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HOPE-3: Statins with or without BP-lowering drugs reduce CV events in intermediate-risk patients
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CHICAGO — 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.”
Salim Yusuf
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.”
Eva Lonn
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
References:
Bosch J., Lonn E., Yusuf S. Joint ACC/JACC Late-Breaking Clinical Trials I. Presented at: American College of Cardiology Scientific Session; April 2-4, 2016; Chicago.
Cushman W, Goff, D. N Engl J Med. 2016; doi:10.1056/NEJMe1603504.
Lonn E, et al. N Engl J Med. 2016; doi:10.1056/NEJMoa1600175.
Yusuf S, et al. N Engl J Med. 2016; doi:10.1056/NEJMoa1600177.
Yusuf S, et al. N Engl J Med. 2016; doi:10.1056/NEJMoa1600176.
Disclosures: The trial was funded by AstraZeneca and the Canadian Institutes of Health Research. Yusuf, Lonn and Bosch report receiving funding from several pharmaceutical companies. Yusuf and Lonn also report receiving consulting fees from several pharmaceutical companies. Cushman reports receiving grant support from Eli Lilly and Merck and unpaid consulting for Takeda. Goff reports no relevant financial disclosures.
Perspective
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B. Hadley Wilson, MD, FACC
This study’s findings are very optimistic. The researchers showed strongly that there is a practical way of administering medications to patients at intermediate risk. Over 5 years, these patients had improved survivorship and reduced CV events. Those who benefited the most were those with high BP, and all patients benefited from a statin. The findings also provide optimism about the polypill concept in the future.
Encouragingly, the findings reaffirm the recent cholesterol guidelines. I believe it will also reaffirm recent trials of patients with mild-to-moderate hypertension, which showed that it is important to treat those people, and now we know they will be doubly benefited by the addition of a statin.Perspective
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Martha Gulati, MD, MS, FACC
My perspective on this study is that the findings agree and match our current atherosclerotic CVD prevention guidelines that came out in 2013 from the American Heart Association and the ACC. It shows, yet again, that a moderate-intensity statin is effective at reducing CVD risk and mortality, regardless of LDL or BP value. Certainly the antihypertensives were effective in those who were hypertensive, but that was the only subgroup that these medications benefitted. On the other hand, statins were powerful and effective in terms of primary prevention over placebo in all these intermediate-risk patients. So a discussion of a polypill is really premature. Certainly in hypertensives, a polypill may be useful to improve adherence to and simplicity of needed drug regimens. But in terms of the remainder of those people who are intermediate risk, they simply need both therapeutic lifestyle changes (which do not come in a pill) and then possibly a moderate-intensity statin.
I hope that no one takes from this study that it was more than a class effect. In the U.S., most people cannot be put on rosuvastatin as a first-choice drug because it is expensive. But we have many choices of moderate-intensity statins that can be used and are lower-cost. What was impressive in this study was the large numbers of women included — almost half women — and the adherence and the follow-up, which was unseen in prior trials. So perhaps we have also learned that close follow-up for side effects and allowing patients to leave with medications will be highly effective in keeping patients taking their medications.
Perspective
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Jacqueline Tamis-Holland, MD, FACC, FAHA, FSCAI
Many cardiologists, including myself, feel that statins do more than just lower cholesterol. We refer to this as their pleiotropic effects. Statins have been proven to be effective in a wide array of clinical circumstances, including patients with known CHD irrespective of LDL level, patients without CHD and with high LDL, and patients without CHD who have elevated inflammatory markers. Until now, statins were not routinely given to patients with intermediate cardiac risk but acceptable cholesterol levels. The HOPE-3 study enrolled patients at intermediate risk for heart disease but without a clinical indication for statin therapy, and in the statin-therapy arm of the trial, randomized them to rosuvastatin 10 mg/day or placebo. This study showed a consistent, across-the-board reduction in cardiac events of approximately 25% with rosuvastatin. This finding supports the hypothesis that the benefit of a statin goes beyond that of LDL-lowering alone. I believe that statins “stabilize” the atherosclerotic plaque, thus preventing events.
The take-home message of this trial is that doctors may now be able to reduce the likelihood for CV events in moderate-risk patients by treatment with statin therapy. I’m not going to prescribe a statin to everybody walking into my office, but if someone has several risk factors — particularly if they have a family history of heart disease — and they are of the right age, then I think a statin should be considered.
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