Results from a trio of papers detailing the Heart Outcomes Prevention Evaluation (HOPE)-3 trial demonstrated that cholesterol-lowering statin therapy plus two blood pressure drugs reduced the risk of cardiovascular events in intermediate risk patients with average cholesterol and blood pressure levels.

However, the blood pressure treatments were only beneficial for hypertensive patients, calling into question the polypill concept for primary prevention.

“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 co-investigator Dr. Salim Yusuf, professor of medicine at McMaster University and executive director of the Population Health Research Institute of McMaster University and Hamilton Health Sciences in Hamilton, Ontario, Canada.

“In particular for patients with hypertension, our study suggests you can essentially double the benefit of lowering [BP] in hypertensives if you also lower cholesterol simultaneously.”

HOPE-3 combined cholesterol and BP lowering strategies

HOPE-3 was a 2×2 factorial design trial that included 12,705 people at intermediate risk without cardiovascular disease randomized to rosuvastatin or placebo and an angiotensin receptor blocker (ARB) plus a thiazide diuretic or placebo. [N Engl J Med 2016;doi:10.1056/NEJMoa1600177]

The first co-primary outcome of a composite of heart attack, stroke, and death from cardiovascular disease occurred in 3.6 percent of patients in the combined therapy group compared with 5 percent in the placebo group after a median 5.6 years of follow up (hazard ratio [HR], 0.71; 95 percent confidence interval [CI], 0.56 to 0.90; p=0.005).

The second co-primary outcome, which added heart failure, cardiac arrest, or revascularization to the first co-primary outcome, occurred in 4.3 percent of combined therapy group and 5.9 percent of the placebo group (HR, 0.72; 95 percent CI, 0.57 to 0.89; p=0.003).

The relative risk reduction was 30 percent overall for the combined therapy group, 40 percent among hypertensive patients, and 20 percent among non-hypertensive patients.

Though not wanting to “minimize” the trial results, Dr. Valentin Fuster, director of Mount Sinai Heart at The Mount Sinai Hospital in New York, New York, US, who was unaffiliated with the trial, emphasized care in interpreting the results, since a 30 percent risk reduction is one way of describing results where the absolute event rate was about 1.2 percent.

Statins alone lowered CV events

An analysis of statin use showed that 3.7 percent of patients on rosuvastatin experienced the first co-primary endpoint versus 4.8 percent of patients on placebo (HR, 0.76; 95 percent confidence interval [CI], 0.64 to 0.91; p=0.002). The second co-primary endpoint similarly favoured the statin group – 4.4 percent occurrence versus 5.7 percent in the placebo group (HR, 0.75; 95% CI, 0.64 to 0.88; P<0.001), and after a year patients on statin therapy had a 25 percent reduction in LDL cholesterol. [N Engl J Med 2016;doi:10.1056/NEJMoa1600176]

“The take-home message is that statins are safe and effective, and that because benefits were similar irrespective of pre-treatment 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 Dr. Jackie Bosch, associate professor of rehabilitation science at McMaster University and director of the prevention program at the Population health Research Institute, who led the rosuvastatin arm of HOPE-3.

BP lowering useful in hypertensive patients

A separate analysis focused on blood pressure lowering showed no significant benefits from treatment compared to placebo, except in patients whose blood pressure was over 143.5 mm Hg at baseline (about one-third of participants). In this group, 4.8 and 5.7 percent of patients experienced the first and second co-primary endpoints, respectively, compared to 6.5 and 7.5 percent experienced by those receiving placebo. [N Engl J Med 2016;doi:10.1056/NEJMoa1600175]

“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 [them],” said Dr. Eva Lonn, a cardiologist and professor of cardiology at McMaster University and senior scientist at the Population Health Research Institute, who led the blood pressure portion of HOPE-3, adding that in the lowest blood pressure tertile, there was a tendency towards harm with treatment.

Putting the polypill in play?

In what was the first formal testing of the polypill concept on clinical events, Yusuf said, the conclusion from HOPE-3 is “that the concept is valid in people with elevated BP. In others, there is no benefit.”

In an accompanying comment, Dr. William Cushman of the University of Colorado, Denver, in Denver, Colorado, US, and Dr. David Goff of the University of Tennessee Health Science Center in Memphis, Tennessee, US wrote in favor of statins for primary prevention.

“These results support a risk-based approach to statin use, which has been recommended in recent [American College of Cardiology/American Heart Association] guidelines, rather than an approach that is based primarily on LDL cholesterol levels, and he results add to the evidence supporting statin use for primary prevention.” [N Engl J Med 2016;doi:10.1056/NEJMe1603504]

They also noted that a higher dose of antihypertensives may have further reduced the risk of cardiovascular events, but Lonn said that, in their population of mostly average blood pressure, avoiding side effects was more important.