PARALLAX: Mixed Results for Sacubitril/Valsartan in HFpEF

With PARAGON-HF, this is the second trial that failed to show an overwhelming benefit in this hard-to-treat population.

PARALLAX: Mixed Results for Sacubitril/Valsartan in HFpEF


(UPDATED) Just one of two co-primary endpoints was met in the PARALLAX trial, which evaluated the impact of sacubitril/valsartan (Entresto; Novartis) on biomarkers and functional outcomes in patients with heart failure and preserved ejection fraction (HFpEF).

Though the angiotensin receptor-neprilysin inhibitor (ARNI) led to a greater reduction in N-terminal pro-B-type natriuretic peptide (NT-proBNP) compared with individualized medical therapy, it did not significantly boost 6-minute walk distance, Burkert Pieske, MD (Charité University Medicine and German Heart Center, Berlin, Germany), reported during the virtual European Society of Cardiology Congress 2020.

There were hints of benefit in post hoc and exploratory analyses, but PARALLAX joins PARAGON-HF—a larger outcomes trial presented last year at ESC 2019—in failing to deliver a win for sacubitril/valsartan in HFpEF, which accounts for more than half of all heart failure cases and for which there are no proven, specific therapies. The latter trial did not show a significant difference in the composite primary endpoint of hospitalization for heart failure or CV death, but exploratory secondary endpoints—including improvements in NYHA class and quality of life and reduced likelihood of worsening renal function—hinted at a benefit of sacubitril/valsartan.

“These results are consistent with the findings from PARAGON-HF and provide further evidence for the potential benefits of sacubitril/valsartan in patients with heart failure and midrange or preserved ejection fraction,” Pieske concluded during his presentation.

American College of Cardiology President Athena Poppas, MD (Lifespan Cardiovascular Institute and Brown University, Providence, RI), said it’s “disappointing but maybe not surprising that this group of patients is so challenging to find a medication [for] that’s effective, perhaps because it’s such a mixed group.”

Despite discussions of suggestions of benefit in certain subgroups and exploratory analyses, both PARAGON-HF and PARALLAX “can be determined to be negative trials,” she told TCTMD. “I don’t think there’s anything here—and combined with PARAGON—to add this routinely to patients.”

That said, Poppas added, it’s possible sacubitril/valsartan could be useful in select groups, such as women, patients who are not tolerating their other diuretics, and those with recurrent heart failure admissions. “I would consider it very selectively, because those patients are so challenging to manage,” she said.


Sacubitril/valsartan was approved by the US Food and Drug Administration in July 2015 for use in patients with heart failure and reduced ejection fraction (HFrEF) based on the strength of the PARADIGM-HF trial results, which raised hopes that the therapy might also prove useful in HFpEF. Heart failure guidelines recommend diuretics, symptom control, and individualized background therapy for comorbidities in these patients, Pieske noted.

PARAMOUNT, a phase II trial, showed that sacubitril/valsartan led to greater reductions in NT-proBNP and left atrial size and a greater improvement in NYHA class relative to valsartan alone in patients with HFpEF.

PARALLAX is a larger trial, including 2,572 patients with symptomatic HFpEF (LVEF greater than 40%) randomized to sacubitril/valsartan or individualized medical therapy, which included either the ACE inhibitor enalapril, the ARB valsartan, or placebo. Mean ejection fraction was 57%.

The trial met one of the two co-primary endpoints. At 12 weeks, the reduction in NT-proBNP was 16% greater in the sacubitril/valsartan arm (adjusted geometric mean ratio 0.84; 95% CI 0.80-0.88). At 24 weeks, however, there was no significant difference between groups in 6-minute walk distance, which improved in both groups (adjusted mean difference -2.5 m; 95% CI -8.5 to 3.5).

Regarding the difference in NT-proBNP, Poppas said “it’s encouraging, but we’ve seen other studies where we have some biomarkers which show a trend but [there isn’t] any hard endpoint difference. And the other objective measure, the 6-minute walk test, wasn’t different, so it’s nice but not enough that I would change practice.”

I don’t think there’s anything here—and combined with PARAGON—to add this routinely to patients. Athena Poppas

Pieske described the reduction in NT-proBNP as “significant and impressive,” acknowledging, however, that he would not rely only on biomarker improvements to make treatment decisions. “A biomarker for me is, in principle, not enough to decide on whether or not treat a patient with a specific disease with a drug, but in the light that we have no specific therapies for HFpEF after years and years of investigations, I think we should take all information that we can get into consideration.”

None of the secondary endpoints, including changes in the Kansas City Cardiomyopathy Questionnaire clinical summary score, NYHA class, or the Short Form-36 physical component clinical summary score, differed between trial arms.

But Pieske pointed to a few other signals, aside from the reduction in NT-proBNP, that the ARNI might have something to offer. A post hoc analysis showed that the risk of heart failure events leading to hospitalization—which were reported as adverse events and not adjudicated—was lower with sacubitril/valsartan after 24 weeks (HR 0.49; 95% CI 0.30-0.81). “This is reassuring and goes [in] the same direction as the PARAGON-HF data, but of course this was clearly not an outcomes study,” Pieske said.

Moreover, a prespecified exploratory analysis suggested that the decline in estimated glomerular filtration rate over 24 weeks was less in the sacubitril/valsartan arm (adjusted mean difference 1.10 mL/min/1.73 m2; 95% CI 0.02-1.99).

Poppas said these exploratory findings are encouraging, but should be used only to spur further studies designed to address those specific questions.

Serving as a discussant after Pieske’s presentation, Rudolf De Boer, MD (University Medical Center Groningen, the Netherlands), said, “I think the exploratory outcomes are important because cardiovascular death is primarily driven by heart failure and renal dysfunction and both of these were positively affected by sacubitril/valsartan.”

And he noted that physicians are already using renin-angiotensin-system (RAS) blockers widely in heart failure patients across the range of ejection fraction, even though guidelines don’t recommend using them in patients with HFpEF. “I think if one intends to use a RAS blocker in patients with HFpEF or [heart failure with midrange ejection fraction] then sacubitril/valsartan is likely the most effective agent,” de Boer said.

Pieske added, “From the data that we have so far, and if we say HFpEF is something [like] heart failure plus additional evidence of cardiac dysfunction and ejection fraction 50% and higher, then I would recommend to treat patients who are on the way to a reduced systolic function with those therapies where we have now data, and I would include sacubitril/valsartan in this armamentarium.”

De Boer said, “I fully agree.”

In a press release, Novartis said the overall benefit-risk profile of the ARNI in PARALLAX was comparable to what was seen in PARAGON-HF and “remains positive.” The drug maker is actively seeking approval of sacubitril/valsartan for HFpEF, saying that the FDA accepted a supplemental new drug application in June.


Todd Neale is the Associate News Editor for TCTMD and a Senior Medical Journalist. He got his start in journalism at …

Read Full Bio
  • Pieske B. Angiotensin receptor-neprilysin inhibition compared with individualized medical therapy for comorbidities in patients with heart failure and preserved ejection fraction: the PARALLAX trial. Presented at: ESC 2020. August 30, 2020.

  • PARALLAX was funded by Novartis.