Prevention of Cardiovascular Disease Using a Single Polypill in an Urban Population—Focus on Liver-Related Variables - PolyIran-Liver

Contribution To Literature:

The PolyIran-Liver trial showed that patients who received a fixed-dose polypill containing aspirin, atorvastatin, hydrochlorothiazide, and valsartan had fewer major cardiovascular events than patients who did not receive the polypill. In a subset of patients with presumed nonalcoholic fatty liver disease, the polypill was safe and well tolerated.

Description:

The goal of the trial was to investigate the effects of a fixed-dose polypill containing aspirin, atorvastatin, hydrochlorothiazide, and valsartan on major cardiovascular events with a secondary focus on outcomes among patients with fatty liver disease or with increased liver enzymes.

Study Design

The PolyIran-Liver study was an open-label, randomized controlled trial nested within a population-based prospective cohort study in the Golestan province of Northern Iran of participants aged >50 years living in Gonbad city. A total of 2,400 patients were randomized in a ratio of 55:45 to receive a polypill of 81 mg aspirin, 12.5 mg hydrochlorothiazide, 20 mg atorvastatin, and 40 mg valsartan (n = 1,320) or a control group (n = 1,080).

After randomization, participants were invited to consent to the study with a 1-day run-in period with expected patient dropout, yielding a final cohort of 787 participants in the intervention arm and 721 participants in the control arm. Results were analyzed with intention-to-treat analysis including all patients and randomized to each treatment arm and again analyzed among those who consented and were enrolled into the study. Patients with increased liver enzymes and fatty liver were analyzed separately.

  • Total selected participants: 2,400
  • Total randomized participants: 1,508
  • Duration of follow-up: 60 months
  • Mean patient age: 58.6 years in the polypill arm; 59.4 years in the control arm
  • Percentage female: 49%

Inclusion criteria:

  • Age >50 years

Exclusion criteria:

  • Alcohol use
  • Active hepatitis B or C
  • Contraindications to constituents of the polypill

Other salient features/characteristics:

  • Approximately 15% with pre-existing cardiovascular disease
  • Approximately 40% with presumed nonalcoholic fatty liver disease, and approximately 20% with presumed nonalcoholic steatohepatitis

Principal Findings:

The primary outcome, occurrence of a major cardiovascular event, including fatal myocardial infarction, sudden death, new-onset heart failure, coronary artery revascularization procedures, fatal and nonfatal stroke, or hospitalization for an acute coronary event, for polypill versus control among the initially randomized population, was 11.0% vs. 13.5% (p = 0.094). Of patients who consented to the study: 8.0% vs. 11.9% (p = 0.002).

Secondary outcomes for polypill vs. control:

  • All-cause mortality: Among the randomized population, 8.7% vs. 11.0% (p = 0.080); among the consenting population: 3.4% vs. 6.8% (p = 0.013)
  • Change in low-density lipoprotein levels from baseline to 60 months: -46.5 vs. -14.0 (p < 0.001)
  • Change in systolic blood pressure from baseline to 60 months: -10.6 vs. -10.5 (p = 0.3)
  • Greater reduction in alanine aminotransferase (ALT) level in the polypill group vs. control group at 30 and 60 months without significant differences in aspartate aminotransferase (AST) and liver stiffness measure between polypill group vs. control group

Interpretation:

The results of this trial provide additional evidence of the benefits of a polypill for primary prevention of major cardiovascular events. This study was nested within a cohort study; thus, patients who were randomized but did not consent to the polypill study were included in the intention-to-treat analysis. While there was a reduction in major cardiovascular events in the polypill arm vs. control arm, this was not statistically significant. Importantly, when outcomes were assessed among patients who consented to the study, there was a statistically significant decreased risk of major cardiovascular events in the polypill arm.

The relative risk reduction observed among this population was similar to previous polypill studies within Iran (PolyIran study) and other geographic areas (aspirin-containing arm of the TIPS-3 trial). Another unique aspect of this study was the inclusion of patients with presumed nonalcoholic fatty liver disease and assessment of liver function. The polypill was found to be safe with possible signal for benefit with regard to liver enzyme levels, highlighting the potential role of statin therapy among this population.

References:

Merat S, Jafari E, Radmard AR, et al. Polypill for prevention of cardiovascular diseases with focus on non-alcoholic steatohepatitis: the PolyIran-Liver trial. Eur Heart J 2022;43:2023-33.

Clinical Topics: Acute Coronary Syndromes, Cardiac Surgery, Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Prevention, Cardiac Surgery and Arrhythmias, Cardiac Surgery and Heart Failure, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Acute Heart Failure, Interventions and ACS

Keywords: Acute Coronary Syndrome, Alanine Transaminase, Aspartate Aminotransferases, Aspirin, Atorvastatin, Blood Pressure, Cholesterol, LDL, Death, Sudden, Dyslipidemias, Fatty Liver, Heart Failure, Hydrochlorothiazide, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Metabolic Syndrome, Myocardial Revascularization, Non-alcoholic Fatty Liver Disease, Primary Prevention, Secondary Prevention, Stroke, Valsartan


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