National Heart and Lung Institute, Imperial College London, London, UK; Royal London Hospital, Barts Health NHS Trust, Whitechapel, London, UK; William Harvey Research Institute, Queen Mary University of London, London, UK.
National Heart and Lung Institute, Imperial College London, London, UK.
Lancet. 2017 Jun 24;389(10088):2473-2481. doi: 10.1016/S0140-6736(17)31075-9. Epub 2017 May 2.
In blinded randomised controlled trials, statin therapy has been associated with few adverse events (AEs). By contrast, in observational studies, larger increases in many different AEs have been reported than in blinded trials.
In the Lipid-Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes Trial, patients aged 40-79 years with hypertension, at least three other cardiovascular risk factors, and fasting total cholesterol concentrations of 6·5 mmol/L or lower, and who were not taking a statin or fibrate, had no history of myocardial infarction, and were not being treated for angina were randomly assigned to atorvastatin 10 mg daily or matching placebo in a randomised double-blind placebo-controlled phase. In a subsequent non-randomised non-blind extension phase (initiated because of early termination of the trial because efficacy of atorvastatin was shown), all patients were offered atorvastatin 10 mg daily open label. We classified AEs using the Medical Dictionary for Regulatory Activities. We blindly adjudicated all reports of four prespecified AEs of interest-muscle-related, erectile dysfunction, sleep disturbance, and cognitive impairment-and analysed all remaining AEs grouped by system organ class. Rates of AEs are given as percentages per annum.
The blinded randomised phase was done between February, 1998, and December, 2002; we included 101 80 patients in this analysis (5101 [50%] in the atorvastatin group and 5079 [50%] in the placebo group), with a median follow-up of 3·3 years (IQR 2·7-3·7). The non-blinded non-randomised phase was done between December, 2002, and June, 2005; we included 9899 patients in this analysis (6409 [65%] atorvastatin users and 3490 [35%] non-users), with a median follow-up of 2·3 years (2·2-2·4). During the blinded phase, muscle-related AEs (298 [2·03% per annum] vs 283 [2·00% per annum]; hazard ratio 1·03 [95% CI 0·88-1·21]; p=0·72) and erectile dysfunction (272 [1·86% per annum] vs 302 [2·14% per annum]; 0·88 [0·75-1·04]; p=0·13) were reported at a similar rate by participants randomly assigned to atorvastatin or placebo. The rate of reports of sleep disturbance was significantly lower among participants assigned atorvastatin than assigned placebo (149 [1·00% per annum] vs 210 [1·46% per annum]; 0·69 [0·56-0·85]; p=0·0005). Too few cases of cognitive impairment were reported for a statistically reliable analysis (31 [0·20% per annum] vs 32 [0·22% per annum]; 0·94 [0·57-1·54]; p=0·81). We observed no significant differences in the rates of all other reported AEs, with the exception of an excess of renal and urinary AEs among patients assigned atorvastatin (481 [1·87%] per annum vs 392 [1·51%] per annum; 1·23 [1·08-1·41]; p=0·002). By contrast, during the non-blinded non-randomised phase, muscle-related AEs were reported at a significantly higher rate by participants taking statins than by those who were not (161 [1·26% per annum] vs 124 [1·00% per annum]; 1·41 [1·10-1·79]; p=0·006). We noted no significant differences between statin users and non-users in the rates of other AEs, with the exception of musculoskeletal and connective tissue disorders (992 [8·69% per annum] vs 831 [7·45% per annum]; 1·17 [1·06-1·29]; p=0·001) and blood and lymphatic system disorders (114 [0·88% per annum] vs 80 [0·64% per annum]; 1·40 [1·04-1·88]; p=0·03), which were reported more commonly by statin users than by non-users.
These analyses illustrate the so-called nocebo effect, with an excess rate of muscle-related AE reports only when patients and their doctors were aware that statin therapy was being used and not when its use was blinded. These results will help assure both physicians and patients that most AEs associated with statins are not causally related to use of the drug and should help counter the adverse effect on public health of exaggerated claims about statin-related side-effects.
Pfizer, Servier Research Group, and Leo Laboratories.
在盲法随机对照试验中，他汀类药物治疗与较少的不良事件（AE）相关。相比之下，在观察性研究中，报告的许多不同 AE 的增加幅度大于盲法试验。
在 Anglo-Scandinavian 心血管结局试验的降脂治疗臂中，年龄在 40-79 岁之间、患有高血压、至少有其他三种心血管风险因素、空腹总胆固醇浓度在 6.5mmol/L 或以下、未服用他汀类药物或贝特类药物、没有心肌梗死史且没有因心绞痛而接受治疗的患者，随机分配至阿托伐他汀 10mg 每日或匹配安慰剂的随机双盲安慰剂对照阶段。在随后的非随机非盲扩展阶段（由于阿托伐他汀的疗效显示试验提前终止而启动），所有患者均接受阿托伐他汀 10mg 每日开放标签治疗。我们使用监管活动医学词典（MedDRA）对 AE 进行分类。我们对所有四个预先指定的感兴趣的肌肉相关、勃起功能障碍、睡眠障碍和认知障碍 AE 报告进行了盲法裁决，并对按系统器官分类分组的所有其余 AE 进行了分析。AE 的发生率以每年的百分比表示。
盲法随机阶段于 1998 年 2 月至 2002 年 12 月进行；我们对 101800 名患者进行了此项分析（阿托伐他汀组 5101 名[50%]，安慰剂组 5079 名[50%]），中位随访时间为 3.3 年（IQR 2.7-3.7）。非盲非随机阶段于 2002 年 12 月至 2005 年 6 月进行；我们对 9899 名患者进行了此项分析（阿托伐他汀使用者 6409 名[65%]，非使用者 3490 名[35%]），中位随访时间为 2.3 年（2.2-2.4）。在盲法阶段，肌肉相关 AE（298[2.03%/年] vs 283[2.00%/年]；风险比 1.03[95%CI 0.88-1.21]；p=0.72）和勃起功能障碍（272[1.86%/年] vs 302[2.14%/年]；0.88[0.75-1.04]；p=0.13）的报告率在随机分配至阿托伐他汀或安慰剂的患者中相似。与随机分配至阿托伐他汀的患者相比，分配至阿托伐他汀的患者报告的睡眠障碍发生率显著降低（149[1.00%/年] vs 210[1.46%/年]；0.69[0.56-0.85]；p=0.0005）。报告的认知障碍病例太少，无法进行统计学上可靠的分析（31[0.20%/年] vs 32[0.22%/年]；0.94[0.57-1.54]；p=0.81）。我们观察到除阿托伐他汀组患者肾和泌尿系统 AE 发生率偏高外（481[1.87%/年] vs 392[1.51%/年]；1.23[1.08-1.41]；p=0.002），所有其他报告的 AE 发生率均无显著差异。相比之下，在非盲非随机阶段，服用他汀类药物的患者报告肌肉相关 AE 的发生率显著高于未服用他汀类药物的患者（161[1.26%/年] vs 124[1.00%/年]；1.41[1.10-1.79]；p=0.006）。我们注意到，他汀类药物使用者和非使用者之间除了肌肉骨骼和结缔组织疾病（992[8.69%/年] vs 831[7.45%/年]；1.17[1.06-1.29]；p=0.001）和血液和淋巴系统疾病（114[0.88%/年] vs 80[0.64%/年]；1.40[1.04-1.88]；p=0.03）外，其他 AE 的发生率没有显著差异，这些疾病在他汀类药物使用者中的报告更为常见。
这些分析说明了所谓的“反安慰剂效应”，只有当患者及其医生知道正在使用他汀类药物治疗时，才会出现肌肉相关 AE 报告的增加，而当药物使用处于盲法时则不会。这些结果将有助于向医生和患者保证，大多数与他汀类药物相关的 AE 并非与药物使用有因果关系，应有助于克服夸大他汀类药物相关副作用对公众健康的不利影响。
辉瑞、Servier 研究组和利奥实验室。
