Scientific letter Early Sacubitril/Valsartan-driven Benefit on Exercise Capacity in Heart Failure With Reduced Ejection Fraction: A Pilot Study

To the Editor,

The hallmark clinical feature of heart failure (HF) is a severe reduction in exercise capacity, which limits patients’ activities of daily living and is a crucial determinant of increased risk of adverse outcomes.¹ In patients with chronic HF and reduced ejection fraction (HFrEF), sacubitril/valsartan reduced the risk of the composite of cardiovascular death or first hospitalization for HF by 20% compared with enalapril at a median follow-up of 27 months.² However, evidence supporting the role of this treatment combination for improving short-term functional capacity is lacking.

In this work, the primary endpoint was to evaluate the short-term effects of sacubitril/valsartan on maximal exercise capacity evaluated by peak oxygen consumption (peak VO₂) in stable patients with symptomatic HFrEF. The secondary endpoint included changes in ventilatory efficiency during exercise (VE/VCO₂ slope).

From March 1, 2017 to July 1, 2017, we prospectively studied a cohort of patients with chronic HF, visited in the HF unit of a tertiary center in Spain. The inclusion criteria were: a) left ventricular ejection fraction < 40%; b) stable New York Heart Association functional class ≥ II; c) ability to perform a valid baseline exercise test, and d) prior treatment with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker.

For eligible patients, treatment with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker was replaced by sacubitril/valsartan. All patients provided informed consent and the protocol was approved by the research ethics committee in accordance with the principles of the Declaration of Helsinki and national regulations.

At each visit (baseline assessment and after 30-day initiation of sacubitril/valsartan), we registered demographic information, medical history, vital signs, 12-lead electrocardiogram, cardiopulmonary exercise testing), quality of life (Minnesota Heart Failure Living questionnaire), standard laboratory data, and pharmacological treatments. Doses of sacubitril/valsartan were prescribed according to established recommendations.¹ By protocol, no treatment changes occurred between the 2 visits.

Maximal functional capacity was evaluated with incremental and symptom-limited cardiopulmonary exercise testing (CORTEX Metamax 3B) on a bicycle ergometer, beginning with a workload of 10 W and increasing stepwise at 10-W increments every 1 minute. Gas exchange data and cardiopulmonary variables were averaged every 10-second values. Peak VO₂ was considered the highest value of VO₂ during the last 20 seconds of exercise. The VE/VCO₂ slope was determined by measuring the slope across the entire course of exercise.

Continuous variables are expressed as mean ± standard deviation or median [interquartile range] as appropriate; discrete variables as percentages. In an ANCOVA design, changes in peak VO₂ were tested with a mixed-effects model for repeated-measures. The model included as covariates the sacubitril/valsartan doses and the baseline value of peak VO₂. A 2-sided P value of < .05 was set as the criterion for statistical significance.

A total of 33 consecutive HFrEF patients were screened for eligibility and 16 were finally included in this study (Figure 1 of the supplementary material). The main reasons for ineligibility were baseline systolic blood pressure < 100 mmHg (n = 7), estimated glomerular filtration rate < 30 mL/min/1.73 m² (n = 5), and orthopedic/neurological inability to perform a valid cardiopulmonary exercise test (n = 4).

Median [interquartile range] age was 72 years [61-75], 75% were men, 56.3% had prior ischemic heart disease, and 37.5% were in New York Heart Association functional class III. The mean ± standard deviation of left ventricular ejection fraction, peak VO₂, and VE/VCO₂ slope were 32 ± 8%, 11.6 ± 2.5 mL/min/kg, and 42.9 ± 8.3, respectively. The starting dose of sacubitril/valsartan was 24/26 mg in 10 patients (62.5%). Baseline characteristics are presented in the Table. Using raw values, an improvement of at least 10% of the baseline peak VO₂ and VE/VCO₂ slope were found in 5 (31.3%) and 4 (25%) patients, respectively.

Table.

Baseline Characteristics of the Study Population

Variables	Included patients (n = 16)
Demographic, medical history and vital signs
Age, y	72 [61-75]
Male	12 (75)
Hypertension	12 (75)
Diabetes mellitus	6 (37.5)
Dyslipidemia	14 (87.5)
Ischemic heart disease	9 (56.3)
Baseline NYHA class III/IV	6 (37.5)
Atrial fibrillation	9 (56.3)
Systolic blood pressure, mmHg	115 ± 20
Diastolic blood pressure, mmHg	64 ± 11
Heart rate, bpm	70 ± 13
Laboratory
Serum potassium, mEq/L	4.3 ± 0.4
Serum sodium, mEq/L	139 ± 3
Serum creatinine, mg/dL	1.28 [0.9-1.72]
eGFR, mL/min/1.73 m^2	52.5 [41.7-75.2]
Hemoglobin, g/dL	14.3 ± 1.5
NT-proBNP, pg/mL	2055 [792-4283]
Echocardiography
LVDD, mm	68 [63-74]
LAV, mL/m^2	88 [75-126]
LVEF, %	32 ± 8
E/e’ ratio	13 [11-16]
TAPSE	20 [16-22]
Treatment
Furosemide	15 (93.8)
Beta-blockers	16 (100)
Antialdosterone	13 (81.3)
Starting dose of sacubitril/valsartan 24/26 mg	10 (62.5)
Exercise performance
6-MWT, m	315 [255-391]
Quality of life
MLHF score	29 [15-33]
Cardiopulmonary exercise test
Peak VO2, mL/min/kg	11.6 ± 2.5
VE/VCO2	42.9 ± 8.3
RER	1.14 ± 0.13

bpm, beats per minute; eGFR, estimated glomerular filtration rate using the Modification of Diet in Renal Disease formula; LAV, left atrial volume by biplane modified Simpson; LVDD, left ventricular diastolic diameter; LVEF, left ventricular ejection fraction; MLHF, Minnesota Living with Heart Failure Questionnarie score; 6-MWT, 6-minute walk test; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association functional class; peak VO₂, peak oxygen consumption; RER, respiratory exchange ratio; TAPSE, tricuspid annular plane systolic excursion; VE/VCO₂ slope, relationship between minute ventilation and the rate of CO₂ elimination.

Data are expressed as No. (%), mean ± standard deviation or median [interquartile range].

Compared with baseline, peak VO₂ increased significantly at 30 days (+Δ = 0.92; 95% confidence interval, 0.06-1.77; P = .035), which corresponded to a 7.9% increase from the baseline value (Figure A). Likewise, a significant improvement in VE/VCO₂ slope was also found at 30 days (-Δ = 3.89; 95% confidence interval, 6.70-1.07; P = .007), which corresponded to a 9.1% of reduction, as shown in Figure B. In parallel, a significant improvement in other surrogates of severity such as quality of life and N-terminal pro-B-type natriuretic peptide (32.22% and 5.29% of reduction, respectively) was registered (Figure 2 of the supplementary material). No significant changes were detected in estimated glomerular filtration rate (Figure 2 of the supplementary material).

Figure.

Thirty-day effects of sacubitril/valsartan on CPET parameters. A: changes in peak VO₂. B: changes in VE/VCO₂ slope. CPET, cardiopulmonary exercise test; peak VO₂, peak oxygen consumption; VE/VCO₂ slope, minute ventilation/carbon dioxide production. Adjusted for baseline values of both exposures.

To the best of our knowledge, this is the first study suggesting that the initiation of sacubitril/valsartan, mostly at low doses, could lead to a short-term increase in peak VO₂. Interestingly, this beneficial effect was associated with a significant improvement in other cardiopulmonary exercise testing surrogates of severity such as ventilatory efficiency. Although the mechanisms by which sacubitril/valsartan might improve early exercise capacity in HFrEF remain unclear, we speculate that neprilysin inhibition mediated by sacubitril would acutely amplify the hemodynamic effects of natriuretic peptides and other vasoactive peptides,³ resulting in an improvement of short-term exercise tolerance.

The main limitation of this study is the small sample size and the lack of a control group. However, we believe these encouraging findings open a new research path aimed at exploring the pathophysiological mechanism by which sacubitril/valsartan improves exercise tolerance in HFrEF. Indeed, a clinical trial evaluating the effect of sacubitril/valsartan on 6-month Exercise Tolerance in Patients With Heart Failure (NEPRIExTol) is currently ongoing (NCT03190304).

FUNDING

This work was supported in part by grants from CIBER CV 16/11/00420, 16/11/00403; FEDER and PIE15/00013.