Bredemeier Markus, Lopes Lediane Moreira, Eisenreich Matheus Augusto, Hickmann Sheila, Bongiorno Guilherme Kopik, d'Avila Rui, Morsch André Luis Bittencourt, da Silva Stein Fernando, Campos Guilherme Gomes Dias
Rheumatology Service at Hospital Nossa Senhora da Conceição, Grupo Hospitalar Conceição, Porto Alegre, RS, Brazil.
Serviço de Reumatologia do Hospital Nossa Senhora da Conceição, Avenida Francisco Trein, 596, sala 2048, Porto Alegre, RS, 91350-200, Brazil.
BMC Cardiovasc Disord. 2018 Feb 7;18(1):24. doi: 10.1186/s12872-018-0757-9.
Xanthine oxidase inhibitors (XOI), classified as purine-like (allopurinol and oxypurinol) and non-purine (febuxostat and topiroxostat) XOI, present antioxidant properties by reducing the production of reactive oxygen species derived from purine metabolism. Oxidative stress is an important factor related to endothelial dysfunction and ischemia-reperfusion injury, and may be implicated in the pathogenesis of heart failure, hypertension, and ischemic heart disease. However, there is contradictory evidence regarding the possible cardiovascular (CV) protective effect exerted by XOI. Our objective is to compare the incidence of major adverse cardiovascular events (MACE), mortality, total (TCE) and specific CV events in randomized controlled trials (RCTs) testing XOI against placebo or no treatment.
PubMed, EMBASE, Web of Science, Cochrane Central, Lilacs databases were searched from inception to Dec 30 2016, along with hand searching. RCTs including exclusively adult individuals, lasting ≥ 4 weeks, with no language restriction, were eligible. Independent paired researchers selected studies and extracted data. Considering the expected rarity of events, Peto and DerSimonian/Laird odds ratios (OR), the latter in case of heterogeneity, were used for analysis. Random-effects meta-regression was used to explore heterogeneity.
The analysis of MACE included 81 articles (10,684 patients, 6434 patient-years). XOI did not significantly reduce risk of MACE (OR = 0.71, 95% CI 0.46-1.09) and death (0.89, 0.59-1.33), but reduced risk of TCE (0.60, 0.44-0.82; serious TCE: 0.64, 0.46 to 0.89), and hypertension (0.54, 0.37 to 0.80). There was protection for MACE in patients with previous ischemic events (0.42, 0.23-0.76). Allopurinol protected for myocardial infarction (0.38, 0.17-0.83), hypertension (0.32, 0.18-0.58), TCE (0.48, 0.31 to 0.75, I = 55%) and serious TCE (0.56, 0.36 to 0.86, I = 44%). Meta-regression associated increasing dose of allopurinol with higher risk of TCE and serious TCE (P < 0.05). Accordingly, lower doses (≤ 300 mg/day) of allopurinol reduced the risk of TCE, unlike higher doses. Non-purine-like XOI did not significantly reduce or increase the risk of adverse CV events, but confidence intervals were wide. Quality of evidence was generally low to moderate.
Purine-like XOI may reduce the incidence of adverse CV outcomes. However, higher doses of allopurinol (> 300 mg/day) may be associated with loss of CV protection.
黄嘌呤氧化酶抑制剂（XOI）分为嘌呤类（别嘌醇和氧嘌呤醇）和非嘌呤类（非布司他和托匹司他）XOI，通过减少嘌呤代谢产生的活性氧来呈现抗氧化特性。氧化应激是与内皮功能障碍和缺血再灌注损伤相关的重要因素，可能与心力衰竭、高血压和缺血性心脏病的发病机制有关。然而，关于XOI可能产生的心血管（CV）保护作用存在相互矛盾的证据。我们的目的是比较在针对安慰剂或未治疗进行测试的随机对照试验（RCT）中，使用XOI与使用安慰剂或未治疗相比，主要不良心血管事件（MACE）、死亡率、总心血管事件（TCE）和特定CV事件的发生率。
检索了从数据库建立至2016年12月30日的PubMed、EMBASE、科学网、Cochrane中心、Lilacs数据库，并进行了手工检索。纳入标准为仅包括成年个体、持续时间≥4周、无语言限制的RCT。由独立的配对研究人员选择研究并提取数据。考虑到事件预期的罕见性，采用Peto法和DerSimonian/Laird比值比（OR）（后者用于存在异质性的情况）进行分析。采用随机效应meta回归来探索异质性。
对MACE的分析纳入了81篇文章（10684例患者，6434患者年）。XOI并未显著降低MACE风险（OR = 0.71，95%CI 0.46 - 1.09）和死亡风险（0.89，0.59 - 1.33），但降低了TCE风险（0.60，0.44 - 0.82；严重TCE：0.64，0.46至0.89）以及高血压风险（0.54，0.37至0.80）。对既往有缺血事件的患者，XOI对MACE有保护作用（0.42，0.23 - 0.76）。别嘌醇对心肌梗死（0.38，0.17 - 0.83）、高血压（0.32，0.18 - 0.58）、TCE（0.48，0.31至0.75，I = 55%）和严重TCE（0.56，0.36至0.86，I = 44%）有保护作用。meta回归显示，别嘌醇剂量增加与TCE和严重TCE风险升高相关（P < 0.05）。因此，与高剂量不同，低剂量（≤300mg/天）的别嘌醇可降低TCE风险。非嘌呤类XOI并未显著降低或增加不良CV事件风险，但置信区间较宽。证据质量总体为低到中等。
嘌呤类XOI可能降低不良CV结局的发生率。然而，高剂量（>300mg/天）的别嘌醇可能与CV保护作用丧失有关。
