The highly anticipated PARAGON-HF trial results, presented at the ESC Congress 2019, indicate that the angiotensin receptor–neprilysin inhibitor sacubitril–valsartan does not have a significant benefit in reducing the risk of hospitalizations for heart failure or death from cardiovascular causes in patients with heart failure with preserved ejection fraction (HFpEF). The trial narrowly missed statistical significance for the primary outcome, but suggests a heterogeneous effect of sacubitril–valsartan, with potential benefit in certain patients such as those with ‘mid-range’ left ventricular ejection fraction (LVEF) and women.

Credit: V. Summersby/Springer Nature Limited

Sacubitril–valsartan is currently approved for the treatment of patients with heart failure with reduced ejection fraction (HFrEF) on the basis of data from PARADIGM-HF. “Although HFpEF accounts for up to 50% of people with heart failure, we have no proven treatment,” explains the PARAGON-HF investigator John McMurray. “PARAGON-HF is the latest and largest attempt to find an effective therapy, testing sacubitril–valsartan,” he adds. The trial included 4,822 patients (52% women) with NYHA class II–IV heart failure, LVEF ≥45%, high natriuretic peptides levels and structural heart disease, who were randomly assigned to receive sacubitril–valsartan or valsartan.

Fewer primary outcome events (hospitalizations for heart failure or death from cardiovascular causes) occurred with sacubitril–valsartan treatment than with valsartan treatment (894 versus 1,009 events), but the overall result narrowly missed statistical significance (rate ratio of 0.87, 95% CI 0.75–1.01, P = 0.059). Therefore, subsequent analyses were considered to be exploratory. The benefit trend was driven by a 15% reduction in hospitalizations for heart failure, with no differences in death from cardiovascular causes. Secondary outcomes suggested an improvement in clinical condition with sacubitril–valsartan. At 8 months, more patients in the sacubitril–valsartan group than in the valsartan group had improvements in the NYHA class (15.0% versus 12.6%) and an improvement of ≥5 points in the Kansas City Cardiomyopathy Questionnaire score. Renal function decline occurred less frequently in the sacubitril–valsartan group (1.4% versus 2.7%). Sacubitril–valsartan was associated with higher rates of hypotension and angio-oedema, but lower rates of elevated creatinine or potassium levels than valsartan.

Interestingly, sacubitril–valsartan had a significant benefit in two prespecified subgroups: patients in the lower LVEF range studied (45–57%) and women. In patients with LVEF ≤57%, sacubitril–valsartan led to a 22% reduction in the rate of the primary outcome compared with valsartan. “This finding makes sense as we know sacubitril–valsartan is highly effective in people with HFrEF (LVEF ≤ 40%) and other drugs effective for HFrEF also show efficacy in patients in the lower part of the HFpEF LVEF range,” explains McMurray. In women, sacubitril–valsartan reduced the rate of the primary outcome by 27.5%.

“The regulatory agencies and guideline committees will have to review the data and consider whether there is enough evidence to recommend use of sacubitril–valsartan in some patients with HFpEF, such as those with a LVEF below normal,” says McMurray. “We need to do more analysis of the very interesting finding of the possibly greater benefit in women, especially as HFpEF is the predominant type of heart failure in women.”