Polypill for primary prevention in individuals with intermediate risk for cardiovascular disease

SUMMARY

Polypill, comprising multiple cardioprotective medications, has been proposed to lower cardiovascular disease (CVD) among intermediate-to-high risk individuals. The International Polycap Study 3 (TIPS-3) was a randomized factorial design placebo-controlled trial done to study the impact of polypill and aspirin individually and in combination. The polypill comprised 40 mg of simvastatin, 100 mg of atenolol, 25 mg of hydrochlorothiazide and 10 mg of ramipril. Aspirin was administered at a dose of 75 mg per day. Patients without CVD having intermediate risk for CVD based on the INTERHEART risk score were included in the trial. Follow-up was at 6 weeks, at 3, 6, 9 and 12 months and every 6 months after that till the end of the trial. A total of 5713 participants underwent randomization between 30 July 2012 and 12 August 2017. Almost half the patients were from India. The mean age of the participants was 64 years, and approximately half of them were women. The mean follow-up was for 4.6 years. Discontinuation of polypill and aspirin was roughly 40%, much more than the anticipated 20% in the study design. The reasons were due to side-effects and more commonly related to administrative barriers to drug distribution and then the Covid-19 pandemic. In the polypill arm, major cardiovascular events plus heart failure, resuscitated cardiac arrest and arterial revascularization (primary outcome) occurred in 4.4% of individuals compared to 5.5% in the placebo group (hazard ratio 0.79; 95% confidence interval [CI] 0.63–1.00). Death from cardiovascular causes, myocardial infarction or stroke (primary outcome for aspirin arm) occurred in 4.1% in the aspirin group and 4.7% in the placebo group (hazard ratio 0.86; 95% CI 0.67–1.10). The primary outcome for the polypill plus aspirin group (major cardiovascular events plus heart failure, resuscitated cardiac arrest or arterial revascularization) occurred in 4.1% of individuals compared to 5.8% in the double-placebo group (hazard ratio 0.69; 95% CI 0.50–0.97). Thus, polypill plus aspirin led to a 31% lower relative risk of cardiovascular events with discontinuation rates due to side-effects similar to the placebo arm.

COMMENT

The prevalence of CVD worldwide is estimated to be 422.7 million, and it causes approximately 18 million deaths per year, most of which are in low- and middle-income countries.^1,2 In India, too, CVD is the leading cause of mortality. This is due to the high cardiovascular risk burden and poor control of these risk factors.³ Polypill is proposed as an important strategy to reduce CVD risk and improve management of hypertension and dyslipidaemia. This was postulated more than 15 years ago with the hope that it would reduce cardiovascular events by more than 80%.⁴ However, to date, its uptake in clinical practice remains low—one of the reasons being inadequate evidence of its benefit. The TIPS-3 trial helps bridge that gap with proof for primary prevention. Among other studies with polypill, the UMPIRE trial, which included 2004 participants with CVD or high risk for CVD, showed significant improvement in adherence and marginal improvement in blood pressure and low-density lipoprotein-cholesterol control with the use of polypill.⁵ The other long-term polypill study, The PolyIran study included 6838 participants from Iran and followed them up for 5 years.⁶ The study used hydrochlorothiazide 12.5 mg, aspirin 81 mg, atorvastatin 20 mg and enalapril 5 mg or valsartan 40 mg (in those who developed cough). Akin to TIPS-3, it showed that once-daily polypills reduced the risk of major cardiovascular events in both those with and without CVD. The effect was more pronounced in participants with high adherence to the polypill.

Thus, the cumulative evidence for clinical benefit of polypill has built up with the TIPS-3 study and should help improve the uptake of this strategy as a CVD prevention therapy. However, additional factors that seem to limit the uptake of polypill include lack of scope of drug titration, discontinuation of all medicines in case of intolerance to any one and low acceptability among physicians.⁷ These barriers may be largely overcome by expanding the menu with multiple polypills with different agents at varied dosages. The polypill used in TIPS-3 included high doses of atenolol, thiazide and statin—all diabetogenic agents⁸ and thus an unsuitable polypill for Indians, who are prone to diabetes. The vibrant pharmaceutical industry in India makes it possible to have diverse polypills tailored to various needs. This needs to be encouraged through its wider use by physicians and the initiation of its use by government health centres. The polypill distribution through government health centres would benefit millions of those with CVD and its risk factors and help economise costs with bulk purchase.

Control of risk factors and improvement in lifestyle factors such as cessation of tobacco use, enhanced physical activity and healthy diet have been shown to reduce CVD mortality by over two-thirds in the western world.⁹ The time is ripe to implement the same in India to help reduce the burgeoning CVD risk. Polypill may be one of the useful tools in this battle.