Polypill in prevention of cardiovascular disease (CVD)

• BMJ editorial describes a paper by Wald and Law that suggests an intervention that would be "a greater impact on the prevention of disease in the Western world than any other known intervention" - it is a new strategy to deliver some of our most well known medicines (1)
  • Wald and Law propose that a single pill ("polypill") containing aspirin, a statin, three blood pressure lowering agents in half dose, and folic acid is provided to people with vascular disease and those aged over 55 years
  • details of the study undertaken by Wald and Law are summarised below (2):
    • synthesised an enormous amount of information (including over 750 trials with 400 000 participants)
    • their study objectives were to determine the combination of drugs and vitamins, and their doses, for use in a single daily pill to achieve a large effect in preventing cardiovascular disease with minimal adverse effects. The strategy was to simultaneously reduce four cardiovascular risk factors (low density lipoprotein cholesterol, blood pressure, serum homocysteine, and platelet function) regardless of pretreatment levels
    • in their study they quantified the efficacy and adverse effects of the proposed formulation from published meta-analyses of randomised trials and cohort studies and a meta-analysis of 15 trials of low dose (50-125 mg/day) aspirin
    • outcome measures used were proportional reduction in ischaemic heart disease (IHD) events and strokes; life years gained; and prevalence of adverse effects.
    • the formulation which met the objectives of the study authors was:
      • a statin (for example, atorvastatin (daily dose 10 mg) or simvastatin (40 mg));
      • three blood pressure lowering drugs (for example, a thiazide, a beta-blocker
      • an angiotensin converting enzyme inhibitor), each at half standard dose; folic acid (0.8 mg); and aspirin (75 mg)
      • study authors estimated that the combination (which we call the Polypill) reduces IHD events by 88% (95% confidence interval 84% to 91%) and stroke by 80% (71% to 87%)
      • one third of people taking this pill from age 55 would benefit, gaining on average about 11 years of life free from an IHD event or stroke
      • summing the adverse effects of the components observed in randomised trials shows that the Polypill would cause symptoms in 8-15% of people (depending on the precise formulation).
    • the authors concluded that Polypill strategy could largely prevent heart attacks and stroke if taken by everyone aged 55 and older and everyone with existing cardiovascular disease. It would be acceptably safe and with widespread use would have a greater impact on the prevention of disease in the Western world than any other single intervention
      
      
• an update in the evidence for a polypill in the secondary prevention of cardiovascular disease (3)
  • investigated the use of a polypill that included three key medications associated with improved outcomes (aspirin, angiotensin-converting-enzyme [ACE] inhibitor, and statin)
  • randomized, controlled clinical trial
    • assigned patients with myocardial infarction within the previous 6 months to a polypill-based strategy or usual care
    • polypill treatment consisted of aspirin (100 mg), ramipril (2.5, 5, or 10 mg), and atorvastatin (20 or 40 mg)
      • different versions of the polypill were available to allow for titration to tolerated doses of the component medications: aspirin (100 mg), ramipril (2.5, 5, or 10 mg), and atorvastatin (20 mg or 40 mg)
    • primary composite outcome
      • cardiovascular death, nonfatal type 1 myocardial infarction, nonfatal ischemic stroke, or urgent revascularization
    • key secondary end point was a composite of cardiovascular death, nonfatal type 1 myocardial infarction, or nonfatal ischemic stroke
  • results
    • 2499 patients underwent randomization and were followed for a median of 36 months
    • primary-outcome event occurred in 118 of 1237 patients (9.5%) in the polypill group and in 156 of 1229 (12.7%) in the usual-care group (hazard ratio, 0.76; 95% confidence interval [CI], 0.60 to 0.96; P=0.02)
    • key secondary-outcome event occurred in 101 patients (8.2%) in the polypill group and in 144 (11.7%) in the usual-care group (hazard ratio, 0.70; 95% CI, 0.54 to 0.90; P=0.005)
    • results were consistent across prespecified subgroups
    • medication adherence as reported by the patients was higher in the polypill group than in the usual-care group
      • researchers used the Morisky Medication Adherence Scale to gauge participants' adherence to their medication regimen and found the polypill group was more adherent. Patients who received the polypill were more likely to have a high level of adherence at 6 months (70.6% vs 62.7%) and 24 months (74.1% vs 63.2%)
    • no significant differences in blood pressure or lipid levels between each group
      • in the group that received the polypill, average systolic and diastolic blood pressure at 24 months were 135.2 mmHg and 74.8 mmHg, respectively. In the group that received usual care, those values were 135.5 mmHg and 74.9 mmHg, respectively
      • no substantial differences were found in LDL-cholesterol levels over time between the groups, with a mean value at 24 months of 67.7 mg/dL in the polypill group and 67.2 mg/dL in the usual-care group
    • adverse events were similar between groups
  • conclusions
    • treatment with a polypill containing aspirin, ramipril, and atorvastatin within 6 months after myocardial infarction resulted in a significantly lower risk of major adverse cardiovascular events than usual care

Reference:

1. BMJ Editorial. A cure for cardiovascular disease? BMJ 2003;326:1407-1408 (28 June)
2. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003;326: 1419-2
3. Castellano JM et al; SECURE Investigators. Polypill Strategy in Secondary Cardiovascular Prevention. N Engl J Med. 2022 Aug 26. doi: 10.1056/NEJMoa2208275