Effect of Sacubitril/Valsartan vs Standard Medical Therapies on Plasma NT-proBNP Concentration and Submaximal Exercise Capacity in Patients With Heart Failure and Preserved Ejection Fraction: The PARALLAX Randomized Clinical Trial

Abstract

Importance: There is limited evidence on the benefits of sacubitril/valsartan vs broader renin angiotensin system inhibitor background therapy on surrogate outcome markers, 6-minute walk distance, and quality of life in patients with heart failure and mildly reduced or preserved left ventricular ejection fraction (LVEF >40%).

Objective: To evaluate the effect of sacubitril/valsartan on N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, 6-minute walk distance, and quality of life vs background medication-based individualized comparators in patients with chronic heart failure and LVEF of more than 40%.

Design, setting, and participants: A 24-week, randomized, double-blind, parallel group clinical trial (August 2017-October 2019). Of 4632 patients screened at 396 centers in 32 countries, 2572 patients with heart failure, LVEF of more than 40%, elevated NT-proBNP levels, structural heart disease, and reduced quality of life were enrolled (last follow-up, October 28, 2019).

Interventions: Patients were randomized 1:1 either to sacubitril/valsartan (n = 1286) or to background medication-based individualized comparator (n = 1286), ie, enalapril, valsartan, or placebo stratified by prior use of a renin angiotensin system inhibitor.

Main outcomes and measures: Primary end points were change from baseline in plasma NT-proBNP level at week 12 and in the 6-minute walk distance at week 24. Secondary end points were change from baseline in quality of life measures and New York Heart Association (NYHA) class at 24 weeks.

Results: Among 2572 randomized patients (mean age, 72.6 years [SD, 8.5 years]; 1301 women [50.7%]), 2240 (87.1%) completed the trial. At baseline, the median NT-proBNP levels were 786 pg/mL in the sacubitril/valsartan group and 760 pg/mL in the comparator group. After 12 weeks, patients in the sacubitril/valsartan group (adjusted geometric mean ratio to baseline, 0.82 pg/mL) had a significantly greater reduction in NT-proBNP levels than did those in the comparator group (adjusted geometric mean ratio to baseline, 0.98 pg/mL) with an adjusted geometric mean ratio of 0.84 (95% CI, 0.80 to 0.88; P < .001). At week 24, there was no significant between-group difference in median change from baseline in the 6-minute walk distance with an increase of 9.7 m vs 12.2 m (adjusted mean difference, -2.5 m; 95% CI, -8.5 to 3.5; P = .42). There was no significant between-group difference in the mean change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (12.3 vs 11.8; mean difference, 0.52; 95% CI, -0.93 to 1.97) or improvement in NYHA class (23.6% vs 24.0% of patients; adjusted odds ratio, 0.98; 95% CI, 0.81 to 1.18). The most frequent adverse events in the sacubitril/valsartan group vs the comparator group were hypotension (14.1% vs 5.5%), albuminuria (12.3% vs 7.6%), and hyperkalemia (11.6% vs 10.9%).

Conclusions and relevance: Among patients with heart failure and left ventricular ejection factor of higher than 40%, sacubitril/valsartan treatment compared with standard renin angiotensin system inhibitor treatment or placebo resulted in a significantly greater decrease in plasma N-terminal pro-brain natriuretic peptide levels at 12 weeks but did not significantly improve 6-minute walk distance at 24 weeks. Further research is warranted to evaluate potential clinical benefits of sacubitril/valsartan in these patients.

Trial registration: ClinicalTrials.gov Identifier: NCT03066804.

Figure 1.. Patient Flow Through the PARALLAX -HF Trial

^aFour hundred fifty-one patients were screened more than once; rescreened patients were included only once. ^bDefined as any untoward medical occurrence or worsening of preexisting medical conditions or diseases at the time of signing the informed consent form. ^cPatients did not qualify for randomization and did not receive study treatment but were inadvertently randomized into the study. ^dPatients were inadvertently randomized within a wrong treatment stratum and did not receive the study treatment. Rerandomized patients were included only once. ^ePatients with baseline 6-minute walk distance of 100 to 450 m. NT-proBNP indicates N-terminal pro–brain natriuretic peptide.

Figure 2.. N-Terminal Pro–Brain Natriuretic Peptide and 6-Minute Walk Distance Primary Outcomes

Median values for N-terminal pro–brain natriuretic peptide (NT-proBNP) and 6-minute walk distance. Patients included had baseline 6-minute walk distances of 100 m to 450 m. Box edges indicate the 25th and 75th percentiles, the horizontal line inbetween the edges, the median. Whiskers extend to the furthest point with 1.5 × IQR of the box ends.

Figure 3.. Effect of Sacubitril/Valsartan and Individualized Medical Therapy on NT-proBNP in Predefined Subgroups

An adjusted geometric mean ratio lower than 1 favors sacubitril/valsartan. The interaction P value is for the subgroup variable × the treatment interaction at week 12. The mixed model for the repeated-measures model includes stratum angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), no renin angiotensin system inhibitors, region, treatment (sacubitril/valsartan, background medication–based individualized comparators), visit, treatment × visit interaction, subgroup, subgroup × visit interaction, treatment × subgroup interaction, and treatment × subgroup × visit interaction as fixed-effect factors; baseline log-transformed N-terminal pro–brain natriuretic peptide (NT-proBNP), stratum × baseline log-transformed NT-proBNP, and visit × baseline log-transformed NT-proBNP interactions as covariates; and models the within-patient covariance using an unstructured covariance matrix (a common matrix for the 2 treatment groups). The analysis includes data observed up to week 12. Test values below lower or above the upper limit of quantification are imputed by 0.5 × the lower limit of quantification × 1.5 × upper limit of quantification. ACE indicates angiotensin-converting enzyme; ARB, angiotensin II blocker; HbA_1c, hemoglobin A_1c; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; RAS, renin angiotensin system.