PARALLAX: Sacubitril/Valsartan Moves Toward a Solution for Heart Failure With Preserved Ejection Fraction

A year ago, the PARAGON-HF trial for sacubitril/valsartan came within a whisker of achieving its primary end point and an elusive goal: finding a therapy that offers a clear morbidity and mortality benefit for heart failure with preserved ejection fraction (HFpEF).

To be sure, the study showed promise in HFpEF, and findings showed the therapy benefited some patients more than others: sacubitril/valsartan (Entresto, Novartis) worked better for women than men, and it offered more benefits for those whose ejection fraction was below 57%.

Since that time, FDA has accepted sacubitril/valsartan for review in HFpEF. And today comes PARALLAX, which simultaneously points to the drug’s benefit while confirming the challenge and complexity of finding a treatment for HFpEF.

Up to 64 million people worldwide have heart failure, and according to the European Society of Cardiology, about half have left ventricular ejection fraction of 40% or greater. This encompasses heart failure with mid-range ejection fraction (HFmEF; ejection fraction 40–49%), and HFpEF (ejection fraction 50% or greater). There are multiple approved drug classes for heart failure with reduced ejection fraction (ejection fraction 40% or less), and the newest, sodium glucose co-transporter 2 (SGLT2) inhibitors, seems poised to transform heart failure care.

PARALLAX, presented today at the ESC 2020 Congress, which is taking place virtually, compared sacubitril/valsartan to individualized therapy, but with a very different co-primary end point. PARAGON-HF assessed outcomes—a composite of hospitalization for heart failure and cardiovascular death. By contrast, PARALLAX assessed a biomarker, NTproBNP, a hormone level that rises and falls to signal disease severity within the heart, as well as a 6-minute walk test, since loss of exercise capacity is a key indicator of heart failure.

“The Million Euro Question”

In an interview with The American Journal of Managed Care®, lead study author Burkert Pieske, MD, of Charité University Medicine & German Heart Center in Berlin, Germany, discussed the search for an effective treatment:

“Why is it so difficult to treat heart failure with preserved ejection fraction? I think this is truly the million euro, or dollar, question,” he said.

Pieske said basic research on this topic has shown that pathophysiology of HFpEF is distinctly different from HFrEF, and there is also great heterogeneity in etiology. This may be why classic therapies, such as ACE inhibitors and ARBs, don’t work the same way in HFpEF, especially once it reaches into the upper edge of the spectrum, above 60% of ejection fraction. “We have to look into other signaling mechanisms and targets,” he said.

PARALLAX enrolled 2572 patients, randomized 1:1 for either sacubitril/valsartan or individual therapy only; guidelines call for diuretics and management of comorbidities; so patients taking ACE inhibitors or ARBs had to have a history of hypertension. The individual therapy groupings were stratified as follows: ACE inhibitors, enalapril; ARBs, valsartan; or no RAAS inhibitor, these patients took placebo.

The average age of the study drug group was 73, and the average age of the individual therapy group was 72. Average body mass index for both groups was 31 kg/m2. Titration occurred over 4 weeks, with follow-up for 20 to 23 weeks.

Mixed Results, Many Good Signs

Results were mixed: PARALLAX aced the biomarker end point, with a 16% relative improvement among the sacubitril/valsartan group at week 12 (HR, 0.84; 95% CI, 0.80-0.88; P < .0001). But while the group taking the study drug showed improvement on the 6-minute walk test at week 24, it did not show a statistically significant difference compared with the individual therapy group: (adjusted mean difference, -2.5 m; 95% CI, -8.5, 3.5 m; P = 0.42).

PARALLAX also fell short of secondary endpoints that included change in the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score, and change in New York Heart Association (NYHA) class; however, study drug patients did show improvement in KCCQ scores at week 4.

However, a post-hoc analysis comparing data from the study drug and placebo groups shows that the sacubitril/valsartan may help HFpEF patients stay out of the hospital:

There was a 51% reduced risk of first hospitalization due to heart failure in the study drug group (HR, 0.49; 95% CI, 0.30-0.81, P = .005).

A composite of time to death due to cardiac failure or HF hospitalization in days favored the study drug group (HR, 0.64; 95% CI, 0.42-0.97, P = .034).

A prespecified exploratory analysis of renal impact showed that estimated glomerular filtration rate (eGFR) declined less in the study drug group over 24 weeks (adjusted mean difference, 1.10 mL/min/1.73 m2 (0.02, 1.99)) compared with the individual therapy group.

Is Combination Therapy the Future?

In the interview, Pieske was asked about ongoing studies of SGLT2 inhibitors in patients with HFpEF, which will start reporting results in 2021. Is it possible that the future of treatment for this complex condition lies not with one drug, but several?

Results from the EMPEROR-Reduced trial in HFrEF, reported during the ESC 2020 Congress on Saturday, showed that the combination of the SGLT2 inhibitor empagliflozin and sacubitril/valsartan had a more pronounced benefit than empagliflozin without the added therapy.

Pieske agrees this is where things are heading. “I do believe in the future, a combination therapy of Entresto (sacubitril valsartan) and an SGLT2 inhibitor, and in addition an MRA antagonist as an anti-fibrotic and blood pressure lowering agent, could be the ideal combination,” he said. “I think this is coming up at the horizon now as an excellent therapy option for these patients, and I think PARALLAX would be in line with this. It adds to the PARAGON-HF finding, so let's wait for the SGLT2 data to be sure.”