Frailty is an issue that is becoming more and more prevalent, and patients who are frail are less likely to obtain novel pharmacologic treatments because the risk-benefit profile is seen to be less favorable than in patients who are not fragile. In the PARAGON-HF (Prospective Comparison of ARNI With ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction) trial, 4,796 patients with heart failure and preserved ejection fraction were randomized researchers for a study examined the efficacy of sacubitril/valsartan according to frailty status.

The Rockwood cumulative deficit technique was used to calculate the degree of fragility. Total heart failure hospitalizations or cardiovascular death were the main endpoints.

In 4,795 patients, a frailty index (FI) could be calculated. A total of 11.4% had class 3 frailty (FI ≥0.311, very frail), 43.5% had class 2 frailty (FI 0.211-0.310, more frail), and 45.2% had class 1 frailty (FI ≤0.210, not fragile). A substantial higher risk was related to increased frailty (class 1: reference; class 2 rate ratio: 2.19 [95% CI: 1.85-2.60]; class 3 rate ratio: 3.29 [95% CI: 2.65-4.09]). There was a graded connection between the FI class and the primary endpoint. From lowest to highest FI class, sacubitril/valsartan had the following effects on the primary endpoint (as a rate ratio): 0.98 (95% CI: 0.76-1.27), 0.92 (95% CI: 0.76-1.12), and 0.69 (95% CI: 0.51-0.95), respectively (Pinteraction = 0.23). The interaction with therapy was significant for the primary outcome (Pinteraction = 0.002) and total heart failure hospitalizations (Pinteraction <0.001) when FI was analyzed as a continuous variable, with the most frail patients benefiting the most.

In cardiac failure with maintained ejection fraction, fragility was frequent and was linked to poorer outcomes. Although it was not significant when FI was looked at as a categorical variable, sacubitril/valsartan appeared to exhibit a larger reduction in the main endpoint with increased frailty compared to valsartan.