Daily polypill plus aspirin lowers risk for CVD, death
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Adults at intermediate CV risk assigned a polypill plus aspirin were 31% less likely to experience a CV event or death compared with those assigned double placebo over a nearly 5-year period, according to new data from the TIPS-3 trial.
“The most important finding is that the combination of a polypill — which includes multiple BP-lowering drugs plus statins — plus aspirin reduced the risk for cardiovascular disease, stroke or death by 30% among those who were randomized, and up to 40% among those who actually took the medicines, Salim Yusuf, MD, DPhil, FRCP, FACC, the Marion W. Burke Chair in Cardiovascular Disease and director of the Population Health Research Institute at McMaster University Medical School, told Healio.
The observed CV benefits of a daily polypill-plus-aspirin regimen were lower than the original hypothesized benefits; however, the findings are still important for the primary prevention population, Yusef said during a press conference at the virtual American Heart Association Scientific Sessions. If half of eligible adults were prescribed a polypill with aspirin, as many as 5 million CV events could be avoided globally, he said.
“I should hasten to add, this is important for the ‘rich’ countries and the poor countries,” Yusuf said.
Study design
Yusuf and colleagues analyzed data from 5,713 adults without CVD at baseline who had an elevated Interheart Risk Score. Researchers randomly assigned participants to receive a once-daily polypill containing 40 mg simvastatin, 100 mg atenolol, 25 mg hydrochlorothiazide and 10 mg ramipril or once-daily placebo; 75 mg aspirin or placebo; or vitamin D or placebo monthly. (Vitamin D was assessed, but those results were not presented here.)
For the polypill-alone and polypill plus aspirin comparisons, the primary outcome was CV death, MI, stroke, resuscitated cardiac arrest, HF or revascularization. For the aspirin comparison, the primary outcome was CV death, MI or stroke. The cohort was followed for 4.6 years.
The findings were simultaneously published in The New England Journal of Medicine.
For the last 18 months of the study, Yusuf noted there was a “substantial decline” in adherence to therapies, due to difficulties getting medications to participants and resupply issues related to the COVID-19 pandemic.
Benefits of polypill alone
Researchers observed a 21% relative risk reduction in CV events for participants assigned polypill therapy vs. placebo (HR = 0.79; 95% CI, 0.63-1), with curves diverging at 6 months after therapy initiation, Yusuf said. In prespecified sensitivity analyses accounting for nonadherence due to nonmedical reasons, participants assigned polypill therapy were 26% less likely to experience a CV event within 30 days of stopping the medication (HR = 0.74; 95% CI, 0.57-0.97).
“After stopping the medication, the number of events were identical, and within 30 days of stopping the medication, there is a 26% risk reduction,” Yusuf said.
Researchers found that polypill therapy had a modest effect on CV risk factors. The mean difference between the polypill and placebo groups in systolic BP reduction was 5.8 mm Hg (95% CI, 5.1-6.4); mean difference between groups for LDL cholesterol was 19 mg/dL (95% CI, 17.3-20.8).
“Initially, we saw a 10-mm Hg reduction in BP, but over time, this attenuated,” Yusuf said. “This cannot be explained by adherence decreasing over time. I think the body gets used to the effects of the BP lowering and there are compensatory mechanisms.”
LDL reduction, too, while significant, was “only about half of what we expected,” Yusuf said.
Benefits of polypill plus aspirin
Researchers observed a 14% relative risk reduction for the primary outcome among participants assigned aspirin alone (n = 2,860) vs. placebo (n = 2,853), for an HR of 0.86 (95% CI, 0.67-1.1). There was no excessive bleeding observed with aspirin vs. placebo, which Yusuf attributed to the lower, 75-mg dose.
“This is hopefully the best evidence yet that aspirin does have a benefit on top of other preventive strategies,” Yusuf said.
Participants assigned polypill plus aspirin (n = 1,429) were 31% less likely to experience a primary event during follow-up compared with those assigned double placebo (n = 1,421), with an HR of 0.69 (95% CI, 0.5-0.97), with event curves again diverging at 6 months, Yusuf said.
In sensitivity analyses adjusted for nonadherence due to nonmedical factors, researchers observed a 39% risk reduction for the primary outcome with polypill-plus-aspirin therapy vs. double placebo (HR = 0.61; 95% CI, 0.41-0.91).
“Each of the pill components contribute to the benefits of the combined therapy,” he said.
‘Consistency of effects’ across trials
During a discussion following the TIPS-3 presentation, Anushka Patel, MBBS, SM, PhD, FRACP, vice principal director and chief scientist at the George Institute for Global Health and professor of medicine at University of New South Wales Sydney, said TIPS-3 adds to the body of evidence demonstrating that polypill therapy significantly reduces CV risk in a primary prevention population.
“With TIPS-3, we now have direct evidence from three randomized trials that evaluated polypill-based strategies in more than 18,000 participants on, importantly, clinical outcomes,” Patel said during the press conference. “These three studies had some important differences, but the consistency of effects on prevention of major CV events is clear.”
Patel noted that risk factor reductions with the polypill were lower than anticipated; the reductions in BP and LDL cholesterol were about 40% of what might be expected with the individual component drugs, assuming 100% adherence to therapy. However, the polypill was shown to be safe and can provide important clinical and public health benefits, Patel said.
“If implementation and adherence challenges can be addressed at the system, prescriber and patient levels, the public health impact of polypill-based strategies could be enormous, particularly if the polypill is affordable,” Patel said. “This is where I believe future research should be prioritized.”
Reference:
Perspective
Back to TopAnubha Agarwal, MD, MSc
In TIPS-3, a polypill-plus-aspirin regimen led to a 31% lower relative risk for CV events during a mean of 4.6 years in a primary prevention population at intermediate CV risk. The direction and magnitude of this effect is congruent with what was observed in prior trials, including PolyIran, and provides additional evidence that a polypill-based approach is effective. The most urgent question now is what will be the regulatory proof needed to advance polypills to commercialization to make them available to our patients who are most likely to benefit?
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Yusuf S, et al. LBS.02: Bending the curve for CV Disease – Precision or Polypill? Presented at: American Heart Association Scientific Sessions; Nov. 13-17, 2020 (virtual meeting).
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