Effect of statin therapy on muscle symptoms: an individual participant data meta-analysis of large-scale, randomised, double-blind trials.
Effect of statin therapy on muscle symptoms: an individual participant data meta-analysis of large-scale, randomised, double-blind trials.
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DOI：
10.1016/s0140-6736(22)01545-8
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发表时间：
2022-09-10
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通讯作者：
Cholesterol Treatment Trialists' Collaboration
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作者：
Cholesterol Treatment Trialists' Collaboration
他汀类药物治疗可有效预防动脉粥样硬化性心血管疾病，并被广泛使用，但人们一直担心他汀类药物治疗可能经常导致肌肉疼痛或无力。我们旨在通过对他汀类药物治疗的大型、长期、随机、双盲试验中所有记录的不良肌肉事件的个体参与者数据进行荟萃分析来解决这些问题。如果他汀类药物治疗的随机试验旨在招募至少1000名受试者，计划治疗持续时间至少为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双盲比较，则符合条件。我们分析了来自19项他汀类药物与安慰剂双盲试验（n=123 940）和4项他汀类药物治疗方案强度更高与强度更低的双盲试验（n=30 724）的个体受试者数据。 根据预先规定的方案，对肌肉结果的影响进行标准的逆方差加权荟萃分析。在19项安慰剂对照试验中（平均年龄63岁[SD 8]，34 533 [27.9%]名女性，59 610 [48.1%]名既往有血管疾病的参与者，22 925 [18.5%]名糖尿病参与者），在4.3年的加权平均中位随访期间，16 835名（27.1%）分配他汀类药物的患者与16 446名（26.6%）分配安慰剂的患者报告了肌肉疼痛或无力（率比[RR] 1.03; 95%CI 1.01 - 1.06）。 在第1年，他汀类药物治疗产生了7%的肌肉疼痛或无力的相对增加（1·07; 1·04-1·10），对应于每1000人-年11（6-16）起事件的绝对过量率，这表明，只有1/15（[1·07-1·00]/1·07）的这些肌肉相关报告的参与者分配到他汀类药物治疗实际上是由于他汀类药物。第1年后，首次报告的肌肉疼痛或无力没有显著增加（0.99; 0.96 - 1.02）。对于所有年份的合并，更强化的他汀类药物治疗方案（即，40-80 mg阿托伐他汀或20-40 mg瑞舒伐他汀，每日一次）产生的RR高于强度较低或强度中等的方案（1·08 [1·04-1·13] vs 1·03 [1·00-1·05]），第1年后，更强化方案存在小幅过量（1·05 [0·99-1·12]）。没有明确的证据表明不同他汀类药物或不同临床情况下的RR不同。他汀类药物治疗导致肌酸激酶中位值小幅升高，但无临床意义，约为正常值上限的0.02倍。他汀类药物治疗引起了轻微的肌肉疼痛。大多数（>90%）接受他汀类药物治疗的参与者报告的肌肉症状不是由于他汀类药物引起的。肌肉症状的小风险远远低于已知的心血管益处。有必要审查肌肉症状的患者服用他汀类药物的临床管理。英国心脏基金会、医学研究理事会、澳大利亚国家健康和医学研究理事会。
Statin therapy is effective for the prevention of atherosclerotic cardiovascular disease and is widely prescribed, but there are persisting concerns that statin therapy might frequently cause muscle pain or weakness. We aimed to address these through an individual participant data meta-analysis of all recorded adverse muscle events in large, long-term, randomised, double-blind trials of statin therapy. Randomised trials of statin therapy were eligible if they aimed to recruit at least 1000 participants with a scheduled treatment duration of at least 2 years, and involved a double-blind comparison of statin versus placebo or of a more intensive versus a less intensive statin regimen. We analysed individual participant data from 19 double-blind trials of statin versus placebo (n=123 940) and four double-blind trials of a more intensive versus a less intensive statin regimen (n=30 724). Standard inverse-variance-weighted meta-analyses of the effects on muscle outcomes were conducted according to a prespecified protocol. Among 19 placebo-controlled trials (mean age 63 years [SD 8], with 34 533 [27·9%] women, 59 610 [48·1%] participants with previous vascular disease, and 22 925 [18·5%] participants with diabetes), during a weighted average median follow-up of 4·3 years, 16 835 (27·1%) allocated statin versus 16 446 (26·6%) allocated placebo reported muscle pain or weakness (rate ratio [RR] 1·03; 95% CI 1·01–1·06). During year 1, statin therapy produced a 7% relative increase in muscle pain or weakness (1·07; 1·04–1·10), corresponding to an absolute excess rate of 11 (6–16) events per 1000 person-years, which indicates that only one in 15 ([1·07–1·00]/1·07) of these muscle-related reports by participants allocated to statin therapy were actually due to the statin. After year 1, there was no significant excess in first reports of muscle pain or weakness (0·99; 0·96–1·02). For all years combined, more intensive statin regimens (ie, 40–80 mg atorvastatin or 20–40 mg rosuvastatin once per day) yielded a higher RR than less intensive or moderate-intensity regimens (1·08 [1·04–1·13] vs 1·03 [1·00–1·05]) compared with placebo, and a small excess was present (1·05 [0·99–1·12]) for more intensive regimens after year 1. There was no clear evidence that the RR differed for different statins, or in different clinical circumstances. Statin therapy yielded a small, clinically insignificant increase in median creatine kinase values of approximately 0·02 times the upper limit of normal. Statin therapy caused a small excess of mostly mild muscle pain. Most (>90%) of all reports of muscle symptoms by participants allocated statin therapy were not due to the statin. The small risks of muscle symptoms are much lower than the known cardiovascular benefits. There is a need to review the clinical management of muscle symptoms in patients taking a statin. British Heart Foundation, Medical Research Council, Australian National Health and Medical Research Council.