Aspirin added significantly to the benefits of a low-cost ‘polypill’ approach for primary prevention of cardiovascular disease in an intermediate-risk population, the TIPS-3 study has found, according to research published in The New England Journal of Medicine. Aspirin has thus proved its mettle in primary prevention, the lead author told the American Heart Association meeting.
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 revascularisation with evidence of ischaemia) over six years compared with the placebo group (4.4% vs 5.5%, HR 0.79, 95% CI 0.63-1.00), writes Nicole Lou in a MedPage article on 13 November 2020.
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 Dr Salim Yusuf of the Population Research Health Institute at McMaster University in Hamilton, Ontario, at this year’s virtual American Heart Association (AHA) meeting, according to MedPage.
Aspirin does the trick
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, MedPage reports. “Aspirin, chosen 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 2019 AHA and American College of Cardiology CVD primary preventin guidelines 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, writes MedPage.
Overall, the benefit of fixed-dose combination therapy has been consistent across trials, including HOPE-3 and PolyIran, according to session discussant Dr Anushka Patel 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 agreed that the polypill approach is applicable to settings worldwide but maintained it is particularly attractive to low-resource settings.
Polypill – Good for all
But Yusuf stressed that the polypill approach can have benefits in both rich and poor countries, MedPage continues.
“Why wouldn’t 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, reports MedPage.
Investigators had 7,534 people enter the run-in period including lifestyle counseling. Ultimately, 5,713 were randomised 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.
According to MedPage, the 30% to 40% reduction of CVD risk by the polypill/aspirin combination was less than originally hypothesised by investigators, Yusuf said, noting multiple challenges to the study conduct.
Recruitment took five years instead of two 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 six to nine 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.
A polypill needs development
“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.
Polypill with or without Aspirin in Persons without Cardiovascular Disease
The New England Journal of Medicine. Published on 13 November 2020.
Salim Yusuf, Philip Joseph, Antonio Dans, Peggy Gao, Koon Teo, Denis Xavier, Patricio López-Jaramillo, Khalid Yusoff, Anwar Santoso, Habib Gamra, Shamim Talukder, Courtney Christou et al for the International Polycap Study 3 Investigators
A polypill comprising statins, multiple blood-pressure–lowering drugs, and aspirin has been proposed to reduce the risk of cardiovascular disease.
Using a 2-by-2-by-2 factorial design, we randomly assigned participants without cardiovascular disease who had an elevated INTERHEART Risk Score to receive a polypill (containing 40 mg of simvastatin, 100 mg of atenolol, 25 mg of hydrochlorothiazide, and 10 mg of ramipril) or placebo daily, aspirin (75 mg) or placebo daily, and vitamin D or placebo monthly.
We report here the outcomes for the polypill alone as compared with matching placebo, for aspirin alone as compared with matching placebo, and for the polypill plus aspirin as compared with double placebo. For the polypill-alone and polypill-plus-aspirin comparisons, the primary outcome was death from cardiovascular causes, myocardial infarction, stroke, resuscitated cardiac arrest, heart failure, or revascularization.
For the aspirin comparison, the primary outcome was death from cardiovascular causes, myocardial infarction, or stroke. Safety was also assessed.
A total of 5713 participants underwent randomization, and the mean follow-up was 4.6 years. The low-density lipoprotein cholesterol level was lower by approximately 19 mg per deciliter and systolic blood pressure was lower by approximately 5.8 mm Hg with the polypill and with combination therapy than with placebo.
The primary outcome for the polypill comparison occurred in 126 participants (4.4%) in the polypill group and in 157 (5.5%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.63 to 1.00). The primary outcome for the aspirin comparison occurred in 116 participants (4.1%) in the aspirin group and in 134 (4.7%) in the placebo group (hazard ratio, 0.86; 95% CI, 0.67 to 1.10).
The primary outcome for the polypill-plus-aspirin comparison occurred in 59 participants (4.1%) in the combined-treatment group and in 83 (5.8%) in the double-placebo group (hazard ratio, 0.69; CI, 0.50 to 0.97). The incidence of hypotension or dizziness was higher in groups that received the polypill than in their respective placebo groups.
Combined treatment with a polypill plus aspirin led to a lower incidence of cardiovascular events than did placebo among participants without cardiovascular disease who were at intermediate cardiovascular risk.
Medpage – Polypill, Aspirin Together Make a Difference in Large Outcomes Trial
New England Journal of Medicine – Polypill with or without Aspirin in Persons without Cardiovascular Disease