To our knowledge, the present analysis is the first evaluation of the effectiveness and safety of INNs in patients with all types of HF using the most recent RCTs. Because HF is a chronic disease, the intervention time was relatively short, and the intervention measures were stable, clinical trials with crossover design were included. The data of all eight crossover trials were complete. Our meta-analysis demonstrated that, compared with placebo, there is insufficient evidence to prove that INNs improve exercise ability in patients with HFrEF and HFpEF. While in patients with HFpEF, INNs reduced RAP, SBP, PAP, PCWP during rest and exercise and DBP during exercise effectively.
Our finding that there is no clear evidence for improving exercise ability in patients with HF using INNs is consistent with the results of a previous meta-analysis . However, there are some limitations in that study: the included studies rarely evaluated the effectiveness and safety of INNs for HF; some trials were supported by pharmaceutical manufacturers or written by the same author teams; this may have resulted in bias. There were different routes of nitrate administration, and the included patients all had HFpEF, both of which limit the generalizability of the findings. There were no studies assessing INNs on the impact of hospitalization or mortality in patients with HF.
Because of the lack of large and longitudinal studies, the present meta-analysis has similar limitations; therefore, more studies are needed to validate our findings. We found that INNs were less effective in patients with HFrEF than in those with HFpEF. These two kinds of HF are different in terms of the mechanism during the absorption of NO and reaction of the INNs [26, 36]. Inflammatory reactions caused by various metabolic diseases promote oxidative stress of vascular endothelium in patients with HF [36–38]. The response of HFpEF patients to INNs is more pronounced due to the opposing mechanisms of myocardial remodeling in HFpEF patients [26, 39]. The effect of INN supplementation on BP may also lead to our positive outcomes of BP in HFpEF patients . There was no significant heterogeneity in these outcomes, probably due to the small number of studies.
Some studies [25, 35, 40] showed that inorganic nitrates supplementation improved skeletal muscle strength; however, the present meta-analysis did not show similar results. This discrepancy may be due to the insufficient number of existing RCT, small sample sizes, and large amounts of bias.
VO2 peak is related to the risk of HF and the cardiac function classification [41–43]. The current guidelines  recommend using VO2 peak to evaluate the improvement of exercise capacity, which is the overall reflection of heart and lung function  and is beneficial to HF outcomes. Although few clinical trials [21, 30, 32–33] reported the increase of VO2 peak after inorganic nitrate intake, the present meta-analysis results did not show the beneficial effect of inorganic nitrate on VO2 peak. According to the current meta-analysis, there is insufficient evidence to support the use of INNs to improve exercise ability.
Cohort studies showed that, in patients with HF, adverse events such as bleeding and stroke are caused by higher baseline SBP and DBP . Therefore, BP control is an essential part of HF management. Hemodynamic parameters of PAP are associated with adverse clinical events, and PCWP determines the volume reserve in patients with HF . The atrial and ventricular pressure measured by echocardiography indicates cardiac function. RAP reflects the preload of the right ventricle and venous blood volume, which is related to right HF. Although inorganic nitrates did not significantly improve exercise capacity, they did improve SBP, DBP, PAP, RAP, and PCWP during rest and exercise, factors that affect the outcome in patients with HF.
Consistent with our finding, another meta-analysis  showed that dietary supplementation of inorganic nitrates in adults reduced SBP, which may be related to nitrates' vasodilator effect; there is no clear evidence of its long-term effectiveness and safety. This is consistent with our results, suggesting that inorganic nitrates reduce BP. Hypertension is associated with an increased risk of HF. Although organic nitrates (as opposed to inorganic nitrates) dilate blood vessels and reduce BP, the side effects of hypotension, headache, and cerebral vascular dilation restrict the use of organic nitrates in patients with HF [16, 49], and long-term use may further reduce the utilization of NO . There were no significant differences between inorganic nitrate and placebo in adverse events in the present meta-analysis. The evidence to support the clinical use of INNs is insufficient, although it may have potential applications owing to their safety profiles.
HF is a chronic disease, and the long-term outcome depends on long-term follow-up. This follow-up should include measurement of outcome-related indicators of HF in large-sample RCT trials. There are several clinical trials in progress (ClinicalTrials. gov: NCT02713126, NCT02840799, and NCT02918552). Results of these trials are expected to determine the safety and effectiveness of INNs. Although the present meta-analysis results did not show that supplementation with inorganic nitrate improved muscle strength or peak VO2, studies found that supplementation with inorganic nitrate improves muscle strength and endurance in healthy people [39, 51]. In the included articles in the HFrEF group [19, 25], motor ability improvement was significant. The improvement of hemodynamic results suggests that INNs are helpful to patients with HF. Large-sample clinical trials are needed further to study the effect of INNs on patients with HF.
The establishment of the safety of INNs is critical. Because about three-quarters of inorganic nitrates are first metabolized through the kidney, patients with renal insufficiency require surveillance [52, 53]. Because these products are oral preparations, the effect on the gastrointestinal tract also requires attention. Inhaled forms may also be considered. However, the safety of the inhaled forms [27, 29] has not been demonstrated.
The strength of the current study is that we comprehensively searched all relevant literature in Chinese and English databases based on pooled results of all eligible RCTs assessing the effects of INNs on patients with HF (including HFrEF and HFpEF). We developed a comprehensive search strategy, strictly included the standard RCT, and strictly evaluated the trials' quality. Second, we divided patients into subgroups to determine the various effects of interventions on HF with reduced and preserved ejection fractions. In terms of outcome evaluation, the choice of different calculation models for parallel RCTs and crossover trials was helpful to reduce the errors of the trial outcome. These patients were compared before and after taking inorganic nitrate in crossover trials  without randomization and washout phase. We extracted the first phase data for analysis, which had no significant impact on the overall results. The other seven crossover trials [20–21, 25–26, 29, 31–32] explained the washout period, which eliminated the effect of the first stage intervention. Results of sensitivity analysis indicated the robustness of our findings. There was no evidence that INNs improve exercise ability, although our analysis provides the basis for future research.
Although we strictly followed the provisions of PRISMA and Cochrane manuals, there remain some limitations. First, there are always problems in comparisons among RCT because of differences in included patients, the blinding methods used, differences of randomization content, differences of outcome evaluation index, and varying sample sizes. Because of the large number of crossover trials, we used standardized mean difference, which may compromise the inherent heterogeneity. Second, the number of included studies was limited, and the sample sizes were small. Most studies suffered from the risk of bias, especially performance and detection bias. Therefore, our results should be interpreted with caution. Third, the present meta-analysis only included patients with HFrEF and HFpEF, and patients with heart failure with median ejection fraction were not included. This omission may have affected the generalizability of our findings. Finally, because of the short follow-up periods of the included trials, we could not assess the long-term effects of inorganic nitrate on patients with HF. Further studies assessing the long-term effects of inorganic nitrate on HF are needed.