Heart rate reduction in coronary artery disease management: what can we expect from the SIGNIFY trial?





Kim FOX,MD, FRCP
Professor of Clinical Cardiology and Head of the National Heart and Lung Institute, Imperial College
Executive Chairman of the Institute of Cardiovascular Medicine and Science, Royal Brompton Hospital
London, UK

Heart rate reduction in coronary artery disease management: what can we expect from the SIGNIFY trial?


Interview with K. Fox, United Kingdom



Patients with stable coronary artery disease (CAD) have high event rates despite modern treatments. Large studies with long-term follow-up have shown that elevated heart rate (HR) is an independent predictor of all cause and cardiovascular mortality in patients with cardiovascular disease, including CAD patients. A high resting HR is a potentially modifiable cardiovascular risk factor. Thus, lowering HR could reduce mortality and cardiovascular events in patients with cardiovascular disease. The data from the BEAUTIFUL trial (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction) indicated that ivabradine prevents coronary outcomes in patients with stable CAD and left ventricular dysfunction who have a HR of ≥70 beats per minute (bpm). The aim of the ongoing SIGNIFY trial (Study assessInG the morbidity-mortality beNefits of the If inhibitor ivabradine in patients with coronarY artery disease) is to test the hypothesis that HR reduction with ivabradine could improve cardiovascular outcomes in patints with CAD and preserved left ventricular systolic function. This trial is a randomized, double-blind, placebo-controlled, multicenter study designed to assess the superiority of ivabradine vs placebo on cardiovascular mortality or nonfatal myocardial infarction (composite primary end point) in patients with stable CAD without clinical heart failure who are receiving appropriate cardiovascular treatment for their disease. It includes patients aged 55 years or older with stable CAD without clinical heart failure (ejection fraction >41%), in sinus rhythm, and with a resting HR ≥70 bpm. If the results of the SIGNIFY trial show that ivabradine treatment reduces cardiovascular morbidity in this population, it will constitute a breakthrough in the treatment of patients with stable CAD.

Medicographia. 2012;34:449-453 (see French abstract on page 453)



What is the prognosis of patients with stable coronary artery disease?

Coronary artery disease (CAD) remains the leading cause of mortality and a major source of morbidity in developed countries. In the European Union, CAD is associated with 744 000 deaths annually, including 17% of all deaths in men and 16% in women.1 CAD mortality has declined in many industrialized, socioeconomically well-established countries thanks to major advances in secondary preventive strategies. However, these favorable trends are accompanied by a shift of the main burden of clinically manifest CAD—particularly its milder manifestations— toward older age groups, resulting in a constant number of deaths from atheroscle rosis related events every year. The prognosis in patients with chronic CAD is not uniform; it depends on several factors, including underlying coronary anatomy, left ventricular function, and comorbidities. Coronary atherosclerosis most commonly manifests as angina pectoris, followed by acute coronary syndromes (acute myocardial infarction [MI] and unstable angina), and finally, as sudden cardiac death. The Heart and Soul Study, which included 937 outpatients with stable CAD, demonstrated that the presence of inducible ischemia is associated with a greater than 2-fold increased rate of recurrent CAD events.2 During an average of 3.9 years of follow-up, coronary events (MI or CAD death) occurred in 7% of participants without angina or inducible ischemia, in 10% of those with angina alone, in 21% of those with inducible ischemia alone, and in 23% of those with both angina and inducible ischemia. The data from outpatients with atherothrombosis from the REACH registry (Reduction of Atherothrombosis for Continued Health)—a large, stable, contemporary outpatient cohort of patients with atherosclerotic arterial disease or with multiple atherothrombotic risk factors—has confirmed that among patients with cardiovascular disease, those with established stable CAD have the highest rates of nonfatal MI and nonfatal stroke. The registry reported annual event rates of 15.2% for death, stroke, MI, or hospitalization for an atherothrombotic event, as well as 6.4% for unstable angina, 4.5% for death, acute MI, and stroke, and 3.8% for revascularization by percutaneous coronary intervention.3 Thus, approximately 3 out of 20 patients with established CAD had a major event or were hospitalized within a year of follow-up. The high event rates observed in the subgroup of patients with established CAD in the REACH registry indicate that continued efforts are needed to improve secondary prevention and clinical outcomes.

What is the importance of heart rate control in the treatment of coronary artery disease?

HR reduction is a well-recognized strategy for ischemia prevention in patients with CAD. HR reduction decreases myocardial work and myocardial oxygen consumption, and increases diastolic filling time and myocardial oxygen supply, thereby minimizing the pathophysiological substrate of angina.4 It is the primary mechanism of the anti-ischemic effects of agents that reduce HR nonselectively—like β-blockers— or selectively—like ivabradine.

Although HR slowing during exercise is important in the prevention of angina pectoris, even a reduction in resting HR may have an impact on long-term outcomes. Experimental and clinical findings suggest that an elevated resting HR predisposes to the development of atherosclerosis and plaque rupture, which can trigger the acute coronary events that are linked to mortality in patients with CAD.4 Furthermore, a meta-regression of randomized clinical trials with β-blockers and calcium channel blockers in post-MI patients strongly suggests that resting HR reduction could be a major determinant of the clinical benefits seen in these trials.5 In addition, the investigators of BEAUTIFUL (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction) have also made a substantial contribution to the understanding of the importance of HR reduction for the prevention of coronary events. BEAUTIFUL was the first study to prospectively evaluate the impact of an elevated resting HR on outcomes in patients with stable CAD and left ventricular systolic dysfunction (LVSD). The prospective analysis of the data from the placebo arm demonstrated that elevated resting HR (≥70 beats per minute [bpm]) is a strong independent predictor of clinical outcomes.6 The BEAUTIFUL study also showed that in patients with HR ≥70 bpm, HR reduction with ivabradine significantly reduces coronary events.7 Given the important role of HR in the pathophysiology of CAD, it seems clear that HR reduction should be considered as a key therapeutic goal in patients with CAD.





What heart rate should be targeted in this population?

In keeping with the important role of elevated HR in the pathophysiology of myocardial ischemia, it is recommended to reduce resting HR to 55-60 bpm in stable coronary patients as well as in acute coronary settings. Thus, the current American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for the management of chronic stable angina stipulate that β-blocker dosages should be ad- justed to reduce resting HR to 55-60 bpm, or to <50 bpm in patients with severe angina. In the management of unstable angina and non–ST-segment-elevation MI, the ACC/AHA and European Society of Cardiology (ESC) guidelines agree that when β-blockers are used as an initial intervention, a target resting HR of 50-60 bpm is appropriate. A new analysis of the TNT trial (Treating to New Targets) in 9602 patients with established CAD evaluated the optimal HR level in relation to the risk of cardiovascular events. In patients with CAD, the relationship between HR and outcomes follows a J-curve pattern.8 This analysis identified a nadir of 52.4 bpm, which was associated with the lowest event rate for the primary end point of death from CAD, nonfatal MI, resuscitated cardiac arrests, and fatal or nonfatal stroke. There was no target-organ heterogeneity and the nadir was similar for all outcomes, indicating that a target range of 50-59 bpm is optimal for best prognosis in patients with CAD.

The existing evidence suggests that a HR of 55-60 bpm may be considered as optimal for both ischemia prevention and—perhaps—the prevention of cardiovascular events.

In daily practice, is heart rate controlled in coronary patients?

Despite a large body of evidence indicating the importance of HR control, survey data have revealed that in a majority of patients, HR is not optimal. For example, in the European Heart Survey of patients with stable angina, the mean resting HR was 73 bpm, suggesting that a majority of patients had a HR above the recommended level of 55-60 bpm.9 The baseline data from the CLARIFY registry (prospeCtive observational LongitudinAl RegIstry oF patients with stable coronary arterY disease), which includes 33177 contemporary outpatients with stable CAD, confirms the previous observations that HR is not well controlled among stable outpatients with CAD and that many coronary patients are still symptomatic. The mean pulse HR was 68.3 bpm, and 22% of coronary patients had angina symptoms.10 These findings suggest that there is room for improving HR control in CAD.

What is the SIGNIFY trial?

SIGNIFY (Study assessInG the morbidity-mortality beNefits of the If inhibitor ivabradine in patients with coronarY artery disease) is an ongoing randomized, doubleblind, placebo-controlled, multicenter study assessing the effect of ivabradine in patients with CAD without clinical heart failure (HF).11

What is the goal of the SIGNIFY trial?

The SIGNIFY trial was designed to determine if lowering resting HR with ivabradine would reduce cardiovascular mortality or nonfatal MI (composite end point) in patients with stable CAD without clinical HF who are receiving appropriate cardiovascular treatment for their disease. The secondary objectives of the trial include assessment of the effect of ivabradine compared with placebo on all-cause mortality, cardiovascular mortality, nonfatal MI, coronary revascularization, and new-onset or worsening HF, as well as some composite coronary end points. In addition, the effect of ivabradine on quality of life and angina symptoms will be assessed in patients presenting with angina symptoms at baseline.

Why was ivabradine chosen for the treatment of these patients?

Ivabradine is a HR-lowering agent that selectively reduces HR by inhibiting the sinoatrial pacemaker If current and thereby decreases HR without having any effect on other cardiac functions.12 Existing evidence on the prevention of myocardial ischemia and coronary- and HF-related events make it an important agent in the management of patients with CAD as well as HF. Ivabradine has been proven to prevent myocardial ischemia effectively and to reduce symptoms in patients with chronic stable angina pectoris. In head-to-head comparisons, its effectiveness on exercise-induced ischemia is comparable with established drugs such as β-blockers or calcium channel blockers. The ASSOCIATE trial (evaluation of the Antianginal efficacy and Safety of the aSsociation Of the If Current Inhibitor ivAbradine with a beTa-blockEr) showed that, when added to chronic treatment with β-blockers, ivabradine further reduces HR and improves exercise capacity while being well tolerated. The BEAUTIFUL trial shed new light on the role of HR control in cardiovascular disease and showed that ivabradine prevents coronary outcomes in patients with stable CAD and LVSD with HR >70 bpm. Moreover, in 1500 BEAUTIFUL patients with angina as a limiting symptom at baseline, ivabradine not only provided significant benefit in the primary outcome as well as in secondary outcomes, but this benefit was also evident throughout the whole HR spectrum. The recent results from the SHIFT trial (Systolic Heart failure treatment with the If inhibitor ivabradine Trial), which showed significant, substantial reductions in CV death or HF hospitalization as well as in HF deaths in patients with chronic CHF, have significantly extended the range of the clinical benefits of ivabradine to patients with HF.13 Thus, by assessing the effect of ivabradine on cardiovascular outcomes in patients with stable CAD without clinical HF, SIGNIFY is a logical extension of the clinical program of ivabradine in CAD.

What is the design of the study?

SIGNIFY is a randomized, double-blind, placebo-controlled, multicenter trial in patients with stable CAD without clinical HF, with two parallel and balanced treatment arms. It is designed to demonstrate the superiority of ivabradine over placebo in the reduction of cardiovascular mortality or nonfatal MI (composite end point).

Following a run-in period of 14 to 30 days, patients will be randomized to the active double-blind treatment period (ivabradine versus placebo). The study has enrolled over 19 000 patients, with a minimal follow-upof at least 18 months. In keeping with current recommendations, the target HR range is 55- 60 bpm. Since the patients included in this trial are clinically stable patients with elevated HR (≥70 bpm), the starting dose of ivabradine is 7.5 mg twice daily, with a possible increase to 10 mg twice daily after 1 month (according to HR and the presence or absence of signs and symptoms indicative of bradycardia). Although a twice-daily dose of 7.5 mg is the current recommended dose for ivabradine after uptitration, the range of ivabradine doses selected for this study has been chosen based on the doses used in the patients with CAD and stable angina who were involved in the development program of ivabradine.

What patient population is included in the study?

The inclusion and exclusion criteria were designed to select a group of patients aged ≥55 years, with stable CAD and without clinical HF (ejection fraction ≥41%), in sinus rhythm, with resting HR ≥70 bpm, and receiving appropriate medication to treat their cardiovascular conditions. Patients should have additional risk factors, which may be either at least one risk factor such as angina symptoms (Canadian Cardiovascular Society class II or higher), objective evidence of myocardial ischemia induced by stress testing within the previous 12 months, and recent hospitalization for major coronary event (acute MI or unstable angina) within the previous 12 months; or at least two of the following risk factors: low HDL cholesterol and/or high LDL cholesterol, treated diabetes mellitus, presence of peripheral artery disease, current smoking, and age >70 years.

What is the importance of the expected results in clinical practice?

Patients with stable CAD have high event rates despite modern treatments. Large studies with long-term follow up have shown that elevated HR is an independent predictor of all-cause and cardiovascular mortality in patients with cardiovascular disease including CAD patients. A high resting HR is a potentially modifiable cardiovascular risk factor and therefore HR lowering could reduce mortality and cardiovascular events in patients with cardiovascular disease. The aim of the SIGNIFY study is to increase the evidence on the prognostic benefits of HR reduction with ivabradine in a population of patients with CAD and preserved LV systolic function. The BEAUTIFUL trial demonstrated that ivabradine improves coronary events in patients with stable CAD and LVSD with HR ≥70 bpm.6 Other antianginal strategies have either never been tested or failed to demonstrate benefits on cardiovascular events in stable CAD patients. The well-known benefits of β-blockade in terms of reduction of mortality are limited to post-MI and HF. Moreover, the post-MI trials with β-blockers were performed without the extensive use of angiotensin-converting enzyme inhibitors and statins, which leaves uncertainty regarding their efficacy on top of modern management strategies. Calcium channel blockade failed to reduce cardiovascular mortality and morbidity in the CAMELOT (Comparison of AMlodipine vs Enalapril to Limit Occurrences of Thrombosis) and ACTION (A Coronary disease Trial Investigating Outcome with Nifedipine gastrointestinal therapeutic system) trials.14,15 In the IONA trial (Impact Of Nicorandil in Angina), treatment with nicorandil resulted in a lower event rate for the composite end point, which included refractory angina. This trial was not powered to show a benefit on major cardiovascular events, such as CAD mortality and nonfatal MI, or allcause mortality. Therefore, it is not possible to draw conclusions regarding these end points.16

So, if the results of the SIGNIFY trial show that ivabradine treatment reduces cardiovascular morbidity and mortality in patients with stable CAD and preserved LV function, it will constitute a breakthrough in the treatment strategies for patients with stable CAD, allowing us to reach the two main goals of treatment in patients with stable CAD: to prevent cardiovascular events, and to reduce symptoms and improve quality of life.

What kind of patients will benefit from the new approach?

The results of the SIGNIFY trial will be important for the large spectrum of patients with stable CAD. In future years, as the general population continues to age, the number of patients with stable CAD is expected to increase. According to global and regional projections of mortality and disease burden, CAD will remain the leading cause of death for the next 20 years. Moreover, a recently published estimation indicates a significant growth in the projected crude prevalence of cardiovascular disease—including CAD—in the next 2 decades.17 In the USA, these increases will translate into an additional 8 million people with CAD in 2030, relative to 2010. Despite all the advances in modern treatments, patients with stable CAD have high event rates. HR reduction is a modifiable risk factor that provides an important therapeutic opportunity to improve prognosis in coronary patients.

However, despite the recommendation to reduce HR to 55- 60 bpm, resting HR remains uncontrolled in a significant proportion of patients in clinical practice. Many surveys conducted in coronary patients have revealed low rates of HR control.

As mentioned previously, the results of the European Heart Survey of patients with stable angina suggest that a majority of patients have a HR >70 bpm. Therefore, the data from SIGNIFY will provide a great therapeutic opportunity for the large population of patients with stable CAD. _

References
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Keywords: cardiovascular outcome; coronary artery disease; heart rate lowering; ivabradine; SIGNIFY