Zhao Na, Xu Jin, Singh Balwinder, Yu Xuerong, Wu Taixiang, Huang Yuguang
Department of Anesthesiology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China.
Cochrane Database Syst Rev. 2016 Aug 4;2016(8):CD010726. doi: 10.1002/14651858.CD010726.pub2.
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.
• 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.
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.
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.
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.
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.
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.
心脏并发症在接受非心脏手术的患者中并不少见，尤其是在患有冠状动脉疾病（CAD）或有CAD高风险的患者中。围手术期心脏并发症可导致死亡率和发病率增加，以及患者护理成本升高。硝酸盐是最常用的心血管药物之一，具有降低心脏前负荷同时改善心脏血液灌注的功能。有时，会对接受非心脏手术的患者使用硝酸盐以降低心脏并发症的发生率，尤其是对于CAD患者。然而，它们对患者相关结局的影响仍存在争议。
•评估与其他干预措施或安慰剂相比，硝酸盐在降低接受非心脏手术患者的心脏风险（如心脏因素导致的死亡、心绞痛、急性心肌梗死、急性心力衰竭和心律失常）方面的效果。•确定不同给药途径和剂量的硝酸盐对患者结局的影响。
我们检索了Cochrane对照试验中心注册库（CENTRAL）、MEDLINE、EMBASE和中国生物医学数据库，检索截至2014年6月。我们还检索了重要麻醉学或心脏病学科学会议的相关会议摘要、正在进行的试验数据库和谷歌学术。我们在2016年1月重新进行了检索。我们将三项潜在的新的感兴趣研究添加到“等待分类的研究”列表中，并将把它们纳入我们的正式综述结果以进行综述更新。
我们纳入了比较硝酸盐与未治疗、安慰剂或其他药物干预措施的随机对照试验（RCT），研究对象为接受任何类型麻醉下非心脏手术的15岁及以上参与者。
我们采用Cochrane预期的标准方法程序。两位综述作者选择试验、从纳入研究中提取数据并评估偏倚风险。我们通过讨论解决分歧，必要时寻求第三位综述作者的帮助和建议。我们使用随机效应模型进行数据分析。
我们纳入了27项随机对照试验（RCT）（共分析8244名参与者）。研究者报告了三种不同硝酸盐（硝酸甘油、硝酸异山梨酯和尼可地尔）与未治疗、安慰剂或其他药物干预措施的12种不同比较。所有参与者年龄均超过15岁。超过一半的试验使用全身麻醉。大多数试验中的手术程序围手术期心脏并发症风险为低到中度。只有两项包含三项研究的比较报告了主要结局——术后30天内的全因死亡率。研究者以可变且异质的方式报告了其他发病率结局和不良事件，导致可纳入荟萃分析的数据有限。我们根据大多数领域的偏倚风险确定，纳入研究的总体方法学质量为中等偏下。总之，我们发现，当将硝酸甘油与未治疗（一项研究，60名参与者，0/30 vs 1/30；风险比（RR）0.33，95%置信区间（CI）0.01至7.87，基于GRADE标准的极低质量证据）或安慰剂（两项研究，89名参与者，1/45 vs 0/44；RR 2.81，95%CI 0.12至63.83，极低质量证据）进行比较时，主要结局——术后30天内的全因死亡率没有差异。关于我们的次要结局，我们注意到在任何比较中，心绞痛、急性心肌梗死、急性心力衰竭、心律失常或心脏骤停方面均无统计学显著差异。在与硝酸甘油的比较中，尽管在接受未治疗或安慰剂的参与者中观察到更多心脏缺血事件，但我们发现除尼可地尔与安慰剂的比较外，在任何比较中均无统计学显著差异。一项研究揭示了尼可地尔对心脏缺血的潜在剂量依赖性保护作用。各比较中不良事件的报告方式各异。总体而言，接受硝酸盐治疗的参与者中更多出现低血压、心动过速和头痛，但研究者报告在任何比较中两组之间均无统计学显著差异。
本系统综述表明，硝酸甘油或硝酸异山梨酯与接受非心脏手术患者的死亡率和心脏并发症改善无关。有限的证据表明，尼可地尔可能降低接受非心脏手术参与者的心脏缺血风险。需要更多研究来巩固证据。然而，本综述中许多分析所纳入的数据稀疏——即充分的数据很少——导致检测硝酸盐与对照之间差异的效能非常低。因此，更客观的结论是，现有证据不足以表明硝酸盐是否与接受非心脏手术患者的死亡率和心脏并发症改善有关。在过去十年中，没有高质量研究关注非心脏手术期间使用硝酸盐与心脏死亡率和发病率之间的关联。本综述强调了该领域进行精心设计试验的必要性。
