Assessment of adverse effects attributed to statin therapy in product labels: a meta-analysis of double-blind randomised controlled trials.

We aimed to assess the evidence for such undesirable effects more reliably through a meta-analysisof individual participant data from large double-blindtrials of statin therapy.

我们旨在通过对他汀治疗大型双盲试验的个体参与者数据进行荟萃分析，更可靠地评估此类不良效应的证据。

Methods

In this meta-analysisof individual participant-level data from double-blindrandomised controlled trials, we generated a list of all undesirable effect terms listed in statin SmPCs by searching an electronic medicines compendium for five statins (atorvastatin, fluvastatin, pravastatin, rosuvastatin, and simvastatin).

在这项双盲随机对照试验的个体参与者数据荟萃分析中，我们通过检索电子药物汇编，为五种他汀类药物（阿托伐他汀、氟伐他汀、普伐他汀、瑞舒伐他汀和辛伐他汀）生成了一份不良反应术语列表。

Randomised trials were eligible for meta-analysisof these effects if they involved at least 1000 participants, had a scheduled treatment period of at least 2 years, and involved a double-blindcomparison of statin versus placebo or of a more intensive versus a less intensive statin regimen.

如果随机试验涉及至少1000名参与者，计划治疗期至少为2年，并且涉及他汀类药物与安慰剂的双盲比较，或者更密集与较不密集的他汀类药物方案的比较，则这些试验符合对这些效果进行荟萃分析的资格。

Event rate ratios (RRs) and 95% CIs were calculated with statistical significance assessed after controlling the false discovery rate (FDR) at 5%.

事件率比（RRs）和95%置信区间（CIs）在控制假发现率（FDR）在5%后计算，并评估了统计显著性。

Results

19 trials compared statin versus placebo (123 940 participants, median follow-up 4·5 years [IQR 3·1-5·4]).

19项试验比较了他汀类药物与安慰剂（123,940名参与者，中位随访时间为4.5年，四分位数间距为3.1-5.4年）。

In addition to previously reported effects on muscle outcomes and diabetes, only four of 66 further undesirable outcomes that had been attributed to statins were FDR significant: abnormal liver transaminases (783 participants [0·30% per annum] allocated statin vs 556 [0·22% per annum] allocated placebo, RR 1·41 [95% CI 1·26-1·57]) and other liver function test abnormalities (651 participants [0·25% per annum] allocated statin vs 518 [0·20% per annum] allocated placebo, RR 1·26 [1·12-1·41]; absolute annual excess of 0·13% for combined liver function test abnormality), urinary composition alteration (556 [0·21% per annum] allocated statin vs 472 [0·18% per annum] allocated placebo, RR 1·18 [1·04-1·33]), and oedema (3495 [1·38% per annum] allocated statin vs 3299 [1·31% per annum] allocated placebo, RR 1·07 [1·02-1·12]).

除了先前报告的对肌肉结果和糖尿病的影响外，只有四项被归因于他汀类药物的66项其他不良结果具有FDR显著性：异常的肝转氨酶（分配他汀类药物的783名参与者[每年0.30%]与分配安慰剂的556名参与者[每年0.22%]，相对风险1.41 [95%置信区间1.26-1.57]）和其他肝功能测试异常（分配他汀类药物的651名参与者[每年0.25%]与分配安慰剂的518名参与者[每年0.20%]，相对风险1.26 [1.12-1.41]；联合肝功能测试异常的绝对年增额为0.13%），尿液成分改变（分配他汀类药物的556名参与者[每年0.21%]与分配安慰剂的472名参与者[每年0.18%]，相对风险1.18 [1.04-1.33]），以及水肿（分配他汀类药物的3495名参与者[每年1.38%]与分配安慰剂的3299名参与者[每年1.31%]，相对风险1.07 [1.02-1.12]）。

Analysis of the four trials of more intensive versus less intensive statin regimens also found significant excesses for abnormal liver transaminases and other liver function test abnormalities (supporting a dose-dependent effect), but no significant excess was found for urinary composition alteration or oedema.

对四项更密集与较不密集他汀类药物方案的试验分析也发现了异常肝转氨酶和其他肝功能测试异常的显著增加（支持剂量依赖效应），但未发现尿液成分改变或水肿的显著增加。

interpretation

Adverse eventdata from blinded randomised trials do not support causal relationships between statin therapy and most of the conditions (including cognitive impairment, depression, sleep disturbance, and peripheral neuropathy) listed in product labels as potential undesirable effects.

双盲随机试验的不良事件数据并不支持他汀类药物治疗与产品标签上列出的大多数条件（包括认知障碍、抑郁、睡眠障碍和周围神经病变）之间存在因果关系。

In light of these findings, such labelling and other official sources of health information should be revised so that patients and their doctors can make appropriately informed decisions regarding statin therapy.

鉴于这些发现，应修订此类标签和其他官方健康信息来源，以便患者及其医生可以就他汀类药物治疗做出适当的信息充分的决策。

funding

British Heart Foundation, UK Medical Research Council, and Australian National Health and Medical Research Council.

英国心脏基金会、英国医学研究委员会和澳大利亚国家健康与医学研究委员会。