Statins, but not antihypertensives, reduce CV events in intermediate risk patients, study finds

Preventative statin therapy significantly reduced the risk of cardiovascular events in patients at intermediate risk for heart disease, while blood pressure-lowering medications reduced cardiovascular events only in those with higher blood pressure levels, according to three separate studies from the large HOPE-3 trial presented April 2, 2016 at the American College of Cardiology’s Annual Scientific Session in Chicago, IL.

“The implications for practice are huge—I think we certainly should consider using statins much more widely than we have used them thus far,” said principal investigator Salim Yusuf, MBBS, DPhil, Professor of Medicine and Executive Director of the Population Health Research Institute of McMaster University and Hamilton Health Sciences, in Hamilton, Canada.

“In particular for patients with hypertension, our study suggests you can essentially double the benefit of lowering blood pressure in hypertensives if you also lower cholesterol simultaneously,” Dr. Yusuf said.

The three HOPE-3 (Heart Outcomes Prevention Evaluation-3) studies were published simultaneously in the New England Journal of Medicine. The entire trial involved 12,705 people in 21 countries on 6 continents. All participants had an intermediate risk for cardiovascular events—each had at least one known cardiovascular risk factor, but none had been diagnosed with cardiovascular disease (CVD).

Current guidelines recommend the use of cholesterol- and blood pressure-lowering drugs mainly in patients at high risk for CVD, the researchers noted. This trial is the first to investigate the following questions in people with intermediate risk of CVD:

• Can statins lower the risk of cardiovascular events in an ethnically diverse, intermediate risk population without CVD?
• Can blood pressure-lowering medications lower the risk of cardiovascular events in this population?
• Can lowering both elevated blood pressure and elevated low-density lipoprotein (LDL) cholesterol substantially reduce the risk of cardiovascular events in this population?

HOPE-3 study on statin treatment only

The study arm that investigated use of statins alone showed that treatment with 10 mg per day of rosuvastatin proved to significantly and safely reduce CVD events by 25% in patients at intermediate risk without CVD.

The benefits of statin treatment were similar across all ethnic groups and across all baseline LDL levels, the researchers found. This suggests that a person’s starting cholesterol levels are not important in determining whether the person will benefit from statins.

In addition, these findings indicate that it’s not only people with high cholesterol levels who can benefit from statins, but also those who have average cholesterol levels and are at average risk for heart disease, the researchers noted.

“The take-home message is that statins are safe and effective, and that because benefits were similar irrespective of pretreatment cholesterol levels or levels of inflammatory markers, no baseline blood tests are required to identify the patients who will derive benefits from this treatment,” said study leader Jackie Bosch, PhD, Associate Professor of Rehabilitation Science and Director of the Prevention Program at the Population Health Research Institute at McMaster University. “Our results were remarkably consistent across all subgroups.”

The treatment was also remarkably safe, researchers found. Although about 5% of patients reported muscle weakness or pain, discontinuing or reducing the dose of the statin usually alleviated these effects.

“We are incredibly encouraged by the study’s results,” Dr. Bosch said.

HOPE-3 study on blood pressure-lowering treatment only

In contrast to the promising findings of the first study, the study arm that investigated the use of only blood pressure-lowering drugs—16 mg of candesartan plus 12.5 mg of hydrochlorothiazide per day—found no significant improvements overall in those receiving the drugs compared with those receiving a placebo.

“Overall in this population, the blood pressure lowering drugs had no clear benefit; but in those with higher blood pressure before therapy—over 143.5 mm Hg—the treatment was effective,” said study leader Eva Lonn, MD, Professor of Cardiology at McMaster University and Senior Scientist at the Population Health Research Institute.

However, people with blood pressure lower than 143.5 mm Hg showed no benefit, and in those in the lowest third of the blood pressure distribution, antihypertensives showed a tendency towards harm.

“These data suggest blood pressure-lowering medications are appropriate for people with hypertension, but that people with lower blood pressure who have no other reasons to use blood pressure-reducing drugs should avoid taking these drugs,” Dr. Lonn said.

HOPE-3 study on combined statin and blood pressure-lowering treatment

In this study, daily combination therapy—10 mg of rosuvastatin and 6 mg of candesartan plus 12.5 mg of hydrochlorothiazide—safely reduced overall risk among participants by 30% without dose titration or the need for frequent blood tests, the researchers found.

In addition, the combination treatment reduced risk by nearly 40% in participants with elevated blood pressure, and by 20% in those without elevated blood pressure.

“Most of the hypertension guidelines right now focus on what agents to use and what blood pressure to aim for, and there has been very little emphasis on the importance of statins in treating patients with hypertension,” Dr. Yusuf noted.

“Our approach, which used a combination of moderate doses of two blood pressure lowering-drugs plus a statin, appears to produce the biggest ‘bang’ in terms of reducing events with few side effects,” he said.

‘Polypill’ not yet ready for prime time

Given these results, could a “polypill”—a single pill that combines a statin drug with antihypertensive medications—be a public health care solution to prevent CVD around the world? Not just yet, wrote William C. Cushman, MD of the Preventive Medicine Section, Veterans Affairs Medical Center in Memphis, TN, and David R. Goff, MD of the Colorado School of Public Health, University of Colorado Anschutz Medical Campus in Aurora, CO, in an accompanying editorial.

In the HOPE-3 study arm that investigated combination treatment, the commentators speculated that it was the statin that produced the lion’s share of the benefit.

“Although the addition of blood-pressure lowering to rosuvastatin therapy appeared to provide more benefit than that observed with rosuvastatin alone in the subgroup of participants who were in the upper third of systolic blood pressure levels, the P value for interaction was not significant,” they wrote.

The HOPE-3 trial was funded by a grant from the Canadian Institutes of Health Research and by an unrestricted grant from AstraZeneca.