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The combination therapy sacubitril/valsartan (Entresto) failed to improve distance in the 6-minute walk test versus individual medical therapy (IMT) in patients with heart failure (HF) marked by preserved ejection fraction (HFpEF), a researcher reported.

In a co-primary endpoint in the PARALLAX trial, there was a 9.7-m improvement in the 6-minute walk test (6MWT) among patients on sacubitril/valsartan and a 12.2-m improvement among patients on IMT for a difference that was not statistically significant, according to Burkert Pieske, MD, of Charite University Medicine/Deutsches Herzzentrum in Berlin.

However, there was an improvement in important biomarkers associated with HF, he stated at a press conference at the virtual European Society of Cardiology meeting. Specifically, levels of NT-pro-BNP, a marker of disease severity, were reduced by 16% versus IMT at week 12 (P<0.0001), and there was a biomarker improvement in the glomerular filtration rate, he stated.

"It seems there are very few pharmacological interventions that have shown any benefit in the 6MW distance," Pieske told 麻豆传媒. "So I doubt now if that in future HF trials the 6MW distance is really a good readout, and that we have used a readout that just doesn't work in this patient population."

While a key primary endpoint was missed, "I still believe that the consistent reduction in NT-pro-BNP is promising," he added, but he cautioned that "I would never rely purely on improvements in biomarkers. A biomarker is not enough to make me decide whether to treat a patient for a specific disease with a drug, but...we have no specific therapies for HFpEF after years and years of investigation. We should take all information into consideration."

Pieske and colleagues enrolled 1,281 patients who were assigned to sacubitril/valsartan 97-103 mg twice daily. The comparator group had 1,285 patients treated with IMT, most often an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker.

Mean patient age in both groups was about 73; half were female; and the majority were white. Patients had to have a left ventricular ejection fraction (LVEF) >40%, and baseline LVEF was about 57%. Patients' New York Heart Association (NYHA) HF class was 2 or 3. BMI was about 31.

The authors reported that the combo therapy had no additional benefits on NYHA class from baseline to week 24 (odds ratio 1.01 for study drug vs IMT, 95% CI 0.75, 1.37, P=0.93), although they explained that "Due to the pre‐defined sequentially rejective multiple testing procedure, NYHA was not formally tested."

"We did find a 50% reduction in severe adverse events, which I think is an interesting signal in this population," Pieske said, specifically first hospitalization due to HF (HR 0.49, 95% 0.30, 0.81, P=0.005) and composite of time to death due to cardiac failure or HF hospitalization (HR 0.64, 95% 0.42, 0.97, P=0.034).

But Pieske also clarified that "this is a post hoc analysis of safety and we cannot derive from this outcome significance. The finding was in the right direction so we can say that sacubitril/valsartan was safe in this population, and we have a clear signal that we have less severe HF events in these hospitalized patients."

"Taken together, we believe that PARALLAX corroborates the findings in and may open the way for a new HFpEF therapy in subsets of these patients," he said.

Steen D Kristensen, MD, DMSc, of Aarhus University Hospital in Denmark, told 麻豆传媒, "NT-pro-BNP is an important biomarker in patients with HF -- reduction in proBNP is taken as a reflection of improvement, and some clinicians use this marker to monitor HF state during HF therapy. The findings are interesting."

"This study is using a surrogate marker," said Kristensen, who was not involved in the study. "It supports other studies showing some benefit of the drug, but we need more studies in HFpEF."

Robert Harrington, MD, immediate American Heart Association past-president, told 麻豆传媒, "The biomarker, suggestive of an improvement in HF, improves with the experimental therapy relative to control, but the functional measures, including 6MWT...are not different between the study arms. Interestingly, the clinical outcomes are improved in the experimental arm but these endpoints were declared post hoc and the clinical outcomes were not adjudicated."

"The results need to be put into a broader context and consider other available sources of data with the drug combination and similar patient populations," added Harrington, of Stanford University in California.

"If we consider marginal results from PARAGON and these results from PARALLAX, then evidence of low-to-modest strength might make one consider using sacubitril/valsartan in some HFpEF patients, but certainly these data don't rise to a broad use recommendation status in this population," stated Harrington, who was not involved in the study.

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