Clinical Trial Design

We designed a two-group, open-label, randomized, controlled, clinical trial comparing polypill therapy with usual care. The trial protocol, which is available with the full text of this article at NEJM.org, was approved by the Vanderbilt University institutional review board, the Oversight Advisory Committee of the AHA Strategically Focused Prevention Research Network, and two committees of the Southern Community Cohort Study (SCCS). The trial was monitored by an independent data and safety monitoring board and by the Food and Drug Administration under a noncommercial Investigational New Drug application. The authors vouch for the completeness and accuracy of the data and for the fidelity of the trial to the protocol.

Setting and Recruitment

The SCCS was initiated in 2001 to examine root causes of health disparities in cancer.26 The study enrolled 85,000 participants, predominantly from minority populations, across a network of community health centers in the southeastern United States; enrollment was completed in 2009. Potentially eligible participants for the polypill trial were identified among previously enrolled SCCS participants living within 50 miles of the Franklin Primary Health Center in Mobile, Alabama, or among current non-SCCS patients or residents near the center.

Eligibility criteria and screening examinations were identical for both the SCCS and non-SCCS participants. Potentially eligible persons 45 to 75 years of age who had no reported history of coronary heart disease, stroke, cancer, liver disease, or insulin-dependent diabetes were sent a prescreening questionnaire. Respondents who were taking no more than two antihypertensive medications were invited to the Franklin Primary Health Center for a clinical examination, which included blood pressure, fasting lipid, and blood chemical measurements. Eligible participants met each of the following criteria: a systolic blood pressure between 120 and 160 mm Hg, an LDL cholesterol level of less than 190 mg per deciliter (4.90 mmol per liter), an estimated glomerular filtration rate of at least 60 ml per minute per 1.73 m2 of body-surface area, normal potassium levels, hepatic aminotransferase levels of less than three times the upper limit of the normal range, no contraindications to any polypill component, status of not being pregnant, and current use of no more than two antihypertensive medications. In June 2016, the criterion for the upper boundary of systolic blood pressure (160 mm Hg) was removed after consultation with the institutional review board and the data and safety monitoring board. Eligible participants who provided written informed consent were randomly assigned to receive either the polypill or usual care.

Treatments

Participants who were assigned to the polypill group received 90-day refillable supplies of daily trial medication prepared by the Vanderbilt Investigational Drug Service. The polypill consisted of four low-dose medications: atorvastatin (10 mg), amlodipine (2.5 mg), losartan (25 mg), and hydrochlorothiazide (12.5 mg). Generic versions were placed securely in sealed gelatin capsules and bottled in 90-day supplies. The trial pills were produced at a cost to the investigators of $26 per month per participant. The initial dispensation of the polypill supply was shipped overnight to the individual participants, with subsequent refills shipped to the Franklin Primary Health Center pharmacy for distribution to participants.

Participants who were assigned to the usual-care group were offered routine care at the Franklin Primary Health Center, in conjunction with any ongoing care that they were receiving from a primary care physician. For participants in either group, our trial team engaged in consistent communication with each participant’s primary care physician, including a standard letter conveying clinical data and the reminder that the physician was free to implement any additional therapies that were deemed to be appropriate.

Follow-up Visits

All participants were scheduled for follow-up visits at 2 months and 12 months after randomization. A clinical examination was conducted, blood pressure measured, and a fasting blood sample obtained. Adherence to the polypill regimen was assessed by means of pill counts performed by the trial coordinator at each trial-related visit. Participants received $50 remuneration for each clinic visit that was completed.

Outcome Measures

The two primary outcomes were the changes in systolic blood pressure and LDL cholesterol level from baseline to 12 months. Blood-pressure data were obtained by calculating the mean of two resting, manual, in-clinic measurements of blood pressure by a trial nurse. An appropriately sized blood-pressure cuff was selected on the basis of the size of the patient. Lipid profiles were obtained by a trained phlebotomist and sent to a single, local laboratory facility. The Martin–Hopkins equation was used to calculate the LDL cholesterol level, with a direct measurement of the LDL cholesterol level when the triglyceride level exceeded 400 mg per deciliter (4.52 mmol per liter). In the polypill group, adherence to therapy was assessed by means of pill count and participant report. Secondary outcomes included changes from baseline to 12 months in the diastolic blood pressure, total cholesterol level, high-density lipoprotein cholesterol level, triglyceride level, and predicted 10-year risk of cardiovascular disease. The 2013 ACC–AHA risk estimator was used to predict the 10-year risk of cardiovascular disease on the basis of the pooled cohort equations; the risk score indicates the likelihood of a person having an atherosclerotic cardiovascular event in the next 10 years.27,28 Safety outcomes, including serious adverse events, were assessed in both trial groups. Specific side effects were assessed, including the incidence of myalgias, hypotension, and light-headedness.

Statistical Analysis

We estimated the power for our trial on the basis of assumptions about the degree of correlation between the baseline and 12-month values for both systolic blood pressure and LDL cholesterol level. Estimates of baseline variability were based on data from the SCCS and the Jackson Heart Study.29,30 Assuming a correlation (r) of 0.7 between the two measurements for the two primary outcomes, we calculated that the enrollment of 150 participants in each group would provide the trial with 80% power to detect a between-group difference of 5.3 mm Hg for the systolic blood pressure and 9.8 mg per deciliter (0.25 mmol per liter) for the LDL cholesterol level. Details are provided in the trial protocol.

For the primary analyses, we evaluated changes in systolic blood pressure and LDL cholesterol level from baseline to 12 months. Similar analyses were conducted for changes from baseline to 2 months. Crude differences were calculated and tested for significance with the use of Student’s t-test, followed by multivariable regression models with the difference as the dependent variable and treatment group as the primary exposure variable; additional covariates were age, sex, body-mass index, presence or absence of diabetes, presence or absence of hypertension of stage 2 or higher (baseline systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg), and cardiovascular risk score.28 In sensitivity analyses, we used multiple imputation to account for outcome data that were missing because of death or discontinuation. Two-sided P values of less than 0.05 were considered to indicate statistical significance for the two primary outcomes.

For secondary outcomes, between-group differences and 95% confidence intervals are reported. The 95% confidence intervals were not adjusted for multiplicity, and therefore inferences drawn from these intervals may not be reproducible. To assess adherence to the polypill regimen, we completed pill counts at each refill and computed the percentage of participants reporting at the 2-month and 12-month visits that they had taken the polypill the day before. Prespecified analyses of subgroups according to sex, hypertension of stage 2 or higher (yes or no), baseline prescription antihypertensive therapy (yes or no), baseline LDL cholesterol level (<130 or ≥130 mg per deciliter [<3.5 or ≥3.5 mmol per liter]), and baseline statin therapy (yes or no) were performed.