更多证据表明阿司匹林降低了HBV / HCV的肝癌风险

StephenW

More Evidence Aspirin Cuts Liver Cancer Risk in HBV/HCV
— Time for definitive randomized clinical trials, researchers say

by Diana Swift, Contributing Writer March 11, 2020

A population-based Swedish study in chronic viral hepatitis patients found that low-dose aspirin was associated with a significant reduction in the risk of incident hepatocellular carcinoma (HCC) and liver-related death, without a significantly higher rate of gastrointestinal bleeding.

"Our findings support the need for randomized clinical trials designed to test the benefits of aspirin for primary prevention of hepatocellular carcinoma," wrote Jonas F. Ludvigsson, MD, PhD, of the Karolinska Institutet in Stockholm, and colleagues.

The population-based study, published online in the New England Journal of Medicine, identified all adults in a Swedish national registry who were diagnosed with chronic hepatitis B (HBV) or C (HCV) from 2005 through 2015 and who did not have a history of aspirin use (50,275 patients).

Those who were starting to take low-dose aspirin of 75 or 160 mg (14,205 patients) were identified by their first filled prescriptions for 90 or more consecutive doses of aspirin -- 2,998 had HBV and 11,207 had HCV.

Over a median 7.9 years of follow-up, the estimated cumulative incidence of HCC was 4.0% among aspirin users versus 8.3% among non-users (difference -4.3 percentage points, 95% CI -5.0 to -3.6; adjusted hazard ratio 0.69, 95% CI 0.62-0.76), the researchers reported.

This inverse association appeared to be duration-dependent. Compared with short-term aspirin use of 3 months to less than a year, the adjusted hazard ratios for dose duration were as follows:

    0.90 (95% CI 0.76-1.06) for use of 1 year to less than 3 years

    0.66 (95% CI 0.56-0.78) for 3 years to less than 5 years

    0.57 (95% CI 0.42-0.70) for 5 or more years

Overall, the study population had 13,276 HBV patients (10,278 non-users) and 36,999 HCV patients (25,792 non-users). Women accounted for 35.9% of aspirin users and 28.4% of non-users. The mean age at hepatitis diagnosis was 39.6 years in aspirin non-users and 50.5 years in users. Among the latter, 7,955 (56%) had coronary artery disease and 12,358 (87%) had at least one cardiovascular risk factor such as diabetes, dyslipidemia, obesity, or hypertension.

Over the median 7.9 years of follow-up, there were 1,612 incident cases of HCC and 5,017 liver-related deaths.

The 10-year risk of gastrointestinal bleeding was not significantly different between users and non-users of aspirin: 7.8% and 6.9%, respectively (difference of 0.9 percentage points, 95% CI -0.6 to 2.4).

Asked for his perspective, Augusto Villanueva Rodriguez, MD, PhD, of Icahn School of Medicine at Mount Sinai in New York City, who was not involved with the study, said the findings are "good news, since there is no approved drug to prevent HCC in viral hepatitis patients."

But, he added that although the study was well conducted in a large, well-documented population, it was retrospective rather than randomized, "and it's possible some bias may have crept in." And while other observational studies have suggested a protective effect of aspirin, "these data suggest that now is the time for a randomized clinical trial to see if aspirin really does prevent liver cancer," he said.

Noted Ludvigsson and co-authors: With results holding across all sensitivity analyses, "our findings extend previous data linking aspirin to a reduced risk of hepatocellular carcinoma, including studies focused on duration of therapy."

The team explained that earlier U.S. and European observational studies were limited by the inclusion of selected populations, imbalanced exposure groups, and lack of detailed data on key determinants of hepatic outcomes.

Preclinical evidence also supports the anti-inflammatory role for aspirin in preventing liver disease progression and HCC, Ludvigsson and colleagues said, noting that the pro-inflammatory cyclooxygenase-2 enzyme is overexpressed in activated hepatic stellate cells and inflammatory cancers.

The team called for research to clarify the appropriate timing of aspirin initiation, minimum necessary duration, and durability of response in diverse cohorts beyond the largely Caucasian Swedish population and in people with non-viral causes of liver disease.

Study limitations, the researchers said, included that the population was mainly white and restricted to viral hepatitis, and there was also a lack of information on smoking, HCV eradication, DNA levels of HBV, fibrosis stages, HCC screening, aflatoxin exposure, coffee consumption, and consumption of larger doses of aspirin and aspirin-containing medications.

Disclosures

This study was supported by the National Institutes of Health, Nyckelfonden (Örebro University Hospital), and Region Stockholm County, the American Association for the Study of Liver Diseases, Boston Nutrition Obesity Research Council, Region Örebro County, and the Karolinska Institutet.

Ludvigsson disclosed grant support from Janssen Biotech outside of the study; several co-authors reported financial ties to various companies.

Rodriguez reported having no conflicts of interest in relation to his comments.

Primary Source

New England Journal of Medicine

Source Reference: Simon TG, et al "Association of aspirin with hepatocellular carcinoma and liver-related mortality" N Engl J Med 2020; 382: 1018-1028.

StephenW

更多证据表明阿司匹林降低了HBV / HCV的肝癌风险
—研究人员说，确定性随机临床试验的时间到了

撰稿人戴安娜·斯威夫特（Diana Swift），2020年3月11日

瑞典一项针对慢性病毒性肝炎患者的基于人群的研究发现，低剂量阿司匹林可显着降低发生肝细胞癌（HCC）和肝相关死亡的风险，且不会明显增加胃肠道出血的发生率。

斯德哥尔摩卡罗林斯卡研究所的Jonas F. Ludvigsson博士及其同事写道：“我们的发现支持需要进行随机临床试验，以测试阿司匹林对肝细胞癌的一级预防的益处。”

这项基于人群的研究在《新英格兰医学杂志》上在线发表，确定了瑞典国家注册中心中所有从2005年至2015年被诊断出患有慢性乙型肝炎（HBV）或丙型肝炎（HCV）且没有病史的成年人阿司匹林使用量（50,275例患者）。

开始服用75或160毫克小剂量阿司匹林的患者（14,205名患者）通过首次补给处方确定了连续服用90剂或更多剂量的阿司匹林2,998的HBV和11,207 HCV。

在平均7.9年的随访中，阿司匹林使用者的HCC估计累积发生率为4.0％，而非使用者为8.3％（差异为-4.3个百分点，95％CI为-5.0至-3.6；调整后的危险比为0.69，研究人员报告说，95％CI 0.62-0.76）。

这种反相关似乎与持续时间有关。与3个月至不到一年的短期阿司匹林使用相比，剂量持续时间的调整危害比如下：

0.90（95％CI 0.76-1.06）使用1年至少于3年

0.66（95％CI 0.56-0.78）3年至少于5年

0.57（95％CI 0.42-0.70）5年或更长时间

总体而言，研究人群有13,276例HBV患者（10,278位非使用者）和36,999例HCV患者（25,792位非使用者）。妇女在阿司匹林使用者中占35.9％，非使用者中占28.4％。非服用阿司匹林者的平均肝炎诊断年龄为39.6岁，服用者为50.5岁。在后者中，有7,955名（56％）患有冠状动脉疾病，而12,358名（87％）患有至少一种心血管危险因素，例如糖尿病，血脂异常，肥胖或高血压。

在7.9年的中位随访中，有1,612例HCC发生病例和5,017例与肝有关的死亡。

服用阿司匹林和不服用阿司匹林的10年胃肠道出血风险没有显着差异：分别为7.8％和6.9％（差异为0.9个百分点，95％CI -0.6至2.4）。

询问他的看法时，纽约市西奈山伊坎医学院的医学博士奥古斯托·比利亚纽瓦·罗德里格斯（Augusto Villanueva Rodriguez）并未参与此项研究，他说，这些发现是“好消息，因为没有批准的药物可以预防病毒性肝炎患者的肝癌。”

但是，他补充说，尽管这项研究在大量有据可查的人群中进行得很好，但是它是回顾性的，而不是随机的，“并且可能会逐渐产生一些偏见。”他说，尽管其他观察性研究表明阿司匹林具有保护作用，但“这些数据表明，现在是时候进行一项随机临床试验，以了解阿司匹林是否确实可以预防肝癌。”

值得注意的是Ludvigsson及其合作者：在所有敏感性分析中均获得了结果，“我们的发现扩展了以前的数据，将阿司匹林与降低肝细胞癌的风险联系起来，包括针对治疗持续时间的研究。”

研究小组解释说，较早的美国和欧洲的观察性研究受到限制，包括选定的人群，不平衡的暴露人群以及缺乏有关肝结局关键因素的详细数据。

Ludvigsson及其同事说，临床前证据也支持阿司匹林在预防肝病进展和HCC中的抗炎作用，并指出促炎性环氧合酶2酶在活化的肝星状细胞和炎性癌症中过表达。

该研究小组呼吁进行研究，以阐明阿斯匹林启动的适当时机，最短必要的持续时间，以及在瑞典白人以外的人群和非病毒性肝病患者中的反应持久性。

研究人员说，研究的局限性包括该人群主要是白人，并且仅限于病毒性肝炎，而且也缺乏有关吸烟，消除HCV，HBV DNA水平，纤维化分期，HCC筛查，黄曲霉毒素暴露，咖啡摄入量的信息。 ，以及大剂量服用阿司匹林和含阿司匹林的药物。

披露事项

这项研究得到了Nyckelfonden国家卫生研究院（厄勒布鲁大学医院），斯德哥尔摩县，美国肝病研究协会，厄勒布鲁县波士顿营养肥胖症研究委员会和Karolinska研究所的支持。

Ludvigsson在研究之外透露了Janssen Biotech的赠款支持。 几位合著者报告了与多家公司的财务往来。

罗德里格斯（Rodriguez）报告说与他的评论没有利益冲突。

主要资源

新英格兰医学杂志

资料来源：Simon TG等，“阿司匹林与肝细胞癌和肝相关死亡率的关联”，《英格兰医学杂志》 2020年； 382：1018-1028。