| Abstract: | AIMS: Individuals with non-alcoholic steatohepatitis or elevated liver enzymes have increased cardiovascular mortality but are often excluded from prevention trials. We investigated the effectiveness of fixed-dose combination therapy for the prevention of major cardiovascular events (MCVE) among individuals with and without presumed non-alcoholic steatohepatitis (pNASH). METHODS AND RESULTS: Two thousand four hundred participants over 50 were randomized into the intervention and control groups. Consent was obtained post-randomization. Consenting participants in the intervention group were given a pill containing aspirin, atorvastatin, hydrochlorothiazide, and valsartan (polypill). Participants were followed for 5 years. Presumed non-alcoholic steatohepatitis was diagnosed by ultrasonography and elevated liver enzymes. The primary outcome was MCVE. ClinicalTrials.gov: NCT01245608. Among the originally randomized population, 138 of 1249 in the intervention group (11.0%) and 137 of 1017 controls (13.5%) had MCVE during the 5-year follow-up [unadjusted risk ratio (RR) 0.83, 95% confidence interval (CI) 0.66-1.03]. Of the 1508 participants who consented to additional measurements and treatment, 63 of 787 (8.0%) intervention group participants and 86 of 721 (11.9%) controls had MCVE (adjusted RR 0.61, 95% CI 0.44-0.83). Although the adjusted relative risk of MCVE in participants with pNASH (0.35, 95% CI 0.17-0.74) was under half that for participants without pNASH (0.73, 95% CI 0.49-1.00), the difference did not reach statistical significance. There was no change in liver enzymes in participants taking polypill but among those with pNASH, there was a significant decrease after 60 months of follow-up (intragroup -12.0 IU/L, 95% CI -14.2 to -9.6). CONCLUSION: Among patients consenting to receive fixed-dose combination therapy, polypill is safe and effective for the prevention of MCVE, even among participants with fatty liver and increased liver enzymes. KEY QUESTION: Can a single daily fixed-dose combination pill of aspirin, atorvastatin, hydrochlorothiazide, and valsartan (polypill) provide protection against major cardiovascular events (MCVE) in the general population? Does this protection extend to individuals with fatty liver and increased liver enzymes? KEY FINDING: We observed no significant decrease in MCVE in participants randomized to the polypill group. However, among participants who consented to receive polypill, there was a significant decrease in MCVE and all-cause mortality regardless of fatty liver or increased liver enzymes. TAKE-HOME MESSAGE: In people aged >50 years, the polypill appears safe, well tolerated, and might reduce the risk of MCVE. Fatty liver and increased liver enzymes do not affect the safety of the polypill. Liver enzymes may decrease during treatment. |
