Data from the HOPE-3 trial support the expanded use of statins in intermediate-risk individuals who do not have CVD, and indicate that statin therapy in combination with antihypertensive medications offers a 30% reduction in CV events, but only in participants with high BP.

The findings could eventually lead to development and use of a polypill for primary prevention, researchers reported.

“The implications for practice are huge — I think we certainly should consider using statins much more widely than we have used them thus far,” Salim Yusuf, MBBS, DPhil, professor of medicine at McMaster University and executive director of the Population Health Research Institute of McMaster University and Hamilton Health Sciences, said in a press release. “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.”

Yusuf said during a press conference at the American College of Cardiology Scientific Session that “this was the first formal testing of the polypill concept on clinical events.

“The trial demonstrated that the concept is valid in people with elevated BP. In others, there is no benefit,” he said. The findings were also published in three articles in the New England Journal of Medicine.

The 2-by-2 factorial trial included 12,705 people in 21 countries. Eligibility for enrollment was based on age and presence of at least one CV risk factor, but not on baseline lipid level. The researchers investigated the effectiveness of rosuvastatin (Crestor, AstraZeneca) 10 mg/day and candesartan 16 mg/day plus hydrochlorothiazide 12.5 mg/day as well as the combination of the two therapies in reducing CV events in patients at intermediate risk for CVD. The first co-primary outcome was the composite of death from CV causes, nonfatal MI or nonfatal stroke and the second co-primary outcome was resuscitated cardiac arrest, HF and revascularization. Median follow-up was 5.6 years.

CV benefit of BP-lowering medications

In the primary analysis of the trial, the effectiveness of candesartan (16 mg/day) plus hydrochloride (12.5 mg/day) was compared against a placebo.

“One of the unique features of the main study results was that it allowed a relatively wide range of BP entry levels,”Eva Lonn, MD, FACC, a cardiologist and professor of cardiology at McMaster University and senior scientist at the Population Health Research Institute, said at the press conference. “This is why we were successful in conducting some subgroups in the trial.”

According to the results, there was a 6 mm Hg systolic/3 mm Hg diastolic greater decrease in BP in the treatment group than in placebo, and 260 participants (4.1%) in the treatment group experienced the first coprimary endpoint compared with 279 (4.4%) in the placebo group (HR = 0.93; 95% CI, 0.79 -1.1; P = .4).

Three hundred and twelve participants (4.9%) in the treatment group met the secondary primary endpoint versus 328 (5.2%) of those assigned placebo (HR = .95; 95% CI, 0.81 to 1.11; P = .51) in the placebo group. However, in a subgroup analysis of patients with systolic BP >143.5 mm Hg, significant reductions were observed in both primary endpoints.

“Overall in this population, the [BP]-lowering drugs had no clear benefit, but in those with higher [BP] before therapy — over 143.5 mm Hg — the treatment was effective. However, there was no benefit in those with lower [BP] and even a tendency towards harm in those in the lowest third of the [BP] distribution,” Lonn said.

Targeting both cholesterol and BP

In a secondary analysis, participants were randomized to either rosuvastatin 10 mg/day and candesartan 16 mg/day plus hydrochlorothiazide 12.5 mg/day (n = 3,180) or to dual placebo (n = 3,168). The researchers observed that participants assigned the combined treatment experienced a reduction in CV events.

“Most of the hypertension guidelines right now focus on what agents to use and what [BP] to aim for, and there has been very little emphasis on the importance of statins in treating patients with hypertension,” Yusuf said in a press release.

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

One hundred thirteen (3.6%) participants in the combined treatment group experienced the first coprimary endpoint compared with 157 (5%) from the dual placebo group (HR = 0.71; 95% CI, 0.56 to .90; P = .005). A reduction in the second coprimary endpoint was seen as well, 4.3% in combined therapy group vs. 5.9% in the dual placebo group (HR = 0.72; 95% CI, 0.57 to 0.89; P = .003).

In addition, those in the combined therapy group had a 33.7 mg/dL-greater decrease in LDL level and a 6.2 mm Hg-greater decrease in systolic BP than those in the dual placebo group.

Expanding statin use

In another analysis, the broad application of statins to an ethnically diverse population at intermediate risk was evaluated.

“Unique features of this arm of the trial included that there was no entry criteria based on lipid levels, no routine monitoring through the study, and no dose titration,” Jackie Bosch, PhD, associate professor of rehabilitation science at McMaster University and director of the prevention program at the Population Health Research Institute, said at the press conference.

Mean LDL cholesterol level was reduced 26.5% in the rosuvastatin group compared with the placebo group, according to the results. Two hundred and thirty-five participants (3.7%) in the rosuvastatin group vs. 304 participants (4.8%) in the placebo group (HR = 0.76; 95% CI, .64-.91; P = .002) met the first coprimary endpoint. Similar results were found with the second coprimary endpoint: 277 patients (4.4%) in the rosuvastatin group vs. 363 participants (5.7%) in the placebo group (HR = 0.75; 95% CI, 0.64 to 0.88; P < .001).

“There were consistent benefits regardless of baseline LDL cholesterol, systolic BP, CV risk and ethnicity,” Bosch said.

The researchers noted a longer follow-up might be needed to see the full effects of the therapies, and that they plan on continuing follow-up for another 3 to 5 years and to further analyze possible ethnic and geographic differences.

In an editorial published in NEJM, William C. Cushman, MD, of the Veterans Affairs Medical Center in Memphis, TN and David C. Goff, Jr., MD, PhD, of the Colorado School of Public Health at the University of Colorado, wrote that “these results support a risk-based approach to statin use, which has been recommended in recent guidelines, rather than an approach that is based primarily on LDL cholesterol levels, and the results add to the evidence supporting statin use for primary prevention.”

Cushman and Goff pointed out that while “neither of the drugs for BP lowering that were used in the trial have been shown to reduce the risk of CV events at such low doses … if higher doses had been used, the risk of CV events might have been significantly reduced, whether from greater BP lowering, additional effects of the antihypertensive drugs or both.”

 “These results may help to define the combined threshold of systolic [BP] (< 140 mm Hg) and [CV] risk (< 5%) below which the use of [BP]-lowering medications may not be useful in the short-term. However, these results do not rule out the possibility of a benefit with longer-term treatment in a portion of this relatively low-risk population,” Cushman and Goff wrote. – Tracey Romero