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Aspirin added to the benefits of a low-cost polypill approach for primary prevention of cardiovascular disease (CVD) in an intermediate-risk population, the found.

People who got the polypill in the trial had a borderline lower incidence of composite CVD events (cardiovascular death, MI, stroke, heart failure, resuscitated cardiac arrest, or arterial revascularization with evidence of ischemia) over 6 years compared with the placebo group (4.4% vs 5.5%, HR 0.79, 95% CI 0.63-1.00).

Given the multitude of problems with study conduct -- including poor medication adherence due to delays in drug supply -- the investigators conducted a sensitivity analysis, counting CVD events within 30 days for people who stopped the drug for non-medical reasons, which slightly improved the treatment effect of the polypill (HR 0.74, 95% CI 0.57-0.97).

The 5,713-person study was presented by Salim Yusuf, DPhil, of the Population Research Health Institute at McMaster University in Hamilton, Ontario, at this year's virtual American Heart Association (AHA) meeting. A full manuscript was simultaneously published in the .

TIPS-3 participants who received aspirin alone did not have a better combined rate of cardiovascular death, MI, or stroke compared with placebo (HR 0.86, 95% CI 0.67-1.10). This finding was unchanged after the sensitivity analysis (HR 0.83, 95% CI 0.62-1.10).

Yet the addition of aspirin to the polypill brought CVD risk even lower compared with double placebo (4.1% vs 5.8%, HR 0.69, 95% CI 0.50-0.97). Results looked even better after the sensitivity test (HR 0.61, 95% CI 0.41-0.91).

"This hopefully is the best evidence that aspirin has a benefit over other treatments," Yusuf said during an AHA press briefing. "Aspirin, chose carefully, does have a role in primary prevention along with lifestyle management and use of the rest of the polypill components."

Notably, aspirin had been downgraded in the after the ASCEND and ARRIVE trials showed no net benefit in older people and those with diabetes, according to press conference moderator and AHA president-elect Donald Lloyd-Jones, MD, of Northwestern University Feinberg School of Medicine in Chicago.

The CVD benefit of aspirin in ASCEND and ARRIVE had been offset by the bleeding rate, which was lower in TIPS-3, perhaps because of a run-in period and the low aspirin dose (75 mg daily), Yusuf suggested.

Overall, the benefit of fixed-dose combination therapy has been consistent across trials, including HOPE-3 and PolyIran, according to session discussant Anushka Patel, MBBS, SM, PhD, of the George Institute for Global Health in Sydney, Australia.

TIPS-3 was mostly conducted in middle-income countries, but it has global relevance, she commented.

"There is a paradigm shift right in front of your eyes today," said Lloyd-Jones, who said he agreed that the polypill approach is applicable to settings worldwide but maintained it is particularly attractive to low-resource settings.

Yusuf stressed that the polypill approach can have benefits in both rich and poor countries. "Why wouldn't the wealthy people benefit from something that is easily taken and can reduce risk by 30 to 40%?" he asked, arguing that there is no basis for the "myth created" that "this is for poor people."

The polypill may serve as background therapy for most, with people at very high risk being candidates for additional treatments, according to Yusuf.

TIPS-3 included people without CVD who had a CVD risk greater than 1.0% per year according to the INTERHEART Risk Score.

Investigators had 7,534 people enter the run-in period including lifestyle counseling. Ultimately, 5,713 were randomized 1:1 to polypill or placebo. Within each group, patients were split between those receiving aspirin or no aspirin.

Most patients were enrolled in India and the Philippines. Mean age was 64 years, and over half of the cohort were women. At baseline, 84% had hypertension or systolic blood pressure (BP) over 140 mm Hg, and 37% had diabetes or glucose over 126 mg/dL.

Mean follow-up in TIPS-3 was 4.6 years.

The polypill in the study contained atenolol 100 mg, ramipril 10 mg, hydrochlorothiazide 25 mg, and simvastatin 40 mg. The once-daily capsule was "cost neutral" and cost 33 cents per day in India, according to Yusuf.

Systolic BP fell by 5.8 mm Hg on average with the polypill. LDL cholesterol was reduced by 19.0 mg/dL.

The 30-40% reduction of CVD risk by the polypill/aspirin combination was less than originally hypothesized by investigators, Yusuf said, noting multiple challenges to study conduct.

Recruitment took 5 years instead of 2 years, and there were regulatory challenges in India, while the protocol was not even approved in China, Brazil, and Argentina.

There was also a high rate of non-adherence due to delayed drug production, export and import barriers, and the COVID-19 pandemic in the last 6-9 months of the trial. Of the patients who discontinued their assigned regimens, 42.2% were in the polypill comparison group and 39.7% were in the aspirin comparison group.

Discontinuation was mostly unrelated to side effects of the polypill or aspirin, given the "excellent" safety data that saw no increase in bleeding rates over placebo, according to Yusuf.

Another reason why CVD risk reduction was less than expected may have to do with the chemical stability of the polypill formulation used in TIPS-3. Yusuf said his group is testing the capsules over the next few months.

"No Big Pharma is funding this," he lamented. "We had incredible difficulty getting the study funded and completed."

"I would encourage some company in the West to develop a polypill. It doesn't matter what the components are, it would be effective," the trial leader said. He suggested that mass polypill purchases, as in the case of vaccines, would make sense for some large payers.

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