Elsevier

American Heart Journal

Volume 239, September 2021, Pages 1-10
American Heart Journal

Clinical Investigations
Sacubitril/valsartan versus enalapril on exercise capacity in patients with heart failure with reduced ejection fraction: A randomized, double-blind, active-controlled study

https://doi.org/10.1016/j.ahj.2021.05.005Get rights and content

Background

Sacubitril/valsartan reduces mortality in patients with heart failure with reduced ejection fraction (HFrEF) when compared with enalapril. However, it is unknown the effect of both treatments on exercise capacity. We compared sacubitril/valsartan versus enalapril in patients with HFrEF based on peak oxygen consumption (VO2) and 6-minute walk test (6-MWT).

Methods

We included 52 participants with HFrEF with a left ventricular ejection fraction <40% to receive either sacubitril/valsartan (target dose of 400 mg daily) or enalapril (target dose of 40 mg daily). Peak VO2 was measured by using cardiopulmonary exercise testing. Six-minute walk test was also performed.

Results

At 12 weeks, the sacubitril/valsartan (mean dose 382.6 ± 57.6 mg daily) group had increased peak VO2 of 13.1% (19.35 ± 0.99 to 21.89 ± 1.04 mL/kg/min) and enalapril (mean dose 34.4 ± 9.2 mg daily) 5.6% (18.58 ± 1.19 to 19.62 ± 1.25 mL/kg/min). However, no difference was found between groups (P = .332 interaction). At 24 weeks, peak VO2 increased 13.5% (19.35 ± 0.99 to 21.96 ± 0.98 mL/kg/min) and 12.0% (18.58 ± 1.19 to 20.82 ± 1.18 mL/kg/min) in sacubitril/valsartan (mean dose 400 ± 0 mg daily) and enalapril (mean dose 32.7 ± 11.0 mg daily), respectively. However, no differences were found between groups (P= .332 interaction). At 12 weeks, 6-MWT increased in both groups (sacubitril/valsartan: 459 ± 18 to 488 ± 17 meters [6.3%] and enalapril: 443 ± 22 to 477 ± 21 meters [7.7%]). At 24 weeks, sacubitril/valsartan increased 18.3% from baseline (543 ± 26 meters) and enalapril decreased slightly to 6.8% (473 ± 31 meters), but no differences existed between groups (P= .257 interaction).

Conclusions

Compared to enalapril, sacubitril/valsartan did not substantially improve peak VO2 or 6-MWT after 12 or 24 weeks in participants with HFrEF.

(NEPRIExTol-HF Trial, ClinicalTrials.gov number, NCT03190304)

Section snippets

Study design

The study was previously registered on ClinicalTrials.gov under the number NCT03190304. This is a single-center, randomized, double-blind, active-controlled study comparing head-to-head the effect of sacubitril/valsartan and enalapril on exercise tolerance in participants with HFrEF. This clinical trial was approved by the local ethics committee (4487-16-153), and all participants provided written informed consent. We followed the CONSORT checklist for randomized clinical trials.10

The study

Results

At baseline, physical and clinical characteristics as well as medications and their respective doses are described in Table I. Particularly, at baseline, ACEI (sacubitril/valsartan group = 24 ± 15 mg and enalapril group = 18 ± 12 mg; P .181) and ARB (sacubitril/valsartan group = 79 ± 33 mg and enalapril group = 75 ± 35 mg; P= .884) doses were similar between groups. At 12 weeks, the mean dose of sacubitril/valsartan was 382.6 ± 57.6 mg daily and enalapril 34.4 ± 9.2 mg daily. At 24 weeks, the

Discussion

To the best of our knowledge, this is the first randomized, double-blind, active-controlled trial evaluating the effect of sacubitril/valsartan and enalapril on maximal exercise capacity (peak VO2) in patients with HFrEF. We found an increase in peak VO2 (approximately 13%) in both groups, but with no statistical and clinical differences between them. Similarly, although we found an increase in 6-MWT at 12 and 24 weeks within groups, we did not observe statistical differences after treatments

Conclusion

Amongst patients with HFrEF previously receiving an ACEI and/or ARB, switching them to sacubitril/valsartan did not substantially improve peak VO2 or 6-MWT after 12 or 24 weeks. Neither were substantial differences in the effects on other measurements observed, including skeletal muscle blood flow, cardiac function and structure, muscle strength, body composition, and quality of life. The trial was not adequately powered to show modest differences but suggests that clinically meaningful effects

Competencies in medical knowledge

This study shows that sacubitril/valsartan or enalapril did not significantly improve peak VO2 and 6-MWT after 12 or 24 weeks in participants with HFrEF.

Translational outlook

A larger sample size and longer follow-up study with older and more severe patients with HFrEF should investigate the possible beneficial effects of both treatments on exercise capacity and its pathophysiological mechanisms.

Disclosures

The authors declare that there are no conflicts of interest.

Funding

This study was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP; 2016/24833-0). M.R.S. by FAPESP (2016/24306-0 and 2019/14938-7). C.E.N. by Conselho Nacional de Pesquisa e Desenvolvimento (CNPq; 303573/2015-5). A.C.P.B. by FAPESP (2016/24833-0).

Data sharing

Unidentified individual participant data and data analysis plan are available from the corresponding author upon reasonable request.

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