Polypill for the prevention of major CV events in individuals with and without NASH
Polypill for prevention of cardiovascular diseases with focus on non-alcoholic steatohepatitis: the PolyIran-Liver trial
Introduction and methods
Individuals with fatty liver (non-alcoholic fatty liver disease) and especially those with non-alcoholic steatohepatitis (NASH) and elevated liver enzymes are at higher risk of CVD [1,2] and may benefit from primary prevention. However, these are not much data on primary or secondary prevention in individuals with increased liver enzyme levels .
This study was an extension of the PolyIran trial , a pragmatic cluster-randomized study in a rural population in Iran in which the effect of a four-component pill including aspirin, atorvastatin, hydrochlorothiazide and either enalapril or valsartan was investigated. Now, the effects of the same polypill on risk of major CV events were studied including participants with increased liver enzyme levels and individuals with fatty liver.
The PolyIran-Liver study is an open-label, individually randomized controlled trial. 2400 Participants ≥50 years from the Golestan cohort study who were resident of Gonbad city were randomized to receive polypill or no polypill. After randomization, participants were invited for participation and consent was obtained for those accepting (the Zelen design) . Laboratory tests, ultrasonography and liver stiffness measurements were performed. Participants were identified as having presumed NAFLD (pNAFLD) and with elevated ALT levels participants were identified as presumed NASH (pNASH).
The polypill included 81 mg aspirin, 12.5 mg hydrochlorothiazide, 20 mg atorvastatin, and 40 mg valsartan.
Results were analyzed among the originally randomized population (n=2266) and among consenting participants who were eligible for polypill (n=1508).
Participants were visited every 6 months for 5 years.
Primary endpoint was the occurrence of major CV events (MCVE), a composite of fatal MI, sudden death, new-onset heart failure, coronary artery revascularization procedures, fatal and non-fatal stroke or hospitalization for an acute coronary event.
The randomized population
- MCVE occurred in 138 patients in the intervention group (11.0%) and in 137 in the control group (13.5%) (unadjusted RR 0.83, 95%CI: 0.66-1.03)
The consenting group
- After adjustment for smoking, baseline cholesterol and pre-existing CVD, treatment with the polypill reduced MCVE (adjusted RR 0.61, 95%CI: 0.44-0.83).
- There was also a lower risk of fatal MCVE, non-fatal MCVE and all-cause mortality in the intervention group compared to controls.
- In participants with pNASH, the RR of MCVE was less than half compared to those without pNASH (adjusted RR 0.35, 95%CI:0.17-0.74 vs. adjusted RR 0.73, 95%CI:0.49-1.00), but this difference was not significant.
- In the consenting group, there was no difference between changes in ALT, AST and LSM from baseline to month 30 and 60 between study arms.
- In participants with pNASH, there was a greater reduction in ALT in the intervention group compared to controls at month 30 and 60.
- In the consenting intervention group, there was a significant reduction in SBP at month 30 and 60 compared to controls. In the intervention group, there were greater reduction in all lipid profiles from baseline to month 30 and 60.
- Incidence of adverse events was similar between the two arms. Frequency of adverse events decreased over time except for dyspepsia and cataract.
The PolyIran-Liver study showed that in the randomized population a polypill did not significantly lower MCVE, but among subjects who consented to take polypill, polypill resulted in benefit. This benefit was similar in participants with and without pNASH. In addition, findings showed that polypill reduced ALT levels in individuals with pNASH.
The authors conclude: “Individuals with fatty liver and NASH are more likely to develop CVD. We do not have an effective medical treatment for the liver but preventing CVD, the main cause of death in this group, is an important management objective.”