SIGNIFY: hope for new perspectives in CAD management





Kim FOX,MD
Ekaterini A. KRITIKOU,1MD, FRCP
National Heart and Lung Institute
Imperial College and Institute of Cardiovascular Medicine and Science
Royal Brompton Hospital
London, UK

SIGNIFY: hope for new erspectives in CAD management

Interview with K. Fox, United Kingdom



Coronary artery disease (CAD) remains the leading cause of death worldwide, despite tremendous progress toward the prevention and cure of cardiovascular (CV) diseases. Thus, any insight into how to improve care and outcomes in CAD patients is of tremendous value both to patients and public health. Reducing risk factors to prevent atherosclerotic events is important in CAD management. An easily modifiable parameter to improve risk management in patients with CV disease is resting heart rate (HR), and reducing HR is a well-recognized strategy for ischemia prevention in CAD patients. Reducing resting HR may also have an impact on long-term outcomes. Much evidence from experimental and clinical studies suggests that elevated resting HR predisposes for development and progression of atherosclerosis and plaque rupture, which can trigger the acute coronary events linked to mortality in CAD patients. Consistent with the important role of HR in the pathophysiology of CAD, HR reduction should be considered a key therapeutic goal in CAD patients. The ongoing SIGNIFY trial (Study assessInG the morbidity-mortality beNefits of the If inhibitor ivabradine in patients with coronarY artery disease) is assessing if lowering resting HR with ivabradine improves outcomes in patients with stable CAD without clinical heart failure (HF) and who are receiving appropriate CV treatment. If ivabradine reduces CV morbidity and mortality in such patients, this trial would constitute a breakthrough in treatment strategies for stable CAD patients, allowing us to reach both treatment goals: CV-event prevention and symptom reduction, improving quality of life.

Medicographia. 2013;36:98-102 (see French abstract on page 102)


What is the rationale and the objective of the SIGNIFY trial?

Coronary artery disease (CAD) is the leading cause of death worldwide and is predicted to remain so for the next 20 years.1 For these reasons, any insight into how to improve care and outcomes in patients with CAD is of tremendous value to patients as well as to public health. Reduction of risk factors to prevent atherosclerotic events is important for the management of CAD. One easily modifiable parameter that could improve risk management in patients with cardiovascular (CV) disease is resting heart rate, and HR reduction is a well-recognized strategy for ischemia prevention in patients with CAD. By reducing myocardial work and myocardial oxygen consumption and by increasing diastolic filling time and myocardial oxygen supply, HR reduction minimizes the pathophysiological substrate of angina.2 Reduction in resting HR may also have an impact on long-term outcomes. The investigators of the BEAUTIFUL (morBidity-mortality EvAlUa- Tion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction) trial have contributed substantially to the understanding of the prognostic importance of elevated HR by prospective evaluation of the impact of high resting HR on outcomes in patients with stable CAD and left ventricular systolic dysfunction (LVSD). The prospective analysis of data from the placebo arm demonstrated that elevated resting HR (≥70 beats per minute [bpm]) is a strong independent predictor of clinical outcomes.3 A large body of evidence from experimental and clinical studies suggests that elevated resting HR predisposes to development and progression of atherosclerosis and plaque rupture, which can trigger the acute coronary events that are linked to mortality in patients with CAD.2 Elevated HR enhances the magnitude and frequency of the tensile stress imposed on the arterial wall and prolongs exposure of coronary endothelium to systolic low and oscillatory shear stress, which modulates endothelial gene expression through complex mechanoreception and mechanotransduction processes, inducing an atherogenic endothelial phenotype and formation of an early atherosclerotic plaque.4 All these processes induce structural and functional changes of the endothelial cells, leading to endothelial dysfunction, and make the endothelium more permeable to circulating low-density lipoprotein (LDL) and inflammatory cells, facilitating entry into the intima. Besides the implication of increased HR in atherogenesis, it may also promote weakening of the fibrous cap, ultimately increasing the risk of plaque disruption and the onset of acute coronary syndrome. Consistent with the important role of HR in the pathophysiology of CAD, HR reduction should be considered a key therapeutic goal in CAD patients. We designed the SIGNIFY trial (Study assessInG the morbidity-mortality beNefits of the If inhibitor ivabradine in patients with coronarY artery disease) to test the hypothesis that lowering resting HR with ivabradine would improve outcomes in patients with stable CAD without clinical heart failure (HF) and who are receiving appropriate CV treatment.5




What is the rationale for ivabradine treatment in patients with stable CAD?

Ivabradine is a HR-lowering agent that reduces HR selectively by inhibiting the sinoatrial pacemaker If current and thereby decreases HR without having any direct effect on other cardiac functions.67,8 The ASSOCIATE trial (evaluation of the Antianginal efficacy and Safety of the aSsociation Of the If Current Inhibitor ivAbradine with a beTa-blockEr) shows that ivabradine further reduces HR and improves exercise capacity, while being well tolerated when added to long-term treatment with β-blockers.9 The BEAUTIFUL trial (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction) suggested further benefits of ivabradine in prevention of coronary outcomes in patients with stable CAD and LVSD with an elevated resting HR of ≥70 bpm (n=5392): ivabradine significantly reduced admission to hospital for myocardial infarction (MI) (relative risk reduction [RRR], 36%; P=0.001), admission to hospital for MI or unstable angina (RRR, 22%; P=0.023), as well as coronary revascularization (RRR, 30%; P=0.016).10 In patients whose limiting symptom at baseline was angina (n=1507), ivabradine reduced the composite of CV mortality or hospitalization for fatal and nonfatal MI or HF by 24%.11 Therapy with ivabradine resulted in a 42% reduction in the risk for hospitalization for fatal and nonfatal MI in all patients with limiting angina and 73% reduction in those with resting HR of 70 bpm and higher. Recent SHIFT (Systolic Heart failure treatment with the If inhibitor ivabradine Trial) results showing statistically significant and substantial reductions in CV death or HF hospitalization as well as in HF deaths in patients with chronic HF have significantly extended the range of clinical benefits of ivabradine to patients with HF.12 The recent meta-analysis in the large pooled population of nearly 12 000 patients from BEAUTIFUL and SHIFT trials demonstrated that ivabradine substantially reduces risk for major outcomes in the broad population of patients with LVSD and a HR ≥70 bpm, whatever the primary clinical presentation (CAD or HF) or clinical status (New York Heart Association [NYHA] class).13 So, the ongoing SIGNIFY trial is a logical extension of the clinical program and is testing the hypothesis that HR lowering with ivabradine reduces CV-event rates in patients with stable CAD without clinical HF.

What is the design of the SIGNIFY trial?

SIGNIFY is a randomized, double-blind, placebo-controlled, multicenter trial in patients with stable CAD without clinical HF, with 2 parallel and balanced treatment arms. It is designed to demonstrate the superiority of ivabradine over placebo in the reduction in CV 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). Consistent with current recommendations, the target HR should be 55-60 bpm. Since the patients included in this trial are clinically stable patients with elevated HR (≥bpm), the starting dose of ivabradine is 7.5 mg bid, with the possibility to increase to 10 mg bid after 1 month (according to the patient’s HR and the presence or absence of signs and symptoms likely to be due to bradycardia). Currently, uptitration of ivabradine is recommended up to 7.5 mg bid. The range of ivabradine doses selected for this study has been chosen based on the range of ivabradine doses used in the patients with CAD and stable angina involved in the development program of ivabradine. The primary objective is to assess whether lowering resting HR with ivabradine reduces CV mortality or nonfatal MI (composite end point). The secondary objectives are to assess the effect of ivabradine compared with placebo on all-cause mortality, CV mortality, nonfatal MI, coronary revascularization, 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 with angina symptoms at baseline.

What is the study population?
We designed the inclusion and exclusion criteria to identify a group of patients aged 55 years or older with stable CAD and without clinical HF (LV ejection fraction >40%) at sinus rhythm, with resting HR equal to or higher than 70 bpm, and who are receiving appropriate medications to treat their CV conditions. They should also have at least 1 major risk factor such as angina symptoms (Canadian Cardiovascular Society [CCS] class II or higher), or objective evidence of myocardial ischemia induced by stress testing within the previous 12 months, or recent hospitalization for a major coronary event (acute MI or unstable angina) within the previous 12 months; or 2 minor CV risk factors such as low high-density lipoprotein (HDL) cholesterol and/or high LDL cholesterol, treated diabetes mellitus, presence of peripheral artery disease, current smoking, or age over 70 years.

What is the prognosis of patients with stable CAD?

Patients with stable CAD have high event rates despite modern treatments. The prognosis in patients with chronic CAD depends on several factors, including underlying coronary anatomy, left ventricular function, the presence of risk factors, and comorbidities. The data from the large REACH registry (REduction of Atherothrombosis for Continued Health) in stable CAD outpatients (n=38 602 patients) have confirmed that among patients with CV disease, those with established stable CAD had the highest nonfatal MI rate and the highest nonfatal stroke rate. The registry reported annual event rates of 15.2% for death, stroke, MI, or hospitalization for an atherothrombotic event; and also 6.4% for unstable angina; 4.5% for death, acute MI, and stroke; and 3.8% for revascularization by percutaneous coronary intervention.14 Thus, approximately 3 out of 20 patients with established CAD had a major event or had been hospitalized within a year of follow-up. The data from the Heart and Soul Study demonstrated that during a mean of 3.9 years, coronary events (MI or CAD death) occurred in 7% of participants without angina or inducible ischemia, 10% of those with angina alone, 21% of those with inducible ischemia alone, and 23% of those with both angina and inducible ischemia.15

The most recent data from the ongoing registry CLARIFY (prospeCtive observational LongitudinAl RegIstry oF patients with stable coronary arterY disease), which enrolled more than 33 000 patients with stable CAD in 45 countries, showed that the 1-year event rate of the composite of CV death, nonfatal MI, or stroke was similar for men and women (1.7% and 1.8%, respectively), all-cause death was 1.5% and 1.6%; and CV death or nonfatal MI was 1.4%.16 These data from the well treated population from this large, stable, contemporary outpatient cohort with established CAD indicate that continued efforts are needed to improve secondary prevention and clinical outcomes.

What is the optimal HR in stable CAD patients and how is it achieved in clinical practice?

Consistent 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 the acute coronary setting. Thus, current American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for the diagnosis and management of patients with stable CAD recommended that β-blocker dosing be adjusted to limit the HR to 55-60 bpm.17 It is stressed that this is important not only for effective prevention of angina, but also due to the prognostic importance of HR. A new analysis from the TNT trial (Treating to New Targets) in 9602 patients with established CAD evaluated the optimal HR level regarding the risk of CV events. In patients with CAD, the relationship between HR and outcomes follows a J-curve pattern.18 This analysis identified a nadir of 52.4 bpm 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 the best prognosis in patients with CAD.

The existing evidence suggests that a HR of 55-60 bpm might be considered optimal for both ischemia prevention and, perhaps, prevention of CV events. However, despite the recommendation to reduce HR to 55-60 bpm, resting HR is not controlled in a significant proportion of patients in clinical practice. Many surveys conducted in coronary patients revealed low rates of HR control. For example, in the European Heart Survey of patients with stable angina, mean resting HR was 73 bpm.19 The most recent data from the CLARIFY registry are consistent with this observation and show that only 22% of patients with angina achieved a HR of <60 bpm.20

These data show that there is a lot of room for improvement in HR control and therefore considerable potential to improve management of stable CAD patients. The ongoing SIGNIFY trial is testing whether lowering HR with ivabradine represents a new therapeutic opportunity to improve prognosis for a large population of patients with stable CAD.

When do you expect the results and how might they advance the management of patients with stable CAD?

The recruitment period was from October 2009 to April 2012. Today [as of May 2012], SIGNIFY has recruited 19 102 patients. We expect to have the results by the end of 2014. These data will be extremely important for clinical practice, as taking into account the prevalence and burden of CAD, any further strategy into how to improve care and outcomes in patients with CAD is of tremendous value to patients as well as to public health. Resting HR is a potentially modifiable CV risk factor and, therefore, HR lowering provides great therapeutic opportunity to reduce mortality and CV events in patients with stable CAD. The SIGNIFY study aims to extend the evidence on prognostic benefits of HR reduction with ivabradine to patients with CAD without HF. BEAUTIFUL suggested that ivabradine improves the coronary event rate in patients with stable CAD and LVSD with a HR of 70 bpm or higher.10

Other antianginal strategies either have never been tested or failed to demonstrate the benefits on CV events in stable CAD patients.21-23 The evidence for β-blocker use is derived from relatively old post-MI studies, most of which antedate modern reperfusion or medical therapy, and from HF trials, but has been widely extrapolated to all patients with CAD.24-27 However, the long-term efficacy of these agents in patients treated with contemporary medical therapies is not known, even in patients with prior MI.

The recently published analysis from the REACH registry assessed whether the use of β-blockers is associated with reduction in CV events in patients with a prior history of MI, in those with CAD without MI, and in those with only risk factors for CAD in a large contemporary population of 21 860 patients included in the propensity score–matched analysis (median follow-up was 44 months).28 The results showed that despite the perception that β-blockers are beneficial in all stable CAD patients, their use in an era of modern medical and reperfusion therapy in stable CAD patients was not associated with lower CV-event rates. This finding raises questions regarding the need for long-term use of β-blockers in patients 1 year after MI or in those who had percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) without MI. These data also suggest the importance of and need for randomized trials in this era of modern medical and reperfusion therapy to identify the optimal therapy in stable CAD. So, if the results show that ivabradine treatment reduces CV morbidity and mortality in patients with stable CAD and preserved LV function, this trial will constitute a breakthrough in treatment strategies for stable CAD patients, allowing us to reach both of our goals when treating such patients: CV-event prevention and symptom reduction, improving quality of life.


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Keywords: cardiovascular; coronary artery disease; heart rate reduction; If inhibitor; ivabradine; myocardial infarction