Abstract: We included 27 randomized controlled trials (RCTs) (8244 participants analysed). Investigators reported 12 different comparisons of three different nitrates (nitroglycerin, isosorbide dinitrate and nicorandil) versus no treatment, placebo or other pharmacological interventions. All participants were older than 15 years of age. More than half of the trials used general anaesthesia. Surgical procedures in most trials were at low to moderate risk for perioperative cardiac complications. Only two comparisons including three studies reported the primary outcome - all-cause mortality up to 30 days post operation. Researchers reported other morbidity outcomes and adverse events in a variable and heterogeneous way, resulting in limited available data for inclusion in the meta-analysis. We determined that the overall methodological quality of included studies was fair to low, in accordance with risk of bias in most domains. In summary, we found no difference in the primary outcome - all-cause mortality up to 30 days post operation - when nitroglycerin was compared with no treatment (one study, 60 participants, 0/30 vs 1/30; (risk ratio (RR) 0.33, 95% confidence interval (CI) 0.01 to 7.87, very low-quality evidence based on GRADE criteria) or with placebo (two studies, 89 participants, 1/45 vs 0/44; RR 2.81, 95% CI 0.12 to 63.83, very low-quality evidence). Regarding our secondary outcomes, we noted no statistically significant differences in angina pectoris, acute myocardial infarction, acute heart failure, cardiac arrhythmia or cardiac arrest in any comparisons. In comparisons versus nitroglycerin, although more events of cardiac ischaemia were observed in participants receiving no treatment or placebo, we found no statistically significant differences in any comparisons, except the comparison of nicorandil versus placebo. One study revealed a potential dose-dependent protective effect of nicorandil for cardiac ischaemia. Adverse events were reported in a heterogeneous way among the comparisons. In general, more participants treated with nitrates had hypotension, tachycardia and headache, but investigators reported no statistically significant differences between groups in any comparisons. This systematic review suggests that nitroglycerin or isosorbide dinitrate is not associated with improvement in mortality and cardiac complications among patients undergoing non-cardiac surgery. Limited evidence suggests that nicorandil may reduce the risk of cardiac ischaemia in participants undergoing non-cardiac surgery. Additional studies are needed to consolidate the evidence. However, the data included in many of the analyses in this review are sparse - that is, adequate data are few - resulting in very low power to detect differences between nitrates and comparators. Thus, a more objective conclusion would state that available evidence is insufficient to show whether nitrates are associated with improvement in mortality and cardiac complications among patients undergoing non-cardiac surgery. Over the past decade, no high-quality studies have focused on association of cardiac mortality and morbidity with use of nitrates during non-cardiac surgery. This review underlines the need for well-designed trials in this field.

Plain-language summary: We identified randomized controlled trials evaluating the benefits and side effects of nitrates by searching major databases for original articles until June 2014. We included 27 studies (8244 participants) in this review. All participants were older than 15 years. Most trial participants had low to mild risk of perioperative cardiac complications. We reran the search in January 2016. We added three potential new studies of interest to the list of ‘Studies awaiting classification' and will incorporate them into our formal review findings for the review update. We examined the following results: death for any reason, angina pectoris (sensation of chest pain due to a restriction in blood supply to heart muscle), acute myocardial infarction (stop in the flow of blood to part of the heart, causing damage to the heart muscle), cardiac ischaemia (restriction in blood supply to heart tissue), acute heart failure (loss of heart function), cardiac arrhythmia (irregular heartbeat), cardiac arrest (sudden stop in effective blood circulation due to failure of the heart) and increased troponin (a biomarker of heart disorder). We also evaluated adverse events, such as low blood pressure, headache, fast heartbeat and nausea and vomiting. We found no significant differences between nitrates and controls, with the exception of nicorandil versus placebo (one study, 248 participants). Nicorandil appeared to decrease the incidence of cardiac ischaemia. We used GRADE criteria to assess the overall quality of evidence as very low for the main results owing to risk of bias, insufficient data and imprecision. Available evidence is insufficient to show whether nitrates are associated with improved mortality and cardiac complications in patients during non-cardiac surgery. Well-designed trials are needed in this field.