The place of ivabradine in the management of patients with CAD: new insights



by P. G. Steg and G. Ducrocq, France

Philippe Gabriel STEG, MD
Gregory DUCROCQ, MD
Centre Hospitalier Bichat- Claude Bernard, Assistance Publique, Hôpitaux de Paris
Université Paris 7 – Paris, FRANCE

Is heart rate optimally controlled in patients with coronary artery disease in clinical practice?

Coronary artery disease remains a major global public health problem. Treatment includes drugs to control anginal symptoms and myocardial ischemia, and treatment to improve clinical outcomes. The latter includes not only recommended lifestyle changes and drugs to control risk factors, but also a series of drugs with established efficacy in preventing adverse cardiac outcomes, such as antithrombotic agents, statins, renin-angiotensin system blockers, and β-blockers. Ivabradine is a specific inhibitor of the If current, whose action produces selective heart rate reduction in patients with elevated heart rate, without adverse hemodynamic side effects. It has established efficacy in preventing or limiting anginal symptoms and myocardial ischemia, and in head to head comparisons, yields comparable efficacy to that of atenolol on exercise-induced ischemia. A recent trial, ASSOCIATE (evaluation of the Antianginal efficacy and Safety of the aSsociation Of the If Current Inhibitor ivAbradine with a beTa-blockEr), demonstrated that when added to chronic treatment with β-blockers, ivabradine further reduces heart rate and improves exercise capacity while being well tolerated. Ivabradine has also now been tested in a large outcome trial, BEAUTIFUL (morBidity mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction), in patients with stable coronary artery disease and left ventricular dysfunction. While it did not affect the primary composite end point of cardiovascular death and hospitalization for acute myocardial infarction or heart failure, it did, in a prespecified subset analysis, reduce coronary events in patients with a baseline heart rate

Medicographia. 2009;31:371-376 (see French abstract on page 376)

Coronary artery disease is a major public health problem worldwide

Cardiovascular disease is currently, and is anticipated to remain in the next 10 years, the leading cause of mortality worldwide. Despite a continuous decline in industrialized countries, a genuine epidemic of cardiovascular mortality is affecting low and middle-income countries worldwide, due to major epidemiologic transition in these countries that is related to westernization of lifestyle, with increased smoking, diabetes, and obesity. Even today, cardiovascular disease is the single most frequent cause of death in these countries.1 Among cardiovascular diseases, coronary artery disease (CAD) is itself the most frequent cause of mortality and morbidity. Just as an example of the public health burden associated with CAD, it is estimated that in the USA alone, every 26 seconds somebody will suffer from an acute coronary event, and every minute someone will die from one.2 Even among patients with stable CAD receiving modern therapy for secondary prevention, the rate of major adverse cardiac events remains high: data from the recent REduction of Atherothrombosis for Continued Health (REACH) registry have shown that the yearly rate of cardiovascular death, myocardial infarction, and stroke is approximately 4.5%, and that an additional 10% of these patients require hospitalization for cardiovascular reasons every year.3

Treatment for coronary artery disease

_ General therapeutic measures
Modern therapy for patients with CAD aims to control anginal symptoms, thereby improving exercise capacity and quality of life. But it also aims to prevent adverse cardiovascular events and improve outcomes. Such treatment includes lifestyle modifications (encouraging patients to quit smoking, to be physically active, and to maintain a healthy diet and a normal body mass index) and drug treatments to control risk factors such as hypertension, dyslipidemia, and diabetes.4,5

_ Treatment to improve clinical outcomes
In addition to strict control of risk factors, four categories of agents have established benefits on clinical outcomes in the treatment of patients with CAD: antiplatelet agents (such as aspirin or thienopyridines), statins, angiotensin-converting enzyme (ACE) inhibitors (and angiotensin receptor blockers after acute myocardial infarction), and, to a lesser extent, â-blockers, which have been shown, beyond their ability to prevent anginal symptoms and minimize myocardial ischemia, to impact favorably on clinical outcomes after acute myocardial infarction.6

_Treatment to control anginal symptoms and prevent myocardial ischemia
There are a host of pharmacologic agents that have been demonstrated to exert antianginal effects and either prevent or delay the occurrence of anginal symptoms on exertion. In addition to β-blockers, calcium channel blockers, long-acting nitrates, potassium channel agonists, metabolic agents (such as trimetazidine and ranolazine), and ivabradine all have established efficacy against angina (usually measured by the number of anginal attacks or the use of rapid acting nitrate preparations) and myocardial ischemia (generally reflected by duration of exercise without either ST-segment depression or anginal symptoms on a stress test). However, despite such efficacy, most of these agents have little demonstrated effectiveness in preventing adverse cardiovascular outcomes.

Nicorandil is one of the few agents that has been tested in a modern randomized trial and has demonstrated an impact on clinical outcomes: in the Impact of Nicorandil in Angina (IONA) trial, the use of nicorandil on top of usual therapy reduced the combination of deaths from coronary heart disease, myocardial infarction, and unplanned hospitalization for chest pain in patients with stable angina.7 Most other agents have not been studied in large randomized outcome trials in the context of stable CAD.

Myocardial revascularization, using either percutaneous coronary intervention or coronary artery bypass grafting, is often used to control anginal symptoms or myocardial ischemia in patients with CAD. While remarkably effective at improving outcomes in the context of acute coronary syndromes,6,8 it has little impact, if any, on clinical outcomes in patients with stable CAD.9 In fact, the recent Clinical Outcomes Utilizing Revascularization And aGgressive drug Evaluation (COURAGE) trial found no additional benefit of an initial strategy of routine revascularization on top of optimal medical therapy compared with medical therapy alone.10

Ivabradine: an antianginal agent

Ivabradine (Procoralan®) is an agent that inhibits the If current of the sinus node, thereby specifically slowing the heart rate of patients in sinus rhythm. Because of the importance of heart rate in myocardial oxygen consumption, reductions in heart rate are associated with a potent anti-ischemic and antianginal effect.

Since ivabradine is a pure heart rate–reducing agent, it has no negative effect on inotropy, preserves left ventricular relaxation, does not lead to coronary vasoconstriction, preserves atrioventricular and intraventricular conduction, and has no effect on blood pressure.11-13 In addition, ivabradine can be added to other antianginal agents and has excellent tolerability and safety. The principal side effect is rare, minor, and reversible visual disturbances, because some retinal cells also harbor the If current.

Figure 1
Figure 1. Efficacy of ivabradine versus atenolol on exercise tolerance test parameters at trough of drug activity in the INternatIonal TriAl on the Treatment of angIna with iVabradinE versus atenolol (INITIATIVE).

Bid, twice daily; od, once daily.
After reference 15: Tardif J-C, Ford I, Tendera M, et al. Eur Heart J. 2005;26: 2529-2536. Copyright © 2005, European Society of Cardiology.

Clinical trials have established the potent antianginal effects of ivabradine. In randomized trials, compared with placebo, ivabradine demonstrated dose-dependent improvements in exercise tolerance and prevention of exercise-induced ischemia.14 In the INternatIonal TriAl on the Treatment of angIna with iVabradinE versus atenolol (INITIATIVE), ivabradine was compared with â-blocker therapy with atenolol, an established treatment for prevention of exercise-induced angina, using stress tests, in 939 patients. In that study, ivabradine at the dose of 5 mg produced essentially similar effects to those of 50 mg atenolol on total exercise duration when tested at the trough of drug activity.15 Likewise, after 4 months of treatment, 10 mg of ivabradine were “noninferior” to 100 mg of atenolol, with in fact, a strong trend toward superiority of ivabradine. Indeed, in that trial, when 7.5 mg ivabradine twice daily was compared with 100 mg atenolol four times daily, all the parameters of the exercise treadmill test (ie, exercise duration, time to limiting angina, time to anginal onset, and time to 1-mm ST-segment depression) fulfilled criteria for noninferiority with ivabradine compared with atenolol (Figure 1). In addition, when examining the increase in exercise capacity (measured by increase in total exercise duration) provided by each beat reduction in heart rate, the “efficiency” of heart rate reduction with ivabradine was greater than that achieved by atenolol (increase in total exercise duration of 10.1 vs 5.6 seconds).

A recent trial, ASSOCIATE (evaluation of the Antianginal efficacy and Safety of the aSsociation Of the If Current Inhibitor ivAbradine with a beTa-blockEr), examined the effects of ivabradine in patients with chronic stable angina pectoris receiving â-blocker therapy. In this double-blind trial, 889 patients who were all on 50 mg of atenolol daily were randomly assigned to additional treatment with either ivabradine up to 7.5 mg twice daily or placebo. Patients were then studied using exercise treadmill tests at the trough of drug activity 2 and 4 months later. Compared with placebo, and in these patients who were already on atenolol, ivabradine treatment led to improved total exercise duration on all parameters of the exercise test at 2 and 4 months (Figure 2). In addition, treatment was well tolerated, with only 1% of patients stopping drug therapy because of bradycardia. Minor reversible visual effects (phosphenes and blurred vision) were reported in 2% of ivabradine-treated patients and 0.9% of the placebo-treated patients.16 Thus, it had already been established that ivabradine is an effective and well-tolerated antianginal agent, alone or in combination with other drugs. ASSOCIATE now also demonstrates that when added to chronic treatment with β-blockers, ivabradine further reduces heart rate and improves exercise capacity, while being well tolerated.

Figure 2
Figure 2. Anti-ischemic efficacy of ivabradine in combination with β-blockers.

Ivabradine on top of usual dose of β-blocker improves all exercise capacity parameters without safety concerns. ETT, exercise tolerance test.
After reference 16: Tardif JC, Ponikowski P, Kahan T; ASSOCIATE study investigators. Eur Heart J. 2009;30:540-548. Copyright © 2009, European Society of Cardiology.

_ Impact of ivabradine on clinical outcomes in patients with coronary artery disease
In order to assess whether treatment with ivabradine was associated not only with symptomatic benefits, but also with improvement in clinical outcomes, several trials have been initiated in patients with CAD. The first of these trials is BEAUTIFUL (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction). This is a large international, double-blind, randomized clinical trial of ivabradine versus placebo on top of optimal medical therapy, in patients with stable CAD, a baseline heart rate of at least 60 beats per minute (bpm), and left ventricular dysfunction (defined as a left ventricular ejection fraction of <40%). The primary end point was a composite of cardiovascular death and hospitalization for acute myocardial infarction or heart failure. Almost 11 000 patients were enrolled in 33 countries. After a median follow-up of 19 months, ivabradine did not affect the primary end point in the overall trial (hazard ratio [HR], 1.00; 95% confidence interval [CI], 0.85- 1.10; P=0.94) nor in a prespecified subgroup of patients with a heart rate of 70 bpm or greater (HR, 0.91; 95% CI, 0.81- 1.04; P=0.17).17 It did, however, reduce secondary end points in that subset: admission to hospital for fatal and nonfatal myocardial infarction (HR, 0.64; 95% CI, 0.49-0.84; P=0.001) and coronary revascularization (HR, 0.70; 95% CI, 0.52-0.93; P=0·016) (Table, Figure 3).

Table

Figure 3
Figure 3. Heart rate as a predictor of cardiovascular death.

Prospective data from the placebo arm of BEAUTIFUL (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction). Bpm, beats per minute.
After reference 18: Fox K, Ford I, Steg PG, et al. Lancet. 2008;372:817-821. Copyright © 2008, Elsevier Limited.

Importantly, these results were achieved despite the fact that patients were receiving excellent background medical therapy, with high rates of the use of antithrombotics, statins, and renin-angiotensin system blockers, and more importantly, with 87% of the patients on β-blockers. It is important to put these results into perspective using the analysis done in the placebo group of the same trial, looking at the impact of heart rate at baseline on clinical outcomes.18 In that analysis, it was apparent that heart rate is a strong prognostic factor in patients with CAD and left ventricular dysfunction, and that in fact, an elevated heart rate (≥70 bpm) identifies those at increased risk of cardiovascular outcomes, with a differential effect on outcomes associated with heart failure and outcomes associated with coronary events: the risk of mortality and heart failure increased continuously with increasing heart rate, whereas the impact of heart rate on coronary events appeared to increase above the threshold of 70 bpm. This suggests that the value of 70 bpm is probably a key threshold in CAD, which deserves consideration in making decisions regarding treatment of these patients (Figures 4-6).

Figure 4
Figure 4. Heart rate as a predictor of hospitalization for heart failure.

Prospective data from the placebo arm of BEAUTIFUL (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction). Bpm, beats per minute.
After reference 18: Fox K, Ford I, Steg PG, et al. Lancet. 2008;372:817-821. Copyright © 2008, Elsevier Limited.

Figure 5
Figure 5. Heart rate as a predictor of hospitalization for myocardial infarction (MI).

Prospective data from the placebo arm of BEAUTIFUL (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction). Bpm, beats per minute.
After reference 18: Fox K, Ford I, Steg PG, et al. Lancet. 2008;372:817-821. Copyright © 2008, Elsevier Limited.

Figure 6
Figure 6. Ivabradine reduces fatal and nonfatal myocardial infarction

(MI) in patients with a heart rate ≥70 beats per minute.
Bpm, beats per minute, RRR, relative risk reduction.
After reference 17: Fox K, Ford I, Steg PG, et al. Lancet. 2008;372:807-816. Copyright © 2008, Elsevier Limited.

These findings have two important implications: first, from a pathophysiologic standpoint, the fact that a drug that specifically slows the heart rate without affecting any of the other determinants of oxygen consumption or any other hemodynamic parameter would affect clinical outcomes, demonstrates that the relationship between elevated heart rate and adverse cardiovascular outcomes that has been demonstrated in several important observational studies19-22 is not solely an association, but is at least in part, causal, since ivabradine has no other hemodynamic action other than slowing sinus rhythm. In addition, from a clinical standpoint, they provide evidence of a benefit of ivabradine far beyond the mere control of anginal symptoms. It now belongs to the small number of drugs that have established prognostic benefits on hard clinical outcomes in patients with CAD, even when such patients receive excellent background medical therapy. This indicates that ivabradine should now be considered for the management of patients with CAD, left ventricular dysfunction, and a heart rate of 70 bpm. It is plausible that these benefits may extend to a similar patient population but who are without left ventricular dysfunction, but this deserves to be tested in a second trial, which is indeed ongoing.

Conclusion

Given the burden that CAD imposes on global public health, it is important to find new treatments that are able to improve clinical outcomes in patients with CAD. Ivabradine is a new treatment that selectively slows the heart rate and is associated with established efficacy against angina and exerciseinduced myocardial ischemia. It has comparable efficacy to that of atenolol, an established treatment for angina, but also provides additional efficacy when added to β-blockers (as recently demonstrated in ASSOCIATE) or to other antianginal background therapy.

BEAUTIFUL showed that in addition to symptomatic improvement, treatment with ivabradine also yields improved clinical outcomes in terms of prevention of fatal or nonfatal myocardial infarction or the need for myocardial revascularization in patients with a baseline heart rate ≥70 bpm when added to modern background therapy. Both prevention of myocardial infarction and reduction of the need for myocardial revascularization are likely to have a substantial impact on global health and health costs. Ivabradine (Procoralan®) therefore has an important role in the management of patients with stable CAD. _

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