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© The European Society of Cardiology 2005. All rights reserved. For Permissions, please e-mail: permissions@oupjournals.org

Heart rate slowing by If inhibition: therapeutic utility from clinical trials

Jeffrey S. Borer*

Division of Cardiovascular Pathophysiology and The Howard Gilman Institute for Valvular Heart Diseases, Weill Medical College of Cornell University, The New York-Presbyterian Hospital—Weill Cornell Medical Center, 47 East 88th Street, New York, NY 10128-1152, USA

* Corresponding author. E-mail address: canadad45{at}aol.com


   Abstract
Top
 Abstract
Introduction
 Ivabradine: results of clinical...
 Conclusions
 References
 
Myocardial ischaemia results from an excess of myocardial oxygen demand in comparison with available supply. Heart rate is a primary determinant of oxygen demand and thus its reduction is a well-accepted strategy for the prevention of angina pectoris, a highly debilitating symptom of coronary artery disease, but does not usually presage imminent myocardial infarction or death. Currently available drugs that reduce heart rate are commonly associated with adverse effects, which may limit their use in many patients. Therefore, it is important to develop additional alternatives with different pharmacological effects. The inward sodium–potassium-mediated If current of sinoatrial node cell membranes (functionally absent elsewhere in the myocardium) modulates sinoatrial diastolic depolarization rate and, thus, heart rate. Heart rate reduction can be achieved by modulating or blocking this current. Ivabradine, a highly selective If current inhibitor, can reduce heart rate by clinically useful decrements at doses that are devoid of other direct cardiovascular effects and generally are well tolerated. The only dose-related adverse effects are visual (phosphenes, stroboscopic effect, and non-typical blurred vision), which occur in 2–15% of patients receiving 2.5–10 mg orally twice daily, usually are no more than mildly bothersome, are fully reversible spontaneously or with cessation of therapy, and are not associated with retinal damage. Clinical trials involving more than 5000 patients indicate that ivabradine as monotherapy is effective in preventing angina. Effects are seen at doses as low as 2.5 mg twice daily. Preliminary data suggest that when employed at 7.5 or 10 mg twice daily, angina prevention with ivabradine is equivalent to that achieved with atenolol 100 mg daily and with amlodipine 10 mg daily.

Key Words: Coronary artery disease • Angina pectoris • Cardiovascular pharmacology


   Introduction
Top
 Abstract
 Introduction
Ivabradine: results of clinical...
 Conclusions
 References
 
Heart rate slowing is universally recognized as a primary strategy for the prevention of angina pectoris, the most common initial manifestation of coronary artery disease in men and women, affecting 30 000–40 000 persons per million in Europe and the United States.1–3 Heart rate slowing directly minimizes myocardial oxygen demand and, experimentally, also enhances myocardial oxygen supply by improving subendocardial blood flow.4,5 Clinical data suggest that heart rate slowing reduces the coronary event risk by minimizing the likelihood of coronary atherosclerotic plaque rupture.6 Moreover, multiple actuarial and other epidemiological studies link heart rate directly to mortality, although the cause specificity of these deaths is not yet known.7–10 The apparent benefits of heart rate slowing for angina are among the primary bases for use of ß-adrenergic antagonists,11 verapamil- and diltiazem-type calcium channel blockers12 and, historically, carotid sinus nerve stimulators.13

Angina can be frightening to the patient, commonly limits capacity for work and recreation, and is a major cause of debility. However, most patients with angina are at relatively low imminent risk of death or myocardial infarction.1,14 Therefore, prevention of angina is a legitimate primary therapeutic objective, achievable with acceptable safety only by preventing ischaemia and its cause.

Myocardial ischaemia results from relative deficiency of myocardial oxygen. In patients with coronary artery disease, inhibition of the If current should be particularly efficacious in mitigating stress-induced ischaemia. Considerable research during the past 25 years indicates that this current is a primary electrophysiological basis of sinoatrial node depolarization,15–17 the frequency of which defines the heart rate. Together with blood pressure, heart rate determines myocardial oxygen demand in any extant myocardial metabolic state. A search for drugs on the basis of If inhibition began with discovery of the current and the hyperpolarization-activated cyclic nucleotide-gated ion channel that underlies this net inward mixed sodium–potassium flux. However, appropriate application of drugs depends on demonstration that clinical benefits can be achieved with acceptable safety for the intended use. For example, in the case of heart rate slowing, reduction in angina may be associated with unacceptable fatigability due to limitation of cardiac output and output reserve, which may outweigh the benefit of angina prevention (and potential improvement in cardiac function due to prevention of ischaemia). Other adverse effects may be related to other pharmacological actions that are not directly related to heart rate slowing. Thus, information needed to support If inhibition for angina prevention can be gained only from appropriately designed clinical trials of a drug manifesting this pharmacological effect.18 Two such drugs have entered late-phase clinical testing. The first was zatebradine,19 which exhibited promising pre-clinical findings but did not achieve angina prevention with the doses employed clinically, despite some heart rate reduction both at rest and during exercise,20,21 perhaps because the dose was limited by unacceptable ocular side effects. If current inhibitors with other molecular structures were then evaluated to seek a more favourable therapeutic to toxic relation. Ivabradine, first reported more than a decade ago,22 evidences unique specificity for the If current and manifests pharmacological properties that compare favourably with those of zatebradine. Pre-clinically, ivabradine causes dose-dependent heart rate slowing with no effect on myocardial contractility,23–26 peripheral vascular resistance, coronary vascular resistance, mean arterial pressure, and myocardial oxygen delivery to myocardial oxygen consumption ratio,22 and, also, minimizes exercise-induced ischaemia and stunning;27 at doses slowing heart rate comparably with the ß-blocker atenolol, ivabradine depresses myocardial relaxation modestly and less than atenolol24 both at rest and during exercise. Pre-clinical data also indicate that ivabradine does not alter the cardiac conduction system28 and does not affect electrocardiographic PR and corrected QT intervals;29 zatebradine, less specific than ivabradine for cyclic nucleotide-gated channels, had been previously shown to cause QTc prolongation, an important risk factor for potentially lethal ventricular arrhythmias, which also had marred research with early selective sinus node blockers.21 Thus, it is reasonable to hope that at clinically relevant doses, ivabradine will be effective and acceptably safe and tolerable. Clinical studies to date have supported this hope.


   Ivabradine: results of clinical trials
Top
 Abstract
 Introduction
 Ivabradine: results of clinical...
Conclusions
 References
 
The clinical development programme of ivabradine for angina prevention has involved more than 5000 patients with coronary artery disease and chronic stable angina,30 the largest anti-anginal drug development effort yet recorded. This population will be supplemented with a similar number now being enrolled in a trial testing the capacity of the drug to reduce mortality and major morbidity among patients with coronary artery disease, prior myocardial infarction, and moderate to severe left ventricular dysfunction and has been supplemented, additionally, with smaller studies of patients with heart failure of various causes.26 However, only one trial in patients with angina, the initial large study assessing the utility of ivabradine as monotherapy, has as yet been published, whereas two others have been recently presented in preliminary form to the European Society of Cardiology (ESC). These will be the basis for this review.

Pivotal clinical trials of ivabradine have maintained active treatment for at least 3 months, the generally accepted minimum duration of studies employed for approval for marketing by legally constituted regulatory authorities.18,31 Exercise tolerance during treadmill or bicycle ergometric testing has been the primary outcome variable employed to assess drug efficacy, consistent with accepted evidentiary standards for such drugs.31 In addition, effect on associated exercise-induced ischaemia has been sought (by analysis of electrocardiographic ST-segment variation) to evaluate the possibility that treatment is ‘masking’ angina by an analgesic effect, which might allow patients to exercise to potentially event-inducing ischaemia without symptomatic warning. In keeping with accepted principles for such testing, drug effects on exercise tolerance have been assessed at the end of the interdose interval (‘trough’), as well as at the time of maximal drug effect (‘peak’). Angina frequency with ambient activity, as recorded in diaries, has also been measured, but is not considered primary evidence of drug effect because the intensity of stress-inducing ambient angina in daily life cannot be determined from diary reports.

Heart rate-slowing effect
In a randomized, double-blinded, multicentre, multinational trial involving 360 patients randomized to placebo or to one of the three doses of ivabradine (2.5, 5, or 10 mg twice daily),32 the drug consistently reduced heart rate at rest and during exercise; the magnitude of this reduction was similar to that expected with therapeutic doses of ß-blocking drugs and greater than usually seen with heart rate-slowing calcium channel blockers, but blood pressure reduction and other functional changes sometimes seen with ß-blockers and calcium channel blockers were absent. The effect was dose-related and was observed across all doses (Figure 1). At the highest dose, 10 mg twice daily, at trough of drug activity, heart rate at rest was almost 15 b.p.m. lower than that when placebo was employed.32 (When later compared directly with the ß-blocker atenolol, heart rate lowering with ivabradine 10 mg twice daily was only modestly less than that with atenolol 100 mg daily.33) Despite substantial heart rate lowering, ivabradine caused little change in blood pressure relative to placebo, and nominally caused modestly less blood pressure lowering than atenolol.



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  		Figure 1 Changes in heart rate at rest (A) and at peak exercise (B) in the different treatment groups during double-blinded dose-ranging of ivabradine. Error bars, standard error of the mean. Asterisk denotes P<0.05 vs. placebo in pairwise comparison. (reprinted from Borer et al.,32 with permission from the American Heart Association, Dallas, TX, USA.)

 
Antianginal efficacy and safety
The initial large clinical trial was performed as a comparison with placebo in the absence of any other chronic (‘background’) therapy. However, an additional placebo-controlled trial was performed with amlodipine as background therapy, and direct comparison has been made with amlodipine and with atenolol, the latter two in trials designed to meet statistical requirements for assessment of comparability (‘non-inferiority’) of the tested regimens. Although presented publicly at satellite symposia of the ESC, the placebo-controlled study on amlodipine background has not yet been published even in abstract form and, therefore, will not be presented here; as noted earlier, only preliminary data from the atenolol and amlodipine comparisons are available. However, in summary, all of these trials support the conclusion of drug efficacy for angina prevention, which can be drawn from the placebo-controlled trial of ivabradine as monotherapy.30

The monotherapy trial was designed to answer several questions: first, does the drug manifest anti-anginal efficacy; secondly, does the effect persist during up to 3.5 months of continual use; and thirdly, after sudden cessation of the drug, do manifestations of ischaemia rebound to intensities greater than those observed before the drug was employed? The study design is indicated in Figure 2. Anti-anginal medications (including ß-blockers, calcium channel blockers, and long-acting nitrates) and drugs that could interfere with ST-segment changes (including class I anti-arrhythmic agents, digitalis, and monoamine oxidase inhibitors) were eliminated during a 2- to 7-day placebo phase (duration depending on half-life; other cardiac and non-cardiac drugs were unaffected by the protocol). An initial bicycle ergometric exercise test was then performed and, during the succeeding week, stability of the test result and capacity for protocol compliance were assessed with single-blind placebo treatment, immediately prior to double-blind randomization to ivabradine or placebo for 2 weeks. With the completion of this parallel arm ‘dose-ranging’ phase, patients were asked voluntarily to enter a 2- or 3-month open-label extension phase (participation was dependent on administrative constraints in participating countries) during which all participants received 10 mg ivabradine twice daily and no other anti-anginal drugs except short-acting nitrates. At the completion of this phase, patients were randomly assigned, in double-blinded fashion, to continue their ivabradine therapy at 10 mg twice daily or to withdraw immediately to placebo, with a final exercise tolerance test performed 1 week after randomization.



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  		Figure 2 Design of the trial of ivabradine as monotherapy. AE, adverse event; CAD, coronary artery disease; ETT, exercise tolerance test; PP, per-protocol population (reprinted from Borer et al.,32 with permission from the American Heart Association, Dallas, TX, USA)

 
During the course of the study, 103 patients withdrew from treatment or violated protocol constraints. Therefore, in addition to analysis of data from the entire cohort (‘intention-to-treat’ population), the 257 ‘per-protocol’ patients were analysed separately and form the core of this review. In this population, time to limiting angina nominally increased more than with placebo at all doses; the comparison reached statistical significance with the maximum dose, 10 mg ivabradine twice daily32 (Figure 3). In addition, across all doses, a dose–effect relation was apparent; a between-group comparison was statistically significant (P=0.049). When protocol violators were included in the analysis (‘intention to treat’), ivabradine remained superior to placebo at trough when 10 mg was administered twice daily, although the difference was less consistent (P=0.058). During open-label extension, approximately three-quarters of patients (including those previously receiving placebo, 2.5 or 5 mg twice daily) increased their dose to 10 mg twice daily. These changes were nominally associated with increased exercise tolerance, to the same level as that observed among the remaining patients who continued to receive 10 mg twice daily (Figure 4). During randomized withdrawal, time to limiting angina fell significantly in patients changed to placebo but did not vary among patients who continued to receive ivabradine 10 mg twice daily (between-group difference: P=0.018).32



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  		Figure 3 Effect of ivabradine, at trough of drug activity, on time to angina sufficient to limit continued bicycle exercise among 257 protocol-compliant patients with coronary artery disease. Measurements were obtained after 2 weeks of double-blind randomized therapy. A dose–response relation is apparent and the dose of 10 mg bid individually is significantly more effective than placebo (reprinted from Borer JS, Advances in heart rate reduction. 2004;1:1–3, with permission).

 


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  		Figure 4 Changes in time to 1 mm ST-segment depression (A) and time to limiting angina (B) measured during exercise tolerance test at trough of drug activity, in ‘per-protocol’ patients continuing in the open-label extension, identified by their treatment group during the double-blinded phase. Data for the ~10% of patients for whom the open-label extension ended after 2 months were pooled with those for whom the extension ended after 3 months (reprinted from Borer et al.,32 with permission from the American Heart Association, Dallas, TX, USA).

 
During the parallel arm phase, exercise-induced ischaemia was significantly mitigated by ivabradine 5 mg twice daily and 10 mg twice daily, as measured by time to 1 mm ST-segment depression. Again, a significant dose–response relation was seen across all doses for this anti-ischaemic effect.32 When compared with pre-treatment values, ambient angina attack rate and nitroglycerin use during routine daily living were also lower on ivabradine at the end of the treatment phase; these secondary effect measures worsened among those randomly withdrawn from placebo at the end of the open-label treatment phase but were unchanged among those who continued treatment.32

Except for visual symptoms, the 2.5- to 3.5-month treatment interval was associated with relatively few adverse events; during the periods of direct comparison, non-visual adverse events generally were similar in frequency and distribution on drug and on placebo. Neither syncope nor untoward hypotension nor heart failure was associated with ivabradine use in the monotherapy trial (or in any of the large clinical trials performed to date). However, phosphenes, stroboscopic effect, and non-typical blurred vision, as a group, were more frequent in patients receiving ivabradine; visual symptoms were dose-related, rarely were sufficiently bothersome to cause voluntary withdrawal of the drug, and invariably were reversible with drug cessation, consistent with the absence of irreversible retinal effects reported in pre-clinical studies. Within the development programme, visual side effects were reported in 2–15% of patients receiving 2.5–10 mg twice daily and led to drug withdrawal in <1% of patients.28 In addition, because the sinoatrial node is the sole target of If inhibiting therapy, patients with sinus node disease (e.g. ‘sick sinus syndrome' or atrial fibrillation) should not receive ivabradine and were excluded from this trial.

Results of the comparison with atenolol supported the inference of ivabradine efficacy drawn from the placebo-controlled trial. In this 4-month double-blind study, 939 patients were randomized, first for 2 weeks, to ivabradine 5 mg twice daily or atenolol 50 mg daily, and then were uptitrated to ivabradine 7.5 or 10 mg twice daily or to atenolol 100 mg daily.33 No statistically significant differences were found when various outcomes were compared among the tested regimens at each stage, and ivabradine's non-inferiority to atenolol was significantly established at the doses employed.33 In doses of either 7.5 or 10 mg twice daily, ivabradine also was non-inferior to amlodipine 10 mg daily.34 In a 3-month randomized, double-blind comparison among 1195 patients with stable angina from coronary artery disease, total exercise duration, time to limiting angina, and time to angina onset were statistically indistinguishable between ivabradine and amlodipine and met the statistical criteria for non-inferiority both at peak and trough of drug effect.

Another randomized, double-blind comparison, involving administration of ivabradine either 5 or 7.5 mg twice daily, was conducted in 386 patients among whom drug administration was continued for 1 year.35 When compared with the pre-treatment values, at the end of study, both doses were associated with a substantial reduction in resting heart rate, consistent in magnitude with that found in earlier studies, and significant reductions in angina attack rate, also consistent in magnitude with prior results. Visual symptoms, like those previously described, were the most frequently reported adverse events, but led to treatment cessation in only 1% of patients. Importantly, no ECG abnormalities were detected in the study, and corrected QT interval was unaffected by ivabradine administration.35


   Conclusions
Top
 Abstract
 Introduction
 Ivabradine: results of clinical...
 Conclusions
References
 
The data from clinical trials, summarized earlier, together with consistent pre-clinical pharmacological information, indicate that If current inhibition, specifically when achieved with the drug ivabradine, is an effective, acceptably safe and tolerable strategy for preventing angina and the underlying ischaemia.

A new drug for angina prevention has particular clinical value when its pharmacological effects differ markedly from those of available agents. Despite increasing popularity of catheter-based coronary angioplasty for symptom relief, drug therapy remains not only viable but also, for most of the world, the primary approach to angina prevention. However, treatment with single or multiple currently available drugs often fails to completely or optimally prevent angina: almost two-thirds of affected patients continue to average two anginal episodes per week despite simultaneous use of multiple currently available anti-anginal drugs.36 A pharmacologically unique agent holds promise for enhancing therapeutic success, while offering a potentially tolerable alternative to patients for whom adverse effects of other drugs limit their applicability. The latter is a particularly important problem. For example, although ß-blockers generally are the first-line drugs of choice for angina prevention, they may increase symptomatic debility from peripheral arterial occlusive disease37 (commonly associated with coronary artery disease), obstructive lung diseases,38 intrinsic atrioventricular node disease,39 and hypotension of non-specific causes while potentially complicating management of metabolic disorders (diabetes mellitus40 or hyperlipidaemia41); their well-known association with impotence in men and depression in both sexes also limits their application. In some patients, atrioventicular node dysfunction, and even congestive heart failure, may be the consequence of administration of certain calcium channel blockers,12 whereas peripheral oedema, gingival hyperplasia, and constipation (a particular problem in the elderly) can result from certain calcium channel blockers. Even long-acting nitrates42 can be intolerable because of associated headaches or lightheadedness (direct results of their beneficial pharmacological effects); intermittent use of nitrates may result in rebound angina and vasoconstriction. If current inhibition does not suppress myocardial inotropy23–26 and, specifically, the previously noted problems associated with other anti-anginals have not been observed with ivabradine. Finally, abrupt cessation of ivabradine does not result in the potentially lethal ‘rebound’ effects reported with short-acting ß-blockers37–43 and is not associated with pharmacological tolerance during prolonged use, a potential problem with long-acting nitrates.44

The effect of heart rate reduction on survival is not known, and currently is under study in a large randomized controlled trial of patients with coronary artery disease and moderate to severe left ventricular dysfunction, as previously noted. However, actuarial and other observational data indicate that survival in large free-living populations is inversely related to heart rate,7–9 an observation that has a parallel among the non-human mammals.45 Consistent with these reports, pharmacological heart rate slowing, specifically mediated by ß-blockade, has been associated with improved survival in clinical trials among patients with heart failure10,46 and after myocardial infarction.10,47 Average heart rate reductions achieved in each of these trials are directly related to average survival enhancement among the trials, whereas drugs causing cardioacceleration have been associated with deleterious outcomes, with magnitude of survival effect again related to magnitude of heart rate effect.

In summary, data from randomized clinical trials, supported by pre-clinical and epidemiological observations, suggest the efficacy and acceptable safety of If current inhibition with ivabradine in managing patients with typical angina pectoris from coronary artery disease. Additional information now is being sought to assess the impact of this approach on the natural history of patients with coronary artery disease.

Conflict of interest: Dr Borer is a consultant to Servier Laboratories.


   References
Top
 Abstract
 Introduction
 Ivabradine: results of clinical...
 Conclusions
 References
 

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Editorial: If inhibition: from pure heart reduction to treatment of stable angina
Eur. Heart J. Suppl., September 1, 2005; 7(suppl_H): H3 - H6.
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