Polypill + aspirin TIPped as CVD primary prevention strategy
A single polypill combining a beta blocker, ACE* inhibitor, statin, and diuretic, in addition to a daily dose of aspirin, significantly reduced the risk of cardiovascular disease (CVD) in patients with intermediate CV risk, according to the TIPS**-3 study presented at the AHA 2020 Scientific Sessions.
“Our study results provide important data regarding the role of the polypill in preventing the development of heart disease,” said co-author Professor Salim Yusuf from McMaster University School of Medicine, Toronto, Canada.
“Aspirin should be prescribed with a polypill in primary prevention for patients at intermediate risk of heart disease,” he added.
This multinational, double-blind study included 5,713 individuals without CVD (men aged ≥50 years and women ≥55 years with INTERHEART risk score [IHRS] ≥10 or aged ≥65 years with IHRS ≥5). They were randomized to receive either a single polypill capsule (containing atenolol [100 mg], ramipril [10 mg], hydrochlorothiazide [25 mg], and simvastatin [40 mg]) or placebo per day, aspirin (75 mg) or placebo per day, or vitamin D (60,000 IU) or placebo per month (2,861 and 2,852 patients received the polypill and placebo, respectively). Baseline characteristics were well-balanced between groups (mean age 63.9 years, 52.9 percent female, mean IHRS ~18, mean systolic blood pressure [SBP] 144.5 mm Hg, mean LDL-cholesterol 120.7 mg/dL). Patients were followed up for a mean 4.6 years.
Patients who received the polypill had significant reductions in SBP (mean difference, 5.8 mm Hg) and LDL-cholesterol (mean difference, 19 mg/dL; p<0.0001 for both) compared with placebo recipients.
Patients who received the polypill had a 21 percent reduction in the composite of CV events*** compared with placebo recipients (4.4 percent vs 5.5 percent; hazard ratio [HR], 0.79, 95 percent confidence interval [CI], 0.63–1.00; p=0.05). [AHA 2020, session LBS.02; N Engl J Med 2020;doi:10.1056/NEJMoa2028220] The results were consistent after accounting for non-adherence# (HR, 0.74).
Serious adverse event (AE) rates were lower in polypill vs placebo recipients (0.8 percent vs 1.2 percent). AE-related discontinuations for dizziness or hypotension (2.7 percent vs 1.1 percent) and cough (1.1 percent vs 0.6 percent) were more common in the polypill group, while discontinuation due to muscle pain or weakness was comparable between groups.
The risk of the composite of CV death, myocardial infarction (MI), or stroke was reduced by 14 percent with aspirin compared with placebo (4.1 percent vs 4.7 percent; HR, 0.86, 95 percent CI, 0.67–1.10; p=0.237), with a significant reduction in stroke risk (0.8 percent vs 1.4 percent; HR, 0.58; p=0.041).
Incidence of major or minor bleeding did not differ between aspirin and placebo recipients (major: 0.7 percent in both groups; minor: 0.6 percent vs 0.5 percent), nor did gastrointestinal bleeding (0.4 percent for both).
Patients who received the polypill plus aspirin had a significant 31 percent reduction in the composite of CV events compared with those who received double placebo (4.1 percent vs 5.8 percent; HR, 0.69, 95 percent CI, 0.50–0.97; p=0.031). The reduced risk was maintained for the secondary outcome of CV death, MI, or stroke (3.6 percent vs 5.3 percent; HR, 0.68; p=0.030) and the primary composite plus angina (4.3 percent vs 6.1 percent; HR, 0.69; p=0.028). There was also a significant reduction in the rate of CVD and cancer (5.3 percent vs 7.5 percent; HR, 0.70; p=0.016). The results for the primary outcomes remained consistent after accounting for non-adherence (HR, 0.61).
The benefits may be greater – about 40 percent in the polypill plus aspirin group – among those who did not discontinue therapy due to non-medical reasons, said the authors.
Discontinuation of trial drugs occurred in 42.2 percent of the polypill comparison and 39.7 percent of the aspirin comparison. The authors acknowledged that the proportion of discontinuations for AEs or poor adherence may have been underestimated, based on the discontinuation rate during the run-in period pre-randomization.
Polypill: A role in primary prevention
“Both [the polypill and aspirin] interventions appear to have contributed to the overall benefit of the combination, with a larger portion of the benefit attributable to the polypill,” noted the authors.
According to Yusuf, the findings have far-reaching implications. “Use of a polypill plus aspirin can avert 3–5 million CV deaths globally. Future polypills, with newer statins, may reduce LDL-cholesterol and BP to a greater extent and could reduce CVD risk [by more] than 50 percent,” he added.
“We were also interested in evaluating if combining BP and cholesterol reduction medications in a single pill would be effective for this population. This is a cost-effective strategy that could help meet global targets of reducing CVD by 30 percent by 2030,” contributed co-author Professor Prem Pais from St. John’s Research Institute, Bangalore, India.
“[A] polypill-based strategy can have substantial impact globally,” echoed Professor Anushka Patel from The George Institute for Global Health, New South Wales, Australia, who discussed the findings.
“Totality of evidence suggests polypill-based approaches in intermediate risk populations is safe and effective, and – even with substantial nonadherence – could translate to important clinical and public health benefits,” she said. Nonetheless, the current study alone is inadequate to establish if aspirin should be added to a polypill, and its inclusion or exclusion in the primary prevention strategy should be individualized, said Patel.