Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA): a randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase
Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA): a randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase
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DOI：
10.1016/s0140-6736(17)31075-9
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发表时间：
2017-06-24
期刊：
影响因子：
168.9
通讯作者：
Sever, Peter
中科院分区：
文献类型：
--
作者：
Gupta, Ajay;Thompson, David;Sever, Peter
背景：在盲法随机对照试验中，他汀类药物治疗几乎没有不良事件。方法在盎格鲁-斯堪的纳维亚心脏结局试验的降脂试验中，年龄40-79岁、有至少三种其他心血管危险因素、空腹总胆固醇浓度低于6.5 mmo1/L、未服用他汀类药物、无心肌梗死病史、未接受心绞痛治疗的患者被随机分配给阿托伐他汀10 mg/d，或在随机、双盲、安慰剂对照阶段服用安慰剂。在随后的非随机、非盲目延长阶段(由于阿托伐他汀的疗效显示试验提前终止而开始)，所有患者每天服用阿托伐他汀10毫克开放标签。我们使用《管理活动医学词典》对企业进行分类。我们盲目地判断了所有关于四个预先指定的感兴趣的AEs的报告--肌肉相关的、勃起功能障碍、睡眠障碍和认知障碍--并分析了所有剩余的AEs，按系统器官类别分组。结果1998年2月至2002年12月采用随机盲法设计，纳入101 80例患者(阿托伐他汀组5101例[50%]，安慰剂组5079例[50%])，中位随访时间为3.3年(IQR 2.7-3.7)。非盲法非随机阶段在2002年12月至2005年6月期间进行；我们纳入了9899名患者(使用阿托伐他汀的6409例[65%]和不使用阿托伐他汀的3490例[35%])，平均随访时间为2.3年(2.2-2.4年)。在失明阶段，随机分配给阿托伐他汀或安慰剂的参与者报告了与肌肉相关的不良反应(298[每年2.03%]比283[每年2.00%]；风险比1.03[95%可信区间0.88-1.21]；p=0.72)和勃起功能障碍(272[每年1.86%]比302[每年2.14%]；0.88[0.75-1.04]；p=0.13)。服用阿托伐他汀的受试者的睡眠障碍报告率显著低于服用安慰剂的受试者(149vs210[每年1.00%]vs210[每年1.46%]；0.69[0.560.85]；p=0.0005)。报告的认知障碍病例太少，无法进行统计可靠的分析(31例[每年0.20%]对32例[每年0.22%]；0.94[057-1.54]；p=0.81)。我们观察到除阿托伐他汀患者的肾脏和尿液不良反应过量外，所有其他报道的不良反应发生率没有显著差异(每年481例[1.87%]对392例[1.51%]；1.23[1.08-1.41]；p=0.002)。相比之下，在非盲法非随机阶段，服用他汀类药物的参与者报告的肌肉相关不良反应的发生率显著高于未服用他汀类药物的参与者(161vs124[每年1.00%]；1.41[1.10-1.79]；p=0.006)。除了肌肉骨骼和结缔组织疾病(992[每年8.69%]对831[每年7.45%]；1.17[1.06-1.29]；p=0.001)和血液和淋巴系统疾病(114[每年0.88%]对80[每年0.64%]；1.4[1.04-1.88]；这些分析说明了所谓的NOCEBO效应，即只有当患者和他们的医生知道他汀类药物正在使用而不是当他汀类药物的使用被盲目使用时，与肌肉相关的AE报告的超标率。这些结果将有助于向医生和患者保证，与他汀类药物相关的大多数不良反应与药物的使用没有因果关系，并应有助于抵消夸大他汀类药物相关副作用对公众健康的不利影响。
Background 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.Methods 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.Results 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%] nonusers), 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 [057-1.54]; 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.Interpretation 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.