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PARAGON-HF: Do patients with HFpEF benefit from sacubitril/valsartan?

ESC Congress News 2019 - Paris, France

The PARAGON-HF trial narrowly missed its primary endpoint but demonstrated promising, clinically meaningful benefits with sacubitril/valsartan in some subgroups of patients with heart failure (HF) with preserved ejection fraction (HFpEF).

Pharmacology and Pharmacotherapy
Heart Failure

esc_paragon_hf_congress_news_monday_2019.jpgThat was the take-home message from yesterday’s Hot Line presentation of the PARAGON-HF trial, which was simultaneously published in the New England Journal of Medicine.1 Presenter and PARAGON-HF Executive Committee Co-Chair, Professor Scott Solomon (Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA) explains the rationale for the study. “Half of all patients with HF have HFpEF but unlike for HF with reduced ejection fraction (HFrEF), we still have no evidence-based therapies for this condition. We know from the PARADIGM-HF trial—which was reported exactly 5 years ago at ESC Congress—that sacubitril/valsartan has outcome benefits in HFrEF.2 Added to that is the evidence showing that the combination reduced NT-proBNP levels more than valsartan alone from the phase II PARAMOUNT trial in HFpEF.3 The logical step was to investigate the effects of sacubitril/valsartan on hard outcomes in HFpEF.”

PARAGON-HF is the largest randomised trial performed in HFpEF to date, with 4,822 patients from 43 countries randomised to receive sacubitril/valsartan or valsartan alone. Patients were required to have a left ventricular ejection fraction (LVEF) ≥45%, natriuretic peptide elevation and evidence of structural heart disease. The primary endpoint was a composite of total HF hospitalisations (first and recurrent) and cardiovascular (CV) deaths, analysed in a recurrent-event analysis. With a median follow-up of 34 months, only
9 patients were lost to follow-up.

“Sacubitril/valsartan reduced the primary endpoint by 13% (rate ratio 0.87; 95% confidence interval [CI] 0.75–1.01) but this just failed to reach statistical significance, with a p value of 0.059,” says Prof. Solomon. The results were driven by a reduction in HF hospitalisations, with the combination having no advantage over valsartan alone in CV deaths. Safety was similar to that seen in the PARADIGM-HF trial, sacubitril/valsartan being associated with a higher rate of hypotension but lower rates of hyperkalaemia and renal dysfunction than the comparator.

“While overall the benefit was just short of statistical significance,” says Prof. Solomon, “analyses indicated benefits on secondary endpoints, including an increase in the number of patients with New York Heart Association class improvements and a reduction in those diagnosed with worsening renal failure.” And the team observed striking heterogeneity among the population enrolled in the response to treatment, with women and patients with an LVEF at or below the median of 57% responding much more dramatically than others. “Just over half of the patients enrolled, 52%, were women. And in women we saw a 27% reduction in the primary endpoint with sacubitril/valsartan (rate ratio 0.73; 95% CI 0.59–0.90). We need to understand why women derived more benefit than men in this trial, but it is of note that women who develop heart failure are much more likely to have HFpEF than HFrEF,” observes Prof. Solomon.

Patients with an LVEF ≤57% had a reduction in the primary endpoint of 22% (rate ratio 0.78; 95% CI 0.64–0.95). Prof. Solomon comments, “The finding that patients with lower LVEF benefitted from sacubitril/valsartan makes a lot of sense. These patients had an ejection fraction that was not frankly reduced, according to the conventional definition of 40% or less, but that was clearly below normal, which is generally considered 55% or greater. Given the demonstration from PARADIGM-HF that sacubitril/valsartan is effective in patients with LVEF ≤40%, it follows that it may also benefit patients in the adjacent LVEF range.”

Prof. Solomon along with PARAGON-HF Co-Chair, Professor John McMurray (University of Glasgow, Glasgow, UK) and their team are continuing to analyse the extensive dataset to try to understand which patients may most benefit from sacubitril/valsartan. Prof. Solomon has confidence in the benefit of sacubitril/valsartan for some patients, concluding, “We believe our findings may translate into clinically worthwhile benefits for certain groups of patients, particularly those with HF with ejection fraction that is not in the conventional ‘reduced’ range, but is below normal.”



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1. Solomon SD, et al. N Engl J Med 2019. doi/10.1056/NEJMoa19086552.1. Solomon SD, et al. N Engl J Med 2019. doi/10.1056/NEJMoa19086552.

2. McMurray JJ, et al. N Engl J Med 2014;371:993–1004.

3. Solomon SD, et al. Lancet 2012;380:1387–1395.

Notes to editor

About the European Society of Cardiology

The European Society of Cardiology brings together healthcare professionals from more than 150 countries, working to advance cardiovascular medicine and help people lead longer, healthier lives.

About ESC Congress 2019

ESC Congress is the world’s largest and most influential cardiovascular event contributing to global awareness of the latest clinical trials and breakthrough discoveries. ESC Congress 2019 takes place 31 August to 4 September at the Paris Expo Porte de Versailles, Paris - France. Explore the scientific programme