Predictive Factors for Rebleeding after Aneurysmal

Subarachnoid Haemorrhage

Student: C.E. (Karlijn) van Donkelaar (S2130149)

Faculty supervisor: J. Marc C. Van Dijk MD PhD

Second supervisor: Nicolaas A. Bakker MD PhD

University Medical Centre Groningen

Department of Neurosurgery AB71

P.O. Box 30.001, 9700 RB Groningen, the Netherlands

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TABLE OF CONTENTS

SUMMARY ............................................................................................................................................... 5

SAMENVATTING ...................................................................................................................................... 6

LIST OF ABBREVIATIONS ......................................................................................................................... 7

INTRODUCTION ....................................................................................................................................... 9

METHODS .............................................................................................................................................. 13

RESULTS ................................................................................................................................................ 17

DISCUSSION ........................................................................................................................................... 23

REFERENCES .......................................................................................................................................... 26

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SUMMARY Aneurysmal subarachnoid haemorrhage (aSAH) is a devastating type of stroke associated with high morbidity and mortality. One of the most feared complications before aneurysm repair is early rebleeding of the aneurysm. Predictors for such an often fatal rebleeding are largely unknown. Therefore it was the aim of this study to determine predictors for an early rebleeding after aSAH in relation with time after ictus. This observational cohort study included all consecutive patients admitted with a saccular aSAH between January 1998 and December 2014 (n=1236) at our university neurovascular centre. Clinical predictors for rebleeding ≤24h were identified using multivariable Cox regression analyses. Kaplan-Meier analyses were applied to evaluate the time of rebleeding up to 72h after aSAH. After analyses, a modified Fisher (mFisher) grade of 3 or 4 was revealed as a predictor for an in-hospital rebleeding ≤24h after ictus (aHR 4.7 (95%CI 2.1-10.6) p<0.001). The number of patients with mFisher 3-4 needed to treat on emergency base to prevent one rebleeding was calculated 15 (95%CI 10-32). Also, the initiation of external cerebrospinal fluid-drainage (aHR 1.9, 95%CI 1.4-2.5, p<0.001) was independently associated with a rebleeding ≤24h. Cumulative in-hospital rebleeding rates were 5.8% ≤24h, and 7% <72h after ictus. In view of these results, timing of treatment of aSAH patients, especially those with an mFisher grade of 3 or 4 in a good clinical condition, should be reconsidered. These patients might be regarded a medical emergency, requiring aneurysm repair as soon as possible to prevent rebleeding. In this respect, these findings should provoke the debate on timing of aneurysm repair, especially in patients considered to be at high risk for rebleeding.

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SAMENVATTING Aneurysmatische subarachnoidale bloeding (aSAB) is een verwoestende vorm van beroerte en wordt geassocieerd met hoge morbiditeit en mortaliteit. Een van de meest gevreesde complicaties voorafgaand aan behandeling is een recidief bloeding van het geruptureerde intracraniële aneurysma, welke meestal fataal is. Echter, klinische voorpellers voor een recidief bloeding gerelateerd aan de tijd na initiële bloeding, zijn vrijwel niet bekend. Daarom was het doel van deze studie om voorspellers voor een vroege recidief bloeding na aSAB te identificeren, in relatie tot de tijd. In deze observationele cohortstudie zijn alle patiënten die tussen januari 1998 en december 2014 in ons universitaire centrum zijn opgenomen, geïncludeerd. Klinische voorspellers voor een recidief bloeding, ≤24 uur na initiële bloeding, zijn met behulp van multivariabele Cox regressie analyses geïdentificeerd. Kaplan-Meier analyses zijn gebruikt om het tijdstip van recidief bloeding, tot 72 uur na aSAB, weer te geven. Na analyses is gebleken dat een modified Fisher (mFisher) graad van 3 of 4 een sterke voorspeller was voor het optreden van een recidief bloeding in het ziekenhuis ≤ 24 uur na initiële bloeding (aHR 4.7 (95%CI 2.1-10.6) p<0.001). Het aantal patiënten met mFisher graad 3-4 dat vroeg behandeld moet worden (≤24 uur) om één recidief bloeding te voorkomen is 15 (95%CI 10-32). Ook de plaatsing van een externe cerebrospinale drain is geassocieerd met een recidief bloeding ≤24 uur (aHR 1.9, 95%CI 1.4-2.5, p<0.001). De cumulatieve aantallen van recidief bloedingen in het ziekenhuis zijn 5.8% ≤24 uur en 7% <72 uur na initiële bloeding. Deze resultaten zouden moeten leiden tot een betere afweging wat betreft het tijdstip van behandeling van SAB patiënten, in het bijzonder bij de patiënten met een mFisher graad 3 of 4 en in een goede klinische conditie. Deze patiënten zouden gezien moeten worden als medisch spoedgeval, met een directe behandeling van het aneurysma ter voorkoming van een recidief bloeding. Deze resultaten zouden moeten aanzetten tot een debat over het beste tijdstip van behandeling, vooral bij patiënten met een hoog risico op een rebleed.

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LIST OF ABBREVIATIONS

aHR Adjusted hazard ratios

ARR Absolute risk reduction

aSAH Aneurysmal subarachnoid haemorrhage

CER Control event rate

CSF-drainage Cerebrospinal fluid drainage

CT Computerised tomography

CTA Computerised tomographic angiography

DSA Digital subtraction angiography

EER Experimental event rate

GCS Glasgow Coma Scale

HR Hazard ratio’s

ICU Intensive care unit

IQR Interquartile ranges

mFisher scale Modified Fisher scale

MRA Magnetic resonance angiography

MRI Magnetic resonance imaging

NNT Number needed to treat

SAH Subarachnoid haemorrhage

WFNS scale The World Federation of Neurosurgeons scale

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INTRODUCTION

Subarachnoid haemorrhage

A subarachnoid haemorrhage (SAH) is a devastating type of stroke, accounting for 5% of all strokes.(1) The average incidence of an SAH is 9.1 per 100.000 people annually and highest incidence rates are reported in Japan and Finland, with respectively 22.7 and 19.7 per 100.000 people.(2) Mortality rates after SAH are significant (35%), and one-third of the survivors remain functional dependent, also in the long-term.(3) Due to the relatively young age at which SAH usually occurs (mean 55 years); the loss of productive life years from SAH is comparable with that of ischemic stroke, even though the latter has a much higher incidence.(3)

Pathophysiology

An intracranial aneurysm is the most frequent cause for a spontaneous subarachnoid haemorrhage, accounting for 85% of all cases. (4) In the remaining 15%, no symptomatic aneurysm can be detected. Two-third of these cases fit into the pattern of a so-called non-aneurysmal perimesencephalic haemorrhage, with the presence of blood from an unknown origin, limited to the subarachnoid spaces around the midbrain (i.e. mesencephalon). (4) This is a relatively harmless type of SAH.(5) In the other one-third of the cases, either no cause (non-aneurysmal SAH) or relatively rare causes can be detected, among others intracranial artery dissections, arteriovenous malformations, (inflammatory) disorders of the cerebral or spinal blood vessels, bleeding disorders and bleeding caused by an intracranial tumour. (6)

Intracranial aneurysms develop in the course of life and are not congenital, as once was believed. A saccular aneurysm arises when a weakness in the wall of a cerebral artery becomes enlarged, notably located in the circle of Willis and its branches (figure 1). For an average adult, the frequency of intracranial aneurysms is around 2.3% and increases with age. (6) However, most of the aneurysms will never rupture. A larger aneurysm size increases the risk of rupture, as well as the presence of risk factors for SAH.(6) Well known riskfactors are history of hypertension, smoking, the use of sympathomimetic drugs and excessive alcohol intake.(7) Also women are more likely to have an SAH as well as people with a (family) history of previous SAH and certain genetic syndromes such as polycystic kidney disease.(7)

Symptoms and diagnosis

The classic symptom of SAH is a thunderclap headache, a headache developing over a few

Figure 1. Circle of Willis with the most common sites of aneurysms (circles).

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Figure 2. CT-scan of a patient with subarachnoid blood (arrow).

seconds. (8) Neck stiffness, vomiting, confusion, lowered level of consciousness and seizures are other well-known symptoms. In case of compression of a cranial nerve by an aneurysm or an associated haematoma in the brain parenchyma, focal neurological deficits can occur.(6) Intraocular haemorrhage, also known as Terson syndrome, may occur in severe SAH, as result of rising intracranial pressure.(9) Also associated with SAH are systemic features such as severe hypertension, hypoxemia and electrocardiographic changes, which can mimic acute myocardial infarction.(6) This can subsequently lead to erroneous examinations and treatment.

Misdiagnosis and treatment delay is associated with higher risk of morbidity and mortality. (4) Therefore, early and accurate diagnosis of SAH is necessary. If an SAH is suspected, imaging with a cranial computerised tomography (CT) scan without contrast is examination of first choice. Within 24h after ictus, sensitivity is reported to be 90%-100%.(7) However, in the subsequent days, the amount of blood is significantly decreasing and 7 days after the ictus, the sensitivity is below 50%.(4) In a minority of the cases (3%), the initial CT scan is false negative for subarachnoid blood. Consequently, it is common practice to perform a diagnostic lumbar punction (LP) after a negative scan, at least 12h after the occurrence of symptoms. In case of subarachnoid blood, spectrophotometry can confirm the presence of bilirubin in the cerebrospinal fluid (CSF).(4) Nowadays, advances in magnetic resonance imaging (MRI), can often allow the diagnosis of SAH to be made in case of a negative cranial CT scan, avoiding the need for LP.(7)

After the diagnosis of subarachnoid blood, angiography is required to detect the underlying cause, notably the presence of a symptomatic aneurysm. Digital subtraction angiography (DSA) is still the regarded as the gold standard; however it is an invasive and time consuming procedure and associated with a risk for complications such as ischemia and rebleeding of the aneurysm. Nowadays, CT-angiography (CTA) and MR-angiography (MRA) are more convenient. CTA can easily be performed immediately after the initial CT-scan without contrast. It is simple and fast to perform and minimal invasive for the patient thus also suitable for critical ill patients. The sensitivity rate is close to 100%, which is comparable with MRA imaging.(4) The advantage of MRA over CTA is the absence of harmful radiation. However, MRA is less suitable for imaging in the acute stage and

therefore more feasible in the follow-up of patients with a history of familiar aneurysms.(4) Besides the diagnostic value, angiographic imaging in general is also useful for study of the anatomical configuration of the aneurysm in relation to adjoining arteries, which allows optimum selection of treatment.(6)

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Management of patients in poor condition

In patients who are in a poor clinical condition, neurological resuscitation is required before aneurysm repair is instigated. Clinical condition is indicated by the World Federation of Neurosurgical Societies (WFNS) SAH grading scale (table 1).(10) This scale is based on the Glasgow Coma Scale (GCS), which measures the level of consciousness, with in addition the presence or absence of neurological deficits such as aphasia or (hemi)paresis. Patients with grade IV and V are regarded to be in a poor clinical condition, which is associated with a poor prognosis.(11)

A decreased level of consciousness can be caused by acute hydrocephalus, requiring immediate cerebrospinal fluid (CSF) drainage with an external ventricular of lumbar drain.(7) In at least one–third of the patients in a poor clinical condition, the presence of a space-occupying intracerebral haematoma is the cause of the lowered consciousness. A haematoma in the brain parenchyma is most frequently the result of a ruptured middle cerebral artery and urgent surgical evacuation is necessary, preferably with subsequent aneurysm repair.(12) Subdural haematoma is rare in SAH patients (less than 2%), but nevertheless life-threatening and should be treated as soon as possible.(13)

Table 1. World Federation of Neurosurgical Societies (WFNS) SAH grading scale

Aneurysm repair

Aneurysm repair can be performed via craniotomy with microsurgical clip obliteration (‘clipping’) or via an endovascular route using electrolytically detachable coils for occlusion (‘coiling’, figure 3). In 1991, Guglielmi was the first describing treatment with these coils, and over the last decades, endovascular coiling is increasingly being used. In 2002, the International Subarachnoid Aneurysm Trial, a multicentre randomized trial, compared microsurgical and endovascular repair in 2143 patients whom both treatment modalities where eligible.(14) This study described a significantly better outcome after 1 year using endovascular coiling, although the risk of rebleeding after coiling was slightly higher compared to clipping. However, after five-year follow up, the benefit of coiling seems to have vanished, and both methods were considered equivalent in the long term.(15)

Coiling of the aneurysm is associated with an increased risk for incomplete occlusion and subsequent increased risk of rebleeding after treatment In case of incomplete occlusion, additional coiling is indicated to achieve complete obligation (figure 3). After coiling, a five year follow-up is recommended. After clipping of the aneurysm, the change of incomplete occlusion is negligible and thus long-term follow up is superfluous. Therefore, clipping is preferred in patients <40 years. Also patients with an aneurysm located in middle cerebral artery are preferably clipped, due to the favourable approachability with craniotomy.(7)

Grade GCS-score Motor deficit I 15 absent II 14+13 absent III 14+13 present IV 12-7 present or absent V 6-3 present of absent

GCS indicates Glasgow Coma Scale

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Traditionally, the critical time-frame for aneurysm repair is set at <72 hours after ictus, unless the patient is in a moribund condition. (16,17) Treatment is associated with increased risks between day 3 and day 14 after the ictus, due to the observed increased risk of intracerebral vasospasm, which can lead to cerebral ischemia and a subsequent poor prognosis.(18) In these situations, treatment is sometimes postponed to overcome this period.

Early rebleeding of the aneurysm

After an aneurysmal SAH (aSAH), the most feared complication is early rebleeding of the aneurysm, with reported incidences of 8-23 % in the first 72h after the ictus.(19) The consequences of early rebleeding are severe, with reported mortality rates up to 60%.(19) As soon as the aneurysm is successfully repaired, the chance of rebleeding is negligible.(20) Therefore, treatment is instigated as soon as soon as possible, preferably <72 hours.(7)

In current clinical practice a swift and accurate diagnosis of SAH is usually quickly established, but particularly its subsequent treatment is often delayed by several factors. Logistical issues, e.g. transfer time and availability of neurovascular centres, as well as the 24/7 treatment capacity within these centres may contribute to a treatment delay. Treatment of concomitant disorders, such as acute hydrocephalus, can also interfere with early treatment.

Recent studies have already extensively focused on the incidence of a rebleeding after aneurysm repair, especially related to the type of treatment.(18,20) Although studies in the past have already showed that a rebleeding most frequently occurs in the first 24h after ictus,(21-23) exact rebleeding rates in relation to time after ictus have never been undisputedly established.(19) Moreover, though several risk-factors have been linked to an early rebleeding in retrospective analyses of rather small series of patients,(24-27) firm evidence regarding risk-factors is lacking. In clinical practice, it is therefore still unknown which patients are at an increased risk for a rebleeding and thus require emergency aneurysm repair. In view of the aforementioned it was the aim of this study to identify risk-factors for early rebleeding in relation to the exact time after ictus.

Figure 3. (A) Endovascular coiling of an anterior communication artery aneurysm (B) Aneurysm before packing with platinum coils. (C) Aneurysm after packing with platinum coils. (D) Partial reopening of aneurysm after six months after coiling. (E) Complete occlusion of the aneurysm after additional coiling.

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METHODS

Patients

All patients with a spontaneous SAH admitted to the University Medical Centre Groningen between January 1998 and December 2014 were included in this study, leading to 1620 consecutive patients. All clinical relevant data of these patients were obtained from the electronic patient files and collected in a database. Informed consent was not required, due to the observational design of this study and the fact that treatment of patients was according to standard clinical care.

Treatment-protocol

A standardized multidisciplinary protocol was applied to all SAH patients admitted to the UMCG. Before 2002, SAH patients were subject to emergency DSA imaging within 12 hours after admission. Since 2002, all patients have undergone immediate CTA, followed by DSA within 48 hours in the case of a negative CTA. All imaging studies were evaluated immediately both by an interventional neuroradiologist and a vascular neurosurgeon. If an underlying aneurysm was detected, patients in a good neurological condition on admission (WFNS grade I-III) were treated as soon as technically and logistically feasible by endovascular coiling or neurosurgical clipping, preferably within 72 hours. In the meantime, patients with hydrocephalus requiring CSF-drainage received an external lumbar or ventricular catheter. Patients in a poor neurological condition on admission (WFNS grade IV-V) were not immediately considered for aneurysm repair; instead, an external ventricular catheter was instigated, followed by close monitoring on the intensive care unit. If their clinical condition improved, aneurysm repair was instigated. Patients with a space-occupying intracranial hematoma, e.g. because of a ruptured middle cerebral artery aneurysm, underwent immediate craniotomy with evacuation of the hematoma and concomitant clipping of the aneurysm regardless of their clinical condition (except for moribund patients).

Study inclusion

In this study, only patients with an aneurysmal SAH are included. Therefore, of the total of 1620 patients, 283 patients with a non-aneurysmal or perimesencephalic SAH were excluded. In addition, 101 patients with a fusiform or dissecting intracranial aneurysm were not considered eligible, since pathophysiology and treatment of these aneurysms is substantially different when compared with saccular aneurysms. Last, 31 patients had a history of aSAH. The occurrence of multiple aSAH’s in one patient might be caused by a yet unknown factor. Hence to prevent potential bias, these patients were also excluded from this study. As such, 1205 patients with a ruptured saccular intracranial aneurysm were considered eligible for this study (figure 4).

Data collection and analysis

The following data of the patient were collected from the electronic patient files and available imaging: age at time of aSAH, sex, history of aSAH, presence of hypertension, use of platelet inhibitors or vitamin-K antagonist, date and time of ictus, the WFNS score on initial in-hospital assessment, aneurysm location and maximum diameter, the presence of

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hydrocephalus, the timing of placement of an external ventricular or lumbar catheter system for CSF-drainage, and time to aneurysm repair, rebleeding or death due to any cause.

Hypertension was defined as a systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg during multiple recent measurements or controlled using antihypertensive drugs. The location of the aneurysm was classified into:

i. the anterior cerebral arteries (including the anterior cerebral artery, anterior communicating artery, and pericallosal artery)

ii. the middle cerebral artery iii. posterior communicating artery iv. other internal carotid arteries v. the basilar artery vi. other arteries in the posterior circulation (including the vertebral artery, cerebellar

arteries, and posterior cerebral artery).

Age of the patient and aneurysm size and were both categorized in five consecutive groups, similar to the recently published PHASES study.(28) The modified Fisher scale (table 2) was used to indicate the amount of blood on the initial CT-scan.(29)

All SAH patients n=1620

Aneurysmal SAH

n=1337

Non-aneurysmal or Perimesencephalic SAH

n=283

Excluded: - Non-saccular aneurysms (101) Intracranial dissection (69) Fusiform (32)

1205 patients eligible

Excluded: - Previous aSAH (31)

Saccular aneurysms n=1236

Figure 4. Flowchart of the included patients

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Imaging

All available radiological imaging of the included patients was re-analysed to determine the mFisher score as well as the maximum diameter of the aneurysm. Imaging of patients admitted before 2000 was not available for re-evaluation. Although the radiological reports of these patients were available, mFisher grade and maximum aneurysm diameter were considered ‘unknown’. If it was not possible to identify the symptomatic aneurysm because the patients died before CTA or DSA could be performed (n=21), the aneurysm location was designated ‘unknown’. In patients harbouring multiple intracranial aneurysms in whom it was not possible to identify the symptomatic aneurysm (n=22), the aneurysm location was as well designated as ‘unknown’. These factors were frequently not taken into account.

Table 2. The modified Fisher scale

Outcome

The primary endpoint of this study was an in-hospital rebleeding ≤24h after the ictus. Rebleedings up to 72h were also analysed. A rebleeding of the ruptured intracranial aneurysm was defined as a sudden clinical deterioration with a concomitant increase of subarachnoid, intracerebral, or intraventricular blood on the subsequent CT-scan (performed <1 hour after onset of symptoms; n=65, 80%). A clinical deterioration was defined as a decrease in Glasgow Coma Scale (GCS) in awake patients. In patients who are already in a poor clinical condition and are intubated and sedated, a clinical detoration could not be observed. However, these patients are closely monitored on the intensive care unit (ICU) with the large majority already having an external ventricular catheter. In case of a sudden change of blood pressure, pupil size or production of fresh blood in the CSF-drainage system, a CT scan is performed to confirm a rebleeding. Patients who suddenly died without CT confirmation (n=16, 20%) were classified as a rebleeding if similar signs and symptoms occurred and/or if the external CSF-drainage system produced fresh blood. The time of rebleeding after ictus was determined at time of onset of symptoms or by the time of the confirmatory CT-scan.

Grade Focal or

diffuse thin SAH

Focal or diffuse thick SAH

Intra- ventricular

haemorrhage

0 - - - No subarachnoid haemorrhage; no intraventricular blood

1 + - - Thin diffuse or focal

subarachnoid blood; no intraventricular blood

2 + - + Thin diffuse or local

subarachnoid blood; with intraventricular blood

3 - + - Thick focal or diffuse

subarachnoid blood; no intraventricular blood

4 - + + Thick local or diffuse subarachnoid blood;

intraventricular blood

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Statistical analysis

To obtain the incidence rates as exact as possible, rebleedings ≤24h were measured from time of ictus until time of rebleeding in hours. Patients who were not anymore at risk for rebleeding, due to treatment of the aneurysm or death of the patient, were censored. Kaplan-Meier analyses were applied to evaluate the time of rebleeding up to 72 hours, depicted in one minus survival curves. Log-rank tests were applied when deemed necessary. Categorical data are presented as counts and percentages. Continuous variables are presented as mean with SD or medians with interquartile ranges (IQR), depending on normality of data.

For identification of the riskfactors, cox proportional hazard survival analyses are used to obtain the hazard ratios (HR) for rebleeding. After univariate analysis of all collected covariates, those with a p-value <0.15 were included in the multivariate analysis. Multivariate analysis is used to achieve the most suitable and predictive risk profile for the occurrence of a rebleeding. After entering of the significant covariates, a backward elimination strategy was used to obtain the most significant risk profile, only including covariates associated with a rebleeding at a level of p<0.10.

After determination of the riskfactors, numbers needed to treat (NNT) of patients at high risk for rebleeding to prevent one rebleeding ≤24h were calculated. The NNT are based on a theoretically ultra-early treatment strategy (24/7) with treatment <3h considered as unachievable. The NNT are calculated as the reciprocal of the absolute risk reduction (table 3).

A two-tailed p-value of 0.05 was considered to indicate statistical significance. All analyses were performed using SPSS software (version 22.0, SPSS Inc.).

Table 3. Formulas for the calculation of the numbers needed to treat

Formulas Abbreviations

NNT= 1/ARR

ARR=CER - EER

NNT: number needed to treat

ARR: absolute risk reduction

EER: experimental event rate

CER: control event rate

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RESULTS

Baseline patient characteristics

Patient characteristics are shown in table 4. Of all patients, a female predominance was observed (67%), and median age was 55 years (IQR: 46-64 years). A group of 374 patients (31%) was in a poor clinical condition (WFNS 4/5) at time of admission. Aneurysms of the anterior cerebral arteries followed by the middle cerebral artery were most frequently observed. A group of 286 patients (21%) required external CSF-drainage before aneurysm repair because of acute hydrocephalus (≤ 24h after the ictus).

Cumulative incidence of early rebleeding after aSAH and treatment

From a total of 1205 patients, rebleeding ≤24 hours was confirmed in 70 patients (5.8%); an additional 11/906 patients (1.2%) had a rebleeding between 24 and 72 hours after the ictus; 299 patients had already been censored during the first 24h. Of the 81 patients, 46 patients (57%) died as a result of a rebleeding. The mortality attributed to a rebleeding was not associated with time of rebleeding after ictus (data not shown). The incidence of an early rebleeding in relation to the exact time after ictus is depicted in the Kaplan-Meier analyses with a peak incidence of rebleeding between 6-12 hours (figure 5). The survival curve is censored for patients at time of aneurysm repair or death due to any cause, with a median time of aneurysm repair in all patients treated <72h after ictus (n=648) of 31h (IQR 21-47h).

Figure 5. Kaplan Meier one minus survival analyses of patients with a rebleeding <72 hours after ictus

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Table 4. Baseline patient characteristics

All patients rebleeding ≤24hours

no early rebleeding ≤24h

Number (%) Number (%) Number (%) Total 1205 (100) 70 (6) 1135 (94) Female 808 (100) 49 (6) 759 (94) Age

<40 years 123 (100) 4 (3) 119 (97) 40-49 years 291 (100) 13 (5) 278 (95) 50-59 years 343 (100) 26 (8) 317 (92) 60-69 years 272 (100) 17 (6) 255 (94) >70 years 176 (100) 10 (6) 166 (94)

History Hypertension 268 (100) 21 (8) 247 (92) Platelet inhibitor 44 (100) 2 (5) 42 (95) Vitamin-K antagonist 18 (100) 2 (11) 16 (89)

WFNS1 grade on admission 1 538 (100) 17 (3) 521 (97) 2 264 (100) 11 (4) 253 (96) 3 29 (100) 1 (3) 28 (97) 4 205 (100) 19 (9) 186 (91) 5 169 (100) 22 (13) 147 (87)

Aneurysm location Anterior cerebral arteries 483 (100) 30 (6) 453 (94) Middle cerebral artery 246 (100) 14 (6) 232 (94) Posterior communicating artery

187 (100) 9 (5) 178 (95)

Internal carotid arteries 73 (100) 3 (4) 70 (96) Basilar artery 91 (100) 6 (7) 85 (93) Posterior circulation (other) 82 (100) 4 (5) 78 (95) Unknown 43 (100) 4 (9) 39 (91)

Aneurysm size 0-4.9 mm 221 (100) 9 (4) 212 (96) 5-6.9 mm 310 (100) 15 (5) 295 (95) 7-9.9 mm 230 (100) 14 (6) 216 (94) 10-19.9 mm 196 (100) 15 (8) 181 (92) ≥20 mm 31 (100) 6 (19) 25 (81) Unknown 217 (100) 11 (5) 206 (95)

Modified Fisher scale 0 38 (100) 1 (3) 37 (97) 1 267 (100) 1 (<1) 266 (99) 2 226 (100) 5 (2) 221 (98) 3 177 (100) 10 (6) 167 (94) 4 406 (100) 48 (12) 358 (88) Unknown 91 (100) 5 (5) 86 (95)

Intracerebral haematoma 187 (100) 19 (10) 168 (90) Subdural haematoma 19 (100) 2 (11) 17 (89) External CSF-drainage2 286 (100) 22 (8) 264 (92) 1World Federation of Neurosurgeons scale 2Cerebrospinal fluid drainage ≤ 24 hours, before treatment

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Risk factors for a rebleeding ≤24 hours

After univariate Cox regression analysis (Table 6) the following covariates were associated (p<0.15) with a rebleeding ≤24h: hypertension, WFNS-score at admission, larger aneurysm size, presence of an intracerebral haematoma, a higher mFisher grade and external CSF-drainage before aneurysm repair. Because of the observed strong dichotomization between mFisher grade of 0-2 and 3-4, the mFisher scale was dichotomized accordingly for further analysis.

After multivariable analysis, an mFisher grade of 3-4 was associated with the occurrence of an early rebleeding (aHR 4.7, 95%CI 2.1-10.6) p<0.001). If the mFisher scale was not dichotomized but included as a categorical covariate in the initial multivariable model, it remained significantly associated with a rebleeding (table 7). Also initiation of external CSF-drainage was statistically associated with a rebleeding (aHR 1.9, 95%CI 1.4-2.5, p<0.001). The rebleeding occurred with a median of 1h after initiation of CSF-drainage (IQR 0-2h, data not shown). Overall, the size of the aneurysm in relation with the risk of a rebleed ≤24h showed a trend (p=0.07), with a larger aneurysm being at a greater risk for a rebleeding, especially those with a diameter ≥20mm (aHR 4.4, 1.6-13.2, p=0.007). The association between a rebleeding and the mFisher grade is illustrated in figure 6, in which the dichotomized mFisher scale in relation with the occurrence of a rebleeding as a function of time is graphically presented (Log-rank: p<0.001).

Numbers needed to treat with ultra-early treatment strategy

Of all patients, 583 with a high mFisher grade (3-4) on initial imaging could potentially benefit from ultra-early treatment. Of this group, 78 patients were already treated or deceased within 24 hours, resulting in a control group of 505 patients still at risk for a rebleed. In 58 patients, a rebleed ≤24h occurred. A rebleed ≤3h was considered non-preventable. Consequently, 25 patients with rebleed ≤3 hours remained in the experimental group. Mortality rate attributed to a rebleed of this group was 60% (15/25 patients).

The NNT using an ultra-early treatment strategy in patients with a high mFisher grade (n=583) to prevent one rebleeding ≤24h was calculated 15 (95%CI 10-32). As the mortality rate of patients suffering from a rebleeding ≤24h was 60%, the NNT to prevent one death was 25 (95%CI 15-75).

Table 5. The calculation of the numbers needed to treat (NNT)

EER=25/505=0.049

CER=58/505=0.115

ARR=0.066

NNT to prevent one rebleed= 1/0.066= 15

NNT to prevent one death= 25

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Figure 6. Kaplan Meier one minus survival analyses of patients with a rebleeding <72 hours after ictus, dichotomized according to the modified Fisher scale

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Table 6. Univariate and multivariable Cox regression analysis of rebleeding ≤24h after ictus.

Predictor HR 95% CI p-value aHR 95% CI p-value

Univariate Cox regression Multivariable Cox regression*

Female 0.9 0.5-1.5 0.61 Age 0.36

<40 years 1.0 40-49 years 1.4 0.4-4.2 0.59 50-59 years 2.4 0.8-6.8 0.11 60-69 years 1.9 0.6-5.7 0.25 >70 years 1.7 0.5-5.5 0.36

History Hypertension 1.5 0.9-2.5 0.13 Platelet inhibitor 0.8 0.2-3.1 0.70 Vitamin-K antagonist 1.9 0.5-7.6 0.38

WFNS1 grade on admission <0.001 1 1.0 2 1.3 0.6-2.8 0.46 3 1.1 0.2-8.2 0.93 4 3.1 1.6-6.0 0.001 5 4.6 2.4-8.6 <0.001

Aneurysm location2 0.96 Anterior cerebral arteries 1.0 Middle cerebral artery 1.0 0.5-1.8 0.87 Posterior communicating artery

0.8 0.4-1.6 0.51

Internal carotid arteries 0.7 0.2-2.2 0.49 Basilar artery 1.1 0.5-2.6 0.86 Posterior circulation (other) 0.8 0.3-2.2 0.63

Aneurysm diameter2 0.02 0.07 0.0-4.9 mm 1.0 1.0 5.0-6.9 mm 1.2 0.5-2.8 0.65 1.7 0.7-3.9 0.24 7.0-9.9 mm 1.5 0.7-3.5 0.32 1.7 0.7-4.1 0.22 10.0-19.9 mm 2.0 0.9-4.5 0.10 2.2 0.9-5.4 0.07 ≥20.0 mm 5.2 1.9-14.6 0.02 4.4 1.6-13.2 0.007

Modified Fisher scale2 <0.001 0 1.0 1 0.1 0.0-2.2 0.17 2 0.8 0.1-7.2 0.87 3 2.2 0.3-17.4 0.45 4 4.8 0.7-34.9 0.12

Modified Fisher grade 3-42 8.1 3.7-17.7 <0.001 4.7 2.1-10.6 <0.001 Intracerebral haematoma 2.2 1.3-3.8 0.003 Subdural haematoma 2.0 0.5-7.9 0.35 External CSF-drainage3 1.4 0.9-2.4 0.146 1.9 1.4-2.5 <0.001 1World Federation of Neurosurgeons scale 2Missing data: aneurysm location 3.6%, aneurysm diameter 18.0%, mFisher scale 7.6%

3Cerebrospinal fluid drainage *Effect estimates from the multivariable regression are adjusted for all other variables in the model Cut off point for final multivariate model p=0.10. 21

Table 7. Univariate and multivariable Cox regression analysis of rebleeding ≤24h after ictus, with the ordinal mFisher score.

Predictor HR 95% CI p-value aHR 95% CI p-value

Univariate Cox regression Multivariable Cox regression*

Female 0.9 0.5-1.5 0.61 Age 0.36

<40 years 1.0 40-49 years 1.4 0.4-4.2 0.59 50-59 years 2.4 0.8-6.8 0.11 60-69 years 1.9 0.6-5.7 0.25 >70 years 1.7 0.5-5.5 0.36

History Hypertension 1.5 0.9-2.5 0.13 Platelet inhibitor 0.8 0.2-3.1 0.70 Vitamin-K antagonist 1.9 0.5-7.6 0.38

WFNS5 score on admission <0.001 1 1.0 2 1.3 0.6-2.8 0.46 3 1.1 0.2-8.2 0.93 4 3.1 1.6-6.0 0.001 5 4.6 2.4-8.6 <0.001

Aneurysm location 2 0.96 Anterior cerebral arteries 1.0 Middle cerebral artery 1.0 0.5-1.8 0.87 Posterior communicating artery 0.8 0.4-1.6 0.51 Internal carotid arteries 0.7 0.2-2.2 0.49 Basilar artery 1.1 0.5-2.6 0.86 Posterior circulation (other) 0.8 0.3-2.2 0.63

Aneurysm size2 0.02 0.06 0.0-4.9 mm 1.0 1.0 5.0-6.9 mm 1.2 0.5-2.8 0.65 1.6 0.7-3.7 0.30 7.0-9.9 mm 1.5 0.7-3.5 0.32 1.7 0.7-4.2 0.20 10.0-19.9 mm 2.0 0.9-4.5 0.10 2.4 1.0-5.6 0.05 ≥20.0 mm 5.2 1.9-14.6 0.02 4.6 1.6-13.4 0.005

Modified Fisher scale2 <0.001 0.002 0 1.0 1.0 1 0.1 0.0-2.2 0.17 0.2 0.0-2.2 0.17 2 0.8 0.1-7.2 0.87 0.8 0.1-6.8 0.81 3 2.2 0.3-17.4 0.45 1.9 0.2-15.0 0.56 4 4.8 0.7-34.9 0.12 3.1 0.4-24.0 0.27

Intracerebral haematoma 2.2 1.3-3.8 0.003 Subdural haematoma 2.0 0.5-7.9 0.35 External CSF-drainage3 2.1 1.3-3.4 0.003 1.8 0.9-3.3 0.09 1 World Federation of Neurosurgeons scale 2 Missing data: aneurysm location 3.6%, aneurysm diameter 18.0%, mFisher scale 7.6% 3 Cerebrospinal fluid drainage * Effect estimates from the multivariable regression are adjusted for all other variables in the model. Cut off point for final multivariate model p=0.10.

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DISCUSSION

Novel findings

This study revealed some novel issues regarding rebleeding in the first 24h after aSAH. First and most importantly, a high mFisher grade (3 or 4) on the initial CT-scan, i.e. thick SAH with or without blood in both lateral ventricles, was identified as the strongest independent predictor for rebleeding ≤24h. Second, initiation of external CSF-drainage, with either a lumbar or ventricular catheter, was also found independently associated with a rebleeding ≤24h. In this study, an mFisher grade 3 or 4 was by far the strongest risk factor associated with a rebleeding ≤24h, also independent of the patient’s clinical condition as assessed by the WFNS-score at admission. This is remarkable, since this observation illustrates that not the clinical condition on admission (WFNS score) is predictive for a rebleeding, as suggested by others,(19,25) but rather the amount of subarachnoid blood as measured by the mFisher scale. A speculated explanation is that the amount of blood is a surrogate marker of the defect size and stability of the ruptured aneurysm wall, which is irrespective of the patient’s clinical condition. The more subarachnoid blood on the initial-scan, the larger is the defect in the aneurysm wall, and the less stable is the aneurysm. Therefore, these patients have an increased risk of rebleeding of the aneurysm. The results also suggest that patients might be at an increased risk of rebleeding in case of external CSF-drainage before repair of the aneurysm. This observation confirms previous reports in the literature already suggesting the association between external CSF-drainage and a rebleeding.(30-32) Although the majority of rebleedings occurred almost immediately after initiation of CSF-drainage (median 1h), a causal relation is still difficult to prove. In this respect it would be also of interest to know whether the amount of CSF-drainage plays a role in this association. An explanation of rebleeding after initiation of CSF-drainage might be the sudden change of the transluminal pressure over the already damaged and vulnerable aneurysm wall. This, in turn, interferes with the critically stable local anatomical situation of the aneurysm after aSAH. Apart from larger aneurysm size,(27) additional risk-factors as identified in the past could not be confirmed.(19,24,25) This is probably explained by the methodological design and small sample size of these previous studies.

Research in context

Both the European Stroke Organization (17) and the American Stroke Association (7) have issued a guideline in which it is recommended that treatment of a ruptured intracranial aneurysm should be instigated as soon as logistically feasible preferably <72h after the ictus to reduce the risk of a rebleeding. However, in clinical practice interpretation of this recommendation is highly heterogeneous; some neurovascular centres treat aSAH-patients on an emergency basis, but a significant proportion of centres consider the treatment of a ruptured intracranial aneurysm a ‘daylight job’, both endovascularly as well as surgically.

Some authors advocate the use of antifibrinolytic therapy in the timeframe between ictus and aneurysm-repair to avoid a rebleeding. Although this seems to be the case, the incidence of delayed cerebral ischemia is also significantly increased. It is therefore still unknown whether the application of antifibrinolytic therapy is really useful. (33) Because of this, there was no

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use of antifibrinolytic therapy in patients with aSAH admitted to the UMCG. Currently, a prospective trial investigates whether ultra-early tranexamic acid administration prevents rebleeding and subsequently also leads to a better outcome.(34) It is clear that emergency aneurysm repair avoids the possible use of antifibrinolytic therapy. Such an early treatment strategy was already advocated by Phillips et al., reporting that treatment of ruptured intracranial aneurysms ≤24h was associated with improved clinical outcomes compared to delayed treatment.(35) The same conclusion was drawn by Wong et al. in their sub analysis of the Intravenous Magnesium after Aneurysmal Subarachnoid Haemorrhage trial (36) as well as by Sandstrom et al.(37) Oudshoorn et al. made a plea for a delayed treatment strategy, as outcome in their series did not depend on aneurysm repair ≤24h instead of 24-72h.(38) Their study, however, was based on a retrospective chart review of a highly heterogeneous cohort. Moreover, the 24h cut-off point used in their study is highly questionable, as the large majority of rebleedings occurred much earlier. Of interest, in a recently published large retrospective comparative cohort study (n=1224), Park et al. clearly showed that emergency treatment (median time from admission to start of aneurysm repair 3h) was not only associated with a significantly lower rebleeding rate, but also with an improved clinical outcome.(39)

Implications of this study

This study identified strong independent clinical predictors for a rebleeding ≤24h after ictus in a large prospectively kept cohort of aSAH patients. In our opinion, these results should lead to reconsideration of current clinical practice; patients with a high mFisher grade (3 or 4) might benefit from immediate aneurysm repair 24/7, particularly if they are in a relatively good clinical condition (WFNS I-III). This change in treatment paradigm would be in line with recent changes in the treatment of ischemic stroke, in which it has become apparent that immediate endovascular intervention (<6h) is beneficial in a subgroup of patients.(40)

Obviously, these findings provoke the question whether ultra-early treatment with the inevitable avoidance of rebleedings is also associated with improved clinical outcome. Theoretically, a possible disadvantage of an ultra-early treatment strategy, especially when performed at night, might be an increase in treatment-related complications. Although Park et al. recently showed that this is not likely,(39) a randomized controlled trial comparing ultra-early treatment versus conventional treatment would be needed to unequivocally answer this question. Apart from the highly questionable ethical feasibility of such a trial, it is to be expected that prevention of a rebleeding at least improves survival. Strengths and limitations An important strength of this study is the large sample size, which is by far the largest study preformed on this subject. Moreover, this is a highly heterogeneous cohort of patients, notably when compared to the International Subarachnoid Aneurysm Trial (ISAT), with an inclusion percentage of 22%.(18) Furthermore, only early and easy to determine parameters are used in the analyses, not taking laboratory parameters into account, to create a risk profile as soon as possible, which is favourable for early decision making in clinical practice. Some limitations of this study need to be addressed. The analyses of this cohort were retrospectively performed. As a result, not all aforementioned reported predictors for a

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rebleeding could be assessed. This might have influenced the results, as some variables have been associated with a rebleeding in these previous studies. Also, missing imaging at the re-evaluation of the mFisher scale and aneurysm size may theoretically have influenced our results. Though, from a clinical point of view, there is no reason to believe that cases with an unknown mFisher scale and/or aneurysm size differ in any other way from the fully observed data-set. Regarding the generalisability of the conclusions and recommendations, a remark has to be made regarding non-densely populated areas and countries with fewer resources; in such areas it obviously will be very difficult to achieve an ultra-early treatment strategy. Finally, an underestimation of the incidence of an early rebleeding after aSAH is very likely, since a group of patients may already have suffered from a rebleeding before admission to our hospital. Conclusions Rebleeding of the aneurysm occurs in 7% of all SAH patients <72 hours with a peak incidence between 6-12 hours. Riskfactors for rebleeding are a large amount of subarachnoid blood on the initial CT-scan (mFisher grade 3-4), initiation of CSF-drainage and a larger aneurysm size. The NNT with an ultra-early treatment strategy in patients with mFisher grade 3-4 is calculated 15. In view of these results, timing of treatment of aSAH patients, especially those with an mFisher grade of 3 or 4 in a good clinical condition, should be reconsidered. This category of aSAH patients might be regarded as a medical emergency, requiring aneurysm repair as soon as possible, preferably 24/7, to prevent rebleeding. In this respect, these findings should provoke the debate on the best timing of aneurysm repair and subsequent the treatment-guidelines, especially in patients considered at a high risk for rebleeding.

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