Trial Design

We conducted this double-blind, randomized, placebo-controlled trial at 228 centers in 21 countries, using a 2-by-2 factorial design. The trial evaluated blood-pressure–lowering therapy with a fixed-dose combination of an angiotensin-receptor blocker (ARB) and a thiazide diuretic, cholesterol-lowering therapy with a statin, and the combination of both interventions in persons at intermediate cardiovascular risk (Table S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org).9 The results of the cholesterol-lowering analysis and the analysis of the combination of blood-pressure lowering and cholesterol lowering are reported in accompanying articles in the Journal.10,11

The trial was designed by an international steering committee of academic investigators and sponsored by AstraZeneca and the Canadian Institutes of Health Research. AstraZeneca provided the trial drug, served as a single voting member on the 24-member steering committee, and had no other role in the trial. The Population Health Research Institute, McMaster University, Canada, coordinated data collection and monitoring and conducted all statistical analyses independent of the sponsors. Ethical approval was obtained at all centers, and all the participants provided written informed consent. An event-adjudication committee whose members were unaware of the trial-group assignments reviewed primary and secondary outcome events and deaths. An independent data and safety monitoring board reviewed the accumulating data. The authors vouch for the accuracy and completeness of the data and all the analyses, as well as for the fidelity of this report to the trial protocol (available at NEJM.org). The first author drafted the manuscript, and all the authors made the decision, with approval from the steering committee, to submit the manuscript for publication.

Trial Population

The trial included men 55 years of age or older and women 65 years of age or older who had at least one of the following cardiovascular risk factors: elevated waist-to-hip ratio, history of low concentration of high-density lipoprotein cholesterol, current or recent tobacco use, dysglycemia, family history of premature coronary disease, and mild renal dysfunction; details of the eligibility criteria are provided in Table S2 in the Supplementary Appendix. We also included women 60 years of age or older who had at least two such risk factors.9 We excluded persons with known cardiovascular disease, clear indications or contraindications to the trial drugs or angiotensin-converting–enzyme (ACE) inhibitors, moderate or advanced renal dysfunction, or symptomatic hypotension.

Fasting lipid, glucose, and creatinine levels and blood pressure were measured before enrollment. However, participants were not selected on the basis of history of either hypertension or hyperlipidemia, and the trial did not mandate strict blood-pressure or lipid levels for entry. Persons with a history of hypertension could be enrolled if the blood pressure was adequately controlled (in the assessment of the recruiting physician) with lifestyle or drugs other than an ARB, ACE inhibitor, or thiazides. Recruiting physicians were informed about local guidelines regarding the prevention of cardiovascular disease (including guidelines for the management of hypertension and dyslipidemia), and they used local standards as an additional guide to determine trial eligibility, on the basis of the uncertainty principle.12

Trial Procedures

Eligible participants entered a single-blind run-in phase, during which they received both active treatments (for blood-pressure lowering and for cholesterol lowering) for 4 weeks. Serum creatinine, potassium, creatine kinase, and alanine aminotransferase (or aspartate aminotransferase) levels were measured at 3 weeks. Participants who adhered to the regimen (taking ≥80% of the tablets) and who did not have an unacceptable level of adverse events underwent randomization with the use of a central concealed randomization procedure, stratified according to center. Participants were randomly assigned to the daily administration of either a fixed-dose combination of candesartan at a dose of 16 mg and hydrochlorothiazide at a dose of 12.5 mg or placebo; participants were also randomly assigned to receive either rosuvastatin at a dose of 10 mg or placebo.

All the participants received individualized structured lifestyle advice, according to identified needs. Follow-up visits occurred at 6 weeks and 6 months after randomization and every 6 months thereafter. Adherence to the regimen (as measured by pill count), safety, and trial outcomes were evaluated at each visit. The blood pressure was measured at each visit during the first year and annually thereafter (average of two measurements after 5 minutes of quiet rest) with the use of a standardized protocol (see the Supplementary Appendix) and an automated measurement system (Omron model HEM-711DLXCAN). Fasting blood samples were obtained at baseline from all the participants and during follow-up from 10 to 20% of the participants (with representation across geographic and racial and ethnic subgroups), and the samples were shipped for central storage and analyses of lipid levels and additional markers (see the Supplementary Appendix).

Trial Outcomes

The two prespecified coprimary efficacy outcomes were the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke and the composite of these events plus resuscitated cardiac arrest, heart failure, or revascularization. There were two secondary outcomes: the composite of events comprising the second coprimary outcome plus angina with evidence of ischemia, and for the comparison of blood-pressure lowering, fatal or nonfatal stroke. The secondary outcomes were modified from the original trial protocol and were formally adopted by the steering committee without a protocol amendment on July 15, 2015, before unblinding on November 3, 2015.

Additional prespecified outcomes were total mortality, the components of the coprimary and secondary outcomes (stroke was a component of the coprimary outcomes and also a distinct secondary outcome for the comparison of blood-pressure lowering), new-onset diabetes, cognitive function (in participants ≥70 years of age), and erectile dysfunction in men. The latter two outcomes are not reported here. Event definitions are provided in the Supplementary Appendix.

Renal dysfunction was a tertiary outcome in the original trial protocol and was removed because of limitations of statistical power. The main safety outcomes included cancer, myopathy, rhabdomyolysis, and hospitalization. In addition, we collected data on adverse events leading to temporary or permanent discontinuation of the trial regimens and on suspected unexpected serious adverse reactions. Safety monitoring is summarized in the Supplementary Appendix.

Statistical Analysis

With an expected annual event rate of 1% for the first coprimary outcome in the dual-placebo group (i.e., the group of participants assigned to placebo in both the comparison of blood-pressure lowering and the comparison of cholesterol lowering), an average duration of follow-up of 5.5 years, cumulative nonadherence rates of 23%, drop-in rates of 11% (participants who were projected to use open-label ARBs, ACE inhibitors, thiazides, or statins), and rates of loss to follow-up of less than 1%, we estimated that a sample of 12,700 participants would provide the trial with 80% power to detect a risk with candesartan plus hydrochlorothiazide that was at least 22.5% lower than the risk with placebo, after the occurrence of at least 500 first and 600 second coprimary outcomes.9

The main analyses were performed according to the intention-to-treat principle. Survival curves were computed with the use of the Kaplan–Meier procedure. A Cox proportional-hazards model, stratified according to the opposite group of the factorial design, was used to estimate treatment effects and possible interactions and to evaluate effects in subgroups. No significant interaction between the two factorial treatments was observed. Prespecified hypothesis-based subgroup analyses were conducted according to thirds of baseline cardiovascular risk, of systolic blood pressure, and of low-density lipoprotein (LDL) cholesterol concentration (with P values for trend), with additional confirmatory prespecified subgroup analyses according to age, sex, diastolic blood pressure, waist-to-hip ratio, additional lipid measurements, and race or ethnic group. A post hoc recurrent-events analysis was performed with the use of proportional-means models to describe the effect on the risk of total cardiovascular events.13

To preserve an overall type I error rate of 5%, the first coprimary outcome was tested at a P value of 0.04 and the second at a P value of 0.02 (considering an 80% overlap between the coprimary outcomes). A nominal P value of less than 0.05 was used for all other analyses. Further details are provided in the Supplementary Appendix.