Effect of inorganic nitrate or nitrite supplementation on exercise capacity for heart failure: a systematic review and meta-analysis of randomized controlled trials

Background: Some studies showed beneficial effects for exercise capacity of inorganic nitrates or nitrites (INNs) in heart failure (HF). However, the evidence is inconsistent. Objective: We performed a meta-analysis to evaluate effects of INNs on exercise intolerance for heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). Methods: Seven databases were searched from inception until September 2020 for randomized controlled trials (RCTs) assessing effects of INNs for HFrEF or HFpEF. RCTs comparing INNs with placebo, no treatment, or organic nitrates in patients. Primary outcomes were parameters of the exercise test. Secondary outcomes were N-terminal fragment of the prohormone brain natriuretic peptide (NT-Pro-BNP), cardiac function, and quality of life. Results: Four RCTs with 43 patients in HFrEF and seven RCTs with 224 patients in HFpEF were included with high quality. The meta-analysis showed INNs didn’t improve the muscle function of peak power in HFrEF, or peak oxygen uptake (VO 2 peak) in HFrEF; neither in HFpEF. In HFpEF group, INNs significantly decreased right atrial pressure, systolic blood pressure, pulmonary arterial pressure and pulmonary capillary wedge pressure during rest and exercise. No effect of INNs on NT-Pro-BNP, quality of life, or diastolic cardiac function. No serious adverse event was reported. Conclusions: INNs don’t improve exercise capacity in HF; however, they improved hemodynamic status, especially in HFpEF patients. More high-quality large-sample trials are needed to provide evidence for clinical application. PROSPERO registration number: CRD42020210266