HOPE-3: Statins Lower CV Events in Intermediate-CHD-Risk Patients

Deborah Brauser

April 02, 2016

CHICAGO, IL ( updated ) — Cholesterol-lowering therapy alone and with blood-pressure (BP)–lowering treatment may prevent CV events in patients considered at "intermediate risk" for CHD—but BP lowering alone doesn't do the trick unless BP was high to begin with, suggests primary results from the randomized Heart Outcomes Prevention Evaluation-3 (HOPE-3) trial.

At a late-breaking clinical-trial session here at the American College of Cardiology (ACC) 2016 Scientific Sessions, investigators gave three different presentations from HOPE-3, which had a 2x2 factorial design and included almost 13,000 participants without CVD. The findings were simultaneously published today in the New England Journal of Medicine.

"It's interesting that statins are not a new antihypertensive. It very clearly showed that it had no effect on blood pressure—but it stopped the events in the hypertensive people," ACC president Dr Kim Alan Williams (Rush University Medical Center, Chicago, IL) told heartwire from Medscape.

"To see that half of the benefit was in that group with the statin and half in antihypertensive treatment, that's not something people thought of before," said Williams, who was not involved with the trial. "We don't need to give dyslipidemic people an antihypertensive. But we may need to give antihypertensive therapy and statins to those who are hypertensive."

Dr Kim Allan Williams

In HOPE-3's first arm[1], those who received BP-lowering treatment consisting of candesartan 16 mg/day and hydrochlorothiazide 12.5 mg/day did not have significantly fewer occurrences of a composite of CV-related death, nonfatal MI, or nonfatal stroke (the first co-primary outcome) a mean of 5.6 years later compared with those who received placebo (4.1% vs 4.4%, respectively). The second co–primary outcome, which added heart failure, cardiac arrest, or revascularization to the composite, was also not significantly different between the groups (4.9% vs 5.2%).

However, prespecified subgroup analysis, which divided baseline systolic BP into thirds, showed that the participants with upper-third measurements (>143.5 mm Hg) receiving candesartan/hydrochlorothiazide did meet the co–primary outcomes.

In the second arm[2], the participants who were randomized to rosuvastatin 10 mg/day also met both primary outcomes vs placebo (P=0.002 and P<0.001 for both group comparisons, respectively) and had a 24% lower risk for CV events.

The trial's third arm[3] assessed patients randomized to rosuvastatin plus candesartan/hydrochlorothiazide vs rosuvastatin plus placebo vs candesartan/hydrochlorothiazide plus placebo vs two placebos. The findings showed that those who received both of the treatment drugs together had significantly lower rates of the first primary outcome vs the double-placebo group (3.6% vs 5.0%, respectively, P=0.005), as well as the second primary outcome (4.3% vs 5.9%, P=0.003).

"In this arm, we found about a 30% reduction for the major end points," coinvestigator Dr Eva M Lonn (McMaster University, Hamilton, Ontario) said to heartwire .

"Overall, in an intermediate-risk population, it appears that everybody benefits from statins and that statins are safe. But in terms of blood-pressure lowering, those without elevated BP do not derive any benefit," said Lonn.

Unclear Role

Although antihypertensives have been shown to decrease CV-event risk in those considered high risk who have a systolic BP >160 mm Hg, "its role in persons at intermediate risk and with lower blood pressure is unclear," note the investigators.

For HOPE-3, they enrolled 12,705 participants (54% men; mean age 65.7 years) from 228 centers in 21 countries. After participating in a 4-week run-in phase where they received both the BP-lowering and cholesterol-lowering medications, all were randomly assigned to either the candesartan/hydrochlorothiazide (n=6356) or placebo groups (n=6349). Follow-ups were conducted 6 weeks and 6 months after and then continued every 6 months.

The study population was quite diverse, with 29% of each group Chinese, 27% Hispanic, 20% white, 20% South Asian or other Asian, 2% black, and 2% considered "other." In addition, 37.9% of the entire population had hypertension and the overall mean BP was 138.1/91.9 mm Hg. The mean total cholesterol level was 201.4 mg/dL and mean LDL-cholesterol level was 127.8 mg/dL.

In addition to no significant between-group differences in either of the composite co–primary outcomes in this first arm of the trial, there were no differences in the individual composites' individual CV events, total mortality, or diabetes onset. Also, no differences were found in CV- or non-CV–related hospitalization or non-CV death.

Among the participants with systolic BP greater than 143.5 mm Hg (mean 154.1 mm Hg), those taking the active medication had a hazard ratio (HR) of 0.73 for the first co–primary outcome (95% CI 0.56–0.94) and an HR of 0.76 for the second primary outcome (95% CI 0.57–0.90).

Still, "our data indicate that in this population overall, there was no significant benefit of blood-pressure lowering with the tested treatment," note the researchers.

On the Other Hand . . .

After the single-blind run-in phase, and in addition to the BP-lowering drug or placebo, the participants were also randomly assigned to take either rosuvastatin (n=6361) or placebo (n=6344).

The rates of the composite outcome of CV death, nonfatal stroke, or nonfatal MI were significantly lower for those receiving rosuvastatin (3.7%) vs placebo (4.8%; HR 0.76), as were the rates for the composite plus HF, resuscitated cardiac arrest, and revascularization (4.4% vs 5.7%, respectively; HR 0.75).

Dr Eva Lonn

Although fewer members of the active-treatment group had CV-related hospitalizations vs the placebo group (4.4% vs 5.8%, P<0.001), they had significantly more rates of cataract surgery (3.8% vs 3.1%, P=0.02) and more reports of muscle symptoms (5.8% vs 4.7%, P=0.005). However, only 1.3% and 1.2% of each group, respectively, discontinued treatment because of muscle symptoms—which wasn't significantly different. "And this muscle weakness was usually temporary," said Lonn.

In the third-arm analysis, the HR for the first co–primary outcome was 0.71 in the combined-treatment group vs the placebo-placebo group (95% CI 0.56–0.90). The HR was 0.72 for the second co–primary outcome (95% CI 0.57–0.89).

Lonn noted that the risk was better for those with upper-third BP levels. "However, treating those with lower blood pressure with the combination is not justifiable. Only statins should be used for them," she said.

Muscle symptoms were reported more often in the dual-treatment vs dual-placebo groups, as was dizziness. But overall discontinuation rates were similar (26.3% vs 28.8%)

Finally, the first co–primary outcome occurred in 3.8% of the rosuvastatin/placebo group vs 4.6% of the candesartan-hydrochlorothiazide/placebo group, which wasn't significant (P=0.1). But the difference in the second co–primary outcome was significant at 4.4% vs 5.5%, respectively (P=0.04).

Reinforces, Influences Guidelines

"The HOPE-3 trial provides evidence to reinforce some current guideline recommendations and to influence future guidelines," write Dr William C Cushman (Veterans Affairs Medical Center, Memphis, TN) and Dr David C Goff, Jr (University of Colorado Anschultz Medical Campus, Aurora) in an accompanying editorial[4].

"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 . . . add to the evidence supporting statin use for primary prevention."

Regarding the BP-lowering analysis, the editorialists note that the drugs used were given at low doses, but if they had been higher, "the risk of cardiovascular events might have been significantly reduced.

When asked about this, Lonn answered that because their population mostly had high-normal BP, the half doses were chosen for safety purposes. "In lower-risk individuals, you don't want to pay the price in side effects," added coinvestigator Dr Salim Yusuf (McMaster University). A more aggressive approach might have given better results, "but at what cost?"

Overall, "although these results do not exclude the possibility that more effective therapy for blood-pressure lowering might be beneficial in a relatively low-risk, older population, they provide support for the use of statins as a safe and effective intervention to prevent cardiovascular events in such patients," the editorialists conclude.

After the trial's presentations, panel member Dr Jeroen J Bax (Leiden Medical Center, the Netherlands) noted that new prevention guidelines are expected to come from the ACC "soon," so asked the investigators what should be changed based on these new findings.

Lonn answered that perhaps the guidelines should be simplified, while coinvestigator Dr Salim Yusuf (McMaster University) said that simple treatment strategies are needed.

Later, when asked what he thought about all of this, the ACC's Williams told heartwire that "we're taking the prevention guidelines one step at a time" and hope to have the first one, on hypertension, out by early 2017. "The whole point of the guidelines is to [take into account] cutting-edge data," he said, adding that all of the results from HOPE-3 and the recent SPRINT trial will be examined together.

Additional Comments

Session panelist Dr Pamela B Morris (Medical University of South Caroline, Charleston) complimented the researchers on assessing such a "good and ethnically diverse" group. However, she urged caution when generalizing the results to the US, which has a large black population.

In addition, Dr Patrick T O'Gara (Brigham and Women's Hospital, Boston, MA) wondered why aspirin was not included in the trial design. Yusuf said there were two reasons for this: its role in this type of treatment "is still being debated" and this was a primary-prevention, not secondary-prevention, trial.

"A 2x2x2 trial is theoretically possible, but it would have been difficult," he said, adding that the investigators didn't leave out aspirin because of bleeding concerns.

Dr Valentin Fuster (Mount Sinai Medical Hospital, New York) said that the three arms of this complex trial "were performed beautifully." He noted that he expected the results from the BP-lowering arm—and repeated the common comment that it'll be interesting to see how the findings fit together with SPRINT.

As for the second arm, he cautioned that those findings should be presented carefully as to not confuse people. "If you say a relative risk reduction of 30%, everybody will feel that you discovered the world," said Fuster. "However, I do not want to minimize" the results.

When discussing clinical implications at a press conference, Yusuf noted that the trial had a "pragmatic strategy," including no entry criteria or targets for BP or lipids, no dose titration, and infrequent safety monitoring.

Still, "this approach is very simple, safe, effective, and widely applicable. And that itself is an important message."

HOPE-3 was funded by a grant from the Canadian Institutes of Health Research and by AstraZeneca. Lonn reports grant support from Canadian Institutes of Health Research and AstraZeneca during the conduct of the study and grant support from Bayer, GlaxoSmithKline, Merck Schering, and Eli Lilly and personal fees from Amgen, Sanofi, and Novartis outside the submitted work. Yusuf reports grant support from Canadian Institutes of Health Research and AstraZeneca during the conduct of the study; grant support from AstraZeneca, Novartis, Bristol-Myers Squibb, and Cadila Pharma; and personal fees and nonfinancial support from Bayer outside the submitted work. Disclosures for the coauthors are listed in the articles. Cushman reports being an uncompensated member of the steering committee for the Takeda-sponsored EXAMINE trial and providing uncompensated consulting to Takeda related to hypertension clinical trials. Goff has no relevant financial relationships.

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