他汀类药物在肝癌中的预防信号支持预防

StephenW

Prevention Signal for Statins in Liver Cancer Supports Prophylaxis

San Antonio—Statins appear to provide significant protection against liver cancer and should be considered in patients at high risk for the disease, according to the investigator of the largest meta-analysis conducted to date on the question.

In 20 studies with approximately 2.6 million patients worldwide, use of the cholesterol agents was associated with a 43% reduction in the risk for hepatocellular carcinoma (HCC), said Muhammad T. Sarmini, MD, a gastroenterologist affiliated with the Cleveland Clinic in Cleveland. This new study is not the first meta-analysis, but it is the largest, Dr. Sarmini added.

Three of the studies he assessed were randomized controlled trials, six employed a cohort design, and 11 were case–control studies.

When the data were combined, the odds ratio (OR) of developing HCC was 0.57 for statin users compared with statin nonusers. The confidence intervals were relatively tight and statistically significant (95% CI, 0.49-0.66; P<0.05), he said.
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The data were consistent when stratified by geographic location: 45% in Asia and 46% in North America, but 29% among studies conducted in Europe (P<0.05 for all). In people infected with the hepatitis B virus, statins reduced the risk for HCC by 45%, which was about the same for those without the virus.

When the data were stratified by study design, the risk reduction for statins was 47% for case–control studies and 37% for cohort studies. The data from the three randomized controlled trials constituted the exception. In these, the risk reduction did not reach significance (OR, 0.7; 95% CI, 0.63-1.5).

Randomized trials represent the strongest test of clinical effectiveness, so the lack of statistical significance raises questions about the potential benefit of the therapy. But Dr. Sarmini maintained that long-term data are critical for showing a treatment effect.

“The follow-up in the randomized trials was relatively short, and this limited the ability to demonstrate a protective effect,” Dr. Sarmini said. In this data set, there were only 81 cases of HCC. Despite the greater weight typically given to randomized trials, Dr. Sarmini doesn’t believe this finding negated the overall conclusion, even if he acknowledged that definitive evidence of benefit from statins requires “prospective randomized research.”

However, he believes, based on this large meta-analysis, “statins should be considered in high-risk patients for HCC, such as those with a viral hepatitis infection.”

One of the limitations of the new work was a lack of information about types, doses or duration of statin exposure. The relevance of these characteristics was underlined by a recently published study of Swedish registry data that explored this same question (Ann Intern Med 2019;171[5]:318-327). This study, which Dr. Sarmini did not include in his meta-analysis, looked at 8,334 statin users matched to the same number of nonusers. The researchers found that lipophilic (hazard ratio [HR], 0.57) but not hydrophilic (HR, 0.95) statins were associated with a significant HCC risk reduction. The risk reduction with lipophilic statins appeared to be dose dependent.

The new meta-analysis “shows a remarkably strong signal that statins might have salutary effects in patients with cirrhosis and reduce carcinogenesis,” said David E. Kaplan, MD, an associate professor at the University of Pennsylvania, in Philadelphia. But Dr. Kaplan cautioned that meta-analyses “cannot remove the fundamental inherent bias, confounding by indication.”

Such bias is not only present in general but might be particularly relevant in this specific situation, he added. “Only cirrhotic patients whose livers are still compensated enough to make enough cholesterol to have hypercholesterolemia receive statins, so prescriptions are given predominantly to patients with lower intrinsic risk of hepatocellular carcinoma,” Dr. Kaplan explained. “Only an adequately powered large randomized controlled trial can truly answer this critical question.”

—Ted Bosworth

StephenW

他汀类药物在肝癌中的预防信号支持预防

迄今为止，最大的荟萃分析的研究者认为，他汀类药物似乎可以为肝癌提供显着的保护作用，因此，对于这种疾病的高风险患者，应考虑使用他汀类药物。

克利夫兰克利夫兰诊所的胃肠病学家Muhammad T. Sarmini医师表示，在全球约260万名患者的20项研究中，使用胆固醇药物可使肝细胞癌（HCC）的风险降低43％。 。 Sarmini博士补充说，这项新研究不是首次进行荟萃分析，而是最大的荟萃分析。

他评估的研究中有三项是随机对照试验，六项采用了队列设计，而十一项是病例对照研究。

合并数据后，他汀类药物使用者与非他汀类药物使用者发生HCC的优势比（OR）为0.57。他说，置信区间相对较紧且具有统计学意义（95％CI，0.49-0.66； P <0.05）。
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按地理位置分层时，数据是一致的：亚洲为45％，北美为46％，但在欧洲进行的研究中为29％（所有数据均P <0.05）。在感染了乙型肝炎病毒的人群中，他汀类药物可将HCC的风险降低45％，与未感染该病毒的人相同。

通过研究设计对数据进行分层后，病例对照研究和队列研究的他汀类药物风险降低分别为47％和37％。来自三个随机对照试验的数据构成例外。在这些方法中，降低风险没有达到显着性（OR，0.7； 95％CI，0.63-1.5）。

随机试验代表了最强的临床疗效测试，因此缺乏统计学意义引起了人们对该疗法潜在益处的质疑。但萨米尼博士坚持认为，长期数据对于显示治疗效果至关重要。

Sarmini博士说：“随机试验的随访时间相对较短，这限制了其显示保护作用的能力。”在此数据集中，只有81例HCC病例。尽管通常对随机试验给予更大的重视，但萨米尼博士并不认为这一发现会否定总体结论，即使他承认他汀类药物获益的确凿证据需要“前瞻性随机研究”。

但是，他认为，基于这项大规模的荟萃分析，“对于高风险的HCC患者，例如病毒性肝炎感染的患者，应考虑他汀类药物的使用。”

新工作的局限性之一是缺乏关于他汀类药物暴露的类型，剂量或持续时间的信息。这些特征的相关性最近在瑞典发表的一项有关注册表数据的研究中得到了强调（Ann Intern Med 2019; 171 [5]：318-327）。 Sarmini博士未在他的荟萃分析中包括该研究，研究了8334名他汀类药物使用者与相同数量的非使用者。研究人员发现，亲脂性（危险比[HR]为0.57）而不是亲水性（HR为0.95）他汀类药物可显着降低HCC风险。亲脂性他汀类药物降低的风险似乎与剂量有关。

费城宾夕法尼亚大学副教授戴维·卡普兰（David E. Kaplan）医学博士说，新的荟萃分析“显示出强烈的信号表明他汀类药物可能对肝硬化患者产生有益作用并减少致癌作用。”但是卡普兰博士警告说，荟萃分析“不能消除基本的固有偏见，因指示而混淆。”

他补充说，这种偏见不仅普遍存在，而且在这种特定情况下可能特别相关。 “只有肝硬化仍能补偿足够胆固醇以产生高胆固醇血症的肝硬化患者才接受他汀类药物，因此处方主要针对肝癌固有风险较低的患者。”卡普兰解释说：“只有足够强大的大型随机对照试验才能真正回答这个关键问题。”

特德·博斯沃思（Ted Bosworth）