Ivabradine,a novel treatment for clozapine-induced sinus tachycardia: a case series

Abstract

Objectives:

Clozapine is the most efficacious treatment for treatment-resistant schizophrenia; however its use can be limited by intolerability. Sinus tachycardia is a common adverse event associated with clozapine use, which may lead to the premature discontinuation of clozapine. Traditionally, β blockers are used to treat clozapine-associated tachycardia, though problems with intolerability and ineffectiveness can limit their utility.

Methods:

In this article, we present two cases of patients with treatment-resistant schizophrenia who developed symptomatic tachycardia associated with clozapine therapy.

Results:

We demonstrate that the novel heart rate controlling agent ivabradine can be effectively and safely used to control the heart rate and to allow for continued treatment with clozapine.

Conclusion:

This is the first report in the literature demonstrating that ivabradine appears to be a well tolerated agent, which should be considered as a symptomatic treatment of clozapine-induced tachycardia if the use of a β blocker fails due to a lack of response or intolerability.

Clozapine is the most efficacious therapy for treatment-resistant schizophrenia [McEvoy et al. 2006] improving positive and negative symptoms, cognitive deficits [Burton, 2006] and functional outcomes [Wheeler et al. 2009] and reducing the risk of suicide in patients [Meltzer, 2005; Siris, 2001]. Clozapine’s’ exceptional position in the pharmacopeia for treatment-resistant schizophrenia necessitates that adverse events secondary to its usage are minimized and aggressively treated to reduce morbidity and maximize patient adherence, particularly since adverse effects are a frequent reason for clozapine discontinuation [Pai and Vella, 2012; Taylor et al. 2009].

Tachycardia is one of the more common adverse events with clozapine, reported to occur in 25% of patients [Lieberman, 1998; Safferman et al. 1991]. The development of tachycardia is often transient [Young et al. 1998] and may be related to the rapid dose titration of clozapine [Marinkovic et al. 1994; Merrill et al. 2005]. Rapid clozapine titration rates (to 300 mg over 1 week) have been associated with increased pulse rates of 20–25 beats per minute (BPM) above baseline rates [Sandoz, 1987]. Patients with schizophrenia taking clozapine at daily doses of 300–700 mg have been shown to have a significantly higher heart rate (mean 107 ± 3 BPM) than patients treated with haloperidol (mean 86 ± 4 BPM or olanzapine (mean 89 ± 3 BPM) or unmedicated healthy controls (mean 62 ± 12 BPM) [Cohen et al. 2001]. However, for some patients, the tachycardia persists and is symptomatic with palpitations occurring.

The pathophysiology of tachycardia associated with clozapine is thought to involve its direct effects on the autonomic nervous system. These include blockade of cardiac muscarinic M₂ receptors leading to vagal inhibition [Buckley and Sanders, 2000] and of presynaptic α₂ adrenoceptors causing increased sympathetic activity and indirect activation of the β adrenoceptors [Leung et al. 2012]. Sinus tachycardia associated with clozapine use is found in both standing and supine positions and is therefore not merely a homeostatic response to postural hypotension [Leung et al. 2012].

Substantial epidemiological evidence shows resting tachycardia to be a risk factor for coronary artery disease and cardiovascular morbidity and mortality [Borer, 2008; Diaz et al. 2005; Kannel et al. 1987]. An ongoing resting tachycardia is also recognized as a risk factor for cardiomyopathy [Shinbane et al. 1997]. The need to minimize adverse effects in relation to clozapine use and to reduce the risk of cardiovascular morbidity are pertinent reasons to reduce the resting heart rate. Traditionally β blockers are used to reduce the heart rate by dampening sympathetic hyperactivity [Stryjer et al. 2009], with a retrospective study indicating that 75% of patients treated with clozapine respond to β blockers [Stryjer et al. 2009] .

Cardio-selective β blockers (with a much higher affinity for β₁ receptors, e.g. bisoprolol, atenolol, metoprolol) are usually preferred for treating clozapine-induced tachycardia. However, β blockers are ineffective in some patients and there may be problems associated with their use, such as hypotension, bronchospasm and unwanted side effects [Ko et al. 2002; Ramahi, 2000].

Ivabradine is a novel class of cardiac drug which regulates heart rate through selective and specific inhibition of the I_f current across the cardiac pacemaker [Brown et al. 1979], hence inhibiting spontaneous depolarization in the sinus node [DiFrancesco, 2006]. Ivabradine can be used in the management of stable angina [Sulfi and Timmis, 2006; Tardif et al. 2005], cardiac failure [Fox et al. 2008; Swedberg et al. 2010] and inappropriate sinus tachycardia [Ptaszynski et al. 2013; Wichterle, 2013]. The selective action of ivabradine on the sinus node ensures that the heart rate is exclusively lowered without directly affecting other aspects of cardiac function such as arterial vascular tone (thus avoiding hypotension) [Ferrari, 2009; Speranza et al. 2012] and myocardial contractility [Camm and Lau, 2003; Ragueneau et al. 1998]. It is generally well tolerated, with treatment withdrawal from randomized controlled trials due to symptomatic bradycardia reported in only 1–3% of patients [Borer et al. 2003; Fox et al. 2008]. An uncommon side effect of ivabradine is the occurrence of visual phosphenes in 1–2% of patients, a phenomenon which is thought to be related to its action on I_H retinal channels [Swedberg et al. 2010; Tardif, 2005]. Contraindications to its use include the following: a resting heart rate below 60 BPM in angina; a resting heart rate below 75 BPM in cardiac failure; acute heart failure; acute myocardial infarction; unstable angina [BNF, 2013].

We present details of two patients with treatment-resistant schizophrenia who were prescribed ivabradine for persisting tachycardia induced by clozapine. The patients were treated with clozapine at varying doses. The objective of compiling these case reports is to report the effectiveness and tolerability of ivabradine for clozapine-induced tachycardia.

Informed consent was obtained from the patients and families if appropriate.

Case report 1

A 34-year-old white British man with a 12-year history of treatment-resistant psychosis had been commenced on clozapine titrated to a dose of 400 mg twice daily. However, clozapine was discontinued after a period of 4 months due to persistent tachycardia despite the use of bisoprolol (10 mg daily dosage). This tachycardia was reported to have been present prior to the initiation of clozapine but was exacerbated upon its use. An echocardiogram conducted during the clozapine treatment and after the onset of the tachycardia demonstrated a non-dilated left ventricle with mild global systolic dysfunction. There was no valvular abnormality. The patient had multiple vascular risk factors, including obesity, an abnormal lipid profile (total cholesterol 6.4 mmol/liter, low-density lipoprotein cholesterol 3.9 mmol/liter, high-density lipoprotein cholesterol 0.8 mmol/liter and triglyceride 2.2 mmol/liter) and smoking (a 15-pack-year history). There was no evidence of impaired glucose metabolism (haemoglobin A1c 5.6%/fasting serum glucose 5.5 mmol/liter).

The patient continued to display a treatment-resistant illness course, leading to the recommencement of clozapine. Cardiac investigations were repeated prior to clozapine rechallenge. A resting electrocardiogram (ECG) showed a sinus tachycardia (105 BPM). The mean resting pulse rate in the fortnight prior to clozapine treatment was 108 BPM. Echocardiogram prior to clozapine rechallenge was normal. A 24 h ECG demonstrated sinus rhythm throughout the entire 24 h period, with a predominant sinus tachycardia during the day that settled at night (mean heart rate 76 BPM, range 50–152 BPM).

To manage the expected symptomatic tachycardia upon clozapine initiation, bisoprolol was recommenced prior to the clozapine rechallenge and increased to 2.5 mg twice daily. The mean pulse rate (by serial clinical measures) following this increase was 97 BPM (decreased from a mean pulse rate of 105 BPM) and his mean blood pressure was 111/73 mmHg (decreased from a mean blood pressure of 122/79 mmHg). The patient was then recommenced on clozapine with a slow titration regimen, rising to a dose of 300 mg daily over a 28-day period, during which time he was also treated with a reducing dose of risperidone. Risperidone had been prescribed for 2 months without any reported adverse cardiovascular events.

Due to a symptomatic tachycardia (palpitations) of up to 130 BPM, during initial titration (which began over week 2 and 3 of the clozapine titration), bisoprolol was further increased to 6.25 mg daily, in divided doses. Subsequent to this dose increase, symptomatic hypotension became prominent, with pronounced dizziness described by the patient. A mean pulse rate of 104 BPM was recorded at this stage, with a mean blood pressure of 99/66 mmHg, with a postural drop in systolic blood pressure of over 10 mmHg. This hypotensive picture remained persistent at 6 weeks after the commencement of clozapine, when a dose of 300 mg daily (serum clozapine level 0.30 mg/liter) was being utilized. Full blood count (FBC), urea and electrolytes, thyroid function tests (TFTs), C-reactive protein (CRP) and troponin T were all reported as normal. A 24 h urinary-free cortisol was normal, but 24 h urinary-free noradrenaline was elevated at 838 nmol (normal <570), as was a 24 h adrenaline 118 nmol (<100), with a normal 24 h urine dopamine of 2431 nmol (<2500). The patient refused a repeat 24 h urinary collection, but random urinary free catecholamines and normetanephrines were normal on repeated collections.

A cardiology consultation was sought due to the symptomatic tachycardia, the hypotension and the intolerability of bisoprolol. Subsequently, the patient was commenced on ivabradine (5 mg twice daily and uptitrated to 7.5 mg twice daily). Bisoprolol was discontinued prior to starting ivabradine. Within 4 weeks of starting ivabradine, mean blood pressure was 113/76 mmHg and mean pulse rate was 96 BPM. An ECG showed a normal sinus rhythm (at 93 BPM) with no conduction abnormalities. The symptoms of dizziness resolved and the ivabradine was well tolerated without any reported adverse effects. Ivabradine has continued for 8 months without any adverse events, maintaining a pulse rate in the range of 85–95 BPM, and remaining normotensive (mean 120/75 mmHg), on a maintenance dose of 600 mg daily of clozapine (serum clozapine level 0.55 mg/liter).

Case report 2

A 28-year-old British Asian gentleman with a 3-year history of treatment-resistant schizophrenia and persisting positive symptoms of schizophrenia, namely prominent auditory and visual hallucinations, previously had to discontinue clozapine due to intolerable sedation. The patient was recommenced on clozapine and it was increased at a slow titration rate to 250 mg daily. He was treated concurrently with fluoxetine 40 mg once daily and a reducing dose of asenapine (reduced from 10 mg twice daily) during the clozapine titration period (asenapine had been commenced 4 months previously, with no cardiac adverse effects). He developed a sustained tachycardia (from week 2 of the clozapine titration onwards) during treatment with clozapine which persisted beyond the titration period of 4 weeks. He was symptomatic with palpitations. He remained on fluoxetine concurrent to clozapine therapy. Over the course of the treatment with clozapine, his pulse rate increased from a mean of 80 BPM (at baseline) to a mean rate of 120 BPM (at week 8, post clozapine commencement), while on a maintenance dose of 250 mg of clozapine (serum clozapine level 0.37 mg/liter). His blood pressure fell from 120/80 mmHg at baseline to 100/60 mmHg during the same period. Although the patient reported dizziness on standing, no orthostatic hypotension was found.

There was no significant medical history. He was a nonsmoker with no cardiac risk factors identified in his history; specifically there was no evidence of dyslipidaemia, impaired glucose tolerance, truncal obesity or hypertension. Besides palpitations, a review of systems was negative for fever, dyspnoea on exertion, chest pain and general malaise. His physical examination was positive for tachycardia only. His thyroid function remained normal and the full blood chemistry profile, FBC, CRP and troponin T were normal. His ECG showed a sinus tachycardia (rate 115 BPM) with no evidence of abnormalities of ventricular repolarization, such as T-wave abnormalities or QT_c prolongation (QT_c interval 425 ms).

Due to the reduction in blood pressure which the patient experienced on clozapine, treatment with a β blocker was contraindicated. Ivabradine was commenced at 5 mg twice daily. Within 1 week of treatment his resting heart rate had reduced to a mean of 92 BPM, and he no longer complained of palpitations. There were no adverse effects encountered with ivabradine therapy and the patient remained on 5 mg ivabradine twice daily for 12 months, with a sustained normal pulse rate (mean 88 BPM) and remaining normotensive (mean blood pressure 120/72 mm/Hg). The ivabradine was discontinued at 1 year from its commencement. This was well tolerated by the patient, with no evidence of a recurring sinus tachycardia 5 months after discontinuation of ivabradine.

Discussion

To the best of our knowledge, this is the first description within the literature of the use of ivabradine for clozapine-induced tachycardia. Ivabradine is an alternative, selective heart rate lowering agent, without the adverse side effects of β blockers, notably hypotension [Manz et al. 2003; Riccioni, 2011; Rosano et al. 2010].

In the assessment and management of sinus tachycardia occurring with clozapine treatment, the primary focus is to identify the cause and treat it effectively. Pathological causes of a sinus tachycardia should be excluded, with specific attention in clozapine use paid to infective processes and an evaluation for myocarditis [Ronaldson et al. 2011]. A persisting sinus tachycardia of greater than 120 BPM or a change in pulse rate greater than 30 BPM from baseline have been identified as risk markers for myocarditis, specifically during dose titration with clozapine [Ronaldson et al. 2011]. Their occurrence should lead to close observation for signs or symptoms of myocarditis, such as influenza-like symptoms, fever, chest pain, palpitations, syncope, dyspnoea, diarrhoea, vomiting or nausea. This should be accompanied by the performance of an ECG recording and serum CRP and troponin T measurements to optimize monitoring for myocarditis.

Other causes of a tachycardia should also be excluded, such as hypovolaemia, pulmonary emboli, thyrotoxicosis and phaeochromocytoma, concurrently prescribed medications (e.g. salbutamol) and the use of or withdrawal from alcohol or illicit drug use [Blomstrom-Lundqvist et al. 2003].

The rate of clozapine titration may be slowed and serial measurements of pulse rate be sought to monitor for any change in the heart rate in response to a reduction in the dose of clozapine or a slowed titration rate [Young et al. 1998]. A tolerance to clozapine-induced tachycardia may develop over 4–6 weeks of treatment [Marinkovic et al. 1994] and clinicians should remain cognizant of this before considering the use of medication for asymptomatic tachycardia.

Currently no drugs are licensed for the treatment of clozapine-induced tachycardia and no approach has been adequately investigated within randomized trials. Traditionally the treatment intervention for the management of persisting or symptomatic clozapine-associated sinus tachycardia has been the use of β blockers [Lieberman et al. 1989; Safferman et al. 1991]. This recommendation has persisted over the past 30 years without there being well designed prospective studies to document their effectiveness and tolerability. We would suggest that bisoprolol as a cardioselective β blocker be considered as a first-line treatment for sustained or symptomatic clozapine-induced sinus tachycardia due to it being cardioselective and a nonvasodilating agent, with a lower propensity for central nervous system effects, metabolic dysregulation and bronchoconstriction. However, the risk of exacerbation of any clozapine-associated hypotension remains and may limit its tolerability.

In these cases, ivabradine has demonstrated a sustained reduction in heart rate to normal ranges without any adverse events, such as hypotension or bradycardia. Ivabradine would appear to be a well tolerated agent which should be considered for symptomatic treatment of clozapine-induced tachycardia if the use of a β blocker fails due to a lack of a response or intolerability. Ivabradine should only be commenced following a cardiology consultation. It is generally commenced at a dose of 5 mg twice daily for angina and heart failure, with recommendations that it can be increased to a licensed maximum dose of 7.5 mg twice daily after a further 2 weeks [BNF, 2013]. A similar dose strategy could be pursued in the treatment of clozapine-induced tachycardia.

Conclusion

This is the first report in the literature suggesting that the use of ivabradine in clozapine-associated tachycardia is effective and well tolerated. It might represent a useful alternative treatment option for patients who are intolerant to β blockers. There is a need for pragmatic randomized controlled trials to evaluate treatments for clozapine-induced tachycardia in clinical practice. The cases presented here indicate that ivabradine should be considered in any such trial to assess efficacy, adverse events and patient satisfaction of various agents used to treat clozapine-induced tachycardia.