Daily Aspirin Use Tied to Lower Risk of Fibrosis Progression in Nonalcoholic Fatty Liver Disease

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Studies in animal models and humans have suggested that aspirin is a promising antifibrotic strategy for nonalcoholic fatty liver disease (NAFLD). However, the human studies were cross-sectional, and no histological examinations were used to stage the severity of NAFLD.

In a well-phenotyped prospective cohort with biopsy-confirmed NAFLD and long-term follow-up, Tracey G. Simon, MD, MPH, hepatologist in the Division of Gastroenterology at Massachusetts General Hospital, Kathleen E. Corey, MD, MPH, MMSc, director of the Fatty Liver Center, and colleagues observed an inverse relationship between daily aspirin use and nonalcoholic steatohepatitis (NASH) and fibrosis. Their findings are published in Clinical Gastroenterology and Hepatology.

Study Participants and Design

The researchers identified 361 consecutive patients with biopsy-confirmed NAFLD who enrolled in the Mass General NAFLD Repository between 2006 and 2015. The biopsies were staged at enrollment and patients underwent an extensive evaluation that allowed calculation of three noninvasive indicators of liver fibrosis: the fibrosis-4 index, the NAFLD fibrosis score (NFS) and the aspartate aminotransferase-to-platelet ratio index (APRI).

Self-reported aspirin use was ascertained at enrollment and at follow-up visits every three to 12 months. At baseline, 151 patients were daily aspirin users, most of them (84%) for primary or secondary prevention of cardiovascular disease (CVD). Average fibrosis-4, NFS and APRI scores were similar between daily aspirin users and nonregular users at baseline. (Nonregular users included patients who reported never taking aspirin.)

Aspirin and NAFLD Histology

In the cross-sectional analyses, the primary outcome measure was prevalent fibrosis. The researcher found that:

• Daily aspirin use was associated with 46% lower adjusted odds of fibrosis, compared with nonregular use. This association was unchanged after accounting for use of nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs)
• Compared with nonregular use of aspirin, daily aspirin use was inversely associated with NASH histology, including 54% lower odds of advanced (stage 3 or 4) fibrosis
• Shorter duration of pre-enrollment aspirin use was associated with significantly higher odds of prevalent fibrosis. Specifically, for patients who reported less than two years of aspirin use at enrollment, the odds of prevalent fibrosis were 28% higher than for those who reported between two and four years of use and 52% higher than for those who reported four or more years of use
• The inverse associations between aspirin use and prevalent fibrosis were similar across all prespecified strata (age, sex, diabetes status, race/ethnicity, smoking history, statin use and use of nonaspirin NSAIDs)

Aspirin Use and Incident Advanced Fibrosis

For longitudinal analyses, the researchers limited the cohort to the 317 patients with early NAFLD (stage 0 to 2) on enrollment biopsy. The primary outcome was incident advanced fibrosis, defined as fibrosis-4 score >2.67 or NFS >0.67 or APRI >1.0 during follow-up. The median length of follow-up was seven years. They found that:

• On multivariable analysis, the risk of developing advanced fibrosis was 37% lower among daily aspirin users than nonregular users
• Longer duration of aspirin use during follow-up was associated with progressively reduced risk of advanced fibrosis
• Similar associations were not found with nonaspirin NSAIDs, suggesting that these benefits are specific to aspirin
• Again, the associations between aspirin use and study outcomes were similar across all predefined strata

Sensitivity Analyses

Daily aspirin use remained associated with a lower risk of advanced fibrosis in analyses where the cohort:

• Included only patients with stage 0 or 1 fibrosis
• Included only patients with paired liver biopsies
• Included only patients who met a more stringent definition of advanced fibrosis (two consecutive measurements of fibrosis-4 score >2.67 or NFS >0.67 or APRI >1.0)
• Excluded users of statins, metformin, any antidiabetic medication or vitamin E
• Excluded nonaspirin NSAID users

Applying the Findings to Practice

NAFLD is not considered a CVD risk equivalent by the United States Preventive Services Task Force, the American Heart Association or the American Diabetes Association. Nevertheless, there is evidence of a strong link between NAFLD-related fibrosis and CVD mortality.

Because of the accelerating incidence and mortality of NAFLD, the benefits of aspirin could be profound. In patients with progressive liver disease, the potential benefit of aspirin must be carefully balanced with the risk of bleeding.

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