CHICAGO – The success in the HOPE-3 trial of a two-pronged strategy of a statin plus moderate-dose antihypertensive therapy has expanded the boundaries of primary preventive pharmacotherapy to incorporate many intermediate-cardiovascular-risk patients without cardiovascular disease.
In the Heart Outcomes Evaluation (HOPE)-3 trial, the combination of rosuvastatin (Crestor) at 10 mg/day plus antihypertensive therapy with 16 mg/day of candesartan and 12.5 mg/day of hydrochlorothiazide reduced cardiovascular events in intermediate-risk patients with hypertension, regardless of their baseline LDL-cholesterol and inflammatory biomarker levels. In nonhypertensive study participants, however, blood pressure-lowering therapy provided no added benefit beyond that achieved with the statin alone, which yielded a 25% relative risk reduction in cardiovascular events compared with placebo, Dr. Salim Yusuf reported at the annual meeting of the American College of Cardiology.
The HOPE-3 trial was the first formal study of the polypill concept of fixed-dose, low-dose combination therapy as a public health tool for primary prevention in an intermediate-risk population without cardiovascular disease. It’s a simple, low-cost, safe, pragmatic preventive strategy that doesn’t require baseline laboratory measurements, dose titration visits, or frequent safety monitoring, he noted.
“The original concept of the polypill was to give it to everyone over age 55. We found in HOPE-3 that the polypill concept is not valid for everybody. It demonstrated benefit in hypertensives but not in nonhypertensives, where a statin alone was beneficial,” said Dr. Yusuf, professor of medicine and executive director of the Population Health Research Institute at McMaster University in Hamilton, Ont.
“The clinical implication is that statins should be used much more widely than they currently are. Most guidelines for hypertension don’t say to give a statin. But HOPE-3 is saying hypertensives will benefit. About half of the 40% reduction in the risk of cardiovascular events we saw with combination therapy in patients in the highest third for baseline systolic blood pressure – that is, above 143.5 mm Hg, with a mean of 154 mm Hg – was due to the rosuvastatin and half to the antihypertensive therapy. Our study suggests you can essentially double the benefit of lowering blood pressure in hypertensives if you also lower cholesterol simultaneously,” he noted. Dr. Yusuf discussed the findings in a video interview.
The double-blind trial included a diverse population of 12,705 men age 55 or older and women age 65 or older in 21 countries. All were at intermediate cardiovascular risk by conventional stratification methods; none had a history of cardiovascular disease. They were randomized to rosuvastatin or placebo, dual antihypertensive therapy or placebo, or to all three medications or double placebo. The combined-therapy group experienced a 33.7 mg/dL greater drop in LDL-cholesterol and a 6.2 mm Hg bigger reduction in systolic blood pressure than in patients on dual placebo.
During a median followup of 5.6 years, the composite rate of cardiovascular death, nonfatal MI, or nonfatal stroke was 3.6% in the combined-therapy group and 5.0% with dual placebo, for a relative risk reduction of 29%. The number needed to treat for 5.6 years in order to prevent one event of the composite outcome was 72. However, the separation in the event rate curves for the two groups grew larger over time. With an additional planned followup of 3-5 years in HOPE-3, it’s likely the benefits will become even greater, according to Dr. Yusuf.
Combination therapy proved safe. Muscle aches and weakness as well as lightheadedness were more common in the combined treatment group than with dual placebo. However, permanent discontinuation rates were similar in the two groups.
HOPE-3 coinvestigator Dr. Eva Lonn presented the comparison between patients randomized to antihypertensive therapy without rosuvastatin or to placebo. In a prespecified subgroup analysis, active treatment resulted in a significant 27% reduction in the risk of the composite outcome compared with placebo in patients in the top one-third of baseline systolic blood pressure, no benefit in those with a systolic blood pressure of 131.6-143.5 mm Hg, and a suggestion of possible harm in patients whose systolic pressure at enrollment was 131.5 mm Hg or less.
Thus, the study helps define the minimum blood pressure at which antihypertensive therapy becomes beneficial, noted Dr. Lonn, professor of cardiology at McMaster University.
Dr. Yusuf said enthusiasm for the polypill concept as a means of reducing the growing global burden of cardiovascular disease remains strong among many experts. There is broad interest in a polypill for secondary prevention that will include aspirin, a beta blocker, and an ACE inhibitor of angiotensin receptor blocker as a low-cost means of improving medication adherence. And several large clinical trials of the polypill concept for primary prevention are underway, including a randomized trial conducted by Dr. Yusuf and coworkers in which several thousand high-risk subjects without baseline cardiovascular disease will receive a combination of a statin plus not two but three antihypertensive drugs.