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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Pieske reported receiving personal fees from Bayer, Bristol Myers Squib, Medscape, MSD, Novartis, and Servier and grants and personal fees from Astra-Zeneca. Dr Wachter reported receiving personal fees from Daiichi Sankyo, Gilead, Novartis, Pfizer, Pharmacosmos, and Servier; grants and personal fees from Boehringer Ingelheim, CVRx, and Medtronic; grants from Bundesministerium für Bildung und Forschung, the European Union, and Deutsche Forschungsgemeinschaft. Dr Shah reported receiving grants and personal fees from Actelion, AstraZeneca, Novartis, and Pfizer; grants from Corvia; and personal fees from Abbott, Amgen, Aria CV, Axon, Bayer, Boehringer-Ingelheim, Boston Scientific, Bristol Myers Squib, Cardiora, CVRx, Cyclerion, Cytokinetics, Edwards Lifesciences, Eisai, Imara, Ionis, Ironwood, Janssen, Lilly Medical, Merck, MyoKardia, Novo Nordisk, Prothena, Regeneron, Sanofi, Shifamed, Tenax, and United Therapeutics. Drs Szecsödy, Shi, and Zhao and Ms Ibram, reported being employees of study sponsor (Novartis). Dr Cowie reported receiving personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Medtronic, Novartis, Novo Nordisk, Roche, and Servier and grants and personal fees from Abbott and Boston Scientific. No other disclosures were reported.

Figures

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; HbA1c, hemoglobin A1c; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; RAS, renin angiotensin system.