Trial Design and Oversight

We conducted this randomized, double-blind, parallel-group, placebo-controlled, event-driven study at 1139 centers in 51 countries. The study was designed to determine the effect of the addition of ivabradine to standard therapy in patients with stable coronary artery disease.12 The study protocol, available with the full text of this article at NEJM.org, was approved by the ethics committee at each participating institution.

The trial was sponsored by Servier. The executive committee, which included nonvoting representatives of the sponsor, was responsible for the study design, the interpretation of the results, the writing of the manuscript, and the decision to submit the manuscript for publication. The sponsor was responsible for data management. All the statistical analyses were performed by the Robertson Centre for Biostatistics at the University of Glasgow. The trial was overseen by an independent data monitoring committee. The executive committee had full access to the data and takes full responsibility for the accuracy and completeness of the data and analyses reported, as well as for the fidelity of this report to the trial protocol.

Participants

Eligible patients were at least 55 years of age and had documented and treated stable coronary artery disease but no evidence of clinical heart failure.12 Participants had to be in sinus rhythm, have a resting heart rate of 70 beats per minute or more on two consecutive electrocardiographic readings, and have at least one major adverse prognostic factor (angina pectoris of class ≥II on the Canadian Cardiovascular Society [CCS] scale, which ranges from I to IV, with higher classes indicating greater limitations on physical activity owing to angina; evidence of myocardial ischemia within the previous year; or hospital discharge after a major coronary event within the previous year) or two minor adverse prognostic factors (a high-density lipoprotein cholesterol level <40 mg per deciliter [1 mmol per liter, according to the study protocol] or a low-density lipoprotein cholesterol level >160 mg per deciliter [4 mmol per liter, according to the study protocol], despite lipid-lowering treatment; type 1 or 2 diabetes mellitus; peripheral artery disease; current smoking; or an age of ≥70 years). Patients with left ventricular dysfunction (left ventricular ejection fraction ≤40%) or an unstable cardiovascular condition were excluded. Additional details of the selection, inclusion, and exclusion criteria are provided in Table S1 in the Supplementary Appendix, available at NEJM.org.

Interventions and Assessments

After providing written informed consent, all the participants entered a 2-to-4-week placebo run-in phase to confirm eligibility and clinical stability. All the patients whose eligibility and clinical stability were confirmed and who had complied with taking the study drug during the run-in phase were randomly assigned by means of an interactive voice-response or Web-response system to receive ivabradine at a dose of 7.5 mg twice daily or matching placebo (except for patients ≥75 years of age, who received 5.0 mg twice daily). Randomization was stratified according to study center and baseline status with respect to angina (no symptoms or CCS class I vs. CCS class ≥II). Patients and investigators were unaware of the treatment assignments.

In addition to the study drug, participants were to receive stable background therapy according to contemporary guidelines (notably aspirin, statins, angiotensin-converting–enzyme [ACE] inhibitors [class I, level of evidence A in all guidelines], and beta-blockers [class I, level of evidence B in all guidelines]).13,14 The treating clinicians were given recommendations for adjusting the beta-blocker dose to achieve the greatest efficacy prior to the run-in phase and for keeping the dose constant thereafter.

Follow-up visits occurred at 1, 2, 3, and 6 months and every 6 months thereafter. The study-drug dose could be adjusted to 5.0, 7.5, or 10.0 mg twice daily, according to the heart rate as measured by electrocardiography at every visit (target heart rate, 55 to 60 beats per minute) and symptoms of bradycardia. If a patient was receiving the lowest dose, treatment was stopped if the heart rate was less than 45 beats per minute, if there was symptomatic bradycardia, or if they had a heart rate of less than 50 beats per minute that persisted at a newly scheduled control visit 1 week later.

End Points

The primary end point was a composite of death from cardiovascular causes or nonfatal myocardial infarction. The secondary end points included the components of the primary end point — death from cardiovascular causes and nonfatal myocardial infarction — as well as death from any cause. A description of all the secondary end points is provided in Table S2 in the Supplementary Appendix. Other variables assessed during the trial included heart rate (in all the patients) and change in angina symptoms (in patients with angina at baseline). All outcomes were adjudicated by an independent end-point validation committee.

Statistical Analysis

We estimated that we would need to enroll 16,850 patients for the study to have 90% power to detect an 18% reduction in the relative risk of the primary composite end point with ivabradine, assuming a 2.7% annual incidence with placebo and a mean follow-up period of 2.75 years, at a significance level of 5%. Additional details of the sample-size calculations are provided in the Supplementary Appendix. During the trial, the data monitoring committee performed two planned interim analyses — after 35% and 60% of the anticipated number of primary end points had occurred. A P value of less than 0.001 was required for early termination due to benefit.

The baseline characteristics are shown according to study group as means and standard deviations for continuous variables and as numbers and percentages for categorical variables. The efficacy analysis was based on the intention-to-treat principle. A Cox proportional-hazards model was used to estimate the effect of study treatment on the primary end point and other time-to-event end points, with adjustment for the presence or absence of activity-limiting angina pectoris (CCS class ≥II) at baseline. Results are presented as hazard ratios and 95% confidence intervals with corresponding P values. Prespecified subgroup analyses were performed according to the presence or absence of activity-limiting angina (CCS class ≥II) at baseline (the main subgroup analysis), as well as according to seven other prespecified subgroup variables. Time-to-event curves were prepared with the use of the Kaplan–Meier method. Adverse events were tabulated according to study group with appropriate P values (calculated with the use of the chi-square test or Fisher's exact test). The type I error was set at 5% (two-sided) for all statistical tests. SAS software, version 9.2 (SAS Institute), was used for statistical analyses.