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Patients with chronic hepatitis B (CHB) who take daily aspirin may lower their risk for developing hepatocellular carcinoma (HCC), according to a study published online March 18 in JAMA Internal Medicine.

“Although [nucleos(t)ide analogue (NA)] therapy remains the mainstay for the prevention of [hepatitis B virus (HBV)]-related HCC, most HBV carriers do not receive NA therapy],” write Teng-Yu Lee, MD, MBA, PhD, Taichung Veterans General Hospital, Taichung, Taiwan, and colleagues. Therefore, “daily aspirin therapy may be of help to further improve the chemoprevention of hepatitis B virus-related [HCC].”

Lee and colleagues evaluated claim data from a Tawainese nationwide database, identifying 204,507 patients with CHB from 1997 and 2012. Patients who received daily aspirin therapy for 90 or more days were included in the aspirin-treated cohort (n = 2123). Approximately 98% of patients in the aspirin group received ≤ 100 mg of aspirin/day.

Treated patients were matched 1:4 with patients who did not receive aspirin therapy (untreated cohort, n = 8492). Patients with other viral hepatitis, HIV, or alcoholic liver disease were excluded. Patients were followed for 180 days or until HCC diagnosis or death.

After adjusting for mortality, Lee and colleagues found that the 5-year cumulative incidence of HCC was lower in the aspirin-treated group (5.20%; 95% confidence interval [CI], 4.11% – 6.29%) compared with the untreated group (7.87%; 95% CI, 7.15% – 8.60%; P < .001).

Overall, the study authors noted that aspirin therapy was associated with a 29% reduction in the risk for HCC after adjusting for age, male sex, liver cirrhosis, diabetes, hyperlipidemia, hypertension, statin use, metformin use, and NA use (hazard ratio [HR], 0.71; 95% CI, 0.58 – 0.86; P < .001).

However, liver cirrhosis was still found to be associated with a higher risk for HCC (HR, 2.89; 95% CI, 2.45 – 3.40; P < .001) and NA use was associated with a lower risk for HCC (HR, 0.54; 95% CI, 0.41 – 0.71; P < .001).

With respect to the adverse event of developing a peptic ulcer (PUB) secondary to aspirin therapy, the authors found the 5-year cumulative incidence among those receiving aspirin was not significantly higher than in the untreated group (6.13% [95% CI, 5.05% – 7.21%] vs 5.52% [95% CI, 4.99% – 6.06%]; P = .09). This was also true when concurrent liver or cardiovascular disease were taken into account.

The authors note, however, that those patients in the aspirin group were able to tolerate aspirin therapy for at least 90 days, and therefore the risk for PUB development may be underestimated.

“Our findings may be of help in future efforts to further improve the chemoprevention of HBV-related HCC, and a proof-of-concept study is thus warranted,” Lee and colleagues conclude.

Interesting Results but Questions Remain

In an accompanying editorial, lead author Rena K. Fox, MD, from the University of California, San Francisco, and colleagues, note that, while these results appear promising, different prescribing patterns for aspirin among patients in Taiwan, compared with the United States, as well as differing indications for aspirin use within the study, may have resulted in confounding by indication, leading to the inclusion of aspirin users who had less severe hepatic disease and therefore, a lower risk for HCC.

They also note that the researchers also did not discuss factors affecting the decision to not prescribe aspirin to patients in the untreated group. For example, were there concerns for aspirin-induced bleeding in this group?

“Such confounders in indication and selection biases are challenging to eliminate in retrospective administrative studies, and thus, while provocative and hopeful, these results should be validated using randomized clinical trials,” Fox and colleagues write.

“In the meantime, physicians can individually counsel patients who have an indication for aspirin about the potential for HCC risk reduction, especially if they are not candidates for NA therapy,” the editorialists conclude.

Funding for this study was provided through a grant from the Ministry of Science and Technology, National Health Research Institutes, and Taichung Veterans General Hospital, Taiwan. One of the study authors reported grants and personal fees from Gilead and personal fees from Bristol-Myers Squibb outside the submitted work. The other authors and the editorialists disclosed no relevant financial relationships.

JAMA Intern Med. Published online March 18, 2019. Abstract, Editorial

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