Study Design and Oversight

The background and design of the Risk and Prevention Study have been described in detail elsewhere.8 For this community-based trial, 860 general practitioners were selected because of their involvement in previous research projects4,9 or from general practitioner–investigator registries in local health units. The trial was designed by the steering committee (for a list of members, see the Supplementary Appendix, available with the full text of this article at NEJM.org) and approved by the ethics committees of the local health units. Standard operating procedures complied with the Harmonized Tripartite Guideline for Good Clinical Practice from the International Conference on Harmonisation.10 An independent data and safety monitoring board oversaw the study and monitored patient safety, with a planned blind interim analysis when the investigators had reported half the expected number of end-point events.

The steering committee had the full and sole responsibility for planning and coordinating the study, analyzing and interpreting the data, and preparing the manuscript and submitting it for publication. Società Prodotti Antibiotici, Pfizer, and Sigma Tau funded the trial but had no role in the study design, planning, conduct, or analysis or in the interpretation or reporting of the results. All the authors vouch for the accuracy and completeness of the data and analyses and for the fidelity of this report to the trial protocol, which is available at NEJM.org.

Study Participants

Eligible patients were men and women who met at least one of the following criteria: multiple cardiovascular risk factors, clinical evidence of atherosclerotic vascular disease, or any other condition putting the patient at high cardiovascular risk in the opinion of the patient's general practitioner. The criterion of multiple cardiovascular risk factors was defined as at least four of the following (or, for patients with diabetes, at least one of the following): an age of 65 years or older, male sex, hypertension (clinical history of hypertension or use of antihypertensive treatment), hypercholesterolemia (clinical history of hypercholesterolemia or use of lipid-lowering treatment), status as a current smoker, obesity (a body-mass index [the weight in kilograms divided by the square of the height in meters] of 30 or more), or a family history of premature cardiovascular disease (defined as cardiovascular disease at <55 years of age in the patient's father or a brother or at <65 years of age in the patient's mother or a sister). Clinical evidence of atherosclerotic vascular disease was defined as angina pectoris, peripheral artery disease, a history of ischemic stroke or transient ischemic attack, or previous treatment with an arterial revascularization procedure.

Exclusion criteria were previous myocardial infarction, hypersensitivity to n−3 fatty acids, pregnancy, clinical conditions with poor short-term prognosis, and conditions that would affect the ability to provide informed consent or comply with the protocol. All patients coming to the attention of one of the participating general practitioners and meeting the criteria for inclusion in the study were consecutively enrolled over a period of time that was prespecified by each general practitioner. All patients provided written informed consent before enrollment.

Study Procedures

Study patients were randomly assigned to receive one capsule daily containing 1 g of n−3 fatty acids (polyunsaturated fatty acid ethyl esters with eicosapentaenoic acid and docosahexaenoic acid content not <85%, in a ratio that could range from 0.9:1 to 1.5:1) or placebo (olive oil). Treatment was centrally assigned by means of telephone on the basis of a concealed, computer-generated randomization list, stratified according to general practitioner. Patients, general practitioners, coordination and statistical staff, and outcome assessors were unaware of the study assignments until the final analyses were completed.

At baseline and at the scheduled yearly follow-up visits, the patient's general practitioner collected prespecified study information, including anthropometric measures, blood pressure, heart rate, lifestyle habits, current clinical conditions, any new diagnosis of cardiovascular disease, essential laboratory tests, current medical therapies, treatment compliance (according to patient self-report), and clinical outcomes. During these visits, the general practitioner also evaluated the patient for the presence and treatment of cardiovascular risk factors and considered, in light of current guidelines, how to reduce the patient's overall cardiovascular risk. Patients whose treatment was stopped for any reason were followed until the end of the study.

End Points

At the beginning of the trial, the primary efficacy end point was defined as the cumulative rate of death, nonfatal myocardial infarction, and nonfatal stroke.8 However, after a blinded assessment at 1 year showed an event rate that was lower than expected, the primary efficacy end point was revised as the composite of time to death from cardiovascular causes or hospital admission for cardiovascular causes.

Secondary efficacy measures included the composite of time to death, nonfatal myocardial infarction, or nonfatal stroke (the original primary end point); the composite of time to death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke; death from coronary heart disease; and sudden death from cardiac causes (see the Supplementary Appendix for definitions). Fatal and nonfatal coronary events and major ventricular arrhythmic events were included in preplanned exploratory analyses. All events included in the primary efficacy end point were documented with the use of a narrative summary and supporting documentation and were adjudicated on the basis of prespecified criteria by an ad hoc committee consisting of a cardiologist, an internist, and a neurologist who were unaware of the study assignments. All serious adverse events, including those that were not necessarily related to the study drugs, were reported.

Statistical Analysis

The primary efficacy end point was initially defined as the cumulative rate of death, nonfatal myocardial infarction, and nonfatal stroke; the event rate was expected to be 2% per year. However, on blinded assessment at 1 year, the event rate was lower than expected, at 1.4% per year.8 Therefore, the primary end point was redefined as the time to death from cardiovascular causes or first hospital admission for cardiovascular causes. For this revised primary end point, we assumed an event rate in the placebo group of 15% at 5 years and a relative risk reduction of 15%, with a withdrawal rate of 10%. We adopted an event-driven design; to achieve a power of 90% at an alpha level of 0.05, a total of 1383 events were necessary to close the trial, which required an enrollment of approximately 11,200 patients. However, we decided that randomization could continue until all the participating general practitioners had had the opportunity to recruit patients.

Baseline characteristics of the patients who underwent randomization were compared by means of the chi-square test for categorical variables and the t-test or nonparametric test for continuous variables. Changes from baseline to 5 years in systolic and diastolic blood pressure; heart rate; total, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol levels; triglyceride levels; and blood glucose and glycated hemoglobin levels were assessed by means of analysis of variance, with adjustment for baseline values, and were reported as least-square means (±SE).

Analyses were performed in the intention-to-treat population, except for a prespecified per-protocol analysis of the primary end point in patients with no major protocol violations who did not permanently stop treatment. Treatment effect on the study end points was analyzed by fitting Cox proportional-hazards models. Unadjusted hazard ratios and 95% confidence intervals were calculated for analyses of the primary and secondary end points and for the prespecified subgroup analyses. For the primary end point, results are also reported as hazard ratios adjusted for baseline variables that were unbalanced (P<0.05) between the study groups. The assumption of proportional hazards for the randomly assigned treatments was assessed by estimating the log(−log[survival distribution]) plotted against the log(failure time) and by the time-dependent covariate test. Kaplan–Meier estimates of survival curves were based on the results of the log-rank test.

The effect of the study treatment on the primary end point was assessed in subgroups defined by risk level or coexisting condition, age (<65 years vs. ≥65 years), sex, and inclusion criteria. We performed Cox analyses of the primary outcome in subgroups by fitting a Cox model with one term representing the study group, one representing the covariate of interest, and an interaction term to test for heterogeneity of the effect of n−3 fatty acids. All reported P values are two-sided. All analyses were performed with the use of SAS software, version 9.2 (SAS Institute).