HOPE-3 Blood Pressure and Lipid Lessons for Practice

Clyde W. Yancy, MD, MSc; Jennifer G. Robinson, MD, MPH


April 18, 2016

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Clyde W. Yancy, MD, MSc: Hi. This is Clyde Yancy from the Northwestern University Feinberg School of Medicine here in Chicago.

This is the culmination of the 2016 meeting of the American College of Cardiology (ACC16) in Chicago. This has been a great meeting, with lots of new data. One study that was particularly interesting to many of us was the Heart Outcomes Prevention Evaluation-3 (HOPE-3) trial.[1,2,3]

I could not be more delighted to have Jennifer Robinson with us. She is professor of medicine from the University of Iowa in Iowa City. Dr Robinson is here to help put HOPE-3 into the context of what more we know about prevention now than we knew before HOPE-3. Jennifer, welcome to this discussion.

Jennifer G. Robinson, MD, MPH: Thank you so much.

Dr Yancy: First, let us summarize HOPE-3, because a lot of people have heard tidbits about it, but I would like to provide more detail about the study.

Blood Pressure Arm of HOPE-3

Dr Robinson: HOPE-3 enrolled more than 12,000 people from around the world. In fact, almost one third were Chinese and South Asian. It was a true international trial. They included men over age 55 years and women over age 65 years with at least one risk factor for heart disease.

The study had a 2 × 2 factorial design. In the first arm of the study,[1] participants were randomly assigned to receive placebo or a low dose of a candesartan/hydrochlorothiazide combination. Then, in the second arm,[2] they were again randomly assigned to receive rosuvastatin 10 mg or placebo. Investigators analyzed the blood pressure changes, then the cholesterol changes, and finally blood pressure and cholesterol levels in those who received both treatments vs placebo.[3]

Dr Yancy: This is very interesting, and I want to be sure our audience understands. In one part of HOPE-3, patients were randomly assigned to fixed-dose combination therapy to lower blood pressure. But blood pressure did not dictate whether they got into HOPE-3. The enrollment criteria required only one risk factor for heart disease plus age.

Dr Robinson: Correct.

Dr Yancy: The investigators were testing something that was quite novel.

Dr Robinson: Correct. Surprising or not, the blood pressure arm of the study showed absolutely no benefit for lowering blood pressure with active treatment vs placebo. However, if you look at the one third of patients whose systolic blood pressures were above 140 mm Hg, they actually had a significant reduction. But those whose systolic blood pressures were below 140 mm Hg had no benefit. In fact, those in the bottom tertile with the lowest blood pressures had a trend toward harm.

This tells us that 140 mm Hg may be a good level at which to begin treating hypertension. This is great to know.

Dr Yancy: I want to get a bit more granular here, because I want the audience to understand this. The risk profile for those patients was slightly less than we typically talk about.

Dr Robinson: It was about 8%-9% risk, extrapolated over 10 years. The guidelines[4] recommend statins for patients with a 10-year atherosclerotic cardiovascular disease (ASCVD) risk at 7.5%. So these patients were right on that line.

Dr Yancy: In the SPRINT study,[5]we saw significant blood pressure lowering, understanding that the risk profile was at about 15%.

Dr Robinson: Yes—15% risk with a 15-mm Hg reduction in blood pressure vs a 6-mm Hg reduction in the HOPE-3 study.

Dr Yancy: So these results are entirely consistent with SPRINT.

Dr Robinson: They are totally consistent with SPRINT.

Dr Yancy: Both show the relationship between a risk phenomenon and the delta magnitude blood pressure change.

Dr Robinson: Correct. And thank goodness you do not have to treat everyone, because you can stop at a systolic blood pressure below 140 mm Hg. I like that.

Lipid-Lowering Arm of HOPE-3

Dr Yancy: Let's move on to the second part of HOPE-3[2] and the cholesterol, or lipid, intervention.

Dr Robinson: Unlike the blood pressure arm, this arm did show a benefit of active treatment. Rosuvastatin reduced cardiovascular events by about 25%, and we seemed to have found no lower limit. The extrapolated 10-year ASCVD risk was 8%-9%—again, right on that borderline.

What was interesting, however, was the 25% reduction in low-density lipoprotein cholesterol (LDL-C), or a difference of about 30 mg/dL. The number needed to treat was 91. Thus, the absolute risk reduction in people with low risk and a small amount of lipid-lowering is not very much.

Again, we may be defining the lower range for broad prevention in everyone on the basis of age. But I also believe the results tell us that whatever we said in the guidelines, you really need to look at the pooled cohort equations or whatever is appropriate for your country; estimate the patient's risk; and think about the patient's potential to benefit from adding a moderate-intensity statin to get a 30%-35% reduction in LDL-C, not 25%. So, there is potential for a reduction in events, and potential for harms.

Fortunately, in the statin arm of HOPE-3, there was only a small excess of muscle events, but really no adverse events, unlike in the blood pressure arm. In the end, you have to decide what the potential net benefit is for that specific patient.

Dr Yancy: And that is the point—that it really does validate the notion that the statin therapy in those at intermediate risk was beneficial, but not as much as we have seen before, and the benefit is a function of risk.

Dr Robinson: Right.

Dr Yancy: Those are the first two components of HOPE-3: blood pressure lowering, number one; statin therapy, number two. Now, let us talk about the third component of HOPE-3[3]: putting antihypertensive and statin therapy together. What do we come up with?

Dr Robinson: We saw a 25% reduction in cardiovascular events, which were attributable primarily to the amount of LDL-C reduction from the rosuvastatin. Thus, it was kind of the first outcomes trial for the polypill concept. Obviously, they used two separate pills, but it reinforced that we probably do not want to be using a polypill in primary prevention on the basis of age only. Actually, what HOPE told us is that we probably would only want to treat blood pressure in those whose risk is higher, with a blood pressure over 140 mm Hg, and it begins to look like what we are already doing.

Takeaways for Practice

Dr Yancy: What are the big takeaways for the practitioners who say that there is perhaps too much information about risk prevention? Some people are still wedded to the blood pressure being some magic number and the LDL-C being some magic number. Give me two or three pithy comments that the listeners, the practitioners, can take away and say, I get it, this is a different world, these are the new marching orders.

Dr Robinson: Cholesterol is perhaps the most straightforward. The 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines[4] say to consider moderate- or high-intensity statin therapy for those patients up to age 75 years who have 7.5% or greater ASCVD risk, and engage in a shared decision—a clinician/patient discussion to discuss the potential for benefit, the potential for harm, and the patient preferences. Some patients want to be aggressive, and others not so much. I believe the results of HOPE-3 reinforce the 2013 guidelines.

Regarding hypertension, in 2014, the Joint National Committee made an expert recommendation[6]to treat systolic blood pressure above 140 mm Hg or diastolic over 90 mm Hg, but we had no evidence. Now we have evidence that says yes, we should treat systolic blood pressure above 140 mm Hg by adding perhaps one drug that lowers it by a good amount.

Dr Yancy: But arguably, you can distill those two. Listen, if a patient has a relatively high risk profile—15% by the ASCVD risk calculator—then we need to not only treat the blood pressure, but we need a target number that is a substantial improvement, understanding that blood pressure medicines have side effects. If your blood pressure is not quite as elevated, but is right at the 140-mm Hg threshold and you have intermediate risk, then we can hold a conversation about the benefits and risks of treating the blood pressure, with some evidence that it would be beneficial, particularly if you concomitantly are taking a statin drug.

Dr Robinson: Exactly.

Dr Yancy: I believe we are getting closer to being able to be slightly more prescriptive, but never without the conversation with our patients.

Dr Robinson: Very well said. Thank you.

Dr Yancy: It has been delightful for us to revisit yet another prevention-significant database. Jennifer, your perspectives have been enlightening, profound, terrific, and fun.


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