Nitrates for reducing death and cardiac complications in participants during non-cardiac surgery

Review question

We reviewed the evidence on effects of nitrates on death and cardiac complications in people undergoing non-cardiac surgery (that is, surgery on any part of the body except the heart).

Background

Cardiac complications (heart diseases and problems) are not uncommon in people undergoing non-cardiac surgery, especially among those with heart disease. Furthermore, anaesthesia and surgery can put stress on the cardiovascular system. The incidence of cardiac events can be up to 50% in non-cardiac surgery, especially for some seriously ill people. Nitrates increase the delivery of blood and the supply of oxygen to the heart, improving cardiac function and reducing cardiac problems. Nitrates are also used in the operating room. However, the effects of nitrates in reducing the incidence of death and cardiac problems with non-cardiac surgery remains unclear.

Study characteristics

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.

Key results

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.

Quality of the evidence

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.

Conclusion and future research

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.

Authors' conclusions: 

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.

Read the full abstract...
Background: 

Cardiac complications are not uncommon in patients undergoing non-cardiac surgery, especially in patients with coronary artery disease (CAD) or at high risk of CAD. Perioperative cardiac complications can lead to mortality and morbidity, as well as higher costs for patient care. Nitrates, which are among the most commonly used cardiovascular drugs, perform the function of decreasing cardiac preload while improving cardiac blood perfusion. Sometimes, nitrates are administered to patients undergoing non-cardiac surgery to reduce the incidence of cardiac complications, especially for patients with CAD. However, their effects on patients' relevant outcomes remain controversial.

Objectives: 

• To assess effects of nitrates as compared with other interventions or placebo in reducing cardiac risk (such as death caused by cardiac factors, angina pectoris, acute myocardial infarction, acute heart failure and cardiac arrhythmia) in patients undergoing non-cardiac surgery.

• To identify the influence of different routes and dosages of nitrates on patient outcomes.

Search strategy: 

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and the Chinese BioMedical Database until June 2014. We also searched relevant conference abstracts of important anaesthesiology or cardiology scientific meetings, the database of ongoing trials and Google Scholar.

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.

Selection criteria: 

We included randomized controlled trials (RCTs) comparing nitrates versus no treatment, placebo or other pharmacological interventions in participants (15 years of age and older) undergoing non-cardiac surgery under any type of anaesthesia.

Data collection and analysis: 

We used standard methodological procedures as expected by Cochrane. Two review authors selected trials, extracted data from included studies and assessed risk of bias. We resolved differences by discussion and, when necessary, sought help and suggestions from a third review author. We used a random-effects model for data analysis.

Main results: 

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.

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