HOPE-3: Reducing LDL Cholesterol Improves Outcomes in Intermediate-Risk Patients, but BP-Lowering Does Not

CHICAGO, IL—In a large group of intermediate-risk patients without cardiovascular disease, treatment with a low-dose statin plus an angiotensin receptor blocker (ARB) and thiazide diuretic significantly reduced the risk of cardiovascular events when compared with placebo.

Those are the main findings from the Heart Outcomes Prevention Evaluation (HOPE)-3 study, a large randomized, placebo-controlled clinical trial presented here today at the American College of Cardiology 2016 Scientific Sessions. The study, which is published as a series of papers in the New England Journal of Medicine to coincide with the late-breaking trial session, included 12,705 intermediate-risk patients from 21 countries.

For Salim Yusuf MBBS (Population Health Research Institute, Hamilton, Canada), who led the HOPE-3 study, the trial is the formal testing of the polypill concept and its potential effects on hard cardiovascular events. And while investigators say the results don’t support blanket lipid- and blood pressure-lowering in all patients at intermediate risk, they maintain that certain individuals, particularly those with higher baseline systolic blood pressure, could benefit from the simple, low-cost combination of statin therapy and two antihypertensive medications.  

“It’s not a polypill, but it’s a concept, and it demonstrates the concept is valid in those with elevated blood pressure, but not in others,” said Yusuf. “The idea behind the polypill originally was to give it to everybody in the population over age 55 years. I don’t think that’s the case anymore. If you have blood pressure that’s not elevated, our data show that you shouldn’t treat. Of course, if you have high risk, then that’s a different issue.”

The HOPE-3 findings—which included patients randomized to statin therapy and blood-pressure-lowering therapy in a 2x2 factorial design—showed the combination of rosuvastatin 10 mg, candesartan 16 mg, and hydrochlorothiazide 12.5 mg per day resulted in a statistically significant 1.4% absolute reduction in the risk of cardiovascular mortality, nonfatal MI, and nonfatal stroke among patients treated for a median of 5.6 years. 

Regarding the second coprimary endpoint, which included death from cardiovascular causes, nonfatal MI, and nonfatal stroke, along with resuscitated cardiac arrest, heart failure, and coronary revascularization, active treatment with the lipid-lowering and blood pressure-lowering therapy led to a statistically significant 1.6% absolute reduction in risk when compared with patients treated with dual placebo.

The benefit of treatment, however, was largely derived from the reduction in LDL cholesterol levels. When analyzed separately, treatment with rosuvastatin reduced the risk of both coprimary endpoints by approximately 25% compared with placebo-treated patients, whereas treatment with candesartan and hydrochlorothiazide alone had no significant impact on clinical outcomes.  

Speaking with the media, Yusuf argued that while the benefits of treatment in the overall trial are largely derived from the reduction in LDL cholesterol levels, the benefit of blood pressure-lowering is evident among patients with higher baseline systolic blood pressures. For example, when investigators analyzed clinical outcomes among patients with systolic blood pressures less than 131.5 mm Hg, 131.6 to 143.5 mm Hg, and more than 143.5 mm Hg, they did observe an additional reduction in cardiovascular events with blood pressure-lowering therapy on top on statin therapy.  

“While overall, it seems that most of the benefit in the combination arm comes from statins and little comes from candesartan and hydrochlorothiazide, it’s hiding the fact there is a different effect in those with elevated blood pressure,” said Yusuf. “For those with elevated blood pressure, the benefit was a 40% risk reduction, with about half coming from the statin and half coming from the blood pressure-lowering.”

Among patients with systolic blood pressures less than 143.5 mm Hg, the entire benefit is derived from statin therapy, and there is even some suggestion the antihypertensive medications might cause harm among patients with baseline systolic blood pressures less than 131.5 mm Hg, said Yusuf.     

Analyzing the Interventions Separately

HOPE-3 was designed as a relatively simple, low-cost clinical intervention. The trial included men 55 years of age and women 65 years of age and older with at least one cardiovascular risk factor. There were no lipid or blood-pressure entry criteria, and patients were infrequently monitored in order to minimize costs, according to investigators. Eligible patients received active treatment for 4 weeks before randomization.  

In the cholesterol-lowering arm of the trial, which was led by Jackie Bosch, PhD (Population Health Research Institute), the mean LDL cholesterol level at baseline in the rosuvastatin- and placebo-treated patients was 128 mg/dL, but by 1 year, the mean LDL cholesterol level was 39.6 mg/dL lower among patients treated with the statin. The mean overall difference in the LDL cholesterol level achieved with therapy was 34.6 mg/dL averaged over the entire study duration. 

Regarding clinical outcomes, treatment with rosuvastatin reduced the absolute risk of death from cardiovascular causes, nonfatal MI, and nonfatal stroke by 1.1% when compared with placebo (HR 0.76; 95% CI 0.64-0.91). Regarding the secondary coprimary endpoint, treatment with rosuvastatin resulted in an absolute risk reduction of 1.3% compared with placebo (HR 0.75; 95% CI 0.64-0.88).

Steven Nissen, MD (Cleveland Clinic, OH), who was not involved in the trial, said that most of the patients included in HOPE-3 would qualify for statin therapy based on the current American College of Cardiology/American Heart Association cholesterol guidelines. “These people had a lot of risk factors, 25% or more were smokers, they had a strong family history, abdominal obesity, and LDL cholesterol levels of 130 mg/dL,” said Nissen. “If you put them into a risk calculator, they’re going to have about a 10% risk [of cardiovascular events over 10 years].”

For Nissen, the results confirm that “moderate-risk patients benefit from statin therapy,” but he said it takes some time for such benefits to become evident. In HOPE-3, the event curves began to separate at 1 year, but it was nearly 3 years before the difference between active treatment and placebo was statistically significant. 

Howard Weintraub, MD (NYU Langone Medical Center, New York, NY), said he views the results not so much as supportive of the clinical guidelines, but rather as support for the lower-is-better hypothesis. “Even when you think you don’t have to lower LDL cholesterol any further, even in a group of intermediate-risk patients without cardiovascular disease, lowering LDL cholesterol more creates benefit,” said Weintraub. 

Weintraub noted that the study did not show any increase in the risk of new-onset diabetes with statin therapy, in contrast with the JUPITER study, although the investigators did report a higher rate of muscle pain/weakness among those treated with rosuvastatin. These side effects were reversible, according to the researchers. There was also a higher rate of cataract surgery among patients treated with statins compared with placebo. 

HOPE-3: Blood Pressure-Lowering Arm 

On the other side of the HOPE-3 study, investigators reported less impressive results with blood pressure-lowering. Overall, the mean blood pressure of participants at baseline was 138/82 mm Hg and following treatment, patients in the active-therapy arm had a 6.0-mm Hg larger reduction in systolic blood pressure and a 3.0-mm Hg larger reduction in diastolic blood pressure over the follow-up period when compared with those treated with placebo. 

The main coprimary endpoint—death from cardiovascular causes, nonfatal MI, or nonfatal stroke—occurred in 4.1% of patients randomized to candesartan plus hydrochlorothiazide and 4.4% of patients in the placebo arm, a nonsignificant difference. The second primary endpoint occurred in 4.9% of patients treated with active therapy and 5.2% of patients randomized to placebo, also a nonsignificant difference.

However, like the overall results, the benefit of blood pressure-lowering was evident among individuals with the highest systolic blood pressure levels: those with a baseline systolic blood pressure greater than 143.5 mm Hg. In these patients, treatment with candesartan and hydrochlorothiazide reduced the risk of cardiovascular mortality, nonfatal MI, and nonfatal stroke by 27% compared with placebo. Similarly, the second coprimary endpoint was reduced 24% compared with placebo. In contrast, for individuals with a baseline systolic blood pressure less than 131.5 mm Hg, there was a trend toward a higher risk of cardiovascular events when treated with candesartan and hydrochlorothiazide.  

For Eva Lonn, MD (Population Health Research Institute), who led the blood pressure-lowering arm of HOPE-3, the results suggest individualizing treatment is necessary in hypertension. The bottom line, she said, is “to treat blood pressure when it’s elevated, and don’t treat it when there is no increase in blood pressure.” And while that statement might appear self-evident, Lonn said, the Eighth Joint National Committee (JNC-8) and the European guidelines for the treatment of high blood pressure are still debating when to start treatment for patients with uncomplicated hypertension.

Weintraub told TCTMD the blood-pressure results create a little confusion for physicians in light of the SPRINT data. In that trial, which included high-risk patients without cardiovascular disease who had a baseline systolic blood pressure > 130 mm Hg, the use of antihypertensive medication significantly reduced the risk of death from any cause and cardiovascular events. Patients in SPRINT, however, were required to have subclinical cardiovascular disease or a 10-year risk of cardiovascular disease that was 15% or greater, a higher-risk profile than those randomized in HOPE-3. 

“There is real ambivalence and ambiguity about the right systolic blood pressure, and this trial did not help,” said Weintraub. In addition, others might question if treatment with different antihypertensive agents might have had an impact on clinical events. For him, if a patient has a systolic blood pressure of 131 mm Hg, Weintraub is “not going to chase it down any further.” If it was 138 mm Hg, like it was in HOPE-3, he would work to lower blood pressure, he said.

In an editorial, William Cushman, MD (Veteran Affairs Medical Center, Memphis, TN), and David Goff, MD, PhD (University of Colorado Anschutz Medical Center, Aurora), say the results of HOPE-3 may help to define the combined threshold of systolic blood pressure and cardiovascular risk below which the use of blood pressure-lowering medication might not be useful in the short term. For the editorialists, individuals with a systolic blood pressure > 140 mm Hg would appear to benefit from treatment, especially given that the high rate of cardiovascular events among those with elevated systolic blood pressure in HOPE-3 treated with placebo.