Europace (2013) 15, 116-121 CLINICAL RESEARCH society of do¡:i 0.1093/europace/eus204 Syncope and implantable loop recorders

Metoprolol succinate vs. ivabradine in the treatment of inappropriate sinus tachycardia in patients unresponsive to previous pharmacological therapy Pawel Ptaszynski1*, Krzysztof Kaczmarek1, Jan Ruta1, Thomas Klingenheben2, and Jerzy K. Wranicz1

1 Department of Electrocardiology, Medical University Lodz, Regional Sterling Heart Disease Center, Sterling 1/3, 91-425, Lodz, Poland; and 2Cardiology Practice Bonn, Bonn,

Germany

Received 12 March 2012; accepted after revision 30 May 2012; online publish-ahead-of-print 6 July 2012

Aims Inappropriate sinus tachycardia (IST) is a clinical syndrome characterized by excessive resting heart rate (HR) or

disproportional increasing HR during exercise. The treatment of IST symptoms using beta-blockers or calcium

channel-blockers is often non-effective or not well tolerated. Ivabradine is a new agent inhibiting sinus node If

current, resulting in a decrease of HR without haemodynamic compromise.

Methods We enrolled 20 patients (36 + 10 years; 14 women) affected by IST and resistant to previous administered therapy

and results by using beta-blockers or verapamil. After 4 weeks of treatment with metoprolol succinate (up to 190 mg once a day)

the therapy was switched to ivabradine up to 7.5 mg twice daily. Holter monitoring and treadmill stress test were

performed after 1 and 2 months following start of the study. We observed a significant reduction of resting HR

both for metoprolol and for ivabradine compared with baseline (92.8 vs. 90.2 vs. 114.3 b.p.m.; P < 0.001). During

daily activity there was an even larger decrease of HR on ivabradine (mean daytime HR 94.6 vs. 87.1 vs.

107.3 b.p.m.; P < 0.001). Ivabradine was very well tolerated whereas in 10 patients on metoprolol we observed hypo­

tension or bradycardia requiring dose reduction. Significantly lower incidence of IST-related symptoms were regis­

tered on ivabradine therapy than on metoprolol. Fourteen patients (70%) treated with If blocker were free of

IST-related complaints.

Conclusions Metoprolol and ivabradine exert a similar effect on resting HR in patients with IST. Ivabradine seems to be more

effective to relieve symptoms during exercise or daily activity.

Keywords Inappropriate sinus tachycardia • Heart rate • Metoprolol • Ivabradine

Introduction Inappropriate sinus tachycardia (IST) is a relatively uncommon dis­

order characterized by persistent increase in resting sinus rate or

disproportionate elevation of heart rate (HR) with minimal exer­

tion.1 The most prominent clinical symptoms are palpitation, dizzi­

ness, chest discomfort, orthostatic intolerance, and fatigue.2-5 In

some cases the symptoms can be severe and debilitating. The aeti­

ology of 1ST is not well understood. Autonomic dysfunction,

abnormal automaticity of the sinus node, and atrial focal tachycar­

dia originating near the sinus node have been proposed to be

underlying mechanisms.2'3'6- The syndrome is associated neither

with structural heart disease nor with any reversible causes of

sinus tachycardia (i.e. fever, anaemia, infection, hyperthyroidism,

drug abuse). Therefore, the diagnosis is generally one of exclusion.

Beta-blockers are most frequently used as first-line therapy.

Other potentially effective drugs are non-dihydropyridine

calcium antagonists or amiodarone. The limitation of these

* Corresponding author. Tel: +48 42 6644 304; fax: +48 42 6644269, Email: pawel_ptaszynski@wp.pl

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2012. For permissions please email: journals.permissions@oup.com.

Metoprolol vs. ivabradine in 1ST 117

What's new? • This is the first prospective study comparing the effect of

ivabradine therapy with metoprolol succinate in patients

with IST.

• We adapted the EHRA score for symptoms assessment in

patients with IST.

• The results of the present study indicate that orally adminis­

tered ivabradine is effective and safe in rate control in

patients with IST, especially as a second-line therapy in

cases of lack of efficacy or intolerance of beta-blockers

(metoprolol).

Table I Patient characteristics*

pharmacological approaches is their relatively small effectiveness,

intolerance, or side-effects of the respective drugs.2'5'9 Non-

pharmacological interventions such as sinus node modification by

means of catheter ablation have been tried but are limited by

their lack of efficacy or significant incidence of complications.5,9-13

Ivabradine is a specific inhibitor of the If current in the sinoatrial

node that induces HR reduction without influence on intraventri­

cular conduction, contractility, or haemodynamics. The effect of lf current blockade is dependent on dose and baseline HR.14 The ex­

pression of If in the sinoatrial node makes ivabradine a promising

treatment option in patients with IST. Several studies with clinical

follow-up15-18 and a number of case reports19-24 have suggested

that ivabradine administration is a safe and effective second-line

therapy in patient affected by IST.

The aim of this study was to evaluate the safety and efficacy of

ivabradine in comparison with conventional therapy with metopro­

lol in patients with IST.

Methods

Patient population The study population consisted of consecutive patients who were re­ferred to the arrhythmia outpatient clinic because of high symptomatic, persistent sinus tachycardia. Previous antiarrhythmic treatment was discontinued for at least 4 weeks. Subsequently, all patients were screened for IST. Those with a confirmed diagnosis of IST, defined as sinus tachycardia at rest (HR > 100 b.p.m.) in sitting position or/ and as an average HR > 90 b.p.m. during 24 h Holter monitoring, were considered to participate in the present study.3 There were 14 women and 6 men (mean age 37 + 18 years). The patients suffered mainly from palpitation (n = 20; 100%), dyspnoea (n = 8; 40%) physic­al stress intolerance (n = 12; 60%), or chest discomfort (n = 8; 40%). No patients had a history of orthostatic intolerance or postural ortho­static tachycardia. Secondary causes of tachycardia and structural heart disease had been excluded through careful examination or additional tests (blood samples, echocardiography).

None but two patients were on concomitant cardiovascular medica­tion (ramipril) due to a history of hypertension. All patients had irregu­larly been pretreated with beta-blockers or verapamil prior to the study, without clinical effect or poor tolerance. However, no patient had previously received the slow releasing form of metoprolol—meto­

prolol succinate. The patient characteristics are depicted in Table 1.

No. of patients 20

Age (years) 36 ±10

Female gender 14 (70%)

Concomitant diseases

Hypertension 2 (10%)

Presenting symptoms

Palpitations 20 (100%)

Exercise intolerance 12 (60%)

Dyspnoea 8 (40%)

Dizziness 8 (40%)

Chest discomfort 4 (20%)

Pre-syncope 4 (20%)

Pre-treatment therapy and mean maximal daily dosage

Metoprolol (tartrate) 8 (40%) 106 + 37 mg

Bisoprolol 2 (10%) 10 + 0 mg

Nadolol 1 (5%) 10 mg

Verapamil 9 (45%) 230 + 76 mg

ACE inhibitors 2 (10%) 5 ± 0 mg

^Values are given as n (%) and mean ± SD.

Patients gave informed consent prior to enrolment in the study. The study protocol has been approved by the local ethics committee.

Study protocol All patients fulfilling clinical and baseline Holter criteria for IST diagnosis—as depicted above—were included in the study. In all patients, previous antiarrhythmic and/or rate control medication for IST had to be discontinued 4 weeks prior to entry into the first treat­ment phase of the study.

During the first 4 weeks of the study the patients received metopro­lol succinate 47.5 mg in the morning, up to 190 mg once a day (OD). After 4 weeks of treatment with metoprolol the therapy was switched to ivabradine without interruption. Initially, we administered ivabradine 5 mg twice daily (BID), up to 7.5 mg BID if well tolerated. In the absence of side-effects the dose of drugs was augmented after every 7 days of therapy to the maximal dose level. Patients were evaluated at baseline and after the end of each treatment periods. During the visits resting electrocardiogram (ECG) and 24 h Holter monitoring (Medilog Darwin, Schiller AG, Switzerland) were recorded. The fol­lowing parameters were calculated from ECG recordings; resting HR, mean HR, maximum HR, daytime mean HR (defined as a mean HR between 6.00 am and 10.00 pm). From Holter monitoring we obtained also the number of events triggered by patients as IST -related symptoms (palpitations, dizziness, fatigue, etc.).

Additionally, in order to assess physical activity, treadmill exercise tests were performed. The patients underwent fatigue-limited stress tests by using the standard Bruce protocol (GE Marquette CASE T2100, Great Britain) at baseline and after 4 weeks of each drug therapy. We recorded the maximal workload expressed in metabolic equivalent of task (MET) and total duration of test after both treatment phases. Although exercise capacity may somewhat improve with learn­ing during the time course of a treatment study, we decided to use treadmill exercise testing since it is an objective measure in routine clinical practice.

118 P. Ptaszynski et al.

140 i 140

Baseline Metoprolol Baseline Ivabradine

Figure I Resting heart rate during metoprolol or ivabradine administration in comparison with baseline. Red line represents mean heart rate (P < 0.001 for both therapies).

Subjective perception of symptoms in patients affected by IST was assessed by European Heart Rhythm Association (EHRA) score. The EHRA score was previously developed and widely accepted as a useful tool to describe symptoms of atrial fibrillation, very similar to IST-related symptoms.25 The following items during presumed arrhyth­mias episodes were checked to determine the score: palpitation, exer­cise tolerance, dyspnoea, dizziness, chest discomfort, and pre-syncope. The symptoms severity was classified as EHRA I—'no symptoms', EHRA II—'mild symptoms', EHRA III—'severe symptoms', and EHRA IV—'disabling symptoms'.

Statistics Statistical analysis was performed using Statistica software (version 9.0, StatSoft, Inc., Tulsa, OK, USA). Continuous variables are expressed as mean + standard deviation (SD), and categorical variables are pre­sented as frequency (%). As not all analysed data had normal distribu­tion (Shapiro-Wilk W test), the non-parametric analysis of variance Friedman test were used for multiple group comparison with subse­quently non-parametric post hoc test. The significance of the relation­ship between the categorical variables were tested with x Pearson and its modifications for 2 x 2 tables (Yates Correction and Fisher's exact test). Values of P < 0.05 were considered statistically significant.

p<0,001

p<0,C01

Baseline Metoprolol Ivabradine

Figure 2 Mean heart rate during 24 h Holter monitoring in patients treated with metoprolol or ivabradine vs. baseline. Results shown as mean + SD. For the multiple comparison P< 0.001.

Results The maximal daily dose was achieved in 10 (50%) patients treated

with metoprolol and in all (100%) patients on ivabradine (P<

0.001). The mean dose of metoprolol was 157 + 38 mg. We

observed significant and similar reduction of resting HR for both

metoprolol and ivabradine when compared with baseline (92.8

vs. 90.2 vs. 114.3 b.p.m.; P < 0.001) (Figure 1). The value of HR re­

duction did not depend on baseline HR. The mean HR in Holter

monitoring was significantly lower in patients treated with ivabra­

dine or metoprolol in comparison with baseline (78.8 + 8 vs.

80.9 + 7 vs. 99.7 + 7 b.p.m.; P < 0.001) (Figure 2). The maximal

HR during monitoring was 151 + 14 b.p.m. at pre-treatment

period, 125.6 + 18 b.p.m. on ivabradine, and 131.6 + 19 b.p.m.

on metoprolol (P < 0.001). During daily activity the HR reduction

on ivabradine was higher than for metoprolol therapy (mean

daytime HR 87.1 + 5 vs. 94.6 + 4 b.p.m.; P< 0.001) (Figure 3).

A significant effect of ivabradine administration on exercise cap­

acity was observed during treadmill-stress test. The maximal

dose of exertion was 10.6 + 1.2 METs at baseline, 13.5 + 0.9

METs during ivabradine therapy, and 12.03 + 1.1 METs on meto­

prolol (P < 0.001). The maximal duration of exercise was longer in

patients on ivabradine therapy compared to baseline and to treat­

ment with metoprolol (680.2 + 52.2 vs. 529.3 + 69.7 vs. 630.5 +

65.2 s; P< 0.001). The analysis of events reported by patients

during 24 h Holter monitoring revealed significant reduction of

symptoms associated with IST for both drugs. For ivabradine this

effect was significantly better than for metoprolol (mean events

6 + 3 vs. 14 + 3; P < 0.05) when compared with baseline

(mean 18 + 5).

Metoprolol vs. ivabradine in 1ST 119

125

120

115

110

S g 105

E ¡B 100

H ai cû

p<0,001

p<0,001 p<0,001

107.3

94.6 _

87.1

Baseline Metoprolol Ivabradine

Figure 3 Daytime mean heart rate on metoprolol or ivabra­dine therapy comparing to baseline. Results shown as mean + SD. For the multiple comparison P < 0.001.

Table 2 European Heart Rhythm Association score for

assessment of inappropriate sinus tachycardia-related

symptoms

No. of patients: 20

Baseline Metoprolol Ivabradine

EHRA I 0(0%) 9 (45%) 14 (70%)

EHRA II 8 (40%) 9 (45%) 6 (30%)

EHRA IIIa 10 (50%) 2 (10%) 0 (0%)

EHRA IVa 2 (10%) 0 (0%) 0(0%)

Definition of EHRA score—see Methods section; for whole multiceli table

comparison x2 = 28.9; df = 6; P < 0.001; baseline vs. metoprolol P < 0.001;

baseline vs. ivabradine P < 0.001 ; metoprolol vs. ivabradine P > 0.05; P = 0.16. aEHRA l-ll vs. EHRA III—IV; for whole multiceli table comparison x2 — 19.9;

df = 2; P < 0.001 ; baseline vs. metoprolol P < 0.001 ; baseline vs. ivabradine

P < 0.001; metoprolol vs. ivabradine P > 0.05; P = 0.47.

Using EHRA score we revealed significant reduction of

IST-related symptoms for both drugs. However, in the ivabradine

group no patient reported symptoms severity as 'severe' or 'disab­

ling'. Fourteen patients (70%) treated with If blocker were free of

IST-related complaints (Table 2).

We did not observe side-effects such as visual disturbances or

severe bradycardia during ivabradine therapy even on maximal

dose. In five (25%) patients treated with metoprolol asymptomatic

periods of sinus bradycardia (40-50 b.p.m.) were observed during

night hours. Hypotension on metoprolol occurred in six (30%)

patients requiring a reduction of drug dose.

Discussion Inappropriate sinus tachycardia is characterized by persistently

increased HR with sinus P-waves in the ECG, and an exaggerated

response to minimal physical effort or stress.2 Using 24 h Holter

5,9

definition the average HR in patients with IST should be

>90 b.p.m. or daytime HR > 100 b.p.m.3 Inappropriate sinus

tachycardia is usually present in young women. Symptoms

reported by patients vary in frequency and severity. Main com­

plaints associated with IST include palpitations, dyspnoea, fatigue,

and exercise intolerance. A nocturnal dip in HR is usually

present. The diagnosis is confirmed by exclusion of all other

causes of sinus tachycardia related to primary diseases and affec­

tions.3-5,9 Treatment options in patients with IST are limited.

Initial pharmacological therapy is empiric and usually includes beta-

blockers. In cases of intolerance non-dihydropyridine calcium

channel blockers are considered as a second-line therapy.

Some patients do not respond to pharmacological therapy or

may suffer from non-tolerable side-effects (hypotension, transient

bradycardia). Ablation or modification of the sinus node is an

option of invasive treatment in subgroups of symptomatic patients

with IST. However, there are no series evaluating the efficacy and

safety of such therapy. The risk of severe bradycardia requiring

pacemaker implantation limits the usefulness of this strategy.10-13

In such circumstances a new selective inhibitor of If channels is

considered as an attractive alternative for patients with 1ST.14

The benefit of ivabradine therapy for HR control has been recently

confirmed in patients with stable angina pectoris26 and in patients

with heart failure.27

Some case reports have described the benefit of ivabradine in

patients with drug refractory, high symptomatic 1ST.19-23 The

authors showed that /^channel blockers are a safe and effective treat­

ment option in such group of patients. In a first observational study,

Rakovec et oí.15 presented results of ivabradine therapy in 13 con­

secutive patients with IST. Ivabradine was taken by patients 15 mg

per day over 2 weeks. After this period a 24 h Holter ECG was per­

formed. They observed significant decrease of HR on ivabradine

compared with baseline (19.4 ± 6.7 b.p.m.). A recently published

study of Calò et al.16 showed significant reduction of medium HR

and maximal HR (assessed through 24 h ECG) after 3-6-month

treatment with ivabradine in patients affected by 1ST. Also the

study revealed an increased tolerance to physical stress, which was

confirmed during exercise tests at the third and sixth months of

oral administration of ivabradine. No patientshowed significant side-

effects of ivabradine and the dose of 10 mg was sufficient to signifi­

cantly reduce daytime HR and symptoms. Noteworthy, the

minimal Holter HR stabilized after 3-month follow-up, despite an in­

crease in drug dose without episodes of bradycardia.

The present prospectively designed study yields important find­

ings with respect to the clinical applicability of ivabradine treatment

to patients with resistant IST. It demonstrates that oral administra­

tion of ivabradine reduced resting HR similar to beta-blockers after

4 weeks of therapy. To our knowledge this is the first study com­

paring ivabradine with metoprolol in symptomatic patients with

IST. During daily activity ivabradine showed higher reduction of

HR compared with metoprolol therapy. In our study, the magni­

tude of HR reduction did not depend on baseline HR. This phe­

nomenon was reported in previous studies and is explained by

special ivabradine acting properties on currents and channels in

pacemaker cells.11 Probably, in patients affected by IST the effect

of ivabradine on HR is significantly modified by autonomic

imbalance.