The risk of liver cancer and liver-related death in patients with chronic viral hepatitis was substantially reduced with the use of low-dose aspirin, results from a nationwide study from Sweden suggest.
The risk of hepatocellular carcinoma (HCC) was reduced by 31% compared with no aspirin use, and liver-related mortality dropped by 27%, as long as aspirin use continued.
"We were excited to find for the first time in a nationwide Western population that low-dose aspirin use was associated with substantial reduction in risk of developing incident HCC," lead author Tracey G. Simon, MD, MPH, of Massachusetts General Hospital and Harvard Medical School in Boston, told Medscape Medical News.
The study was published in the March 12 issue of the New England Journal of Medicine.
HCC is the fourth-leading cause of cancer mortality worldwide, and is driven mostly by viral hepatitis B (HBV) and viral hepatitis C (HCV) infection, noted Jennifer A. Flemming, MD, of Queen's University, Kingston, Canada, an expert not involved with the study. HCC is also one of the only cancers to show a rising incidence over the past several decades, she added .
However, the results of this do not change clinical practice. "It is premature to prescribe low dose ASA [acetylsalicylic acid] in patients with viral hepatitis for the sole indication of HCC prevention in routine clinical practice without support from prospective randomized data," she said.
"The results of this study make it clear that a prospective randomized study comparing ASA to placebo in patients with viral hepatitis without an indication for low-dose ASA is justified to evaluate the risk of incident HCC," she told Medscape Medical News.
The study authors agree, and they also emphasize that the findings from this observational study "should not yet change clinical practice."
More research is needed in populations with compensated and decompensated cirrhosis to determine the optimal timing of aspirin initiation — or cessation of therapy — that will maximize benefit and prevent adverse events, said Simon.
Although several earlier studies have suggested a duration-dependent benefit of aspirin use in preventing HCC in smaller populations, this study is the first to confirm a duration-response relationship with low-dose aspirin use in an unselected European population with confirmed viral hepatitis, Simon pointed out.
For their study, Simon and colleagues used the Swedish Register for Surveillance of Communicable Diseases database to identify 50,275 adults diagnosed between 2005 and 2015 with acute and chronic HBV and HCV infection. Some 13,276 adults had HBV and 36,999 had HCV, and this included 14,205 low-dose (75 mg or 160 mg) aspirin users and 36,070 nonusers.
The analysis showed that in aspirin users, the 10-year cumulative incidence of HCC was 4% compared with 8.3% in nonusers. After multivariable adjustment, aspirin users had a risk of HCC that was 31% lower compared with nonusers (adjusted subhazard ratio, 0.69; 95% confidence interval [CI], 0.62 - 0.76).
Patients taking low-dose aspirin had a 10-year liver-related mortality of 11% compared with 17.9% among nonusers. The adjusted risk of liver-related mortality was 27% lower in aspirin users than in nonusers.
There was no significant difference in the 10-year risk of gastrointestinal bleeding between users and nonusers of aspirin (7.8% and 6.9%, respectively). In addition, the analysis showed that the risks of any gastrointestinal bleeding were similar among aspirin-users with compensated cirrhosis and those without cirrhosis (8.3% and 7.5%, respectively).
Notably, the risk of HCC was significantly lower after 3 to 5 years of aspirin use and after 5 or more years of use (adjusted hazard ratio [HR], 0.66, 0.57, respectively) compared with short-term use (3 months to <1 year; adjusted HR, 0.90) or with intermittent, discontinued, or no aspirin use. But when those with chronic viral hepatitis stopped taking aspirin, their risk of HCC rose to become 22% higher compared with peers who continued to use aspirin.
The risk of liver-related death also rose by 31% in aspirin users who stopped taking aspirin compared with those who did not stop (subhazard ratio, 1.31). Again, this relationship appeared to be duration-dependent, with the risk of incident HCC rising sharply among those who discontinued aspirin and increasing in magnitude over time.
The consistency of aspirin use also influenced risk. In individuals who had an on-again, off-again pattern of aspirin use, the incidence of HCC was 5.9% compared with 1.1% in those who used it consistently.
"Our results were consistent regardless of sex, cause of hepatitis, or underlying compensated cirrhosis," the authors write. "The consistent duration-response associations lend further credence to a potential causal relationship."
Limitations of the Study
The current study findings are not new, but this is the best-designed study to date, commented Flemming. Still, there were a number of limitations, she noted. Although cirrhosis is the strongest risk factor for HCC in patients with viral hepatitis, for instance, it was assessed only at cohort entry, and not during the median 8 years of follow-up. There was also a lack of information about sustained virologic response (SVR) rates.
Since less than 25% of patients with HCV received HCV therapy, this indicates they were likely treated with interferon-based therapy, Flemming suggested. Interferon-based therapy is associated with much lower SVR rates than direct acting antiviral (DAA) therapy, which can produce SVR in approximately 95% of patients, she pointed out.
"Therefore, a large proportion of the study patients were likely viremic and at a higher baseline risk of HCC than contemporary HCV populations."
Evidence from a number of studies indicates that achieving SVR with DAA therapy is associated with a 70% risk reduction for incident HCC and liver-related events, Flemming said. "Whether the use of ASA in patients who have achieved SVR provides the same HCC risk reduction and decrease in hepatic outcomes is unknown."
Also, the study did not provide information on the specific type of HBV therapy used in patients with HBV, Flemming noted. When considering the prevention of HCC in patients with chronic HBV infection, recent data support a differential protective effect of tenofovir disoproxil fumarate (multiple brands) compared with entecavir (Baraclude, Bristol-Myers Squibb), she pointed out. As previously reported by Medscape Medical News, these data also indicate that tenofovir may be more effective than entecavir in reducing the risk of liver failure and all-cause mortality.
This study was funded by the US National Institutes of Health, Nyckelfonden, Region Stockholm County, the American Association for the Study of Liver Diseases, Boston Nutrition Obesity Research Council, Region Örebro County, and Karolinska Institutet. Simon has disclosed no relevant financial relationships. A number of study coauthors disclosed having relationships with industry; the full list can be found with the original article. Flemming reported relationships with Gilead Sciences Canada, AbbVie, and Lupin Pharmaceuticals.
N Engl J Med. Published online March 12, 2020. Abstract
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