during real life. Europace 2004;6(4):287-291.


19. Kapoor WN, Fortunato M, Hanusa BH, Schulberg HC. Psychiatric illnesses in patients with syncope. Am J Med 1995;99(5):505-512.


21. Arrindell WA, Ettema JHM. SCL-90. Handleiding bij een multidimensionale psychopathologie-indicator. Lisse: Swets & Zeitlinger; 1986.

22. Derogatis LR, Morrow GR, Fetting J et al. The prevalence of psychiatric disorders among cancer patients. JAMA 1983;249(6):751-757.

23. Romme JJCM, Reitsma JB, Go-Schon IK et al. Prospective evaluation of non-pharmacological treatment in vasovagal syncope. Submitted 2009.

24. Kazis LE, Anderson JJ, Meenan RF. Effect sizes for interpreting changes in health status. Med Care 1989;27(3 Suppl):S178-S189.

25. Cohen J. Statistical power analysis for the behavioral sciences. 2 ed. Hillsdale, NJ: Lawrence Erlbaum Associates; 1988.

26. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40(5):373-383.

27. Gracie J, Baker C, Freeston MH, Newton JL. The role of psychological factors in the aetiology and treatment of vasovagal syncope. Indian Pacing Electrophysiol J 2004;4(2):79-84.

28. Leftheriotis D, Michopoulos I, Flevari P et al. Minor psychiatric disorders and syncope: the role of psychopathology in the expression of vasovagal reflex. Psychother Psychosom 2008;77(6):372-376.

29. Oh JH, Kapoor WN. Psychiatric illness and syncope. Cardiol Clin 1997;15(2):269-275.30. McGrady AV, Kern-Buell C, Bush E, Devonshire R, Claggett AL, Grubb BP. Biofeedback-assisted

relaxation therapy in neurocardiogenic syncope: a pilot study. Appl Psychophysiol Biofeedback 2003;28(3):183-192.

31. Di Girolamo E, Di Iorio C, Sabatini P, Leonzio L, Barbone C, Barsotti A. Effects of paroxetine hydrochloride, a selective serotonin reuptake inhibitor, on refractory vasovagal syncope: a randomized, double-blind, placebo-controlled study. J Am Coll Cardiol 1999;33(5):1227-1230.

32. Theodorakis GN, Leftheriotis D, Livanis EG et al. Fluoxetine vs. propranolol in the treatment of vasovagal syncope: a prospective, randomized, placebo-controlled study. Europace 2006;8(3):193-198.

33. Calandra-Buonaura G, Cortelli P, Pierangeli G et al. Central and cardiovascular responses to emotional stimuli are normal in non-phobic subjects with Reflex Syncope. Clin Neurophysiol 2008;119(9):1966-1972.

34. Chobanian AV, Bakris GL, Black HR et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42(6):1206-1252.

35. Olatunji BO, Connolly KM, David B. Behavioral avoidance and self-reported fainting symptoms in blood/injury fearful individuals: an experimental test of disgust domain specificity. J Anxiety Disord 2008;22(5):837-848.

36. Accurso V, Winnicki M, Shamsuzzaman AS, Wenzel A, Johnson AK, Somers VK. Predisposition to vasovagal syncope in subjects with blood/injury phobia. Circulation 2001;104(8):903-907.

37. McGrady A, Kern-Buell C, Bush E, Khuder S, Grubb BP. Psychological and physiological factors associated with tilt table testing for neurally mediated syncopal syndromes. Pacing Clin Electrophysiol 2001;24(3):296-301.


38. Clark DM. A cognitive approach to panic. Behav Res Ther 1986;24(4):461-470.39. Colman N, Nahm K, van Dijk JG, Reitsma JB, Wieling W, Kaufmann H. Diagnostic value of

history taking in reflex syncope. Clin Auton Res 2004;14 Suppl 1:37-44.40. Newton JL, Kenny RA, Baker CR. Cognitive behavioural therapy as a potential treatment for

vasovagal/neurocardiogenic syncope—a pilot study. Europace 2003;5(3):299-301.41. Sheldon RS, Sheldon AG, Serletis A et al. Worsening of symptoms before presentation with

vasovagal syncope. J Cardiovasc Electrophysiol 2007;18(9):954-959.42. First MB, Pincus HA. The DSM-IV Text Revision: rationale and potential impact on clinical

practice. Psychiatr Serv 2002;53(3):288-292.

Chapter 6

Drugs and pacemakers for vasovagal syncope, carotid sinus syncope and situational syncope

Based on Cochrane protocol published in Cochrane Library 2008; Issue 4.

Full review submitted

Jacobus J.C.M. RommeJohannes B. ReitsmaCatherine N. BlackNancy ColmanRob J.P.M. ScholtenWouter WielingNynke Van Dijk

Chapter 6 Drugs and pacemakers104 Drugs and pacemakers

Abstract

Background: Neurally mediated reflex syncope is the most common cause of transient loss of consciousness. In patients not responding to non-pharmacological treatment, pharmacological or pacemaker treatment might be considered.

Objectives: To examine the effects of pharmacological therapy and pacemaker implantation in patients with vasovagal syncope, carotid sinus syncope and situational syncope.

Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2008, Issue 1), MEDLINE (1950 until February 2008), EMBASE (1980 until February 2008) and CINAHL (1937 until February 2008).

Selection criteria: We included parallel randomized controlled trials and randomized cross-over trials of pharmacological treatment (beta-blockers, fludrocortisone, alpha-adrenergic agonists, selective serotonine reuptake inhibitors, ACE inhibitors, disopyramide, anticholinergic agents or salt tablets) or dual chamber pacemaker treatment. Studies were included if pharmacological or pacemaker treatment was compared with any form of standardised control treatment (standard treatment), placebo treatment, or (other) pharmacological or pacemaker treatment. We did not include non-randomized studies.

Data collection and analysis: The risk of bias was assessed independently by two reviewers. Characteristics and results of the various studies were extracted according to a standardised data extraction form. A consensus meeting was used to deal with any disagreements that had occurred during data extraction. If no agreement could be reached, a third reviewer was asked to make a decision. Summary estimates with 95% confidence intervals of treatment effect were calculated using relative risks, rate ratios or weighted means differences depending on the type of outcome reported.

Results: We included 46 randomized studies, 40 on vasovagal syncope and 6 on carotid sinus syncope. No studies on situational syncope matched the criteria for inclusion in our review. Studies in general were small with a median sample size of 42. A wide range of control treatments were used with 22 studies using a placebo arm. Blinding of patients and treating physicians was applied in 8 studies. The type of outcomes reported by studies varied considerably with only 16 studies reporting on non-provoked recurrences during follow-up. As a consequence of all these differences, results varied considerably between studies and between types of

Drugs and pacemakersDrugs and pacemakers 105

outcomes. In some studies significant results were reported for one type of outcome, but not for other outcomes.

Authors’ conclusions: There is insufficient evidence to support the use of any of the pharmacological or pacemaker treatments for vasovagal syncope and carotid sinus syncope. Larger studies using patient relevant outcomes are needed. For situational syncope no relevant studies were retrieved.


Background

In neurally mediated reflex syncope a reflex is triggered that induces vasodilatation and/or bradycardia, resulting in a systemic hypotension and cerebral hypoperfusion.1 It is by far the most common cause of transient loss of consciousness both in general practice and in clinical settings.2, 3 The three main types of neurally mediated reflex syncope are vasovagal syncope, carotid sinus syncope and situational syncope.1

Vasovagal syncope is characterised by premonitory signs and provoked by triggering events such as prolonged standing, emotion or pain.1 Carotid sinus syncope is caused by stimulation of the carotid sinus baroreceptors, which may lead to hypotension or bradycardia or both. Situational syncope is defined as loss of consciousness at the onset of, during or directly after swallowing, defecation, micturition or coughing.The life-time prevalence of neurally mediated reflex syncope in the general population ranges between 30 and 50% for people up to 60 years of age.4, 5 Vasovagal syncope accounts for the vast majority (75%) of episodes of reflex syncope in patients under 60 years of age that come to medical attention.6, 7 Around 20% of reflex syncopal episodes are caused by situational syncope and about 4% by carotid sinus syncope.6 Although the prognosis of neurally mediated reflex syncope is usually benign, it can be disabling and have a profound effect on quality of life.6, 8

Treatment of neurally mediated reflex syncope is aimed at ensuring an adequate blood supply to the brain.1 Treatments options might however vary considerably among different types of neurally mediated reflex syncope. Most patients with a diagnosis of vasovagal syncope and situational syncope can be treated by counselling and advice. Avoiding or ameliorating the triggering event is a crucial treatment component for situational syncope, but is also applicable to patients with vasovagal syncope.1, 9 For both conditions, recognition of premonitory signs are also important as well as increasing fluid and salt intake.9 Patients with recognizable premonitory signs and symptoms are instructed to apply counterpressure manoeuvres (e.g. leg-crossing, muscle-tensing).10 Tilt-training has been put forward to prevent the recurrence of neurally mediated syncope.11 Recent studies indicate that this intervention might only be effective in highly motivated patients,12, 13 limiting widespread use of this intervention.The treatment of carotid sinus syncope depends upon the nature of its condition.14 Pharmacological treatment is advocated in the predominantly vasodepressor form; pacemaker treatment for its mixed and predominantly bradycardic forms. Pharmacological and pacemaker treatment can also be considered for vasovagal syncope and situational syncope upon failure of the aforementioned non-pharmacological treatment measures.15 Many pharmacological interventions have been proposed for treating neurally


mediated reflex syncope but the evidence to suggest their effectiveness is limited to small studies, sometimes showing conflicting results. Medications used to prevent syncope include beta-adrenergic blockers, alpha-adrenergic agonists (e.g. etilephrine, midodrine), ACE-inhibitors, anticholinergic agents, anti-arrhythmic agents (e.g. disopyramide), serotonine re-uptake inhibitors (e.g. paroxetine) and medication for fluid retention, such as salt tablets and fludrocortisone.1, 16, 17 Pacemakers are also sometimes used in cases of neurally mediated reflex syncope with severe bradycardia or asystole.18

Apart from the clinical effectiveness, it is also important to address the isssue of cost-effectiveness of pharmacological and pacemaker treatment for neurally mediated reflex syncope. In the Netherlands, the average treatment costs per year vary between EUR 6 and 2,614 (USD 8 and 3,570) for the suggested pharmacological treatment measures.19 The costs associated with the implantation of a dual-chamber pacemaker system are about EUR 1,145 (USD1,560) per year. Costs might however vary considerably across countries and types of health care systems.Though pharmacological and pacemaker treatment are frequently prescribed to a large number of patients suffering from recurrent neurally-mediated reflex syncope, little is known about the clinical effectiveness of these treatments. Therefore, the aim of this review was to determine the effects of both pharmacotherapy and pacemaker therapy in patients with different forms of neurally mediated reflex syncope.


Methods

Description of the condition

SyncopeA temporary loss of consciousness due to inadequate blood flow to the brain (generalised cerebral ischaemia).1

Vasovagal syncopeVasovagal syncope is diagnosed if precipitating events such as fear, severe pain, emotional distress, or prolonged standing are associated with prodromal symptoms (e.g. lightheadedness, sweating, feeling nauseous) or when a vasovagal response is observed during tilt-table testing.1, 15 A vasovagal response is defined as a sudden drop of blood pressure, heart rate or both in association with syncope or near syncope.

Carotid sinus syncopeThe diagnosis of carotid sinus syncope is based on either a typical history (spontaneous carotid sinus syncope as a consequence of pressure in the carotid area or turning of the head) or on the reaction to carotid sinus massage (induced carotid sinus syncope).15

Situational syncopeA typical history of situational syncope is defined as loss of consciousness occurring during or immediately after micturition, defaecation, coughing or swallowing.1, 15

Criteria for considering studies for this review

Types of studies We included parallel randomized controlled trials, and randomized cross-over trials in our review.

Types of participants Adults (>16 yrs) diagnosed with neurally mediated reflex syncope. The three types of neurally mediated reflex syncope that were addressed in this review are vasovagal syncope, carotid sinus syncope and situational syncope.Studies also reporting on patients with other causes of syncope like autonomic failure, medications inducing transient loss of consciousness, cardiac rhythm disturbance (e.g. complete heart block, ventricular tachycardia) or structural heart


disease were included only if the results of patients with neurally mediated reflex syncope were reported separately. Furthermore, studies including patients with a transient ischaemic attack (TIA) or epilepsy were excluded.

Types of interventions

PharmacotherapyThe following drugs were considered for inclusion in our review: beta-blockers (both selective and non-selective), fludrocortisone, alpha-adrenergic agonists, selective serotonine reuptake inhibitors (SSRIs), ACE-inhibitors, disopyramide, anticholinergic agents and salt tablets.Studies were included if drugs were compared with standard treatment, placebo treatment, counselling and advice, with any another drug, or with pacemaker therapy. Standard treatment consisted of any treatment physicians would offer to patients not including the intervention under investigation.

Pacemaker therapyThere are different types of pacemakers, which can be classified by a three-letter abbreviation.20 The first letter stands for the heart chambers paced (Atrial, Ventrical, Dual), the second for the heart chambers sensed (Atrial, Ventrical, Dual, or none (O)), the third for the response (Inhibited, Triggered, Dual (I and T) or none (O)). Sometimes a fourth letter is added to denote the presence or absence of rate modulation.In this review, we included all different types of dual-chamber cardiac pacemakers, either with or without rate hysteresis, or rate drop response sensing, provided that a comparison was made with no therapy or counselling and advice or pharmacotherapy, another type of pacemaker therapy or with pacemaker ‘off’.Studies in which concomitant treatment had been applied, were accepted if these treatments were applied in both arms of the trial.We included studies irrespective of the length of follow-up.

Outcome measuresThe general aim of this review was to determine the effectiveness of pharmacological and pacemaker treatment for neurally-mediated reflex syncope. We extracted data on several clinical outcomes, putting patient relevant outcomes higher in hierarchy:Average number of episodes per year per patient (syncope burden). Proportion of patients with one or more syncopal episode(s) during follow-up.Average time elapsed from start of an intervention until the first episode of


syncope.Quality of life, measured with a validated questionnaire.Cumulative incidence of minor and major physical trauma due to syncope.Number and severity of side effects.Average number of episodes of near syncope. Proportion of patients with syncopal episodes induced by provocation testing or carotid sinus massage.

Search methodsA comprehensive search of the Cochrane Central Register of Controlled Trials (CENTRAL) on the Cochrane Library (2008 Issue 1), MEDLINE (1950 until February 2008) on Pubmed, EMBASE (1980 until February 2008) on Ovid, and CINAHL (1937 unitl February 2008) on EBSCOHost was performed. We did not use language restriction.Reference lists of included studies and review articles were reviewed to identify potential relevant citations. Inquiries regarding other published or unpublished studies known and/or supported by the authors of the primary studies were made so that these results could be included in this review. Finally, personal contact with colleagues, collaborators and other trialists working in the field of neurally mediated syncope was made to identify potentially relevant studies.

Data collection and analysis

Selection of studies Publications identified from the search were assessed for eligibility for inclusion by 2 reviewers independent of each other. Firstly, a selection was made based on title. Next, the selected articles were assessed for eligibility based on both title and abstract. If any doubt occurred with respect to an article’s relevance, the full text of the reference was obtained. Disagreement was resolved by consensus or third party adjudication.Two reviewers independently, read the full text of retained studies and included trials that met the inclusion criteria. A pre-defined form was used for this task. Articles finally selected for the review were checked to avoid including duplicates. Records of this were kept as advised in the QUOROM statement.21

A consensus meeting was used to deal with any disagreements arising in the selection of the articles. If no agreement could be reached, a third reviewer decided whether the paper had to be included.


Data extraction and management Characteristics of the various studies were extracted independently by two reviewers according to a standardised data extraction form. Information was collected regarding:1. Design of study: parallel randomized controlled trial (RCT) or randomized cross-over trial.2. Characteristics of the patients: age, gender, (lifetime) number of syncopal episodes, number of episodes of syncope in previous year, history of physical trauma due to syncope; setting (primary, secondary, or tertiary care setting).3. Type, dose and duration of interventions and control interventions.4. Outcomes as addressed by the original authors. For each study, we extracted data for as many appropriate outcome measures as possible. In case of premature stopping of allocated treatment or loss to follow-up, we extracted data according to an intention-to-treat-principle, if present in the study report. In other cases, we extracted data as presented in the study report.A consensus meeting was used to deal with any disagreements arising in data extraction. If no agreement could be reached a third reviewer decided which data of a given paper could be extracted.

Assessment of risk of bias in included studies Risk of bias was assessed by 2 reviewers independent of each other.22 Any disagreement between reviewers was resolved by consensus. In case no consensus could be reached, a third reviewer assessed the risk of bias of the study. In studies where it was unclear whether the risk of bias criteria had been met, the reviewers tried to contact the first author to get additional information.If the risk of bias in an included study was very high according to the Cochrane assessment criteria for risk of bias, we did not proceed to data extraction.

Data synthesis Since the aetiology of the different subtypes of neurally mediated reflex syncope is quite different,1 we presented the studies for vasovagal syncope, carotid sinus syncope and situational syncope in different sections. Within these sections, studies were categorized by pharmacological or pacemaker treatment modality. Next, for each treatment modality, studies were classified depending on the type of control treatment. Thus, all studies were classified at three levels: 1) subtype of neurally mediated reflex syncope, 2) pharmacological or pacemaker treatment modality, 3) treatment comparison.Next, for each study, summary estimates of treatment effect (with 95% confidence intervals (95% CI)) were calculated for each outcome measure provided that

Chapter 6 Drugs and pacemakersDrugs and pacemakers112

study data were available for a particular treatment comparison. For dichotomous outcomes risk ratios (RR) were calculated. For continuous outcomes we calculated the weighted mean difference (WMD) or weighted standardised mean difference (SMD), when appropriate. For data with discrete numbers we determined the rate ratio by dividing the mean number of syncopal episodes by the number of person years of follow-up. For time-to-event data we calculated the hazard ratio with the help of the p-value of the log rank statistic.23

For the pooling of a dichotomous outcome measure from studies with and without a cross-over design we calculated a combined odds ratio (OR) according to the Becker-Balagtas method.24, 25 In case the results of cross-over trials were presented as in parallel studies and no additional information was provided by contacting the corresponding authors of these studies, we assumed that there was no correlation between observations on the same patient. This means that such studies received less weight in the analyses because the effect estimate would have been more precise in case of a positive correlation.Results of clinically and statistically homogeneous studies (i.e. studies for which the participants, interventions, outcome measures and timing of the follow-up measurements were considered to be similar) were combined using a fixed effect model. In case of statistical heterogeneity (as assessed by visual inspection of the forest plots, the Q-statistic and the I2-statistic26) and the availability of at least 5 studies, a random effects model was used. In any other case, no pooling was performed.

Subgroup analysis and investigation of heterogeneity If results of two or more studies were available for a particular outcome measure, we presented the results of parallel and cross-over studies in different subgroups. If there was little variation in the results of these studies, we determined a combined treatment effect. We did not calculate a combined treatment effect if there was substantial variation between study results.

Sensitivity analysis If sufficient studies were retrieved for a certain outcome measure, sensitivity analyses were performed to examine the robustness of the results using the following quality criteria: concealment of allocation (yes/no/unclear), blinded outcome assessment (yes/no/unclear) and completeness of follow-up (>=80%/ <80%/ unclear).


Results

Search and inclusion With the electronic search strategy we obtained 14,844 publications (3015 in MEDLINE, 540 in CENTRAL, 6640 in CINAHL and 4649 in EMBASE). After removal of duplicates 12,409 publications remained. Based on title, we considered 701 publications eligible. Of these, 90 publications remained after assessment based on title and -if available- abstract. Efforts were made to obtain the full articles. Based on the assessment of the full articles of these studies, 27 publications were excluded. Of these, 26 publications did not appear to be study reports of randomized controlled trials or cross-over studies (study reports on non-randomized trials (9), case reports (8), reviews (6), editorials (3)); one publication was excluded, because the exclusion criteria were positive in at least some of the patients in the respective trial.27 The remaining 63 publications were included in this review. Of these, 46 publications were original publications of randomized controlled trials or cross-over studies. We extracted data from 43 of these 46 publications (being study reports); we considered the 3 remaining studies to be insufficiently valid and applicable for data extraction. Six of the remaining 17 included publications were preliminary study reports or double publications of original studies in a different language. We have added the references of these publications to the primary study reference. Eight of the remaining publications were either study protocols (2 of included primary studies, 2 of different studies) or abstracts (2 of included primary studies, 2 of different studies). We were unable to judge three other publications for inclusion/exclusion either because we were unable to find translators and asessors (one Japanese publication) or because we were unable to find the text of these references (2 publications). We made an adjusted flow diagram to represent the selection of publications relevant for our review (Figure 1).To summarize, we included 46 original publications (32 randomized controlled trials and 14 cross-over studies), which were subjected to further analysis (Table 1).


Figure 1. Search and inclusion of publications

Potentially relevant publications

identified and screened for retrieval

N= 12409

Publications retrieved for more

detailed evaluation after assessment

of title and abstract, if available

N= 90

Publications not meeting the criteria

for inclusion in review based on title

N= 11708

Publications included in final review

N= 63

Excluded publications

N= 27

Non-randomized studies N= 9

Case report N= 8

Review N= 6

Editorial N= 3

Exclusion criteria positive N= 1

Other, included publications

N= 17

Double publication of original study report N= 6

Abstracts of full study reports already

included in review N= 2

Other abstracts N= 2

Protocols of full study reports already

included in review N= 2

Other protocols N= 2

Publications not found N= 2

Study report to be assessed N= 1

Included studies

N= 46

Studies included in data-extraction

N= 43

Potentially relevant publications after

assessment of titles

N= 701 Publications not meeting the criteria

for inclusion in review based on title

and abstract, if available

N= 611

Studies considered insufficiently valid

and applicable for data-extraction

N= 3


Tabl

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Incl

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stud

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Chapter 6 Drugs and pacemakers116 Drugs and pacemakersSt

udy

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Included studies

Of the 46 included original publications, 42 were found in MEDLINE, 2 were identified in CENTRAL, one in Embase and one in Cinahl. Forty-two studies were written in English, 3 in Chinese and one in Italian. We found 40 studies on vasovagal syncope, 6 studies on carotid sinus syncope and none on situational syncope. Of the included studies, 32 were parallel randomized controlled trials, the 14 remaining studies were randomized cross-over trials.In total, 2,386 patients participated in the 46 studies that were analyzed. The trial sizes ranged from 8-208 participants with a median sample size of 42 (interquartile range 23 - 62). The mean age of patients within these trials was 49.7 ± 12.3 years of age (range 13-86). On average, 45% of the study participants were men. The studies were undertaken between 1992 and 2006, mainly in developed countries. As far as the duration of the wash-out period was reported in cross-over trials, it varied between 1-2 hours to 7 days. The mean follow-up time accross the included studies was 9.4 ± 12.6 months.

Vasovagal syncopeThe treatment of vasovagal syncope was investigated in 40 studies (2,028 patients). In 29 studies drug treatment was investigated and in 10 studies pacemaker treatment. One study compared drug treatment (beta-blocker) with pacemaker treatment. In some of these studies more than 2 treatment modalities were compared.

Carotid sinus syncopeOf the 6 studies (358 patients) on carotid sinus syncope, one investigated pharmacological treatment57 and the remaining pacemaker treatment.32, 34, 35, 49, 56

Situational syncopeNo studies on situational syncope matched the criteria for inclusion in our review.

Risk of bias in included studies The individual scores on all risk of bias items of the included studies and a summary of the scores are presented in Figure 2 and Figure 3.The randomization method was reported in 19 of the 46 included studies. Ten of these studies were randomized by a computer-generated randomization list.30, 40,

55, 61, 63, 68, 71-74 The other studies were randomized by a randomization table,33, 34, 64 telephone,36 cards in envelopes35 or any kind of central process.37, 45, 49, 53 In 27 studies the randomization method was not described in sufficient detail to make a judgement.The allocation was concealed in 9 of the 46 included studies.30, 35-37, 55, 61, 63, 68, 71 In the other 37 studies, insufficient information was available to make a clear judgement.We made separate judgements for patients, physicians/personnel and outcome


acessors with respect to blinding. In 10 studies none of them were blinded. In 7 of these studies blinding was not possible, because pacemaker treatment was compared with non-pacemaker treatment.30, 34-36, 43, 49, 68 In the other studies, pharmacological treatment was compared with any form of standadised non-pharmacological control treatment (standard treatment).39, 62, 70

Incomplete outcome data had been adequately addressed in 29 studies. In 9 studies incomplete outcome data had not been adequately addressed. In 7 of these 9 studies 20% or more of the patients dropped out of the study;54-56, 63, 67-69 in the other 2 studies no information was given about incomplete outcome data.51, 59 The risk of this bias was unclear in 8 studies.37 Studies were free of selective outcome reporting. The risk of this bias was unclear in 4 studies.32, 33, 58, 65 We judged selective outcome reporting to be present in 5 studies.41, 51, 56, 57, 67 In one of these studies the result of the tilt test was not reported.51 In three of the studies it was unclear whether real syncope was present.41, 56, 57 In one of the studies, the outcome measure ‘quality of life’ was not reported in the study report, though this had been specified in the study protocol.67

We judged that 33 studies were free of other sources of bias. We detected other potential sources of bias in 13 studies. In three of these studies selection bias might have occurred.33, 51, 58 In one study, it remained unclear whether the primary condition of interest was vasovagal syncope or orthostatic hypotension.71 Except for the treatment under investigation, patients in the intervention and control group were treated or were likely to have been treated differently in 5 studies (performance bias).28, 34, 36, 37, 65 Five studies were terminated ahead of time.30, 36, 61, 63, 64 In 4 studies, the risk of bias was unclear.41, 62, 72, 74 Based on the ‘risk of bias’ assessment we considered three included studies to be insufficiently valid and applicable for data-extraction.33, 41, 51

Figure 2

Methodological quality graph: review authors’ judgments about each methodological quality item presented as percentages across all included studies.

Figuur 2 hoofdstuk 6

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Adequate sequence

generation?

Allocation concealment?

Blinding? (Patients)

Blinding?

(Physicians/personnel)

Blinding? (Outcome

acessors)

Incomplete outcome

data addressed?

Free of selective

reporting?

Free of other bias?

Yes (low risk of bias) Unclear No (high risk of bias)


Figure 3

Methodological quality summary: review authors’ judgments about each methodological quality item for each included study.

Adequate

sequence

generation?

Allocation

concealment?

Blinding

patients?

Blinding

physicians/

personnel?

Blinding

outcome

acessors?

Incomplete

outcome data

addressed?

Free of

selective

reporting?

Free of

other bias?

Ammirati 1998 ? ? ? ? ? + + -

Ammirati 2000 ? ? + - - + + +

Ammirati 2001 + + - - - + + -

Biffi 1997 ? ? + ? + + + +

Brignole 1988 ? ? + - - + ? +

Brignole 1992 + ? ? ? ? + ? -

Brignole 1992a + ? - - - + + -

Claesson 2007 + + - - - + + +

Connolly 1999 + + - - - ? + -

Connolly 2003 + + + + + + + -

Deharo 2003 ? ? ? ? ? + + +

Di Girolamo 1998 ? ? - - - + + +

Di Girolamo 1999 + ? + + + + + +

El-Bedawi 1994 ? ? ? ? ? + - ?

Eldadah 2006 ? ? + ? ? + + +

Flammang 1999 ? ? - - - + + +

Flevari 2002 ? ? + ? ? + + +

Guan 1999 + ? ? ? ? ? + +

Haghjoo 2006 ? ? + + + + + +

Jhamb 1996 ? ? ? ? ? + + +

Kaufmann 2002 + ? + + + + + ?

Kenny 2001 + ? - - - ? + +

Kluger 1998 ? ? + ? ? + + +

Kurbaan 2000 ? ? ? + ? - - -

Lee 1996 ? ? + ? ? + + +

Lin 2000 + ? ? ? ? ? + +

Madrid 2001 ? ? + ? ? - + +

Mahanonda 1995 + + + + + - + +

McIntosh 1997 ? ? + + + - - +

Moore 2005 ? ? + ? + ? - +

Morillo 1993 ? ? + ? ? + ? -

Moya 1995 ? ? + ? ? - + +

Nakagawa 1998 ? ? ? ? ? + + +

Occhetta 2004 + + + - - ? + -

Perez-Lugones 2001 ? ? - - - + + ?

Raviele 1999 + + + ? ? - + -

Raviele 2004 + ? + ? + + + -

Raviele 2005 ? ? + - - ? ? -

Santini 1999 ? ? + ? ? + + +

Sheldon 2006 ? ? + ? + - - +

Sutton 2000 + + - - - - + +

Theodorakis 2006 ? ? ? + ? - + +

Ventura 2002 ? ? - - - + + +

Ward 1998 + + + + + + + -

Zeng 1998 + ? + + + + + ?

Zeng 1998a + ? ? ? ? ? + +


Effects of interventions For vasovagal syncope, data extraction was possible for studies in which the effectiveness of treatment with beta-blockers, alpha-adrenergic agonists, selective serotonin reuptake inhibitors, ACE-inhibitors, disopyramide, anticholinergic agents or pacemaker treatment were determined. The recurrence of syncope during follow-up or upon head-up tilt testing was lower in patients treated with anticholinergic agents compared to patients treated with placebo or standard treatment. The trial sizes were however small.Studies that investigated treatment with beta-blockers, alpha-adrenergic agonists and pacemakers showed conflicting results. In general, significant treatment effects for these treatments were observed with respect to syncopal recurrence upon unblinded comparison with standard treatment. However, no significant differences were observed upon comparison with an inactive pharmacological substance or pacemaker.The occurrence of syncope upon provocational head-up tilt testing was lower during ACE-inhibitor treatment compared to standard treatment or placebo treatment, but no significant differences were observed with respect to the recurrence of syncope during follow-up. In general, the treatment effects for placebo-controlled treatment with selective serotonine reuptake inhibitors and disopyramide were not statistically significant.For carotid sinus syncope, we obtained studies in which the effectiveness of alpha-adrenergic treatment and pacemaker treatment was investigated. In a small study, the occurrence of syncope upon provocational head-up tilt testing was lower during treatment with midodrine compared to placebo treatment. The effectiveness of different types of pacemakers was investigated for carotid sinus syncope, but these studies showed conflicting results.In subsequent sections, the results of treatment comparisons for vasovagal syncope and carotid sinus syncope are discussed in more detail.

Vasovagal syncope

Beta-blockers

Unblinded comparison with standard treatmentBeta-blocker treatment was compared with conventional therapy in four studies.39, 45,

53, 70 The occurrence of syncope during follow-up was lower for patients that received beta-blocker treatment compared to patients that received standard treatment (risk ratio 0.36; 95% CI 0.21 to 0.62)(Analysis 1.1).45, 53, 70 In one study, the number of pre-syncopal recurrences per year was 0 for patients that received atenolol treatment and


4.8 for patients that received standard treatment.53 The occurrence of syncope upon provocation by head-up tilt testing was lower for patients that received beta-blocker treatment compared to patients that received standard treatment (risk ratio 0.75 (95% CI 0.58 to 0.97)(Analysis 1.2).39, 53 The occurrence of side effects was determined in two studies.45, 53 Patients treated with atenolol experienced side effects such as: bradycardia, palpitations, lightheadedness. In both studies, the occurrence of side effects in patients that received standard treatment was not assessed.

Analysis 1. Vasovagal syncope. Beta-blockers vs. standard treatment.

Outcome or Subgroup Studies ParticipantsStatistical Method

Effect Estimate

1.1 Proportion of patients with one or more syncopal episode(s) during follow-up.

3 129 Risk Ratio (M-H, Fixed, 95% CI)

0.36 [0.21, 0.62]

1.2 Proportion of patients with syncopal episodes induced by provocation testing.


0.75 [0.58, 0.97]

Comparison with placebo treatmentBeta-blocker treatment was compared with placebo treatment in 8 studies (491 patients).33, 42, 44, 50, 54, 55, 67, 69 However, one of these studies was considered insufficiently valid and applicable for data extraction.33 In the remaining studies, no significant differences were found with respect to the average number of syncopal episodes per patient per year (syncope burden), syncopal episode(s) during follow-up (Analysis 2.1) or average number of episodes of near syncope.42, 44, 50, 54, 55, 67, 69 However, there was a significant reduction of the proportion of patients with syncopal episodes induced by provocation testing during beta-blocker treatment compared to placebo (odds ratio 0.35; 95% CI 0.19 to 0.66)(see Analysis 2.2).42, 44, 50, 55, 69 The occurrence of side effects was investigated in 4 studies.44, 54, 55, 67 No major differences were found, as far as analysis is possible for these studies. Quality of life was assessed in 3 studies.44, 55, 69 Comparison between these studies for the outcome measure quality of life was not possible. Propranolol, nadolol and placebo treatment all improved patients’ self-assessed well-being (p< 0.0001; but no comparative data were available).44 In one study, quality of life improved in more patients treated with atenolol (71%) compared to patients treated with placebo (29%; p= 0.02).55 By contrast, quality of life was lower after beta-blocker treatment than after placebo treatment in another study (mean difference 0.60; 95% CI 0.20 to 1.00)


Analysis 2. Vasovagal syncope. Beta-blockers vs. placebo.


Effect Estimate



1.07 [0.80, 1.44]


5 211 Odds Ratio (IV, Fixed, 95% CI)

0.35 [0.19, 0.66]

Comparison with other pharmacological treatmentIn 10 studies beta-blocker treatment was compared with other kinds of pharmacological treatment, namely: other beta-blocker treatment,44, 46 clonidine,31 domperidon, dihydroergotamine and cafedrine,33 scopolamine,45 disopyramide,60 enalapril,53 etilefrine,39 verapamil,47 and fluoxetine.69 The study comparing atenolol, domperidon, dihydroergotamine and cafedrine treatment was found to be insufficiently valid and applicable for data extraction.33

In the aforementioned studies, no significant differences were observed with respect to syncope burden, pre-syncope burden, or occurrence of syncope during follow-up.The proportion of patients experiencing syncope upon provocotional head-up tilt testing did also not differ significantly between propranolol and several other kinds of pharmacological treatment.39, 44, 46, 60, 69 Similar findings were obtained in a study comparing atenolol and enalapril.53 However, the proportion of patients experiencing syncope upon provocotional head-up tilt testing was significantly different in the studies that compared metoprolol treatment with clonidine31 or verapamil.47 With respect to the occurrence of side effects, no significant differences were observed between beta-blocker treatment and comparative treatment. Though quality of life improved in all patients treated with propranolol, nadolol and placebo (p< 0.0001; but no comparative data were available),44 quality of life was worse in patients treated with propranolol compared to patients treated with fluoxetine.

Comparison with pacemaker treatmentOne study comparing beta-blocker treatment (atenolol) with DDD-pacemaker treatment observed that the occurrence of syncope during follow-up was higher in patients treated with atenolol compared to patients treated with a DDD-pacemaker (12 vs. 2; risk ratio 5.87; 95% CI 1.39 to 24.80).30 However, with respect to the time to syncopal recurrence, minor physical trauma due to syncope, and side effects, no significant differences were observed. Major physical trauma did not occur in any of the patients studied. Reported side effects were: palpitations (pacemaker group) and fatigue, depression, anxiety and impotence (beta-blocker group).


Alpha-adrenergic agonists

Unblinded comparison with standard treatmentTwo studies compared treatment with alpha-adrenergic agonists with standard treatment.39, 62 No significant differences were observed with respect to the syncope burden and occurrence of syncope upon head-up tilt testing. However, the proportion of patients experiencing syncope during follow-up was lower during treatment with an alpha-adrenergic agonist (midodrine) than conventional treatment (19.4% vs. 86.7%; risk ratio 0.22; 95% CI 0.11 to 0.46). The time to the first syncopal recurrence was also longer in patients treated with alpha-adrenergic agonists (hazard ratio 0.31; 95% CI 0.16 to 0.62). Finally, quality of life (Endicott Questionnaire) was higher after midodrine treatment compared to conventional treatment (mean difference 20.00; 95% CI 17.43 to 22.57).

Comparison with placebo treatmentTreatment with alpha-adrenergic agonists was compared with placebo treatment in 7 studies.29, 39, 59, 63, 65, 71, 74 In a single study, no significant differences were found with respect to the proportion of patients experiencing syncope during follow-up, the median time to recurrence of syncope as well as the number of episodes of near syncope per patient.63 From all studies, data about the proportion of patients with syncopal episodes induced by provocation testing could be derived. The studies fall into 2 categories: 1) treatment initiation before the provocational head-up tilt test.39, 59, 63, 71, 74 or 2) treatment initiation upon the occurrence of signs and symptoms of an impending syncopal episode during provocation testing.29, 65 We discuss the results for treatment initiation before the provocational head-up tilt test first.In general, the occurrence of syncope upon provocation testing after the initiation of treatment was not different for treatment with alpha-adrenergic agents compared to placebo treatment (odds ratio 0.76; 95% CI 0.48 to 1.20). For these studies, the results differed considerably for randomized cross-over trials (P-value Chi2-test= 0.02; I2=75%). The treatment effects within subgroups by type of alpha-adrenergic treatment (etilefrine or midodrine) were much more consistent (P-values Chi2-tests ≥ 0.65;I2= 0%). Though no statistically significant differences were observed for etilefrine treatment (Analysis 3.1, Subgroup1), the occurrence of syncope upon head-up tilt testing was lower in patients treated with midodrine compared to patients that received placebo treatment (odds ratio 0.08; 95% CI 0.02 to 0.42)(Comparison Analysis 3.1, Subgroup 2). In studies in which treatment was started after the occurrence of symptoms, the occurrence of syncopal episodes induced by provocation testing was also lower in patients treated with alpha-adrenergic agents


compared to patients that received placebo treatment (odds ratio 0.02, 95% CI 0.01 to 0.08)(Analysis 3.2). One study evaluated the occurrence of trauma due to syncope.63 Major trauma did not occur in any of the patients; the occurrence of minor trauma was not assessed.The occurrence of side effects was investigated in 5 studies.29, 59, 63, 65, 71 No significant differences were found with respect to the occurrence of side effects. Reported side effects in patients receiving treatment with alpha-adrenergic agonists were: goose bumps, tingling, chills, agitation, depression, anxiety, insomnia, gastro-intestinal discomfort, palpitations, hypertension. Reported side effects in patients receiving placebo treatment were: gastro-intestinal discomfort, palpitations, hypertension. One study reported that psychiatric side effects such as agitation, depression, anxiety and insomnia were exclusively observed in patients treated with etilefrine (20% vs. 0%).63

Quality of life was assessed in one study and was found to be improved upon treatment with an alpha-adrenergic agonist (no comparative data were available).71

Analysis 3. Vasovagal syncope. Alpha-adrenergic agents vs. placebo.

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate

3.1 Proportion of patients with syncopal episodes induced by provocation testing. Treatment initiation before provocation testing.


0.76 [0.48, 1.20]

3.1.1 Etilefrine treatment 3 299 Odds Ratio (IV, Fixed, 95% CI)

0.92 [0.57, 1.49]

3.1.2 Midodrine treatment 2 56 Odds Ratio (IV, Fixed, 95% CI)

0.08 [0.02, 0.42]

3.2 Proportion of patients with syncopal episodes induced by provocation testing. Treatment initiation after the occurrence of symptoms.


0.02 [0.01, 0.08]

Comparison with other pharmacological treatmentAlpha-adrenergic agonist (etilefrine) and beta-blocker (propranolol) treatment were compared in one study.39 No significant differences were observed with respect to the occurrence of syncope upon provocation testing.


Selective serotonin reuptake inhibitors

Comparison with placebo treatmentIn 2 studies comparing treatment with selective serotonin reuptake inhibitors and placebo treatment, no significant differences were found with respect to the syncope burden, pre-syncope burden and occurrence of syncope induced by provocation testing (Analysis 4.1).40, 69 However, the occurrence of syncope during follow-up was lower during treatment with selective serotonin reuptake inhibitors than during placebo treatment (risk ratio 0.39, 95% CI 0.20 to 0.76)(Analysis 4.2).40, 69

The occurrence of side effects and quality of life were not significantly different during treatment with a selective serotonin reuptake inhibitor and placebo treatment. Reported side effects during paroxetine treatment were: severe recurrent headaches, transient sexual dysfunction, nausea and diarrhea.40 In the same study, headache was reported by one patient in the placebo group. Study treatment had to be discontinued because of side effects in one patient treated with paroxetine and in none of the patients treated with placebo.

Analysis 4. Vasovagal syncope. Selective serotonin reuptake inhibitors vs. placebo.

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate



0.75 [0.51, 1.11]



0.39 [0.20, 0.76]

Comparison with other pharmacological treatmentOne study also compared the effectiveness of fluoxetine treatment with beta-blocker treatment (propranolol)(n=63 patients for this comparison).69 No significant differences were found with respect to the syncope and pre-syncope burden, the proportion of patients with one or more syncope during follow-up and the occurrence of syncope induced by provocation testing. However, quality of life was better in patients treated with selective serotonin reuptake inhibitors compared to beta-blocker treatment (mean difference -0.70; 95% CI -1.10 to -0.30).


ACE-inhibitors

Unblinded comparison with standard treatmentIn one study, comparing ACE-inhibitor treatment (enalapril) and standard treatment, no significant differences were observed with respect to the occurrence of syncope during follow-up and pre-syncope burden between patients that received enalapril treatment and patients receiving standard treatment..53 However, the occurrence of syncope upon head-up tilt testing was lower for patients treated with enalapril compared to patients that received standard treatment (risk ratio 0.54 (95% CI 0.29 to 0.98).Six of the 16 patients that received enalapril treatment experienced side effects.53 These were: dry cough, low blood pressure, palpitations and lightheadedness. The occurrence of any side effects in patients that received standard treatment was not reported.

Comparison with placebo treatmentTwo studies compared treatment with an ACE-inhibitor (enalapril) with placebo treatment.72, 73 The proportion of patients with syncopal episodes induced by provocation testing was lower during enalapril treatment compared with placebo treatment (risk ratio 0.04, 95% CI 0.01 to 0.29)(Analysis 5.1). In one study, no significant differences were observed with respect to the occurrence of side effects.73 In this study, one patient treated with enalapril discontinued treatment because of dry cough.

Analysis 5. Vasovagal syncope. ACE-inhibitors vs. placebo.


Effect Estimate



0.04 [0.01, 0.29]

Comparison with other pharmacological treatmentACE-inhibitor treatment (enalapril) was compared with beta-blocker treatment (atenolol) in one study.53 No significant differences were observed with respect to the occurrence of syncope during follow-up, syncope upon provocational head up tilt testing and the occurrence of side effects during follow-up.Side effects that occurred during both atenolol treatment and enalapril treatment were: lightheadedness and palpitations.53 Patients treated with atenolol also experienced bradycardia. A dry cough and low blood pressure were also experienced as side effects of enalapril treatment.


Disopyramide

Two studies evaluated the effectiveness of disopyramide treatment for vasovagal syncope.58, 60 One of these studies compared disopyramide treatment with placebo treatment.58 No syncopal episodes occurred during follow-up for both oral treatment modalities. The occurrence of syncope upon provocational head-up tilt testing was not significantly different for disopyramide treatment and placebo treatment. During disopyramide treatment patients in this study reported side effects such as dry mouth, urinary hesitancy or retention. A dry mouth was also reported as a side effect during placebo treatment.No significant differences were observed between disopyramide treatment and propranolol treatment with respect to the proportion of patients experiencing syncope induced by provocation testing.60

Anticholinergic agents

Unblinded comparison with standard treatmentIn one study, the recurrence of syncope during follow-up was lower in patients treated with scopolamine compared to patients that received standard treatment (risk ratio 0.42; 95% CI 0.18 to 0.95).45 Twenty-five per cent of patients treated with scopolamine experienced side effects, such as: severe dry mouth, palpitations, blurred vision.45 The occurrence of any side effects of patients that received standard treatment was not reported.

Comparison with placebo treatmentThe effectiveness of anticholinergic agents versus placebo treatment for vasovagal syncope was evaluated in two studies.52, 66 In both studies, treatment was only initiated when signs and symptoms occurred upon provocation testing. For anticholinergic agents there was a significant reduction in occurrence of syncope induced by provocation testing with treatment initiation after the occurrence of symptoms (risk ratio 0.66; 95% CI 0.50 to 0.86)(Analysis 6.1). At least one patient treated with scopolamine stopped treatment prematurely because of side effects (no further or comparative data available).52


Analysis 6. Vasovagal syncope. Anticholinergic agents vs. placebo.


Effect Estimate

6.1 Proportion of patients with syncopal episodes induced by provocation testing. Treatment initiation after the occurrence of symptoms.


0.66 [0.50, 0.86]

Comparison with other pharmacological treatmentIn one study, scopolamine treatment was compared with beta-blocker treatment (atenolol).45 No significant differences were observed with respect to the occurrence of syncope and side effects during follow-up. Reported side effects upon scopolamine treatment were: severe dry mouth, palpitations and blurred vision. Bradycardia was experienced as a side effect in patients that received atenolol.

DDD-pacemaker

Unblinded comparison with standard treatmentWe obtained 3 unblinded studies evaluating the effectiveness of dual chamber pacemaker treatment in comparison with standard treatment for vasovagal syncope.36,

43, 68 Though dual chamber pacemakers were used in all these studies, the precise pacemaker responses differed between studies. Both rate drop responsiveness36 and DDI-pacing with rate hysteresis68 were applied. In one of these studies, the action made has not been specified.43 The occurrence of syncope during follow-up was found to be lower in patients treated with a DDI-pacemaker compared to patients receiving standard treatment (risk ratio 0.09; 95% CI 0.01 - 0.60).68 The proportion of patients experiencing syncope during follow-up reduced significantly upon dual chamber pacemaker treatment compared to standard treatment (risk ratio 0.20; 95% CI 0.10 to 0.40)(Analysis 7.1).36, 43, 68 The average time elapsed from start of an intervention until the first episode of syncope was also longer for patients treated with a DDD-pacemaker (hazard ratio 0.17; 95% CI 0.06 to 0.45)(Analysis 7.2).36, 43, 68 No significant differences were found with respect to the average number of episodes of near syncope36 as well as the occurrence of syncope upon provocational head-up tilt testing68 and the occurrence of minor trauma due to syncope.36 The occurrence of major trauma was evaluated in one study; it did not occur.36

No significant differences were found with respect to the occurrence of side effects.36 Side effects reported by patients with a dual chamber DDD-pacemaker were: lead


dislodgement, palpitations and pacemaker activity at rest.

Analysis 7. Vasovagal syncope. DDD-pacemaker vs. conventional standard therapy.


Effect Estimate



0.20 [0.10, 0.40]

7.2 Average time elapsed from start of an intervention until the first episode of syncope.

3 116 Hazard Ratio (IV, Fixed, 95% CI)

0.17 [0.06, 0.45]

Blinded comparison with non-active pacemakerActive DDD-pacemaker treatment was compared with non-active pacemaker treatment in 3 studies.37, 41, 64 However, we considered one of these insufficiently valid and applicable for data extraction.41 There were no significant differences with respect to the occurrence of syncope during follow-up and time to first syncopal recurrence (Analysis 8.1).37, 64 Active and non-active pacemaker treatment did also not differ significantly with respect to the occurrence of minor trauma due to syncope (Analysis 8.2).37, 64 Major trauma due to syncope occurred in none of the study patients.Also with respect to the occurrence of side effects no significant differences were observed between active and inactive pacemaker treatment (Analysis 8.4).37, 64 Side effects reported by patients with an active DDD-pacemaker were: infection, pericardial tamponade, lead dislodgement or repositioning, wound hematoma and pain related to pacemaker generator and palpitations.37, 64 Patients with a non-active pacemaker reported no side effects in one study.64 In the other study, these patients reported side effects such as: infection, lead dislodgement or repositioning, vein thrombosis, wound hematoma and pain related to pacemaker generator.37


Analysis 8. Vasovagal syncope. Active dual chamber DDD-pacemaker vs. non-active pacemaker.

Outcome or Subgroup Studies

ParticipantsStatistical Method

Effect Estimate



0.89 [0.58, 1.38]

8.2 Proportion of patients with minor physical trauma due to syncope.


0.79 [0.21, 3.00]

8.3 Proportion of patients with major physical trauma due to syncope.


Not estimableZero events in both groups

8.4 Proportion of patients with side effects.


1.77 [0.84, 3.75]

Comparison with other pacemaker treatmentIn 4 studies, dual chamber DDD-pacemaker treatment was compared with DDI-pacemaker treatment.28, 38, 51, 61 We considered one of these studies insufficiently valid and applicable for data extraction.51 In one of the other studies, syncope did not occur in patients with a DDD-closed loop stimulation pacemaker, while patients treated with a DDI-pacemaker had a mean number of 1.2 syncopes (SD 0.8) during 18 months of follow-up.61 Among patients treated with a DDD-pacemaker the proportion of patients experiencing syncope during follow-up was significantly lower compared to patients with a DDI-pacemaker (risk ratio 0.07; 95% CI 0.01 to 0.34)(Analysis 9.1).28, 38, 61 The time to syncopal recurrence was also longer in these patients compared to patients treated with a DDI-pacemaker (hazard ratio 0.05; 95% CI 0.00 to 0.82).61 No significant differences were observed with respect to the average number of episodes of near syncope,38 syncope induced by provocation testing and quality of life.38

Analysis 9. Vasovagal syncope. DDD-pacemaker vs. DDI-pacemaker.


Effect Estimate



0.07 [0.01, 0.34]

9.1.1 Parallel randomized controlled trials


0.06 [0.01, 0.39]

9.1.2 Randomized cross-over trials 1 46 Risk Ratio (M-H, Fixed, 95% CI)

0.11 [0.01, 1.95]


Comparison with pharmacological treatmentThe occurrence of syncope during follow-up was lower in one study that investigated patients treated with a dual chamber DDD-pacemaker compared to patients that beta-blocker treatment (atenolol)(risk ratio 0.17; 95% CI 0.04 to 0.72).30 However, no significant differences were observed between these treatments with respect to the time to syncopal recurrence and the occurrence of minor trauma and side effects. Palpitations (pacemaker group) and fatigue, depression, anxiety and impotence (beta-blocker group) were reported as side effects. Major trauma did not occur in any of the patients studied.

Other pacemaker

Comparison with other pacemaker treatmentWe obtained three studies in which DDI-pacemaker treatment was compared with dual chamber DDD-pacemaker treatment.28, 38, 61 In the section DDD-pacemaker-comparison with other pacemaker treatment, we have already described the results for these comparisons. Therefore, we refer the reader to this section of our review.

Carotid sinus syncope

Alpha-adrenergic agonists

One cross-over trial compared midodrine treatment with placebo treatment in older adults with carotid sinus syncope.57 The proportion of patients with syncopal complaints induced by carotid sinus massage was lower during midodrine treatment than during placebo treatment (risk ratio 0.13; 95% CI 0.02 to 0.82). Though bloodpressure decrement occurred in some patients, it remains unknown whether true syncope occurred in these patients.

DDD-pacemaker

Two studies evaluated the effectiveness of DDD-pacemaker treatment in patients with carotid sinus syncope.32, 49 One of these studies compared DDD-pacemaker treatment with standard treatment.49 No significant differences were found with respect to the syncope burden and the


proportion of patients that experienced syncope during follow-up.49 The occurrence of syncope during follow-up did also not differ significantly upon comparison of DDD-pacemaker treatment with VVI-pacemaker treatment.32

VVI-pacemaker

The effectiveness of VVI-pacemaker treatment was evaluated in 2 cross-over trials.32,

56 In one of these, the proportion of patients experiencing syncope during follow-up was not significantly different for VVI-pacemaker treatment as compared to DDD-pacemaker treatment.32

In the other study, the proportion of patients with syncopal episodes induced by carotid sinus massage was higher in patients treated with a VVI-pacemaker compared to patients with a DDI-pacemaker (risk ratio 5.50; 95% CI 1.33 to 22.73).56 The occurrence of side effects was also higher during VVI-pacemaker treatment compared to DDD-pacemaker treatment (risk ratio 23.00; 95% CI 1.42 to 373.46).56

Other pacemaker

Comparison with standard treatmentIn one study, the proportion of patients experiencing syncope during follow-up was lower during DDI/VVI pacemaker treatment compared to standard treatment (risk ratio 0.16; 95% CI 0.05 to 0.50).34 However, any differences with respect to the syncope and pre-syncope burden were not statistically significant.The proportion of patients that experienced syncope during follow-up was lower in a study in which pacemaker treatment was compared with standard treatment (risk ratio 0.25; 95% CI 0.08 to 0.80).35 No significant differences were found with respect to the occurrence of major trauma.

Comparison with other pacemaker treatmentDDI-pacemaker treatment was compared with VVI-pacemaker treatment in one study.56 The occurrence of syncopal episodes upon carotid sinus massage was lower in patients treated with a DDI-pacemaker compared to patients with a VVI-pacemaker (risk ratio 0.18; 95% CI 0.04 to 0.75). Side effects occurred less often during DDI-pacemaker treatment compared to VVI-pacemaker treatment (risk ratio 0.04; 95% CI 0.00 to 0.71).


Discussion

In this review we studied different pharmacological and pacemaker treatments for various types of reflex syncope. We identified randomized trials for vasovagal syncope and carotid sinus syncope, but were unable to include any trials about situational syncope. In the following sections, we discuss the different treatment modalities for vasovagal syncope and carotid sinus syncope.

Vasovagal syncopeThere is no consistent evidence for the effectiveness of pharmacological or pacemaker treatments for vasovagal syncope.In individual studies, we found significant effects for beta-blockers, ACE-inhibitors and anticholinergic agents for the outcome occurrence of syncope upon provocational head-up tilt testing (Summary of findings table 1). However, this outcome should be interpreted with caution, because the reproducibility of tilt testing varies between 31% and 94% depending on the tilt test response.1, 15, 75-77 Approximately 50% of patients with a baseline positive tilt test become negative upon repeat of the tilt test.15 Moreover, provocational tilt testing does not provide information about the ability of interventions to prevent (pre-)syncopal recurrence in daily life.1 For all studies in which treatment was initiated only upon symptom recurrence during a provocational head-up tilt test we obtained significant differences (Summary of findings table 1). However, pre-syncope, which is associated with a bloodpressure decrement,78 was already imminent in these patients. Because of this, comparison with patients with treatment initiation before the occurrence of transient loss of consciousness is difficult. The results of studies in which the effectiveness of treatment is determined by provocational head-up tilt testing need therefore to be interpreted with caution.For DDD-pacemaker treatment compared to standard treatment we found significant effects regarding the occurrence of syncope (Summary of findings table 1). However, no significant differences were observed when active DDD-pacemaker treatment was compared with inactive pacemaker treatment. These findings strongly suggest that the primary mechanism of benefit of pacemaker insertion is an expectation response, rather than a true treatment effect.79 Adequate blinding is undoubtedly necessary in future studies. DDD-pacemakers were more effective than DDI-pacemakers with respect to the occurrence of syncope during follow-up (Summary of findings table 1). However, all three studies were very small and firm recommendations can not be based on this body of evidence. Though treatment with fludrocortison is considered to be a useful treatment option for vasovagal syncope, we could not include any studies evaluating the effectiveness


of fludrocortisone, because no randomized trials with adult patients were available.18 A relatively small trial in children found that symptoms disappeared more often in patients treated with fludrocortisone than in patients receiving placebo.80 A study evaluating the tolerance of fludrocortisone in elderly patients also found that side effects were common upon treatment with fludrocortisone.81 The results from these studies indicate that fludrocortisone can not be considered the treatment of choice in patients with recurrent vasovagal syncope.

Drugs and pacemakersDrugs and pacemakers 137Su

mm

ary

of fi

ndin

gs ta

ble

1. P

harm

acol

ogic

al a

nd p

acem

aker

trea

tmen

t for

vas

ovag

al sy

ncop

e.

Com

pari

son

trea

tmen

tSy

ncop

e bu

rden

Prop

ortio

n of

pa

tient

s with

sync

ope

duri

ng fo

llow

-up

Prop

ortio

n of

pat

ient

s with

sync

ope

upon

he

ad-u

p til

t tes

ting

Prop

ortio

n of

pat

ient

s with

sid

e ef

fect

s

Bet

a-bl

ocke

rs v

s. st

anda

rd

treat

men

t

Ris

k ra

tio 0

.36

(95%

C

I 0.2

1 - 0

.62)

(3

stud

ies,

122

patie

nts)

Ris

k ra

tio 0

.75

(95%

CI 0

.58

- 0.9

7) (2

st

udie

s, 15

0 pa

tient

s)

Not

e:he

tero

gene

ous t

reat

men

t effe

cts (

p-va

lue

Chi

2 -tes

t= 0

.02;

I2 =82

%)

Side

effe

cts o

ccur

red

in

inte

rven

tion

grou

p. C

ontro

l gr

oup:

not

ass

esse

d. (2

stud

ies,

81 p

atie

nts)

Bet

a-bl

ocke

rs v

s. pl

aceb

o

Med

ian

2 vs

. 0 (p

= 0.

22)(

1 st

udy,

50

patie

nts)

Rat

e ra

tio 1

.33

(95%

CI 0

.01

- 15

1.63

) (1

stud

y, 6

8 pa

tient

s)

Ris

k ra

tio 1

.07

(95%

CI 0

.80

- 1.4

4)(3

stud

ies,

320

parti

cipa

nts)

Odd

s rat

io 0

.35

(95%

CI 0

.19

- 0.6

6)(5

st

udie

s, 17

3 pa

tient

s)

≥ 12

vs.

≥7 (p

-val

ue n

ot

repo

rted)

(1 st

udy,

208

pat

ient

s)

Odd

s rat

io 5

.31

(95%

CI 0

.85

- 33

.10)

(2 st

udie

s, 11

2 pa

tient

s)

Alp

ha-a

dren

ergi

c ag

onis

ts

vs. s

tand

ard

treat

men

t.R

ate

ratio

3.2

0 (9

5% C

I 0.8

2 -

12.4

6)(1

stud

y, 6

1 pa

tient

s)

Ris

k ra

tio 0

.22

(95%

C

I 0.1

1 - 0

.46)

(1 st

udy,

61

pat

ient

s)

Ris

k ra

tio 0

.99

(95%

CI 0

.78

- 1.2

6)(1

stud

y,

113

patie

nts)

Alp

ha-a

dren

ergi

c ag

onis

ts

vs. p

lace

bo

Ris

k ra

tio 1

.00

(95%

C

I 0.5

4 - 1

.87)

(1 st

udy,

12

6 pa

tient

s)

I. Tr

eatm

ent i

nitia

tion

befo

re p

rovo

catio

nal

head

-up

tilt t

est.

Odd

s rat

io 0

.70

(95%

CI 0

.46

- 1.0

7)(5

st

udie

s, 30

8 pa

tient

s).

Subg

roup

Etil

efrin

e tre

atm

ent:

odds

ratio

0.9

4 (9

5% C

I 0.5

9 - 1

.48)

(3 st

udie

s, 26

6 pa

tient

s).

Subg

roup

mid

odrin

e tre

atm

ent:

odds

ratio

0.

12 (9

5% C

I 0.0

4 - 0

.36)

(2 st

udie

s, 42

pa

tient

s)

II. T

reat

men

t ini

tiatio

n up

on sy

mpt

om

occu

rren

ce d

urin

g pr

ovoc

atio

nal h

ead-

up ti

lt te

st.

Odd

s rat

io 0

.02

(95%

CI 0

.01

- 0.0

8)(2

st

udie

s, 13

4 pa

tient

s)

At l

east

one

pat

ient

with

si

de e

ffect

s in

both

trea

tmen

t gr

oups

(1 st

udy,

30

patie

nts)

Odd

s rat

io 1

.60

(95%

CI 0

.74

- 3.

46)(

3 st

udie

s, 24

2 pa

tient

s)

Sele

ctiv

e se

roto

nin

reup

take

in

hibi

tors

vs.

plac

ebo

Rat

e ra

tio 0

.65

(95%

CI 0

.00

- 18

5.07

)(1

stud

y, 6

3 pa

tient

s)

Ris

k ra

tio 0

.39

(95%

C

I 0.2

0 - 0

.76)

(2

stud

ies,

131

patie

nts)

Ris

k ra

tio 0

.75

(95%

CI 0

.51

- 1.1

1)(2

st

udie

s, 13

1 pa

tient

s)R

isk

ratio

3.0

0 95

% C

I 0.3

3 -

27.4

2)(1

stud

y, 6

8 pa

tient

s)


AC

E-in

hibi

tors

vs.

stan

dard

tre

atm

ent

Ris

k ra

tio 2

.00

(95%

C

I 0.2

0 - 1

9.91

)(1

stud

y, 3

2 pa

tient

s)

Ris

k ra

tio 0

.54

(95%

CI 0

.29

- 0.9

8)(1

stud

y,

32 p

atie

nts)

Inte

rven

tion

grou

p: 6

/16(

38%

)

Con

trol g

roup

: not

repo

rted.

(1 st

udy,

32

patie

nts)

AC

E-in

hibi

tors

vs.

plac

ebo

Ris

k ra

tio 0

.04

(95%

CI 0

.01

- 0.2

9)(2

st

udie

s, 72

pat

ient

s)R

isk

ratio

7.0

0 (9

5% C

I 0.3

8 -

128.

61) (

1 st

udy,

48

patie

nts)

Dis

opyr

amid

e vs

. pla

cebo

No

occu

rren

ce o

f sy

ncop

e in

bot

h tre

atm

ent g

roup

s (1

stud

y, 2

2 pa

tient

s)

Ris

k ra

tio 1

.50

(95%

CI 0

.31

- 7.3

0)(1

stud

y,

22 p

atie

nts)

Ant

icho

liner

gic

agen

ts v

s. st

anda

rd tr

eatm

ent

Ris

k ra

tio 0

.42

(95%

C

I 0.1

8 - 0

.95)

(1 st

udy,

45

pat

ient

s)

Inte

rven

tion

grou

p: 5

/20(

25%

)

Con

trol g

roup

: not

repo

rted.

(1 st

udy,

45

patie

nts)

Ant

icho

liner

gic

agen

ts v

s. pl

aceb

o

Trea

tmen

t ini

tiatio

n up

on sy

mpt

om

occu

rren

ce d

urin

g pr

ovoc

atio

nal h

ead-

up ti

lt te

st. R

isk

ratio

0.6

6 (9

5% C

I 0.5

0 - 0

.86)

(2

stud

ies,

142

patie

nts)

Not

e: h

eter

ogen

eous

trea

tmen

t effe

cts

(p-v

alue

Chi

2 -tes

t < 0

.000

01; I

2 = 9

4%)

One

pat

ient

(1/2

8(4%

)) st

oppe

d sc

opol

amin

e tre

atm

ent a

head

of

time

beca

use

of si

de e

ffect

s (1

stud

y, 5

8 pa

tient

s)

Flud

roco

rtiso

n vs

. any

tre

atm

ent

DD

D-p

acem

aker

vs.

stan

dard

trea

tmen

tR

ate

ratio

1.2

7 (9

5% C

I 0.1

7 -

9.28

)(1

stud

y, 4

2 pa

tient

s)

Ris

k ra

tio 0

.20

(95%

C

I 0.1

0 - 0

.40)

(3

stud

ies,

116

patie

nts)

Ris

k ra

tio 0

.96

(95%

CI 0

.56

to 1

.66)

(1 st

udy,

42

pat

ient

s)R

isk

ratio

15.

00 (9

5% C

I 0.9

0 -

250.

24)(

1 st

udy,

54

patie

nts)

DD

D-p

acem

aker

ver

sus

non-

activ

e pa

cem

aker

Ris

k ra

tio 0

.89

(95%

C

I 0.5

8 - 1

.38)

(2

stud

ies,

129

patie

nts)

Ris

k ra

tio 1

.77

(95%

CI 0

.84

- 3.

75)(

2 st

udie

s, 12

9 pa

tient

s)

DD

D-p

acem

aker

vs.

DD

I-pa

cem

aker

0 vs

. 1.2

sync

opes

(SD

0.8

) du

ring

18 m

onth

s of f

ollo

w-

up(1

stud

y, 2

5 pa

tient

s)

Ris

k ra

tio 0

.07

(95%

C

I 0.0

1 - 0

.34)

(3

stud

ies,

92 p

atie

nts)

Ris

k ra

tio 0

.40

(95%

CI 0

.13

- 1.2

2)(1

stud

y,

20 p

atie

nts)

DD

I pac

emak

er w

ith

rate

hys

tere

sis v

ersu

s no

pace

mak

er

Rat

e ra

tio 1

.27

(95%

CI 0

.17

- 9.

28)(

1 st

udy,

42

patie

nts)

Ris

k ra

tio 0

.09

(95%

C

I 0.0

1 - 0

.60)

(1 st

udy,

42

pat

ient

s)

Ris

k ra

tio 0

.96

(95%

CI 0

.56

- 1.6

6)(1

stud

y,

42 p

atie

nts)


AC

E-in

hibi

tors

vs.

stan

dard

tre

atm

ent

Ris

k ra

tio 2

.00

(95%

C

I 0.2

0 - 1

9.91

)(1

stud

y, 3

2 pa

tient

s)

Ris

k ra

tio 0

.54

(95%

CI 0

.29

- 0.9

8)(1

stud

y,

32 p

atie

nts)

Inte

rven

tion

grou

p: 6

/16(

38%

)

Con

trol g

roup

: not

repo

rted.

(1 st

udy,

32

patie

nts)

AC

E-in

hibi

tors

vs.

plac

ebo

Ris

k ra

tio 0

.04

(95%

CI 0

.01

- 0.2

9)(2

st

udie

s, 72

pat

ient

s)R

isk

ratio

7.0

0 (9

5% C

I 0.3

8 -

128.

61) (

1 st

udy,

48

patie

nts)

Dis

opyr

amid

e vs

. pla

cebo

No

occu

rren

ce o

f sy

ncop

e in

bot

h tre

atm

ent g

roup

s (1

stud

y, 2

2 pa

tient

s)

Ris

k ra

tio 1

.50

(95%

CI 0

.31

- 7.3

0)(1

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Carotid sinus syncopeFor carotid sinus syncope, the occurrence of syncope upon carotid sinus massage was lower for midodrine treatment compared to placebo treatment in one study (Summary of findings table 2). In this study, only 20 patients were included and the effect on symptoms in daily life was not assessed. We could not include any RCTs for other types of pharmacological interventions for carotid sinus syncope.Though DDD-pacemaker treatment was more effective than VVI pacemaker treatment in one study with respect to the occurrence of syncope upon carotid sinus massage, no significant differences were observed in this study regarding the occurrence of syncope during follow-up (Summary of findings table 2). Moreover, DDD-pacemaker treatment and standard treatment were equally effective with respect to this outcome measure and the syncope burden (Summary of findings table 2). In conclusion, there is insufficient evidence for pacemaker treatment in patients with carotid sinus syncope.


Summary of findings table 2. Pharmacological and pacemaker treatment for carotid sinus syncope.

Comparison treatment Syncope burden

Proportion of patients with syncope during follow-up

Proportion of patients with syncope upon carotid sinus massage

Proportion of patients with side effects

Alpha-adrenergic agonists vs. placebo

Risk ratio 0.13 (95% CI 0.02 - 0.82)(1 study, 20 patients)

DDD-pacemaker vs. standard treatment

Rate ratio 0.50 (95% CI 0.00 - 53.40)(1 study, 171 patients)


VVI-pacemaker vs. DDD-pacemaker




Overall completeness and applicability of evidence Despite a reasonable number of included trials in our review, many uncertainties remain. The main reasons for this incomplete picture are that studies are small in sample size, use a variety of control treatments, are often not blinded, and the focus is not always on patient relevant outcomes.Effective treatment for neurally mediated syncope not only reduces the recurrence of syncope and pre-syncope, but also makes patients feel better. It is well known that quality of life is decreased in patients with transient loss of consciousness compared to patients without syncope.6, 8, 82 In previous studies, quality of life appeared to be lower in patients with frequent recurrences of transient loss of consciousness.8, 83 Recurrent episodes were found to be the strongest negative predictor of quality of life in patients with transient loss of consciousness.82 Because of this, improving quality of life is an important goal of treatment for neurally mediated reflex syncope. Unfortunately, quality of life was only addressed in a limited number of included studies.In this review, we have not investigated the cost-effectiveness of pharmacological and pacemaker treatment for neurally mediated reflex syncope. As some of these treatments are quite expensive,19, 84 costs of treatment need to be considered prior to treatment initiation. None of the pharmacological and pacemaker treatments investigated in this review showed clear superiority to control treatment for different treatment comparisons. Therefore, these treatments should only be


applied to patients with frequent (pre-)syncopal recurrences, unresponsive to non-pharmacological treatment. Based on the results from our review, widespread usage of pharmacological and pacemaker treatment for neurally-mediated reflex syncope is not likely to produce a significant increase in patients’ well-being and is in our view therefore not a cost-effective option.Non-pharmacological treatment measures such as ensuring an adequate fluid and salt intake, regular exercise and the performance of physical counterpressure manoeuvres have been shown to be effective, initial treatment measures for vasovagal syncope.9, 10 For this reason, non-pharmacological treatment is currently recommended to all patients diagnosed with neurally mediated reflex syncope in current syncope management guidelines.1 Since non-pharmacological treatment measures are especially useful to increase the circulating blood volume,9 patients with cardio-inhibitory carotid sinus syncope seem to be less likely to benefit from these measures. Except maybe for these patients, pharmacological or pacemaker treatment should only be considered in patients failing to respond to non-pharmacological treatment measures. However, in all studies included in our review, pharmacological and/or pacemaker treatment were prescribed without prior non-pharmacological treatment. Treatment effects could be much different in patients not responding to non-pharmacological treatment measures. Therefore, the fact that the effectiveness of pharmacological and pacemaker treatment in included studies has not been determined in patients not responding to non-pharmacological treatment measures could seriously impair the applicability of study results to clinical practice.

Quality of the evidence We included 13 cross-over studies in our review. Cross-over studies have the advantage that treatment effects are based on comparison within individuals. This can lead to an increased precision meaning that confidence intervals become smaller in cross-over trials compared to parallel studies if outcomes are positively correlated. Unfortunately, the majority of cross-over studies in our review (11 out of 13) did not report on this correlation. In these studies we assumed that correlation would be zero. This is a conservative approach meaning that the weight of those studies could have been larger if they had used or reported this information.A major drawback of cross-over studies arises when carry-over effects are present.25 This means that the size of treatment effect is different when a treatment is given as first compared to second. This greatly reduces the informativeness of cross-over trials. None of our cross-over studies examined the presence of carry-over effects or would have sufficient power to examine it in a meaningful way. The implicit assumption in our review is therefore that the impact of carry-over effects is limited.In 27 of the 46 included studies (59%) the randomization method was described in


insufficient detail to make a judgement. Moreover in 80% of studies, the treatment allocation was not concealed or inadequately concealed. Because of this, there might have been systematic differences between the groups being compared. In other words, selection bias might have occurred.In more than 20% (10/46) of the studies included in this review, patients, physicians, and other study personnel were not blinded. Blinding is difficult in studies comparing pharmacological treatment with pacemaker treatment. The lack of blinding of treatments almost certainly influenced our results. This is illustrated by the fact that pacemaker treatment was found to be more effective than standard treatment for vasovagal syncope (see Summary of findings table 1). However, active pacemaker treatment was not superior to non-active pacemaker treatment. In unblinded studies, systematic differences between treatment groups in the care that is provided, or in exposure to factors other than the interventions of interest (e.g. an expectation effect79) might have occurred. Also, systematic differences between groups might have occurred with respect to the withdrawals from a study (attrition bias) and also in the manners of outcome assessment (detection bias). Thus, the lack of blinding in many of the studies in our review could have caused serious bias.We made comparisons for certain groups of different pharmacological agents (e.g. beta-blockers). In principle, we assumed that the treatment effect of all pharmacological agents within a certain pharmacological group was similar. If the treatment effects of different agents within a certain pharmacological group differ considerably, the general treatment effect might be insignificant, while the treatment effects of certain pharmacological agents can be significant. Except for alpha-adrenergic agents for vasovagal syncope, we did not find clear indications for specific treatment effects within a certain pharmacological group.For different comparisons of pharmacological treatment, the dosage of pharmacological treatment could differ considerably between studies. This could influence the occurrence of syncope and side effects due to dose-effect relationships. Only if more studies would have been available, the effects for certain medication dosages could have been investigated separately. Because of the limited amount of studies we obtained, we decided to analyze the effectiveness of pharmacological treatment independent of the drug dosage in order to be able to draw some conclusions from the available studies.

Implications for practice and researchCurrent evidence does not support pharmacological treatment or pacemaker implantation in patients with vasovagal syncope and carotid sinus syncope.We were unable to include any studies about situational syncope, and therefore cannot make any recommendations for this subdiagnosis of neurally mediated reflex


syncope.For most patients with neurally mediated reflex syncope, pharmacological and pacemaker treatment are only relevant treatment options upon failure of non-pharmacological treatment measures. However, in none of the studies included in this review treatment effects were determined in patients who failed to respond to non-pharmacological treatment. Therefore, in future studies, the effectiveness of pharmacological and pacemaker treatment for neurally mediated reflex syncope should be determined in patients with an insufficient response to non-pharmacological treatment. Non-pharmacological treatment measures aimed at ensuring an adequate blood supply to the brain are probably less appropriate to patients with cardio-inhibitory carotid sinus syncope.No studies on situational syncope were included in this review. Also, we did not include any RCT studying the effectiveness of fludrocortison treatment, though this pharmacological treatment is frequently prescribed in clinical practice. For almost all other kinds of pharmacological and pacemaker treatments, the number of studies and included patients was very limited. Often, a comparison with placebo or standard treatment was not made. We hope that the above information encourages researchers to address these issues in future studies.Preferably, double-blinded randomized controlled trials should be performed. For future research, it is important to select outcome measures that are directly relevant to patients. In many studies included in our review, provocational head-up tilt testing was used to determine the effectiveness of treatment for neurally mediated reflex syncope. However, in daily life, syncopal episodes do not occur while standing upon a tilt table. Because of this, the occurrence of syncope during long-term follow-up is a much better indicator of treatment effectiveness in daily life.Additionally, quality of life needs to be assessed, because an inverse association exists between recurrence of transient loss of consciousness and quality of life. Preferably, both generic quality of life and syncope-related quality of life should be addressed. Information about the occurrence of side effects is an important factor in the decision whether or not to prescribe pharmacological or pacemaker treatment for neurally mediated reflex syncope. Therefore, the occurrence of side effects should be determined in future studies. In case of study drop out or loss of follow-up, an intention-to-treat-analysis is preferable to determine pure treatment effects.Therefore, we hope that the occurrence of syncope during follow-up, quality of life and the occurrence of side effects will be addressed in future studies on the effectiveness of pharmacological or pacemaker treatment for neurally mediated reflex syncope in patients not responding to initial, non-pharmacological treatment.


Acknowledgements

We would like to thank the following persons for their help with the assessment of several non-English articles for our review:- Dr. Kirsten Ward, research follow/temporary review group co-ordinator for the Cochrane Heart Group.- S.T. Cynthia To, data assistant for CRASH2, Londen School of Hygiene and Tropical Medicine.- Nizar Abazid, research degrees student, Disease Control and Vector Biology Unit, London School of Hygine and Tropical Medicine.


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80. Salim MA, Di Sessa TG. Effectiveness of fludrocortisone and salt in preventing syncope recurrence in children: a double-blind, placebo-controlled, randomized trial. J Am Coll Cardiol 2005;45(4):484-488.

81. Hussain RM, McIntosh SJ, Lawson J, Kenny RA. Fludrocortisone in the treatment of hypotensive disorders in the elderly. Heart 1996;76(6):507-509.

82. Van Dijk N, Sprangers MA, Boer KR, Colman N, Wieling W, Linzer M. Quality of life within one year following presentation after transient loss of consciousness. Am J Cardiol 2007;100(4):672-676.


84. Deniz HB, Caro JJ, Ward A, Moller J, Malik F. Economic and health consequences of managing bradycardia with dual-chamber compared to single-chamber ventricular pacemakers in Italy. J Cardiovasc Med (Hagerstown ) 2008;9(1):43-50.

Chapter 7

Effectiveness of midodrine treatment in patients with recurrent vasovagal syncope not responding to non-pharmacological

treatment (STAND-trial)

Submitted

Jacobus J.C.M. RommeNynke van DijkIngeborg K. Go-Schön Johannes B. ReitsmaWouter Wieling

Chapter 7 Midodrine treatment in recurrent vasovagal syncope152 Midodrine treatment in recurrent vasovagal syncope

Abstract

Introduction: Initial treatment of vasovagal syncope (VVS) consists of advising adequate fluid and salt intake, regular exercise and physical counterpressure manoeuvres. Despite this treatment, up to 30% of patients continue to experience regular episodes of VVS.

Methods: In our study, patients with at least three syncopal and/or severe pre-syncopal recurrences during non-pharmacological treatment were eligible to receive double-blind cross-over treatment starting either with midodrine or placebo. Treatment periods lasted for 3 months with a wash-out period of one week in between. At baseline and after each treatment period, we collected data about the recurrence of syncope and pre-syncope, side effects, and quality of life (QoL).

Results: Twenty-three patients (17% male, mean age 32) included in the cross-over trial received both midodrine and placebo treatment. The proportions of patients that experienced syncopal and pre-syncopal recurrences did not differ significantly between midodrine and placebo treatment (syncope: 48% vs. 65%, p=0.22; pre-syncope: 74% vs. 78%, p>0.99). The median number of syncopes and pre-syncopes per 3 months were also not significantly different during midodrine and placebo treatment (0 vs. 1; p=0.57; and 6 vs. 8; p=0.90). The occurrence of side effects was similar during midodrine and placebo treatment (48% vs. 57%; p=0.75). Also, QoL did not differ significantly.

Conclusion: Our findings indicate that additional midodrine treatment is less effective in patients with VVS not responding to non-pharmacological treatment than reported as first-line treatment.

Midodrine treatment in recurrent vasovagal syncopeMidodrine treatment in recurrent vasovagal syncope 153

Introduction

According to the 2009 Syncope Management Guidelines of the European Society of Cardiology (ESC), non-pharmacological treatment is recommended as the first line of treatment for vasovagal syncope (VVS).1-4 This treatment consists of maintaining an adequate fluid and salt intake, regular exercise and the application of physical counterpressure manoeuvres.2, 5-7 Non-pharmacological treatment was found to be effective in about 70% of patients diagnosed with VVS.8 In patients that do not respond adequately to this treatment, pharmacological treatment with midodrine, an alpha-adrenergic agonist, might be considered.2, 7, 9, 10 By constriction of arterioles and veins, midodrine is thought to increase vasoconstrictor tone and reduce venous pooling of blood when standing, and thus prevent the occurrence of reflex syncope.7,

9, 11 A recent systematic review, including 4 studies with a total of 115 patients, evaluated the evidence of the effectiveness of midodrine treatment compared to conventional, non-pharmacological treatment.12 In only one of the included studies, patients were instructed to use physical counterpressure manoeuvres.12, 13 Across different studies, syncopal recurrence was found to be lower during treatment with midodrine than during conventional, non-pharmacological treatment or placebo treatment (odds ratio 0.07; 95% confidence interval (CI): 0.03 – 0.15).12 In the 2 included studies assessing quality of life (QoL), scores were higher upon midodrine treatment than control treatment.14, 15 However, alpha-adrenergic treatment in all studies within this review was started without prior non-pharmacological treatment.12 Since about 70% of patients diagnosed with VVS will respond to simple, inexpensive non-pharmacological treatment,8-10 pharmacological treatment for VVS is only relevant for patients that fail to respond to this treatment. Since it is yet unknown whether pharmacological treatment is beneficial to these patients, we determined the effectiveness of additional, alpha-adrenergic treatment with midodrine in patients with recurrent VVS not responding to non-pharmacological treatment.


Methods

We performed a randomized cross-over trial of midodrine against placebo in patients with VVS who responded insufficiently to non-pharmacological treatment. Midodrine or placebo was given while continuing non-pharmacological treatment measures. Each treatment period lasted for 3 months with a one-week washout period in between. This trial was conducted by the Syncope Treatment and Assessment network Netherlands (STAND). The protocol was approved by the Medical Ethical Committee of the Academic Medical Center in Amsterdam (project number 03/191) and the local Medical Ethical Committees of the other participating centers. The trial was registered in the Dutch Trial Register (ISRCTN29932893) and performed according to the declaration of Helsinki. All included patients gave written informed consent.

Initial phase with non-pharmacological treatmentWe recruited patients between 18 and 70 years of age with a clinical diagnosis of recurrent VVS from the Emergency Department and the syncope units of 4 Dutch medical centers. Recurrent VVS was defined as the occurrence of at least 3 syncopal episodes in the last 2 years. The diagnosis of VVS was based on the definition of the ESC-guidelines and defined as a self-limited complete loss of consciousness with a duration of less than 5 minutes caused by a transient global cerebral hypoperfusion.2,

16 After inclusion, all patients received non-pharmacological treatment consisting of reassurance regarding the benign nature of the condition, maintaining an adequate fluid and salt intake, regular exercise and the application of physical counterpressure manoeuvres.2, 6, 17-20 After at least 6 months of follow-up, patients who experienced 3 or more syncopal and/or pre-syncopal episodes were eligible for the cross-over trial of midodrine against placebo. Non-pharmacological treatment was continued in all patients.

Randomized cross-over trial of midodrine against placeboA research physician screened eligible patients for contra-indications for midodrine treatment by history, blood pressure measurement and laboratory tests. Patients with one or more contra-indications for midodrine treatment, or patients declining pharmacological treatment were not included in the trial. Randomization was performed by a computer program to determine the sequence of midodrine and placebo treatment. Treatment allocation was concealed, and both the patients and all research staff were blinded to the outcome of the randomization. After randomization patients received double-blind cross-over treatment starting


either with midodrine or placebo for 3 months. After the first treatment period there was a wash-out period of one week after which patients started their second treatment period receiving the other medication. The midodrine and placebo used in this trial were both manufactured by Nycomed Austria GmbH and had similar external features. A fixed dosage of 5 mg twice daily (after breakfast and lunch) was prescribed. To avoid supine hypertension, patients were instructed not to take medication after dinner.21

Data collection and outcome measures After 1 week, 1 month and 3 months of study medication, patients were asked whether they had experienced any (pre-)syncopal recurrences of VVS, trauma associated with recurrent VVS or side effects since the start of pharmacological treatment or their previous follow-up visit during both treatment periods. Pre-syncope is defined as any condition in which patients feel as though syncope is imminent but transient loss of consciousness does not occur.2 Only if pre-syncope was associated with near loss of consciousness we considered pre-syncope to be present in this study. Apart from obtaining information about (pre-)syncopal recurrences and quality of life, blood pressure was also checked in upright and supine position to avoid iatrogenic hypertension. Blood pressure measurements were performed using the Maxi Stabil 3 sphygmometer (Welch Allyn, NY, USA) or a similar device. After the study period, patients returned their residual pills. Patient compliance was expressed by the actual number of pills taken divided by the expected number of pills to be taken.

Quality of life (QoL) Before treatment initiation and at the end of each pharmacological treatment period, QoL was evaluated using self-administered questionnaires (short form-36 (SF-36) questionnaire and Syncope Functional Status Questionniare (SFSQ)). The self-administered SF-36 questionnaire is used to measure generic health concepts relevant across age, disease and treatment groups.22, 23 After filling in the 36-item questionnaire, 8 scale scores can be calculated: physical functioning, role functioning physical, bodily pain, general health, vitality, social functioning, role functioning emotional and mental health. The scores can be summarized into 2 scales, the physical and mental component summaries. All raw scale scores are converted linearly to a scale ranging from 0 to 100 (maximum). The higher the scores within this range, the higher levels of functioning or well-being. Translation, validation and norming of the Dutch-language version were performed by Aaronson et al.24


The SFSQ is used to determine syncope-related QoL. This questionnaire consists of 11 yes/no questions to assess syncope interference with a patient’s life and three 8-point Likert-scale questions assessing fear and worry with respect to syncope.25 The impairment score is calculated in two steps. First, the number of areas in which syncope interfered with a patients’ life (range 0-11) is divided by the number of areas that were applicable to that patient. Secondly, the obtained number is multiplied by 100, resulting in a score between 0 and 100, with 100 representing impairment in all areas that are applicable to patients. The 3 Likert-scale questions were linearly converted to a 0-100 scale and subsequently averaged to calculate a fear/worry score scaled from 0 to 100, with 100 indicating maximum fear and worry. The Syncope Dysfunction Score represents the averaged impairment score and fear/worry score. The higher this score, the worse syncope-related QoL. In a previous study, the validity, reliability and responsiveness of the Dutch version of the SFSQ have been determined.26

Power calculation Based on data from the PC-trial, about 10% of VVS patients were expected to experience ≥3 syncopal and/or pre-syncopal recurrences despite non-pharmacological treatment including physical counterpressure manoeuvres during 18 months of follow-up.8 In this patient group, we expected recurrence in 60% of patients during placebo treatment and in 20% of patients in the midodrine group based on the available literature.8, 11, 15 A cross-over trial with 22 patients receiving both midodrine and placebo treatment would have a power of 80% to detect such a difference using the McNemar’s test of equality of paired proportions with a 0.05 2-sided significance level.8, 27 Taking into account loss to follow-up, we aimed at including 25 patients in the cross-over trial. This means that a total of around 250 patients needed to be included at the start of the study to obtain a total of 25 patients with a insufficient response to initial, non-pharmacological treatment.

Statistical analysis The primary end point of the study was the proportion of patients with syncopal recurrence during each 3-month treatment period. We calculated the difference in these proportions between midodrine and placebo together with its 95% CI using the method of Newcombe of paired data.28 Associated p-values were based on the McNemar test for paired proportions. In addition, we compared the total number of recurrences of syncope and pre-syncope during each treatment period of 3 months. For patients with a shorter follow-up period than 3 months due to drop out, we used the actual observed rate (number of recurrences divided by actual follow-up time) to calculate the expected number of recurrences if the follow-up would have been


3 months. The difference in number of syncopal and pre-syncopal episodes during each treatment period of 3 months was analyzed using the Wilcoxon signed rank test. We also used the Wilcoxon signed rank test to compare QoL scores at the end of each treatment period. The proportion of patients with any side effects or trauma during midodrine or placebo treatment was analyzed in the same way as the proportion of patients with recurrent VVS. Because of the low power of our study, we refrained from testing for a period effect and treatment-by-period interaction effect.29, 30 All data were analyzed using SPSS 16.0 (SPSS, Chicago, IL, USA), except for the calculation of confidence intervals for differences in paired proportions for which we used StatsDirect (Statsdirect Ltd., Altrincham, Cheshire, UK). We considered two-sided p-values <0.05 as statistically significant.

Results

Inclusion of patientsWe included 100 patients in the non-pharmacological part of the study (Figure 1). The frequency of syncope during the first year of non-pharmacological treatment in these patients was 75% lower than during the last year before treatment (median 1 (p25-p75: 0 - 3) vs. 4 (p25-p75: 2 - 7); p<0.001). The frequency of severe pre-syncopal recurrence was not significantly lower during non-pharmacological treatment than before this treatment (median 7 (p25-p75: 3-25) vs. 8 (p25-p75: 2-43)). No patients were lost to follow-up.A total of 84 patients were assessed for inclusion in the trial. Sixteen patients were not assessed, mainly because the pre-specified sample size of the cross-over trial was already achieved when these patients were still in their non-pharmacological phase (n=14 patients, Figure 1). Of the 84 patients assessed, 67 patients had experienced ≥3 syncopal and/or severe pre-syncopal recurrences during follow-up and were eligible for the cross-over trial. Cross-over treatment was not started in 39 of these patients because patients were content with their partial reduction in episodes or were not willing to take medication (n=24); had a medical contra-indication at the start of the cross-over trial (n=12); or for other reasons (n=3). The patient characteristics of these patients and patients that received pharmacological treatment did not differ significantly, except for age (mean(standard deviation (SD)): 40(15) vs. 31(12); p=0.02) and syncopal episodes during non-pharmacological follow-up (median (p25-p75): 1 (0-2) vs. 3 (0-10); p=0.03).A total of 28 patients were randomized and started pharmacological treatment (Figure 1). Follow-up information for both midodrine and placebo treatment was


available for 23 out of 28 patients (Figure 1). All our analyses are based on these 23 patients. The mean age of these patients was 32 years and 17% were men (Table 1). Fifteen patients (65%) had experienced both syncopal and pre-syncopal recurrences during the initial non-pharmacological phase. The other patients (35%) had only experienced severe pre-syncopal recurrences. Treatment compliance was 88%. Treatment compliance did not differ significantly between midodrine and placebo treatment (91% vs. 86%; p=0.17).

Figure 1. Flow Diagram.

Midodrine followed by

placebo

N= 11

Placebo followed by

midodrine

N= 17

Randomization

N= 28

Midodrine completed,

placebo started

N= 10

Placebo completed,

midodrine started

N= 13

Midodrine not completed N= 1

Placebo not started N= 0

Placebo not completed N= 3

Midodrine not started N= 1

Patients included in analysis N= 23

- Protocol completed N= 19

- Midodrine completed, placebo not completed N= 2

- Placebo completed, midodrine not completed N= 2

<3 (Pre-)syncopes

N= 17

At least 3 (pre-)syncopes

N= 67

No start study medication N= 39

- Refusal by patient N= 24

- Medical reasons N= 12

- Other/unknown reasons N= 3

Patients included

N= 100

Patients assessed for inclusion in cross-over trial

N= 84

Patients not assessed for inclusion in cross-over trial N= 16

- Sample size cross-over trial already achieved N= 14

- Patient withdrawal N= 2



Patients in analysisNumber 23Mean age (SD) 32 (12)Male gender (%) 17%Race (%)

- Caucasian- Asian- Hispanic

91%4.3%4.3%

Number of syncopal episodes during life Median (p25 – p75) 44 (20 – 104)Number of years with syncope Median (p25 – p75) 10 (6 – 18)Syncope burden (number of syncopal episodes per year)

Median (p25 – p75) 4 (2 – 32)

p25= 25th percentile; p75= 75th percentile

RecurrencesThe proportion of patients that experienced syncopal recurrence(s) was not significantly different during midodrine and placebo treatment (48% vs. 65%; proportion difference: -17% (95% CI -36% to 3.8%); p=0.22) (Table 2). Ten patients (43%) experienced syncopal recurrence during both midodrine and placebo treatment, while 5 (22%) experienced syncopal recurrence only in the placebo period compared to one (4.3%) in the midodrine period. The median number of syncopes per 3 months was 0 (p25-p75: 0 – 5) upon midodrine treatment and 1 (p25-p75: 0 - 7) upon placebo treatment (p=0.57). Nine patients (39%) experienced more syncopal episodes during 3 months of placebo treatment, while 6 patients (26%) experienced more syncopal episodes upon midodrine treatment. In the remaining 8 patients (35%) syncopal recurrence was similar during both periods (Table 2). Pre-syncope occurred in 74% of patients during midodrine treatment and in 78% of patients during placebo treatment (p>0.99) (Table 2). Fifteen patients (65%) experienced pre-syncopal recurrence during both midodrine and placebo treatment. Two patients (8.7%) experienced pre-syncope recurrence only during midodrine treatment compared to 3 (13%) patients only during placebo treatment. The median number of pre-syncopes per 3 months was 6 (p25-p75: 0 – 30) upon midodrine treatment and 8 (p25-p75: 1 - 52) upon placebo treatment (p=0.90). Nine patients (39%) experienced more pre-syncopal episodes during 3 months of placebo treatment, while 10 patients (43%) experienced more pre-syncopal episodes upon midodrine treatment. In 4 (17%) patients the number of pre-syncopal recurrences was equal in both periods


Patient-reported trauma due to (pre-)syncope did not differ significantly between midodrine and placebo treatment (35% vs. 26%; p=0.50) (Table 2).

Side effectsSide effects were reported by 57% of the patients during placebo treatment and by 48% during midodrine treatment (p=0.75; Table 2). During both midodrine and placebo treatment patients reported a wide range of side effects. Headache, cold sensations and nausea were the most frequently reported side effects during midodrine treatment. Headache and fatigue/loss of energy were the most frequently reported side effects during placebo treatment.

Quality of life (QoL)Although QoL scores tended to be higher after midodrine treatment, the Physical and Mental component summary of the SF-36 showed no statistically significant difference between treatments (p=0.24 and p=0.20 respectively; Table 3). Only the scores for the subscales Bodily pain and Mental Health patients were significantly higher after treatment with midodrine than after placebo treatment (p=0.02 and p=0.01 respectively). The Syncope Dysfunction Score of the SFSQ did not differ significantly after midodrine or placebo treatment (mean score of 42 vs. 43; p=0.46; Table 4).

Table 2: Occurrence of (pre-)syncopes, trauma and side effects during pharmacological treatment with midodrine and placebo of the 23 patients included in the analysis.

Midodrine treatment

Placebo treatment

Difference(95% CI)

P-value

Syncopal recurrence (%) 48% 65% -17% (-36% to 3.8%) 0.22

Syncopal episodes per 3 months

Median (p25 – p75) 0 (0 – 5) 1 (0 – 7) - 0.57

Pre-syncopal recurrence (%) 74% 78% -4.3% (-16% to 25%) > 0.99

Pre-syncopal episodes per 3 months

Median (p25 – p75) 6 (0 - 30) 8 (1 – 52) - 0.90

Trauma due to (pre-)syncope (%) 35% 26% -8.7% (-23% to 5.7%) 0.50

Side effects of pharmacological treatment (%)

48% 57% -8.7% (-34% to 18%) 0.75

p25= 25th percentile; p75= 75th percentile; CI= confidence interval


Table 3: General quality of life assessed with the Short Form-36 (SF-36) questionnaire after pharmacological treatment with Midodrine and placebo.*

SF-36 subscale Mean score after midodrine treatment (SD)

Mean score after placebo treatment (SD)

P-value

Physical functioning 68 (28) 66 (26) 0.50Role functioning physical 47 (42) 35 (36) 0.06Bodily pain 69 (28) 56 (31) 0.02General health 48 (20) 45 (20) 0.20Vitality 46 (20) 42 (21) 0.78Social functioning 63 (21) 57 (30) 0.43Role functioning emotional 62 (46) 48 (44) 0.20Mental health 66 (21) 58 (24) 0.01

Physical component summary 43 (12) 41 (11) 0.24Mental component summary 42 (13) 38 (14) 0.20

SD= standard deviation

* General quality of life can vary within a range of 0 and 100 (maximum). The higher the scores for the Physical and Mental Component Summary of the SF-36 questionnaire, the better general quality of life.

Table 4: Quality of life assessed with the Syncope Functional Status Questionnaire (SFSQ) after pharmacological treatment with midodrine and placebo.*

SF-36 subscale Mean score after midodrine treatment (SD)

Mean score after placebo treatment (SD)

P-value

Impairment score 39 (34) 43 (35) 0.24Fear/worry score 44 (25) 44 (25) 0.82

Syncope Dysfunction Score 42 (27) 43 (27) 0.46

Abbreviations as in Table 3.

* Syncope-related quality of life can vary within a range of 0 and 100 (maximum). The lower the scores with respect to the Syncope Dysfunction Score of the SFSQ, the better syncope-related quality of life.


Discussion

To our knowledge, this is the first study examining the effectiveness of additional midodrine treatment in patients with VVS not or unsatisfactory responding to non-pharmacological treatment including physical counterpressure manoeuvres. We were unable to demonstrate the effectiveness of midodrine treatment in these patients. Our findings differ from previous trials, where midodrine treatment was found to be an effective treatment for reflex syncope.11, 13-15, 31-36 There are several reasons that could explain the differences in results between our study and previous studies.Firstly, the criteria for inclusion of patients differed markedly. In our study, pharmacological treatment was only started if patients had experienced at least 3 syncopal and/or pre-syncopal recurrences during non-pharmacological treatment including physical counterpressure manoeuvres. This approach is in line with current recommendations in the ESC-guidelines for the diagnosis and management of syncope.2 In previous studies however, pharmacological treatment was started directly after presentation, usually without prior non-pharmacological treatment.11, 13-

15, 31-34 Because pharmacological treatment was only started in patients with frequent (pre-)syncopal recurrences during non-pharmacological treatment, we selected patients with more severe forms of VVS. Since we were unable to demonstrate the effectiveness of midodrine treatment, our study results indicate that these patients are less susceptive to this treatment. This might be due to psychological distress associated with VVS, as syncope was found to occur more frequently in VVS patients that experienced higher levels of psychogenic distress.37-39 However, also other factors could be involved.There are differences across previous studies in the way the effectiveness of midodrine treatment was determined. In some of the previous studies there was no control group.31-36 Since it is known that patients with VVS present themselves more often to healthcare after a recent worsening of their symptoms,40 a return to the usual frequency of recurrence can be expected, no matter what kind of treatment is being prescribed. Placebo-controlled trials with midodrine are therefore necessary to examine whether midodrine treatment has any significant therapeutic benefit above the expected natural decrease in frequency of recurrence after diagnosis. In 3 out of 4 studies on midodrine that were included in a systematic review about the effectiveness of alpha-adrenergic treatment for VVS, head-up tilt testing was used as one of the outcome measures to determine treatment effectiveness.11-14 The reliability of tilt test outcomes is however low and does not provide information about the effectiveness in daily life.2, 41-43 Since head-up tilt testing is not a reliable diagnostic method to determine treatment effectiveness,2, 44 we did not use head-up tilt tests to determine the effectiveness of treatment. Instead, we contacted patients regularly to obtain information about the recurrence of (pre-)syncope during follow-up.


Side effectsIn previous studies, gastro-intestinal discomfort, nausea, pilomotor reactions (goosebumps, tingling, chills) and headache associated with hypertension have been reported as side effects in 4%13 to 64%33 of the patients.13-15, 32-34 Though the occurrence of side effects in our study is well within this range, surprisingly, in our study the number of patients that reported side effects was higher during placebo treatment (57%) compared to midodrine treatment (48%). The reason for this high number of patients with side-effects is currently unknown.

Quality of life (QoL) We observed no statistically significant differences with respect to QoL between midodrine and placebo treatment as additional treatment measures to non-pharmacological treatment for VVS. In our view, this finding is logical, since the differences with respect to syncopal and pre-syncopal recurrence of VVS were also not significantly different between midodrine and placebo treatment. Limitations A few issues have to be considered when interpreting the results of this trial. First, a low number of patients eligible for study-medication actually received pharmacological cross-over treatment (only 28 out of 67 patients). The main reason for not starting medication was that patients were content with the partial reduction in syncopal recurrences during the non-pharmacological treatment or the fear of side-effects. Patients who experienced a total number of ≥3 pre-syncopal and/or syncopal episodes early during follow-up were probably more willing to receive pharmacological treatment than patients who experienced this total number of episodes in a relatively long time period, reinforcing the selection of patients with more severe VVS in this study. In previous studies examining the effectiveness of midodrine treatment for VVS, the daily dosage of midodrine for adults varied between 5 and 45 mg per day.14, 15,

32-36 The dosage of midodrine in our study was 10 mg per day (5 mg twice daily). A higher dosage could have been more effective, although in earlier studies significant hemodynamic effects occurred upon application of a midodrine dosage of 5 mg, both in normal subjects and patients with reflex syncope.11, 45

In our cross-over trial, we included only a relatively limited number of patients because we expected a substantial difference in effectiveness based on earlier studies. In addition, the use of a cross-over design increases the power to detect a difference as the analysis can be based on paired data. Our results clearly indicate that the difference in effectiveness (if any) was much smaller than expected. However, small differences in effectiveness can not be excluded based on this trial.


Conclusion

We observed no statistically significant differences between additional midodrine and placebo treatment with respect to (pre-)syncopal recurrence, indicating that the effectiveness of midodrine treatment in patients not responding to non-pharmacological treatment was much smaller than expected. Therefore, we do not recommend the routine use of additional treatment with midodrine in these patients. Other treatment strategies need to be developed and examined in these patients.

Acknowledgements

We would like to thank Mark P.M. Harms, MD, PhD (University Medical Center Groningen, the Netherlands), Jaap H. Ruiter, MD, PhD (Medical Center Alkmaar, the Netherlands) and Jacques W.M. Lenders, MD, PhD (Radboud University Nijmegen Medical Center, the Netherlands and University Hospital Carl Gustav Carus Dresden, Dresden, Germany) for their help with the inclusion and follow-up of patients during non-pharmacological treatment. We also would like to thank Nycomed Austria GmbH for providing midodrine and placebo pills free of charge for our study.


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34. Sra J, Maglio C, Biehl M et al. Efficacy of midodrine hydrochloride in neurocardiogenic syncope refractory to standard therapy. J Cardiovasc Electrophysiol 1997;8(1):42-46.

35. Klingenheben T, Credner S, Hohnloser SH. Prospective evaluation of a two-step therapeutic strategy in neurocardiogenic syncope: midodrine as second line treatment in patients refractory to beta-blockers. Pacing Clin Electrophysiol 1999;22(2):276-281.

36. Samniah N, Sakaguchi S, Lurie KG, Iskos D, Benditt DG. Efficacy and safety of midodrine hydrochloride in patients with refractory vasovagal syncope. Am J Cardiol 2001;88(1):A7, 80-A7, 83.





40. Sheldon RS, Sheldon AG, Serletis A et al. Worsening of symptoms before presentation with vasovagal syncope. J Cardiovasc Electrophysiol 2007;18(9):954-959.

41. Blanc JJ, Mansourati J, Maheu B, Boughaleb D, Genet L. Reproducibility of a positive passive upright tilt test at a seven-day interval in patients with syncope. Am J Cardiol 1993;72(5):469-471.

42. Brooks R, Ruskin JN, Powell AC, Newell J, Garan H, McGovern BA. Prospective evaluation of day-to-day reproducibility of upright tilt-table testing in unexplained syncope. Am J Cardiol 1993;71(15):1289-1292.

43. Sheldon R, Splawinski J, Killam S. Reproducibility of isoproterenol tilt-table tests in patients with syncope. Am J Cardiol 1992;69(16):1300-1305.


45. Lamarre-Cliche M, Souich P, Champlain J, Larochelle P. Pharmacokinetic and pharmacodynamic effects of midodrine on blood pressure, the autonomic nervous system, and plasma natriuretic peptides: a prospective, randomized, single-blind, two-period, crossover, placebo-controlled study. Clin Ther 2008;30(9):1629-1638.

Chapter 8

Summary of fi ndings

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Summary of findingsSummary of findings 171

Summary of findings

Transient loss of consciousness (T-LOC) can be caused by various clinical disorders.1 If T-LOC is caused by transient arterial hypotension and hypoperfusion of the brain due to reflex vasodilatation, bradycardia, or both the disorder is called reflex syncope.1, 2 Vasovagal syncope (VVS) is the most common cause of reflex syncope.3,

4 This thesis is about the diagnosis and treatment of reflex syncope, with a focus on VVS.

If patients experiencing T-LOC seek medical attention, attending physicians need to differentiate between the relatively benign and the potentially lethal causes of T-LOC.4, 5 The clinical history plays a critical role in the initial evaluation of patients presenting with T-LOC as it can provide valuable clues about the underlying cause.6,

7 It can be difficult to diagnose patients presenting with T-LOC. One reason is that actual episodes of T-LOC are rarely observed by physicians, and an eyewitness’ account of an episode of T-LOC - if present - is not always reliable.5 Moreover, the signs and symptoms of different causes of T-LOC can be very similar.6

In Chapter 2 we hypothesized that not only the incidence but also the clinical features of reflex syncope might differ by age and gender. In order to investigate this, we used data from the Fainting Assessment Study (FAST), a prospective cohort study designed to assess the accuracy of diagnostic strategies for adult patients presenting with T-LOC.7 In that study, 503 patients (median age 52 years; 56% were men) who presented themselves with T-LOC to one of a number of hospital departments of the Academic Medical Center in Amsterdam were included. Using a structured questionnaire, information about prodromal signs, symptoms and triggers of episodes was collected in a uniform way in all patients. After this evaluation, an initial diagnosis was made and additional tests were performed if necessary. A final diagnosis was made based on all available data after 2 years of follow-up.7 The FAST-study showed that reflex syncope was overall the most common diagnosis in 60% of patients.7 We found that reflex syncope was more common in younger patients (73% among patients under 40 years of age) than in older patients (45% among patients aged 60 years or above). The prevalence of all symptoms and signs, except ‘pallor’, was also higher among patients under 60 years of age. Apart from differences in age, the number of episodes of reflex syncope in the last year was higher in women than in men (2 vs. 1; p= 0.02). In general, women reported more prodromal signs and symptoms than men. The fact that signs, symptoms and triggers of reflex syncope are more often reported by women and young people than by men and elderly people can be of value in diagnosing patients presenting with T-LOC.

Chapter 8 Summary of findings172 Summary of findings

The Calgary Syncope Symptom Score (Calgary Score) has been developed by the group of Sheldon to select a limited number of items from clinical history that are helpful in distinguishing between VVS and other causes of T-LOC.8 The Calgary Score consists of seven diagnostic questions. Each positive answer is associated with a number of points. By summing these points a total score is calculated. If patients have a total score equal or above the cut-off value of -2, they are classified as having VVS. Patients with a total score below this cut-off value are classified as not having VVS. In the study reported in Chapter 3 we evaluated the diagnostic performance of the Calgary Score in the FAST-population. For this purpose, we calculated the Calgary Score for 380 patients presenting with T-LOC. Based on this score, patients were either diagnosed as having VVS or not. The diagnoses based on the Calgary Score were then compared with the final diagnoses, obtained after additional testing and 2 years of follow-up. We found that the sensitivity and specificity of the Calgary Score were 87% (95% CI: 82 to 91%) and 32% (95% CI: 24 to 40%) respectively. In the original study, a sensitivity of 89% and a specificity of 91% had been reported.8 Though the sensitivity we obtained was similar, the specificity in our validation study was lower. Incorrectly labelling patients as having vasovagal syncope occurred most frequently in patients with psychogenic pseudosyncope (specificity 21%), but was also common in patients with cardiac syncope (specificity 32%). Mortality in patients with cardiac syncope, neurological and unknown causes of T-LOC is higher in comparison to the general population, whereas the prognosis in patients with VVS appears to be benign.4, 9 The results of our study indicate that the Calgary Score incorrectly labels many patients as having VVS: their actual final diagnoses were different, and potentially more severe. Because of this poor performance in clinical practice, we concluded that the value of the Calgary Score in patients presenting with T-LOC is limited in a general hospital setting.

Non-pharmacological treatment is recommended as the first line of treatment for VVS in current syncope management guidelines.1 This treatment consists of maintaining an adequate fluid and salt intake, regular exercise and the application of physical counterpressure manoeuvres, like leg crossing, tensing of leg and abdominal muscles and squatting.1, 10, 11 In relatively mildly affected patients, a combination of lifestyle measures and physical counterpressure manoeuvres has been shown to decrease the syncope burden by 39%.12 It was unknown whether severely affected patients would benefit from this treatment not only with respect to (pre-)syncopal recurrence but also with respect to another important treatment goal: improving quality of life. In the study reported in Chapter 4 we prospectively evaluated the effectiveness of non-pharmacological treatment in patients that had


experienced at least 3 syncopal recurrences during the last 2 years. In this open study, we recorded syncopal recurrences and quality of life (QoL) in 100 patients receiving non-pharmacological treatment. General QoL was assessed with the Short Form-36 questionnaire; syncope-related QoL was measured with the Syncope Functional Status Questionnaire. Syncopal recurrence was experienced by 42% of patients within the first 6 months of follow-up, increasing to 49% after one year. Despite these findings, the median number of syncopal recurrences was lower in the first year of non-pharmacological treatment than in the year before treatment initiation (median 0 vs. 3; p< 0.001). In the first year of non-pharmacological treatment, 94% of patients used physical counterpressure manoeuvres. For most of these patients (52%) manoeuvres were beneficial. The most important reasons for failure of this strategy were sudden occurrence of VVS resulting in insufficient time to apply physical counterpressure manoeuvres (56%) and failure of the manoeuvres to stop the process (25%). Four percent of patients had forgotten to apply the counterpressure manoeuvres. In 63% of all patients, we observed both a decrease in syncopal recurrence and an improvement in QoL with non-pharmacological treatment. Since non-pharmacological treatment does have a beneficial effect on both syncopal recurrence and QoL in patients with relatively frequent recurrences of VVS, we recommend that patients diagnosed with VVS, should initially receive non-pharmacological treatment.

A previous study reported that psychiatric symptoms were seen more frequently in VVS patients than in healthy control subjects (71% vs. 23%).13 We hypothesized that treatment effectiveness might be negatively influenced by the amount of general psychological complaints. We analyzed to what extent the effectiveness of non-pharmacological treatment as described in Chapter 4 was influenced by the extent of general psychological complaints assessed before treatment initiation (Chapter 5). We recorded the prevalence of psychological complaints before the start of non-pharmacological treatment using the Symptom Checklist 90-R (SCL-90-R). This 90-item questionnaire is used to evaluate self-reported general psychological symptoms on a 5-point rating scale.14 The items of the SCL-90-R are categorized into 9 subscales: agoraphobia, anxiety, depression, somatization, insufficiency of thinking and acting, interpersonal sensitivity and paranoid ideation, hostility, sleep difficulty.14 The total score, the Global Severity Index, is obtained by summation of all individual subscale scores. The higher the subscale and total scores, the more patients report psychological symptoms. We found that the Global Severity Index before treatment was higher in our patient group than in a reference population (142 vs. 118;p< 0.001). Patients with a 10 points higher Global Severity Index were at increased risk of syncopal recurrence during follow-up (odds ratio 1.11; 95% CI:

Chapter 8 Summary of findings174 Summary of findings

1.01 to 1.21). General psychological complaints remained associated with syncopal recurrence(s) after adjusting for other potential prognostic factors such as age, gender and the frequency of syncope during the last 2 years before the start of non-pharmacological treatment. The frequency of syncope during the last 2 years before treatment initiation had the strongest association with syncopal recurrence.

In patients with reflex syncope who fail to respond to non-pharmacological treatment, different kinds of pharmacological or pacemaker treatment might be considered. In the Cochrane Review reported in Chapter 6 we systematically reviewed the literature on the efficacy of different pharmacological treatments: beta-blockers, fludrocortisones, alpha-adrenergic agonists, selective serotonin reuptake inhibitors, ACE inhibitors, disopyramide, anticholinergic agents and salt tablets. We also reviewed evidence on the efficacy of dual chamber pacemaker treatment in patients with VVS, carotid sinus syncope and situational syncope. We included 40 studies on VVS and 6 on carotid sinus syncope. The criteria for inclusion in our review were not matched by any studies on situational syncope. In total, 2386 patients participated in the 46 included studies. The sample size ranged from 8 to 208 participants, with a median of 42. In many studies head-up tilt testing was used to evaluate treatment effectiveness. The reliability of head-up tilt testing is however low.10 Provocational tilt testing does not provide information about the ability of interventions to prevent (pre-)syncopal recurrence in daily life.18-20 Despite a reasonable number of included trials in our review, many uncertainties remain. The main reasons for this incomplete picture are that studies are small in sample size, use different selection criteria, a variety of control treatments, are often not blinded, and the focus is not always on patient relevant outcomes. Moreover, we decided to analyze the effectiveness of pharmacological treatment independent of the drug dosage in order to be able to draw some conclusions from the limited number of available studies. This could influence the occurrence of syncope and side effects due to dose-effect relationships. In our review, we did not find consistent significant differences for any of the treatment comparisons in our systematic review. We therefore concluded that there is currently insufficient evidence to support the use of any of the pharmacological and pacemaker treatments for VVS and carotid sinus syncope.

In all studies included in our systematic review, treatment was started directly after diagnosis, i.e. without prior non-pharmacological treatment.15 In the study in Chapter 7 we used a different approach: only patients who experienced a total number of three or more syncopal and/or pre-syncopal recurrences during non-pharmacological treatment (life style measures and physical counterpressure


manoeuvres) received additional randomized, cross-over treatment with midodrine and placebo. Patients received both midodrine and placebo treatment, each for the duration of 3 months, with a one week wash-out period in between. The treatment sequence was determined by a computerized randomization procedure. Patients and the research physician were blinded for the treatment given to the patient. At baseline and after treatment initiation, information was collected about the recurrence of (pre-)syncope, occurrence of side effects and QoL. We analyzed and compared (pre-)syncopal recurrence and QoL between additional treatment with midodrine and placebo.

In this cross-over trial, 23 patients were included (19 were women; mean age 32). The median number of syncopal episodes during treatment was not significantly different for midodrine and placebo treatment (0 vs. 1; p= 0.57). We did not observe statistically significant differences with respect to the median number of pre-syncopal episodes (6 vs. 8; p= 0.90) and occurrence of side effects during treatment (48% vs. 57%; p= 0.75). QoL did not differ significantly between midodrine and placebo treatment. We therefore would not recommend prescribing midodrine treatment in patients not responding to non-pharmacological treatment.

This thesis confirms that adequate history-taking is helpful in distinguishing between different causes of T-LOC.16 In addition to signs, symptoms and triggers, information about age and gender may also contribute, because the distribution of signs and symptoms among patients with reflex syncope differs by age and gender. Our validation study of the Calgary Score shows that any diagnostic tool or pathway developed to diagnose patients presenting with T-LOC should be validated in an external population before implementation in clinical practice.Our findings indicate that patients severely affected by VVS are likely to benefit from non-pharmacological treatment measures, not only with respect to syncopal recurrence but also quality of life. We therefore recommend that non-pharmacological treatment measures should be offered to all patients diagnosed with VVS. Based on our systematic review, we conclude there is insufficient evidence to support pharmacological or pacemaker treatment for reflex syncope. However, many of the interventions examined in this review are regularly used in clinical practice. This underlines the importance of designing new trials of good methodological quality and sufficient size to estimate the effectiveness of pharmacological and pacemaker interventions after failure of non-pharmacological treatment. By means of better diagnosis and effective treatment, we may be able to reduce the burden of disease in syncope patients and improve their quality of life.

Chapter 8 Summary of findings176

Reference List



3. Kapoor WN. Syncope. N Engl J Med 2000;343(25):1856-1862.4. Soteriades ES, Evans JC, Larson MG et al. Incidence and prognosis of syncope. N Engl J Med

2002;347(12):878-885.5. Thijs RD, Wagenaar WA, Middelkoop HA, Wieling W, van Dijk JG. Transient loss of consciousness

through the eyes of a witness. Neurology 2008;71(21):1713-1718.6. Colman N, Nahm K, van Dijk JG, Reitsma JB, Wieling W, Kaufmann H. Diagnostic value of

history taking in reflex syncope. Clin Auton Res 2004;14 Suppl 1:37-44.7. Van Dijk N, Boer KR, Colman N et al. High diagnostic yield and accuracy of history, physical

examination, and ECG in patients with transient loss of consciousness in FAST: the Fainting Assessment study. J Cardiovasc Electrophysiol 2008;19(1):48-55.


9. Alshekhlee A, Shen WK, Mackall J, Chelimsky TC. Incidence and mortality rates of syncope in the United States. Am J Med 2009;122(2):181-188.






15. Liao Y, Li X, Zhang Y, Chen S, Tang C, Du J. Alpha-adrenoceptor agonists for the treatment of vasovagal syncope: a meta-analysis of worldwide published data. Acta Paediatr 2009;98(7):1194-1200.


Summary of fi ndingsSummary of fi ndings

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Een wegraking kan door verschillende ziektebeelden veroorzaakt worden.1 Als een wegraking veroorzaakt wordt door tijdelijke arteriele hypotensie en hypoperfusie van de hersenen ten gevolge van reflexmatig vasodilatatie, bradycardie, of beide, wordt de aandoening reflex syncope genoemd.1, 2 Vasovagale syncope (VVS) is de meest voorkomende oorzaak van reflex syncope.3, 4 Dit proefschrift gaat over het diagnosticeren en behandelen van reflex syncope. De nadruk ligt op VVS.

Als patiënten die wegrakingen hebben medische hulp zoeken, moeten poortartsen differentiëren tussen relatief goedaardige en potentieel dodelijke oorzaken van wegrakingen.4, 5 De anamnese speelt een cruciale rol bij de initiële evaluatie van patiënten met wegrakingen, omdat het waardevolle informatie kan geven over de onderliggende oorzaak.6, 7 Het kan moeilijk zijn om patiënten met wegrakingen te diagnosticeren. Een reden hiervoor is dat de feitelijke wegrakingen zelden geobserveerd worden door artsen, en de beschrijving door een ooggetuige van een wegraking –indien aanwezig- is niet altijd betrouwbaar.5 Bovendien kunnen de tekens en symptomen van verschillende oorzaken van wegrakingen erg op elkaar lijken.6

In Hoofdstuk 2 veronderstelden we dat niet alleen de incidentie maar ook de klinische kenmerken van reflex syncope zouden kunnen verschillen wat betreft leeftijd en geslacht. Om dit te onderzoeken gebruikten we gegevens van de ‘Fainting Assessment Study (FAST),’ een prospectief cohort onderzoek dat ontworpen was om de accuratesse van diagnostische strategieën te evalueren bij volwassen patiënten die zich presenteren met wegrakingen.7 In dat onderzoek werden 503 patiënten (mediane leeftijd 52 jaar; 56% van de deelnemers waren man) geïncludeerd die zich presenteerden met wegrakingen bij een van de deelnemende ziekenhuisafdelingen van het Academisch Medisch Centrum in Amsterdam. Met behulp van een gestructureerde vragenlijst werd op een uniforme wijze bij alle patiënten informatie verzameld over prodromale tekens, symptomen en uitlokkende factoren van episoden. Na deze evaluatie werd een initiële diagnose gesteld en werd zo nodig aanvullend onderzoek verricht. Er werd een uiteindelijke diagnose gesteld op basis van alle beschikbare gegevens na 2 jaar follow-up.7 Het FAST-onderzoek liet zien dat reflex syncope over het algemeen de meest voorkomende diagnose was bij 60% van de patiënten.7 Wij vonden dat reflex syncope vaker voorkwam bij jongere patiënten (73% bij patiënten jonger dan 40 jaar) dan bij oudere patiënten (45% bij patiënten van 60 jaar of ouder). De prevalentie van alle tekens en symptomen, behalve ‘bleekheid’ was ook hoger bij patiënten jonger dan 60 jaar. Afgezien van verschillen in leeftijd, was het aantal

Nederlandse samenvatting180 Nederlandse samenvatting

episoden reflex syncope in het afgelopen jaar hoger bij vrouwen dan bij mannen (2 vs. 1; p= 0.02). Over het algemeen rapporteerden vrouwen meer prodromale tekens en symptomen dan mannen. Het feit dat tekens, symptomen en uitlokkende factoren van reflex syncope vaker gerapporteerd worden door vrouwen en jonge mensen dan door mannen en ouderen kan waardevol zijn bij het diagnosticeren van patiënten die zich presenteren met wegrakingen.

De ‘Calgary Syncope Symptom Score (Calgary Score)’ is ontwikkeld door de groep van Sheldon om een beperkt aantal items van de anamnese te selecteren die helpen een onderscheid te maken tussen VVS en andere oorzaken van wegrakingen.8 De Calgary Score bestaat uit 7 diagnostische vragen. Aan elk positief antwoord wordt een aantal punten toegekend. Door deze punten op te tellen wordt een totaalscore berekend. Als patiënten een totaalscore hebben die op of boven de afkapwaarde –2 ligt, worden ze geclassificeerd als het hebben van VVS. Patiënten met een totaalscore onder de afkapwaarde worden geclassificeerd als het niet hebben van VVS.In het onderzoek dat gerapporteerd wordt in Hoofdstuk 3 evalueerden we de diagnostische accuratesse van de Calgary Score in de FAST-populatie. Voor dit doel berekenden we de Calgary Score voor 380 patiënten die zich presenteerden met wegrakingen. Op basis van deze score, werden deze patiënten gediagnosticeerd op basis van het al of niet hebben van VVS. De diagnosen gebaseerd op de Calgary Score werden vervolgens vergeleken met de uiteindelijke diagnosen die verkregen zijn na aanvullend onderzoek en 2 jaar follow-up. Wij vonden dat de sensitiviteit en specificiteit van de Calgary Score respectievelijk 87% (95% BI: 82 tot 91%) en 32% (95% BI: 24 tot 40%) waren. In het originele onderzoek werd een sensitiviteit van 89% en een specificiteit van 91% gerapporteerd.8 Hoewel de sensitiviteit die wij verkregen overeenkomstig was, was de specificiteit in ons validatie-onderzoek lager. Het incorrect labelen van patiënten als het hebben van VVS kwam het vaakst voor bij patiënten met psychogene pseudosyncope (specificiteit 21%), maar het kwam ook veel voor bij patiënten met cardiale syncope (specificiteit 32%). De mortaliteit bij patiënten met cardiale syncope, neurologische en onbekende oorzaken van wegrakingen is hoger in vergelijking met de algemene populatie, terwijl de prognose bij patiënten met VVS gunstig blijkt te zijn.4, 9 Uit de resultaten van ons onderzoek blijkt dat de Calgary Score aan veel patiënten incorrect de diagnose VVS toekent: hun feitelijke uiteindelijke diagnoses waren anders, en mogelijk ernstiger. Op basis van dit slechte functioneren in de klinische praktijk concludeerden we dat de waarde van het Calgary Score voor patiënten die zich presenteren met wegrakingen beperkt is in een algemeen ziekenhuis.

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Niet-medicamenteuze behandeling wordt aanbevolen als de eerste lijn van behandeling voor VVS in de huidige behandelingsrichtlijn voor syncope.1 Deze behandeling bestaat uit het handhaven van een adequate inname van vloeistoffen en zout, regelmatige inspanning en het toepassen van tegendrukmanoeuvres, zoals benen kruisen, het aanspannen van been- en buikspieren en hurken.1, 10, 11 Bij relatief mild aangedane patiënten blijkt een combinatie van maatregelen in levensstijl en tegendrukmanoeuvres de syncope burden met 39% te verlagen.12 Het was onbekend of ernstig aangedane patiënten baat zouden hebben bij deze behandeling, niet alleen met betrekking tot de terugkeer van (pre-)syncope, maar ook wat betreft een ander belangrijk doel van de behandeling: het verbeteren van kwaliteit van leven. In de studie die in Hoofdstuk 4 beschreven wordt evalueerden we prospectief de effectiviteit van niet-medicamenteuze behandeling bij patiënten die minstens 3 wegrakingen hadden gehad in de afgelopen 2 jaar. In deze open studie, registreerden we de terugkeer van syncope en kwaliteit van leven (KvL) bij 100 patiënten die niet-medicamenteuze behandeling kregen. Algemene KvL werd beoordeeld met de ‘Short Form-36’ vragenlijst; KvL gerelateerd aan syncope werd gemeten met de ‘Syncope Functional Status Questionnaire.’In de eerste 6 maanden follow-up hadden 42% van de patienten opnieuw syncope gehad, oplopend tot 49% na één jaar. Ondanks deze bevindingen was het mediane aantal wegrakingen in het eerste jaar van de niet-medicamenteuze behandeling lager dan in het jaar voor het begin van de behandeling (mediaan 0 vs. 3; p< 0.001). In het eerste jaar van de niet-medicamenteuze behandeling paste 94% van de patiënten tegendrukmanoeuvres toe. Voor de meesten van hen (52%) hielpen deze manoeuvres goed. De belangrijkste redenen voor het falen van deze strategie waren: onvoldoende tijd om tegendrukmanoeuvres toe te passen (56%) en falen van de manoeuvres om het proces te stoppen (25%). Vier procent van de patiënten was vergeten de tegendrukmanoeuvres toe te passen. Bij 63% van alle patiënten observeerden we zowel een afname van het aantal syncopes als een verbetering van KvL met niet-medicamenteuze behandeling. Omdat niet-medicamenteuze behandeling een gunstig effect heeft op zowel de terugkeer van syncope als KvL bij patiënten met relatief veel terugkeer van VVS, bevelen wij aan dat patiënten waarbij de diagnose VVS is gesteld in het begin niet-medicamenteuze behandeling ontvangen.

Een eerder onderzoek rapporteerde dat psychiatrische symptomen vaker voorkomen bij VVS patiënten dan bij gezonde controlepatiënten (71% vs. 23%).13 Wij veronderstelden dat de effectiviteit van de behandeling negatief beïnvloed kon worden door de hoeveelheid algemeen psychologische klachten. We analyseerden tot welke mate de effectiviteit van de niet-medicamenteuze behandeling zoals beschreven in hoofdstuk 4 beïnvloed werd door de mate van algemeen psychologische klachten


die beoordeeld waren voorafgaand aan het begin van de behandeling (Hoofdstuk 5). We registreerden de prevalentie van psychologische klachten voorafgaand aan de start van de niet-medicamenteuze behandeling gebruik makend van de ‘Symptom Checklist 90-R (SCL-90-R).’ Deze vragenlijst met 90-items wordt toegepast om de zelfgerapporteerde algemeen psychologische symptomen te evalueren op een rating schaal van 5 punten.14 De items van de SCL-90-R worden onderverdeeld in 9 subschalen: agorafobie, angst, depressie, somatisatie, insufficiëntie van denken en handelen, interpersoonlijke sensitiviteit en paranoïde ideeën, vijandigheid en slaapproblemen.14 De totaalscore, de Global Severity Index, wordt verkregen door de afzonderlijke subschaal scores op te tellen. Hoe hoger de scores op de subschalen en totaalscores, hoe meer patiënten psychologische symptomen rapporteerden. Wij vonden dat de Global Severity Index voorafgaand aan de behandeling hoger was in onze patiëntengroep dan in een referentiepopulatie (142 vs. 118;p< 0.001). Patiënten met een 10 punten hogere Global Severity Index hadden een verhoogd risico op het terugkeren van syncope tijdens follow-up (odds ratio 1.11; 95% BI: 1.01 tot 1.21). Algemeen psychologische klachten bleven geassocieerd met de terugkeer van syncope na aanpassing voor andere potentiële prognostische factoren zoals leeftijd, geslacht en de frequentie van syncope in de laatste 2 jaar voorafgaand aan de niet-medicamenteuze behandeling. De frequentie van syncope in de laatste 2 jaar voor het begin van de behandeling was het sterkst geassocieerd met terugkeer van syncope.

Bij patienten met reflex syncope die niet reageren op niet-medicamenteuze behandeling kunnen verschillende soorten behandelingen met medicijnen of pacemakers overwogen worden. In het Cochrane review in Hoofdstuk 6 bekeken we systematisch de literatuur over de effectiviteit van de verschillende medicamenteuze behandelingen: beta-blockers, fludrocortisonen, alpha-adrenerge agonisten, selective serotonine heropname remmers, ACE-inhibitors, disopyramide, anticholinergica en zouttabletten. We onderzochten ook de effectiviteit van dual chamber pacemaker behandeling bij patiënten met VVS, sinus carotis syncope en situationele syncope. We includeerden 40 studies over VVS en 6 over sinus carotis syncope. Geen enkele studie over situationele syncope voldeed aan de criteria voor inclusie in onze review. In totaal namen 2386 patiënten deel in de 46 geïncludeerde studies. De studiegrootte varieerde van 8 tot 208 deelnemers, met een mediaan van 42. In veel studies werd een kanteltafeltest gebruikt om de effectiviteit van de behandeling te evalueren. De betrouwbaarheid van kanteltafeltesten is echter laag.10 Kanteltafeltests geven geen informatie over het vermogen van de interventie om de terugkeer van syncope te voorkomen in het dagelijks leven.10, 15, 16 Ondanks het feit dat we een redelijk aantal trials geïncludeerd hebben in onze review, blijven veel onduidelijkheden bestaan. De belangrijkste redenen voor dit incomplete beeld zijn dat studies klein


zijn wat betreft de groepsgrootte, verschillende selectiecriteria gebruiken, een variëteit controlebehandelingen en vaak niet geblindeerd zijn. Bovendien ligt de nadruk niet altijd op uitkomsten die voor patiënten relevant zijn. We besloten de effectiviteit van medicamenteuze behandeling te analyseren onafhankelijk van de dosering van het medicament om in staat te zijn bepaalde conclusies te trekken van het beperkte aantal beschikbare studies. Dit zou het optreden van syncope en bijwerkingen kunnen beïnvloeden als gevolg van dosis-effect relaties. In onze systematische review vonden we geen consistent significante verschillen voor elk van de behandelingsvergelijkingen. Om deze reden concludeerden we dat er momenteel onvoldoende bewijs is om het gebruik van elk van de medicamenteuze en pacemaker-behandelingen voor VVS en sinus carotis syncope.

In alle studies die in onze systematische review geïncludeerd zijn, werd de behandeling direct na de diagnose gesteld, i.e. zonder eerdere niet-medicamenteuze behandeling. In de studie in Hoofdstuk 7 gebruikten we een andere benadering: alleen patiënten die minstens 3 of meer wegrakingen en/of bijna-wegrakingen hebben doorgemaakt tijdens de niet-medicamenteuze behandeling (maatregelen wat betreft levensstijl en tegendrukmanoeuvres) ontvingen additionele gerandomiseerde cross-over behandeling met midodrine en placebo. Patiënten ontvingen zowel behandeling met midodrine als placebo, elk gedurende 3 maanden met een week washout er tussen in. De behandelingsvolgorde werd bepaald door een gecomputeriseerde randomisatie procedure. Patiënten en de onderzoeksarts waren geblindeerd voor de behandeling die aan de patiënt gegeven werd. Bij start van het onderzoek en na start van de behandeling werd informatie verzameld over de terugkeer van (bijna-)wegrakingen, het optreden van bijwerkingen en KvL. We analyseerden en vergeleken de terugkeer van (bijna-)wegrakingen en KvL tussen additionele behandeling met midodrine en placebo.In deze cross-over trial, werden 23 patiënten geïncludeerd (19 van hen waren man; gemiddelde leeftijd 32 jaar). Het mediane aantal wegrakingen tijdens de behandeling was niet significant verschillend voor behandeling met midodrine en placebo (0 vs. 1; p= 0.57). We observeerden geen statistisch significante verschillen met betrekking tot het mediane aantal pre-syncopes (6 vs. 8; p= 0.90) en het optreden van bijwerkingen tijdens de behandeling (48% vs. 57%; p= 0.75). KvL verschilde niet wezenlijk tussen behandeling met midodrine en placebo. Om deze reden zouden we behandeling met midodrine niet aanbevelen aan patiënten die niet reageren op niet-medicamenteuze behandeling.

Dit proefschrift bevestigt dat het afnemen van een adequate anamnese helpt om verschillende oorzaken van wegrakingen te onderscheiden. In aanvulling op tekens,


symptomen en uitlokkende factoren, kan informatie over leeftijd en geslacht ook bijdragen, omdat de verdeling van tekens en symptomen onder patiënten met reflex syncope verschilt wat betreft leeftijd en geslacht. Onze validatiestudie van de Calgary Score laat zien dat elk diagnostisch instrument dat ontwikkeld is om patiënten die zich presenteren met wegrakingen te diagnosticeren gevalideerd moeten worden in een externe populatie voordat het in de klinische praktijk geïmplementeerd kan worden. Onze bevindingen laten zien dat patiënten die ernstige aangedaan zijn door VVS waarschijnlijk baat hebben bij niet-medicamenteuze behandelingsmaatregelen, niet alleen met betrekking tot de terugkeer van syncope, maar ook KvL. We bevelen daarom aan dat niet-medicamenteuze behandelingsmaatregelen gegeven moeten worden aan alle patiënten die de diagnose VVS hebben gekregen.

Op basis van onze systematische review concluderen we dat er onvoldoende bewijs is om reflex syncope met medicijnen of pacemakers te behandelen. Toch worden veel interventies die in deze review onderzocht werden regelmatig gebruikt in de klinische praktijk. Het is belangrijk nieuwe studies te ontwerpen van goede methodologische kwaliteit en voldoende grootte om de effectiviteit van medicamenteuze en pacemaker interventies na falen van niet-medicamenteuze behandeling te bepalen. Door een betere diagnose en effectieve behandeling, hopen we de ziektelast bij patiënten met syncope te verminderen en hun kwaliteit van leven te verbeteren.


Reference List



3. Kapoor WN. Syncope. N Engl J Med 2000;343(25):1856-1862.4. Soteriades ES, Evans JC, Larson MG et al. Incidence and prognosis of syncope. N Engl J Med

2002;347(12):878-885.5. Thijs RD, Wagenaar WA, Middelkoop HA, Wieling W, van Dijk JG. Transient loss of consciousness

through the eyes of a witness. Neurology 2008;71(21):1713-1718.6. Colman N, Nahm K, van Dijk JG, Reitsma JB, Wieling W, Kaufmann H. Diagnostic value of

history taking in reflex syncope. Clin Auton Res 2004;14 Suppl 1:37-44.7. Van Dijk N, Boer KR, Colman N et al. High diagnostic yield and accuracy of history, physical

examination, and ECG in patients with transient loss of consciousness in FAST: the Fainting Assessment study. J Cardiovasc Electrophysiol 2008;19(1):48-55.


9. Alshekhlee A, Shen WK, Mackall J, Chelimsky TC. Incidence and mortality rates of syncope in the United States. Am J Med 2009;122(2):181-188.







16. Raviele A, Brignole M, Sutton R et al. Effect of etilefrine in preventing syncopal recurrence in patients with vasovagal syncope: a double-blind, randomized, placebo-controlled trial. The Vasovagal Syncope International Study. Circulation 1999;99(11):1452-1457.

Nederlandse samenvattingList of co-authors

Nederlandse samenvatting 187List of co-authors

List of co-authors

Catherine Black, Department of Clinical Epidemiology Biostatistics and Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.Kimberly R. Boer, PhD, Department of Research and Consultancy, Royal Tropical Institute, Amsterdam, The Netherlands.Patrick M.M. Bossuyt, PhD, Department of Clinical Epidemiology Biostatistics and Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.Gerty Casteelen, MD, Department of Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Nancy Colman, MD, Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Lukas R.C. Dekker, MD, PhD, Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.Nynke van Dijk, MD, PhD, Department of Clinical Epidemiology Biostatistics and Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.Ingeborg K. Go-Schön, Department of Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, and BMEYE Cardiovascular Monitoring B.V., Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Mark P.M. Harms, MD, PhD, Department of Internal Medicine, University Medical Center Groningen, Groningen, The Netherlands.Jacques W.M. Lenders, MD, PhD, Department of Internal Medicine, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands, and Department of Internal Medicine III, University Hospital Carl Gustav Carus Dresden, Dresden, Germany.Jan S.K. Luitse, MD, PhD, Department of Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Johannes B. Reitsma, MD, PhD, Department of Clinical Epidemiology Biostatistics and Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.Jaap H. Ruiter, MD, PhD, Department of Cardiology, Medical Center Alkmaar, Alkmaar, The Netherlands.Rob J.P.M. Scholten, MD, PhD, Dutch Cochrane Centre, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.Jan Stam, MD, PhD, Department of Neurology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.Wouter Wieling, MD, PhD, Department of Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Nederlandse samenvattingDankwoord

Nederlandse samenvatting 189Dankwoord

Dankwoord

Dit proefschrift is het resultaat van onderzoek uitgevoerd op de afdeling Klinische Epidemiologie Biostatistiek en Bio-informatica van het Academisch Medisch Centrum (AMC) in Amsterdam. Bij mijn onderzoekswerkzaamheden ben ik erachter gekomen dat inzet, hulp en steun van anderen onmisbaar zijn voor het doen van goed onderzoek. Allereerst denk ik hierbij aan de patienten die bereid waren deel te nemen aan het onderzoek. Daarnaast zijn nog veel anderen betrokken geweest bij het totstandkomen van dit proefschrift. Hiervoor mijn grote dank. Een aantal van hen wil ik graag persoonlijk bedanken.

Allereerst mijn (co)promotoren.Dr. N. van Dijk, beste Nynke, hartelijk dank voor de mogelijkheden die je geboden hebt om me te ontwikkelen als arts-onderzoeker. Ik vond het heel fijn dat ik als promovendus binnen en buiten het AMC cursussen mocht volgen in het kader van de opleiding tot epidemioloog. Heel vaak dachten we precies hetzelfde over bepaalde zaken. Je kordate manier van aanpakken waardeer ik zeer. Dat maakte onze samenwerking prettig en effectief.

Dr. W. Wieling. Beste Wouter, hartelijk dank voor de hulp en ondersteuning bij mijn werkzaamheden op de polikliniek en bij het schrijven van artikelen. Het was prettig dat je steeds snel reageerde op stukken die ik toestuurde voor commentaar. Ook waardeer ik het dat je hierbij steeds duidelijk kon aangeven of een stuk tekst naar jouw mening goed of niet goed geschreven was.

Dr. J.B. Reitsma. Beste Hans, ik ben je zeer dankbaar voor je waardevolle bijdragen aan de analyses van al mijn artikelen. Je was altijd bereid om hulp te bieden waar dat nodig was. Ondanks het feit dat je het zelf steeds erg druk had, wist je vlak voor deadlines en ook in de laatste fasen van het promotietraject toch tijd vrij te maken om mijn artikelen te bekijken. Dat waardeer ik zeer.

Professor P.M.M. Bossuyt. Beste Patrick, hartelijk dank voor je betrokkenheid bij mijn onderzoek en je waardevolle commentaar op mijn artikelen. Hartelijk dank voor de mogelijkheden die je me hebt geboden om tijdens het promotietraject cursussen te volgen binnen en buiten het AMC.

Prof. Dr. J. Stam, hartelijk dank voor uw hulp bij het samenstellen van mijn eerste wetenschappelijke artikel. Uw commentaar op de conceptteksten van dit artikel was steeds zeer nuttig. Hartelijk dank dat u deel wilde uitmaken van mijn

Dankwoord190 Dankwoord

promotiecommissie. Dat zelfde geldt voor dr. R.D. Thijs. Beste Roland, het was telkens weer leuk je te ontmoeten bij je bezoeken aan het AMC in het kader van je promotie-onderzoek over syncope. Het was voor mij een eer je promotie in Leiden te mogen bijwonen. Mijn hartelijke dank gaat ook uit naar de overige leden van de promotiecommissie, prof. dr. P.W. de Leeuw, prof. dr. A.W. Hoes, prof. dr. R.J. de Haan en prof. dr. M.A.G. Sprangers. Heel hartelijk dank voor uw inspanningen ten behoeve van de beoordeling van mijn proefschrift. Het is een grote eer om mijn proefschrift te mogen verdedigen tegenover geleerden met grote vakinhoudelijke kennis.

Graag wil ik dr. M.P.M. Harms, prof. dr. J.W.M. Lenders en dr. J.H. Ruiter hartelijk danken voor hun deelname aan de trial van het Syncope Treatment and Assessment network Netherlands (STAND-trial). Zonder jullie hulp hadden we nooit zoveel patienten kunnen includeren in dit onderzoek. Wat betreft de inclusie en follow-up van patienten in dit onderzoek wil ik ook graag de medewerkers van de polikliniek Cardiologie van het AMC en het Medisch Centrum Alkmaar bedanken voor hun medewerking. Voor de STAND-trial gaat mijn bijzondere dank uit aan Ingeborg K. Go-Schön. Ingeborg, zonder jouw hulp bij het inplannen en voorbereiden van afspraken met patienten, archiveren van onderzoeksmateriaal en het invoeren van onderzoeksdata zouden we de STAND-trial nooit goed hebben kunnen uitvoeren. Onze besprekingen op maandagochtend waren altijd erg gezellig en effectief.

Het schrijven van een Cochrane review bleek een hele klus. Het was erg fijn dat ik hierbij kon rekenen op hulp van Catherine Black in het kader van haar wetenschappelijke stage. Catherine, hartelijk dank voor je inzet tijdens de stageperiode. Voor het tot stand komen van de Cochrane review was ook de hulp van dr. R.J.P.M. Scholten van het Dutch Cochrane Center onmisbaar. Rob, ik waardeer je optimistische en vrolijke houding enorm.

Ook mijn overige mede-auteurs prof. dr. L.R.C. Dekker, dr. J.S.K. Luitse, dr. K.R. Boer, drs. G. Casteelen, drs. N. Colman en I.K. Go-Schön wil ik graag hartelijk bedanken voor hun commentaar op de conceptversies van de artikelen.

Onderzoek doen lijkt op een rit in een achtbaan. In het begin gaat het langzaam en traag, vervolgens ga je los en ga je door pieken en dalen. Het was fijn mij wetenschappelijke en persoonlijke successen te kunnen delen met kamer-, gang- en afdelingsgenoten op de afdeling Klinische Epidemiologie, Biostatistiek en Bio-informatica. Prof. Martien Borgdorff, hartelijk dank voor je interesse in mijn onderzoek en je waardevolle suggesties bij de werkbesprekingen. Ook wil ik graag

DankwoordDankwoord 191

mijn kamergenoten Anouk, Hans, Barbara, Olga en Mariska bedanken voor hun praktische tips bij de uitvoering van het onderzoek. Iris, Erik, Raha, Sandra, Willem, Annet, Susan, Marjolein, Kim, Fleur, Jolande, Teodora, Miranda, Roy, Sharon en Bart, veel succes met jullie onderzoek en toekomstige werkzaamheden! Gré, Hanni en Petra, fijn dat jullie altijd klaar stonden om mij te helpen. Bedankt voor de gezellige uitstapjes en kerstactiviteiten!

Met veel plezier heb ik me tijdens mijn promotietraject ingezet voor de ondernemingsraad van Academic Medical Research B.V. Het was erg interessant om het AMC op deze manier op een andere manier te leren kennen, van binnenuit.

Verder wil ik al mijn vrienden, familie en bekenden hartelijk danken voor hun interesse en belangstelling voor mijn onderzoek. Dit heb ik altijd zeer gewaardeerd.

Miranda en Edwin, ik ben erg trots dat jullie mijn paranimfen wilden zijn. Heel hartelijk dank voor jullie hulp rondom de promotie.

Beste mam, Jan en Lisette, hartelijk dank voor jullie interesse en belangstelling voor mijn onderzoek. Helaas heeft vader de promotieplechtigheid niet meer kunnen bijwonen. Lisette, ik hoop dat je een goede specialist wordt en dat je daarnaast samen met Mark veel plezier beleeft. Jan, van een ding sta ik steeds weer versteld: het beroep van boer en dokter lijkt heel verschillend in theorie, maar als we samen weer eens een schaap scheren, aardappels scheppen of een ander klusje doen, realiseer ik me dat het in praktijk toch heel goed te combineren valt.

Curriculum Vitae

193Curriculum Vitae

Curriculum Vitae

Joost Romme was born in Hooge Zwaluwe (Noord-Brabant, the Netherlands) on the 3rd of March 1980. At high school (gymnasium) at the Newmancollege in Breda he decided to become a physician. However, directly after his graduation from high school in 1998, he was not allowed to start studying Medicine by the Dutch selection system for medical students (numerus fixus). For this reason, he attended the foundation course of Health Sciences at Maastricht University. He passed the examinations for this course in 1999. In that same year, he started studying Medicine at Maastricht University. From the second year of this study onwards, he was involved in a supervised training program in performing research (Onderzoekstraject Geneeskunde). During this program, he studied neurological aspects of glaucoma. After becoming a medical doctor in 2005, Joost gained clinical experience as a resident in Internal Medicine (Deventer Ziekenhuis). In October 2006, he started working as a PhD-student at the Academic Medical Center (AMC) in Amsterdam. He performed the research described in this thesis under supervision of professor P.M. Bossuyt, doctor N. van Dijk, doctor W. Wieling and doctor J.B. Reitsma. At both the Cardiology out patients clinic of the AMC and the Medical Centre Alkmaar, Joost selected and counselled patients for his own research project and also for the 3rd International Study of Syncope of Uncertain Etiology (ISSUE-3). Apart from his practical research work, he was educated as epidemiologist (epidemioloog B).In December 2009, Joost started working as a resident at the department of Neurology at the Kennemer Gasthuis in Haarlem.

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