Effects of Sacubitril/Valsartan on Physical and Social Activity Limitations in Patients With Heart Failure: A Secondary Analysis of the PARADIGM-HF Trial

Abstract

Importance: Health-related quality of life (HRQL) of patients with heart failure is markedly reduced compared with that in patients with other chronic diseases, demonstrating substantial limitations in physical and social activities. In the Prospective Comparison of ARNI With an ACE-Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, sacubitril/valsartan improved overall HRQL compared with enalapril, as determined by the Kansas City Cardiomyopathy Questionnaire (KCCQ).

Objective: To examine the effects of sacubitril/valsartan on physical and social activities.

Design, setting, and participants: The PARADIGM-HF trial was a randomized, double-blind, active treatment-controlled clinical trial performed from December 8, 2009, to March 31, 2014, in 8399 patients with New York Heart Association class II to IV disease and a left ventricular ejection fraction of 40% or less at 1043 centers in 38 countries. Data analysis was performed from August 1, 2017, to December 25, 2017.

Interventions: Sacubitril/valsartan, 200 mg twice daily, or enalapril, 10 mg twice daily.

Main outcomes and measures: Patients completed HRQL assessments using the KCCQ at randomization, 4-month, 8-month, and annual visits. The effect of sacubitril/valsartan on components of the physical and social limitation sections of the KCCQ at 8 months and longitudinally and related biomarkers and clinical outcomes were studied.

Results: At baseline, 7618 of 8399 patients (90.7%) (mean [SD] age, 64 [11] years; 5987 [78.6%] male and 1631 [21.4%] female) completed the initial KCCQ assessment. Patients reported the greatest limitations at baseline in jogging and sexual relationships. Patients receiving sacubitril/valsartan had significantly better adjusted change scores in most physical and social activities at 8 months and during 36 months compared with those receiving enalapril. The largest improvement over enalapril was in household chores (adjusted change score difference, 2.35; 95% CI, 1.19-3.50; P < .001) and sexual relationships (adjusted change score difference, 2.72; 95% CI, 0.97-4.46; P = .002); both persisted through 36 months (overall change score difference, 1.69 [95% CI, 0.78-2.60], P < .001; and 2.36 [95% CI, 1.01-3.71], P = .001, respectively).

Conclusions and relevance: In patients with heart failure with reduced ejection fraction, sacubitril/valsartan significantly improved nearly all KCCQ physical and social activities compared with enalapril, with the largest responses in household chores and sexual relationships. In addition to reduced likelihood of cardiovascular death, all-cause mortality, and heart failure hospitalization, sacubitril/valsartan may improve limitations in common activities in these patients.

Trial registration: clinicaltrials.gov Identifier: NCT01035255.

Figure 1.. Change Score Differences Between Enalapril and Sacubitril/Valsartan at 8-Month Follow-up, Adjusted for Respective Baseline Mean Score

Positive values indicate greater improvement with sacubitril/valsartan than with enalapril. Results are given for the original analysis and the sensitivity analysis in which a score of 0 was assigned for each physical and social activity question at 8-month follow-up if the patient answered the question at baseline but died before the 8-month visit. P values for change score at 8-month follow-up are given in Table 2.

Figure 2.. Unadjusted Age Equivalency Analysis of Kansas City Cardiomyopathy Questionnaire (KCCQ) Physical and Social Activity Mean Score at 8-Month Follow-up Comparing Sacubitril/Valsartan and Enalapril