Results of the global HOPE-3 trial, released earlier this month, add weight to the argument that treating people with statins in primary care reduces the likelihood of cardiovascular events over their lifetime. The picture is less clear on the benefits of primary prevention with blood pressure-lowering drugs.
The trial included 12,705 men and women in six continents. All of the patients were 55 years of age or older and had at least one cardiovascular risk factor, such as family history of heart disease, smoking or abnormal blood sugar levels, but had never been diagnosed with cardiovascular disease.
During the trial, patients were randomized to receive either a cholesterol-lowering drug or placebo and blood pressure-lowering therapy or placebo, creating four possible treatment combinations. The patients were followed for an average of 5.6 years.
Patients who received 10 mg of rosuvastatin plus 16 mg of candesartan and 12.5 mg of hydrochlorothiazide daily saw a 1.4% lower the risk of cardiovascular death, heart attack and stroke than those on placebo. However, when analyzed separately, the benefits of the drugs were less than even: patients receiving rosuvastatin had a 25% reduction in risk of future serious events, while patient treated with candesartan and hydrochlorothiazide alone saw no significant improvement.
“The implications for practice are huge," Salim Yusuf, executive director of the Population Health Research Institute of McMaster University and Hamilton Health Sciences and senior member of the study team, said in a press release announcing the results. "I think we certainly should consider using statins much more widely than we have used them thus far.”
The results appear to vindicate what has been a controversial recommendation in the American College of Cardiology and American Heart Association’s 2013 guideline for management of blood cholesterol - that people between the ages of 40 to 75 who have an estimated 10-year risk of cardiovascular disease of 7.5% or higher be treated with moderate-intensity stain therapy.
“Those that were against [the recommendation] have been saying, where’s the evidence?” Prakash Deedwania, professor of medicine at the University of California San Francisco-Fresno, said. “Now we have the evidence.”
John Meigs, president-elect of the American Academy of Family Physicians, said the HOPE-3 study reinforces what many in primary practice already knew — that in the appropriate individual, taking all of their situation and risk factors into account, reducing cholesterol and blood pressure does improve outcomes.
“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,” Yusef said. “Our approach, which used a combination of moderate doses of two blood pressure-lowering drugs plus a stain, appears to produce the biggest ‘bang,’ in terms of reducing events, with few side effects.”
For Deedwania, who was not part of the study team, “there’s no question that people who are intermediate risk, even if they have not had any adverse cardiovascular event, they will benefit, and even they will benefit if they live in low-income countries.”
“The benefits are quite universal, and also it was very safe,” said Eva Lonn, Population Health Research Institute, who led the blood pressure-lowering arm of the HOPE-3 study.
Lonn notes, for instance, that the study showed no link between statin use and development of Type 2 diabetes — contrary to the JUPITER trial, although patients did report a notable rate of muscle weakness and pain associated with rosuvastatin. This, however, tended to be temporary, Lonn said.
The results could aid in medication adherence by reinforcing the message that preventive therapy works. “It gives us ammunition, because my patients who push back,” said Sandra Lewis, owner of Northwest Cardiovascular in Portland, OR, and chair of the ACC’s Women in Cardiology Section.
“They don’t push back when they’ve had a heart attack, but if they’re just coming in and … want to take care of themselves, but don’t want to take pills, I have a new set of support for telling them that we really can make a difference,” Lewis added.
“It’s an issue we all struggle with,” Lonn said, noting that the antihypertensives study had a cumulative nonadherence rate of 23%. “What physicians can do is point out in simple words the benefits that can be accrued and the safety — that needs to always be emphasized in primary prevention."
Meigs agreed, but said he favors as lifestyle approach — diet and exercise — for individuals with very low risk of cardiovascular events.
“Understand, these drugs do have side effects,” he said. “They’re very difficult for some people to take … and if some of the side effects are emphasized in the media, that scares off some people.”
For people who could benefit from therapy but are reluctant to go on long-term medication, Meigs said showing them their risk calculation can get them to buy in. Showing someone that they’ve got a 20% chance of having a heart attack in the next 10 years will get their attention quicker than saying their cholesterol is 285, he added. “You have to personalize it a little bit.”
One limitation of the study is its length, because it may take decades for the full effects of primary prevention disease prevention interventions to be seen.
“What we have to do is extrapolate what the benefit would be if you take the therapy not for five years, as in the study, but for 10 years or 15 or 20 or more,” Lonn said. “The expectation is that the benefits would be larger, not smaller.”
In an accompanying editorial, William Cushman, with the Veterans Affairs Medical Center in Memphis, and David Goff, University of Colorado Denver, suggested that increasing the dosage of the antihypertensive drugs, or replacing hydrochlorothiazide with chlorthalidone, may have “significantly reduced” cardiovascular events.
The HOPE-3 study was funded by grants from the Canadian Institutes of Health Research and AstraZeneca.