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PARIS -- Sacubitril/valsartan (Entresto) struck out on heart failure with preserved ejection fraction (HFpEF) in the PARAGON-HF trial but signaled benefit in the lower range of EF.

Among patients with an EF of 45% or higher, the drug failed to reduce hospitalization for heart failure and death from cardiovascular causes compared with valsartan alone (risk ratio 0.87, 95% CI 0.75-1.01, P=0.06), reported Scott Solomon, MD, of Brigham and Women's Hospital and Harvard in Boston.

The findings were presented here at the European Society of Cardiology congress and simultaneously online in the .

In the of heart failure patients with an ejection fraction of 40% or less, the same composite endpoint was reduced somewhat more substantially with sacubitril/valsartan over enalapril alone (HR 0.80, 95% CI 0.73-0.87) and came along with an (HR 0.84, 95% CI 0.76-0.93).

In PARAGON-HF, there was virtually no difference in cardiovascular mortality (8.9% vs 8.5% with valsartan alone), whereas there was a borderline significant difference in hospitalizations for heart failure (RR 0.85, 95% CI 0.72-1.00).

Clinical Implications?

"Given the large unmet need in the treatment of HFpEF patients, I was really hoping for an unequivocally positive outcome," said William Abraham, MD, of Ohio State University in Columbus, who was not involved in the trial.

"Disappointing indeed," agreed Martin Cowie, MD, of Imperial College London, who also was not part of the trial. "Any quality of life improvement was marginal also. As is so often the case in HFpEF, it has proven very difficult to find a therapy that convincingly makes a difference to outcome."

"They were close, I mean really close. Even with the heterogeneity of the patient population, they were so close," said Clyde Yancy, MD, of Northwestern University in Chicago and a past president of the American Heart Association.

Solomon, speaking at a press conference for the late-breaking clinical trial session, pointed to the secondary endpoints favoring sacubitril/valsartan:

• NYHA class improved significantly more (15.0% vs 12.6%, OR 1.45, 95% CI 1.13-1.86)
• Renal function worsened less (1.4% vs 2.7%, HR 0.50, 95% CI 0.33-0.77)
• Health status improved by 1 point on the 100-point KCCQ clinical summary score at 8 months (95% CI 0.0-2.1)

Also, there were two among 12 prespecified groups with possible sacubitril/valsartan benefit for the primary composite endpoint:

• Women (RR 0.73, 95% CI 0.59-0.90)
• Lower EF for those ≤median of 57% (RR 0.78, 95% CI 0.64-0.95)

"Normally we are very cautious about subgroups, at least I am, but this isn't the first time we've seen this," coauthor John McMurray, MD, of the University of Glasgow, Scotland, told 名媛直播 during the press conference. "In the CHARM trial with candesartan, in the TOPCAT trial of spironolactone, in the beta-blocker trial meta-analyses, and even in the retrospective analysis of the , you do see that drugs that work in patients with heart failure with reduced ejection fraction below 40% do seem to have some benefit, perhaps a bit less, if patients have a below-normal ejection fraction. In that sort of gray zone we've ignored in previous trials ... these people have actually got mild systolic dysfunction."

And, Solomon, replied, "it's important to remember that these are arbitrary cutoffs."

Drugmaker Novartis said it would continue discussions with clinical experts and regulators "to determine next steps," albeit without specifying whether it would seek a label expansion.

Yancy, though, argued that there's no room for a label indication or guideline shift based on the negative findings, even though there could be for limited off-label use, he suggested.

For symptomatic patients with EF greater than 35% but less than 50%, "I think the signal in PARAGON-HF is enough to encourage me to say 'I think this will help you' and follow those patients carefully and wrestle with the costs. That's where my role as a doctor is to take advantage of information," Yancy said.

"However, in the U.S., the cost is often prohibitive and several pharmacy benefits managers are refusing coverage for this medication for patients with HFrEF. I would expect an even tougher battle if a patient has HFpEF," noted Mary Norine Walsh, MD, of St. Vincent Heart Center in Indianapolis and a past president of the American College of Cardiology.

HFpEF Population

Yancy suggested it "may also make us go back and think what are the correct cutpoints for HFrEF," suggesting it may be closer to 50%. "The reason I am hopeful is it is within our grasp now to find a therapy that will change the natural history of HFpEF, but we need to define the patient population a little better."

The trial included 4,822 patients age 50 or older who had New York Heart Association (NYHA) class II to IV heart failure, an EF of 45% or higher, elevated level of natriuretic peptides, and evidence of structural heart disease. Participants had to be on a diuretic as well.

They were randomized to take sacubitril/valsartan, with a target dose of 97 mg of sacubitril and 103 mg of valsartan twice daily, or valsartan alone targeted to 160 mg twice daily. Solomon pointed out that these are biologically equivalent doses.

The sacubitril/valsartan group had a higher incidence of hypotension (15.8% vs 10.8%) and angioedema (0.6% vs 0.2%) and a lower incidence of hyperkalemia (13.2% vs 15.3%).

Angioedema had also been elevated, although rare, in PARADIGM-HF. Yancy noted that the community should not overlook the fact that it is still an issue. However, he argued that the low rate of black patients in the trial (2%), which is a higher risk group for angioedema, was unacceptable. "This trial is not representative."

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