From the Journals

Daily aspirin might cut risk of fibrosis progression

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Aspirin may be an option in NAFLD

Slowing, preventing, or reversing fibrogenesis in patients with NAFLD remains an unmet need. Lifestyle interventions are beneficial to this population but challenging because of concerns with adherence and sustainability, thus, favoring pharmacologic interventions.

The study by Simon et al. provides initial prospective evidence of the role of aspirin in reducing progression of fibrosis. In a thoughtful design, authors showed both cross-sectional and longitudinal associations of reduced risk for progressed fibrosis among aspirin users, all with biological coherence and while accounting for various confounding factors. Although the accuracy of blood-based noninvasive assessment of liver fibrosis (by FIB-4, NFS, and APRI) to determine progression of fibrosis in NAFLD has moderate accuracy at its best, the relatively high FIB-4 cutoff value used by the authors and their sensitivity analyses (including liver biopsy and combinations of blood-based markers combined endpoints) bring certainty to their results.

However, before we can start prescribing aspirin to halt progression of fibrosis in NAFLD, larger and adequately powered studies are needed. Caution with the use of aspirin as prophylaxis for atherosclerotic cardiovascular disease (ASCVD) is now advised, based on results from large clinical trials (i.e., ASCEND). NAFLD patients represent a particular population with both a high ASCVD risk and a high risk for gastrointestinal bleeding, and it is unclear what the number needed to treat or to harm would be without confirmatory studies.

Dr. Andres Duarte-Rojo

An “NAFLD polypill” including a combination of drugs addressing multiple metabolic pathways (e.g. aspirin, a statin, and vitamin E) might well tip the scale in favor of improved clinical outcomes, a concept recently shown as beneficial for ASCVD prevention in the PolyIran study. Until then, properly weighing the use of prophylactic aspirin in patients with NAFLD and adhering to standard recommendations is advised.

Andres Duarte-Rojo, MD, PhD, is associate professor of medicine, division of gastroenterology, hepatology, and nutrition at the University of Pittsburgh Medical Center, and Pittsburgh Liver Research Center. He received research support from Echosens, USA.



Taking daily aspirin may help keep nonalcoholic fatty liver disease (NAFLD) from progressing to liver fibrosis and nonalcoholic steatohepatitis (NASH), suggest the results of a prospective study of 361 adults.

Previously, preclinical evidence had linked aspirin to fibrogenesis prevention in fatty liver disease, but this is the first report of a prospective study to do so. Daily aspirin use “was associated with less severe histologic features of NAFLD (nonalcoholic fatty liver disease) at study enrollment and with significantly lower risk for advanced fibrosis over time in a duration-dependent manner,” wrote Tracey G. Simon, MD, MPH, and her associates. Their report is in Clinical Gastroenterology and Hepatology.

The study comprised 361 adults with biopsy-confirmed NAFLD who were enrolled in the Massachusetts General Hospital NAFLD Repository between 2006 and 2015. At baseline, 151 individuals were already on daily aspirin, usually to reduce the primary (54%) or secondary (30%) risk of cardiovascular disease. Median duration of aspirin use was 2.5 years. After a median 7.4 years of follow-up (which was similar between aspirin users and nonusers), daily aspirin use was associated with significantly lower odds of NASH (adjusted odds ratio, 0.68; 95% confidence interval, 0.37-0.89) and fibrosis (aOR, 0.54; 95% CI, 0.31-0.82).

The researchers did not find a similar protective effect for nonsteroidal anti-inflammatory drugs (NSAIDs) other than aspirin (adjusted hazard ratio for advanced fibrosis, 0.93; 95% CI, 0.81–1.05). This might be because of differences between how aspirin and nonaspirin NSAIDs affect COX isoforms – aspirin does so irreversibly, while other NSAIDs have a reversible effect, they added. “Nonaspirin NSAIDs also disrupt the intestinal barrier, increasing delivery of proinflammatory cytokines to the liver,” they wrote. “Finally, aspirin uniquely modulates bioactive lipids by stimulating the biosynthesis of pro-resolving mediators and inhibiting proinflammatory lipids, which in turn may prevent progressive liver damage.”

In this study, a single blinded hepatopathologist interpreted baseline liver biopsy specimens, and patients were followed every 3-6 months with clinical examinations and serial calculations of FIB-4, NFS, and APRI scores. All patients were followed for at least a year. Patients were classified as users of nonaspirin NSAIDs if they reported using an NSAID besides aspirin at least twice weekly, or if they had been prescribed drugs such as ibuprofen, naproxen, ketoprofen, diclofenac, or indomethacin.

In a longitudinal analysis of the 317 patients who had early-stage (F0-2) fibrosis at baseline, 86 developed new-onset advanced fibrosis over a median of 3,692 person-years, the researchers said. In all, 26 individuals developed hepatic decompensation and 18 patients died, including eight from liver-related causes. Importantly, the link between aspirin and decreased risk of fibrosis progression seemed to depend on duration of use (adjusted P trend = .026), with the greatest benefit seen with 4 years or more of use (aHR, 0.50; 95% CI, 0.35-0.73). Although subgroup analyses were limited by lack of power, daily aspirin use was associated with a 36% lower odds of incident advanced fibrosis among the 72 study participants who had paired biopsy samples, even after accounting for the effect of age, sex, baseline fibrosis stage, and time between biopsies (aOR, 0.64; 95% CI, 0.50-0.80).

“Our findings add to the growing literature supporting the potential hepatoprotective effects of aspirin in NAFLD,” the researchers concluded. “Research to uncover the mechanisms by which aspirin might prevent fibrogenesis could help develop urgently needed antifibrotic therapies for NAFLD.”

Funders included the National Institutes of Health and the AASLD Foundation. The investigators reported having no conflicts of interest.

SOURCE: Simon TG et al. Clin Gastroenterol Hepatol. 2019 May 8.

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