TIPS-3: Polypill Provides Meaningful Primary Cardiovascular Prevention

Bruce Jancin

November 14, 2020

A once-daily polypill containing four drugs to lower blood pressure and LDL cholesterol reduced major adverse cardiovascular events by 21% relative to placebo in people at intermediate cardiovascular risk in the landmark TIPS-3 trial.

And with the addition of aspirin at 75 mg per day the combination achieved an even more robust 31% relative risk reduction, investigators reported at the.

"Aspirin contributes importantly to the benefits," Salim Yusuf, MD, DPhil, emphasized in presenting the International Polycap Study (TIPS-3) results jointly with study coprincipal investigator Prem Pais, MD, at the virtual American Heart Association scientific sessions.

The multinational study provides powerful new support for a broad, population health–based approach to primary cardiovascular prevention.

"If half of eligible people [were to] use a polypill with aspirin, 3-5 million cardiovascular events per year would be avoided globally," according to Dr. Yusuf, professor of medicine and director of the Population Health Research Institute at McMaster University in Hamilton, Ont.

"This is likely a cost-effective strategy to meet global targets of reducing cardiovascular disease by 30% by 2020," added Dr. Pais of St. John's Research Institute in Bangalore, India.

TIPS-3 included 5,713 participants at intermediate cardiovascular risk, with an estimated event risk of 1.8% per year using the INTERHEART Risk Score. Half were women. More than 80% of participants had hypertension, and nearly 40% had diabetes or impaired fasting glucose. Nearly 90% of participants came from India, the Philippines, Malaysia, Indonesia, or Bangladesh. All participants received advice about lifestyle management.

They were then randomized to receive a polypill or placebo, and then each group was further randomized to receive 75 mg/day of aspirin or matching placebo. The polypill contained 40 mg of simvastatin, 100 mg of atenolol, 25 mg of hydrochlorothiazide, and 10 mg of ramipril.

During a mean 4.6 years of follow-up, the primary composite major adverse cardiovascular event rate occurred in 4.4% of the polypill group, 4.1% of the polypill-plus-aspirin group, and 5.8% of the double-placebo group. This translated to a 21% reduction in cardiovascular disease with the polypill, a 31% reduction with polypill plus aspirin, and a 14% reduction in the composite of cardiovascular death, MI, or stroke with aspirin alone.

The polypill and placebo groups diverged in terms of the primary outcome starting about 6 months into the study, Dr. Pais noted.

Serious adverse events were less common with the polypill than with placebo. Importantly, there was no difference in major, minor, or GI bleeding between the polypill-plus-aspirin group and placebo-treated controls. Dr. Yusuf attributed the lack of excess bleeding in aspirin recipients to two factors: people with a history of bleeding or GI symptoms were excluded from TIPS-3, and the dose of aspirin used was lower than in other primary prevention trials, where bleeding offset the reduction in cardiovascular events.

Nonadherence was a major issue in TIPS-3, mainly because of delays in polypill production and distribution, coupled late in the trial with the COVID-19 pandemic. The nonadherence rate was 19% at 2 years, 32% at 4 years, and 43% at the study's end. Only 5% of discontinuations were due to side effects. In a sensitivity analysis carried out in participants without discontinuation for nonmedical reasons, the benefits of the polypill plus aspirin were larger than in the overall study: a 39% relative risk reduction in the primary endpoint that probably offers a more accurate picture of the combination's likely real-world performance.

Discussant Anushka Patel, MBBS, PhD, noted that TIPS-3 is the third randomized trial to provide direct evidence that a polypill-based strategy improves clinical outcomes. The effect sizes of the benefits – a 20%-30% reduction in major cardiovascular events – has been consistent in TIPS-3, PolyIran, and HOPE-3, each of which tested a different polypill drug combination.

"If implementation and adherence challenges can be addressed at the system, prescriber, and patient levels, and if high-quality polypills can be made affordable, the public health impact could actually be enormous," said Dr. Patel, chief scientist at the George Institute for Global Health and professor of medicine at the University of New South Wales in Sydney, Australia.

However, she parted company with Dr. Yusuf regarding routine incorporation of aspirin into polypills.

"I think the totality of evidence would still probably favor taking an individualized approach that also considers bleeding risk," the cardiologist said.

Donald Lloyd-Jones, MD, who chaired a press conference highlighting TIPS-3, declared, "You're seeing a paradigm shift right here in front of your eyes today. This could be a game changer in terms of preventing large numbers of cardiovascular events."

While TIPS-3 was conducted mainly in low- and middle-income countries, it's important to recognize that's where 75% of cardiovascular events and cardiovascular deaths now occur.

"This is very much a disease that has emerged in the developing world," commented Dr. Lloyd-Jones, the AHA president-elect, chair of the AHA Council on Scientific Sessions Programming, and professor and chair of the department of preventive medicine at Northwestern University, Chicago.

He also sees a polypill strategy for primary cardiovascular prevention as highly viable in high-resource countries. It makes sense to employ it there initially in underserved communities, where a polypill-based approach sidesteps difficulties in monitoring care and adjusting medication doses due to reduced access to health care while minimizing cost and adherence issues, he added.

Dr. Yusuf and Dr. Pais reported receiving institutional research support from the TIPS-3 major sponsors: the Wellcome Trust, Cadila Pharmaceuticals, the Canadian Institutes of Health Research, and the Heart and Stroke Foundation of Canada.

Simultaneously with their presentation at AHA 2020, the TIPS-3 results were published online in the New England Journal of Medicine.

SOURCE: Yusuf, S. AHA 2020. Session LBS.02.

This article originally appeared on, part of the Medscape Professional Network.


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