HOPE-3 Study Supports Broader Use of Statins in Intermediate-Risk Populations

April 2, 2016—Three separate reports from the large HOPE-3 (Heart Outcomes Prevention Evaluation-3) trial were presented at ACC.16, the American College of Cardiology’s 65th annual scientific session held April 2–4 in Chicago Illinois. The three HOPE-3 reports were simultaneously published online in The New England Journal of Medicine (NEJM).

The HOPE-3 trial is assessing outcomes of preventative treatment with cholesterol- and blood pressure-lowering drugs in a large, globally diverse population at intermediate risk for developing cardiovascular disease.

According to ACC, the presentations showed that lowering cholesterol with statins significantly reduced adverse cardiovascular events in people with average cholesterol and blood pressure levels who were considered to be at intermediate risk for heart disease. Additionally, the use of blood pressure-lowering medications was beneficial only in those with higher blood pressure levels. 

As summarized by ACC, HOPE-3 found that statins—alone or in combination with blood pressure-lowering drugs—were superior to placebo for both the study’s first coprimary endpoint, a composite of cardiovascular deaths, heart attacks, and strokes, and its second coprimary endpoint, a composite of those events plus heart failure, resuscitated cardiac arrest, and revascularization procedures.

For these endpoints, blood pressure drugs were found to improve outcomes compared with placebo only in patients with elevated blood pressure; these drugs were associated with no improvements in patients without elevated blood pressure, and there was a trend toward worse outcomes in those with relatively low blood pressure. 

The HOPE-3 trial included 12,705 people in 21 countries on six continents. All participants had at least one known cardiovascular risk factor, such as smoking, an elevated waist-to-hip ratio, or a family history of heart disease, but none had been diagnosed with cardiovascular disease.

Participants were randomly assigned to receive either a 10 mg of rosuvastatin or a placebo pill daily and either a combination blood pressure-lowering pill (16 mg of candesartan and 12.5 mg of hydrocholothiazide) or a placebo pill daily. Patients were sorted evenly into four categories: those receiving both a cholesterol-lowering drug and a blood pressure-lowering drug, those receiving only a cholesterol-lowering drug, those receiving only a blood pressure-lowering drug, and those receiving only placebo pills. Outcomes were tracked for a median of 5.6 years. 

Cardiovascular death, heart attack, or stroke occurred in 3.5% of patients receiving both drugs and in 5% of patients receiving only placebo. The relative risk reduction in those taking both drugs was 30% overall, 40% in those with elevated blood pressure, and 20% in those without elevated blood pressure. The results for the study’s second coprimary endpoint were identical for this analysis. 

A separate analysis focusing on the use of statins alone showed 3.7% of participants who took statins experienced the first coprimary endpoint (a composite of cardiovascular deaths, heart attacks, and strokes), which was a significant reduction compared with 4.8% among patients taking a placebo. Among patients taking statins, 4.4% experienced the second coprimary endpoint, a composite of the events in the first coprimary endpoint plus heart failure, resuscitated cardiac arrest, and revascularization procedures, which was a significant reduction compared with 5.7% among patients taking a placebo. Patients taking statins experienced, on average, a decrease in low-density lipoprotein (LDL) cholesterol of 39.6 mg/dL (approximately 25%) after 12 months. 

The benefits of statins were similar across all ethnic groups and across all baseline LDL levels, suggesting that a person’s starting cholesterol levels are not important in determining whether the person will benefit from statins. These findings suggest that many people who have average cholesterol and blood pressure levels and are at average risk for heart disease—and not just those with extremely high cholesterol or blood pressure levels—can benefit from statins. The treatment was also remarkably safe; although some patients reported muscle weakness or pain, these effects were generally alleviated by stopping the statins or reducing the dose. 

An analysis focusing on the use of blood pressure lowering drugs alone revealed no significant improvements overall in those receiving the drugs compared with those receiving a placebo. However, in a prespecified analysis, when the patients were stratified into thirds by baseline systolic blood pressure, an analysis of subgroups with the highest, middle, and lowest starting systolic blood pressure revealed significant differences. Among the one-third of participants with the highest blood pressure, a starting systolic blood pressure above 143.5 mm Hg, 4.8% experienced the first coprimary endpoint and 5.7% experienced the second coprimary endpoint, significantly lower than 6.5% and 7.5%, respectively, among patients taking placebo. 

As noted in the ACC announcement, one limitation of the study is that, while it tracked patients for more than 5 years—a long period of time compared to most clinical trials—it can take many more years or even decades to show the full improvements in outcomes from primary disease prevention interventions. It is possible that extending the study for a longer period of time may have revealed larger benefits. 

HOPE-3 participants will be tracked for an additional 3 to 5 years. The investigators will continue to conduct additional analyses examining the effects on cognitive decline, erectile dysfunction, and vision, along with detailed analyses of potential differences among ethnic groups and geographic regions. 

“Blood-Pressure Lowering in Intermediate-Risk Persons without Cardiovascular Disease” was published in NEJM by Eva M. Lonn, MD, et al. The study was presented at ACC.16 by Dr. Lonn as “Blood Pressure Lowering in People at Moderate Risk. The HOPE-3 Trial.” 

“Cholesterol Lowering in Intermediate-Risk Persons without Cardiovascular Disease” was published in NEJM by Salim Yusuf, MBBS, et al. The study was presented at ACC.16 by Jackie Bosch, PhD, as “Effects of Rosuvastatin on Cardiovascular Disease in Moderate Risk Primary Prevention in Diverse Ethnic Groups.” 

“Blood-Pressure and Cholesterol Lowering in Persons without Cardiovascular Disease” was published in NEJM by Salim Yusuf, MBBS, et al. The study was presented at ACC.16 by Dr.Yusef as “Effects of Combined Lipid and BP-Lowering on Cardiovascular Disease in a Moderate Risk Global Primary Prevention Population.”

The trial was funded by the Canadian Institutes of Health Research and AstraZeneca, the manufacturer of the drugs tested. The study was independently designed and conducted by the Population Health Research Institute (PHRI) at McMaster University and Hamilton Health Sciences in Hamilton, Ontario. Dr. Yusef, who is the Executive Director of PHRI, leads the HOPE-3 investigators.