Lancet：Meta分析表明他汀类药物可有效用于一级预防

《柳叶刀》(The Lancet) 5月16日在线发表的一项涉及170,000多例受试者的meta分析表明，对于所有成年人，即便是基线时重大血管事件风险较低的人群，总的来说他汀类药物治疗都能产生确切的益处(doi: 10.1016./S0140-6736(12)60367-5)。

这项研究由英国牛津胆固醇治疗试验合作者(Cholesterol Treatment Trialists Collaborators)团队开展，研究者纳入了来自27项对照试验的174,149例受试者，其基线心血管事件风险各异，5年风险从＜5%到＞30%不等。

分析结果显示，“他汀类药物治疗可使5年风险＜10%(重大冠脉事件的平均风险为2%~6%，其他重大血管事件的平均风险为3%)的人群发生重大血管事件的风险明显降低，哪怕是对于既往没有血管疾病、糖尿病或慢性肾病病史的人群。”具体来说，对于5年重大血管事件风险＜10%的人群，他汀类药物治疗每降低1 mmol/L(39 mg/dl)低密度脂蛋白(LDL)胆固醇，5年治疗期间每1,000例受试者中就会减少11例重大血管事件。

在5年风险＜5%或者介于5%~10%的受试者中，相对风险降低程度与基线5年风险水平较高，甚至与基线风险达30%者的风险降低程度相似。在所有基线风险水平的所有受试者中，经他汀类药物治疗后LDL胆固醇每降低1 mmol/L，总体相对风险就会下降21%。对于基线5年风险＜5%的受试者，LDL胆固醇每降低1 mmol/L，相对风险就会下降38%；对于基线5年风险介于5%~10%的受试者，LDL胆固醇每降低1 mmol/L，相对风险就会下降31%。

因此研究者总结道，即便是对于低危人群，他汀类药物治疗的益处也“明显”大于其风险。“虽然使用他汀类药物可能诱发出血性卒中和略微增加糖尿病，但这远远不及重大血管事件的长期效应，因此他汀类药物治疗的持续效益足以超过其潜在风险。”

在随刊评论中，伦敦卫生与热带医学院的流行病学专家Shah Ebrahim博士和伦敦大学学院的流行病学专家Juan P. Casas博士写道：“上述结果证实了他汀类药物用于一级预防的有效性，消除了人们对可能出现的严重不良反应以及随机试验中潜在偏倚的担忧。”(Lancet 2012 May 16 [doi: 10.1016/S0140-6736(12)60367-5])。

他们称，这项分析显示对于风险最低的两类人群，每1,000例受试者接受他汀类药物治疗5年，如果其基线LDL胆固醇水平能降低1 mmol/L(所需治疗人数分别为167例和67例)，则能分别避免16例和15例重大血管事件。“这些数据很令人振奋，与轻度高血压治疗的结果类似，而轻度高血压的治疗已被公认是初级保健的任务之一。”

但评论者也提醒道，并不是说他汀类是一类完美的药物。首先，对于没有心血管疾病证据的人群而言，他汀类药物很难将LDL胆固醇降低1 mmol/L(39 mg/dL)。当然，研究证据也再次证明提高他汀类药物的用药剂量可以“达到更好的效果，也消除了关于他汀类药物潜在严重不良反应的不确定性”。

再者，在一级预防中常规使用他汀类药物，包括心血管疾病5年风险＜10%的人群，将大大增加他汀类药物的处方量，而且有可能会转移人们对于高危患者积极他汀类药物治疗的注意力。他们认为更好的解决办法是通过更加积极的饮食调节措施来降低LDL胆固醇，不过他们也承认要大范围推广这样的措施是比较困难的。

此外，还有一种实用的解决办法是“将年龄作为使用他汀类药物的唯一指标，就像最初针对多效药丸(polypill)提出的建议一样。因为年龄超过50岁的人群10年内出现心血管疾病的风险大多高于10%”。

该文章的部分作者声明接受了厂家提供的参与学术会议的差旅费补助。2名作者声明因讲解这项meta分析而接受了Solvay公司提供的酬金。Ebrahim 博士和 Casas博士声明无相关利益冲突。

The shifting balance of data for and against broader use of statin treatment tilted again toward more liberal use, with results from a meta-analysis of more than 170,000 participants showing a clear, positive, overall effect from statin treatment in all types of adults, even those with a relatively low baseline risk for major vascular events.

Among people with a 5-year risk of major vascular events lower than 10%, each 1-mmol/L (39-mg/dL) reduction in low-density lipoprotein cholesterol from statin treatment produced an absolute reduction in 11 major vascular events per 1,000 people during 5 years of treatment, reported the Cholesterol Treatment Trialists Collaborators, a team based in Oxford, England, in an article published online May 16 in the Lancet (doi: 10.1016./S0140-6736(12)60367-5).

The analysis showed that “statin therapy significantly reduced the risk of major vascular events in individuals with 5-year risk lower than 10% (in whom the mean risks were 2%-6% for major coronary events plus 3% for other major vascular events), even in those with no previous history of vascular disease, diabetes, or chronic kidney disease.” The meta-analysis included data on 174,149 people from 27 controlled trials, and included participants with a broad range of baseline cardiovascular-event risk, ranging from a 5-year risk of less than 5% to a risk of greater than 30%.

The degree of relative risk reduction among trial participants with a 5-year risk of less than 5%, or 5% to less than 10%, was roughly similar to the risk reduction seen in participants with higher baseline risk levels, even in those with a baseline 5-year risk of 30% or more. The overall relative risk reduction for all people at all baseline risk levels in the analysis was 21% for each 1-mmol/L reduction in LDL cholesterol achieved with statin treatment. For those with a baseline, 5-year risk of less than 5%, the relative risk reduction was 38% for each 1-mmol/L reduction in LDL cholesterol, and for those with a baseline 5-year risk of 5% to less than 10%, the relative risk reduction from statin use was 31% for this level of LDL reduction.

Based on this new analysis, the authors concluded that the benefits of statin treatment, even in people at low risk, “greatly” outweigh the risks: “Any long-term effects of any small excesses in hemorrhagic strokes and in diagnoses of diabetes [triggered by statin use] are not associated with long-term effects on major vascular events that are sufficiently large to outweigh the persistent benefits of statin therapy,” they wrote.

 “These findings confirm the efficacy of statins for primary prevention, resolving concerns about possible serious adverse effects, and potential sources of bias in randomized trials,” wrote Dr. Shah Ebrahim and Dr. Juan P. Casas in a comment that accompanied the meta-analysis (Lancet 2012 May 16 [doi: 10.1016/S0140-6736(12)60367-5]).

The new analysis predicted that 16 and 15 major vascular events would be avoided per 1,000 people treated for 5 years in the two lowest-risk categories, respectively, if they achieved a 1-mmol/L cut in their baseline level of LDL cholesterol, which translates into numbers needed to treat of 167 and 67, said Dr. Ebrahim, an epidemiologist at the London School of Hygiene & Tropical Medicine, and Dr. Casas, an epidemiologist at University College London. “These figures look encouraging, and are similar to those for treatment of mild hypertension, which is widely accepted as a primary-care task,” they noted in their comment.

But the evidence the meta-analysis provides in favor of statin treatment does not make treatment a slam-dunk, the comment authors warned. First, an LDL cholesterol reduction of 1 mmol/L (39 mg/dL) can be hard to achieve in people without evidence of cardiovascular disease, although they note that the evidence presented also gives reassurance about prescription of higher statin doses to “achieve greater benefit and dissipate uncertainty about any potential serious adverse risks of statins.”

In addition, expansion of routine statin use for primary prevention to people with a 5-year risk for cardiovascular disease of less than 10% would sharply boost statin prescribing, and might potentially deflect attention away from aggressive statin treatment of higher-risk patients. An even better solution would be more aggressive dietary measures to lower LDL cholesterol, Dr. Ebrahim and Dr. Casas suggested, but they acknowledged that taking such steps on a national basis is hard.

Still, a practical solution would be “to use age as the only indicator for statin prescription, as was originally proposed for the polypill,” they suggested, “because most people older than 50 years are likely to be at greater than 10% 10-year risk of cardiovascular disease.”

Some members of the study-writing committee said that they received reimbursement of costs to participate in scientific meetings from the pharmaceutical industry. Two of the authors received honoraria from Solvay for lectures related to the meta-analysis. Dr. Ebrahim and Dr. Casas said that they had no disclosures.