Combining aspirin, an ACE inhibitor, and a statin into a single “polypill” improved cardiovascular outcomes in secondary prevention compared with prescribing the medications separately, the SECURE randomised trial has showed
The polypill reduced the primary composite risk of cardiovascular death, non-fatal type 1 MI, non-fatal ischaemic stroke, and urgent revascularisation by a relative 24% over usual care, with a rate of 9.5% versus 12.7%, respectively (P=0.02), reported Dr Valentin Fuster, PhD, of the Icahn School of Medicine at Mount Sinai in New York, during the European Society of Cardiology (ESC) Congress (26-29 August).
Looking at just the hard outcomes without revascularisation likewise favoured the polypill (8.2% vs 11.7%, HR 0.70, 95% CI 0.54-0.90).
“Using a cardiovascular polypill as a substitute for several separate cardiovascular drugs could be an integral part of an effective secondary prevention strategy,” Fuster and colleagues wrote in their study, which was published simultaneously in the New England Journal of Medicine.
“By simplifying treatment complexity and improving availability, the polypill is a widely applicable strategy to improve accessibility and adherence to treatment, decreasing the risk of recurrent disease and cardiovascular death,” they added.
The trial didn’t show much difference between groups in blood pressure or LDL cholesterol levels; rather, the researchers chalked the differences up to improved adherence leading to greater anti-platelet exposure, perhaps along with pleiotropic effects of statins and ACE inhibitors beyond those measures.
The trial was consistent with the propensity-matched NEPTUNO study, which showed a 27% reduction in major adverse cardiovascular event risk with a similar polypill in a secondary prevention setting, which was also attributed to higher medication persistence.
Moreover, the study’s results add to the evidence for the benefits of fixed-dose combo pills seen in primary prevention as well.
“There is a history here of 15 years,” said Fuster. The group first showed that adherence to medication after MI was a big problem, then showed in the FOCUS study that the polypill improved adherence. Fuster said that this advantage now translates into a “striking” clinical benefit.
The event curves began to separate for both the primary and key secondary endpoints right from the beginning and continued to do so at the median three years of follow-up in the trial.
“I would like to emphasise one thing: that the impact of the data I presented is not different from the impact of aspirin,” he said. “We have in front of us something that could be simple and for countries middle-income and low-income, which is how we started the trial, it actually could be meaningful. The next step is we have to go to the agencies for approval.”
A combination pill with atorvastatin was approved for use in Europe but now it was time to go to the FDA, he added.
Dr Martha Gulati, director of cardiovascular disease prevention at the Barbra Streisand Women’s Heart Centre at Cedars-Sinai Heart Institute in Los Angeles, said the polypill wouldn’t just be useful in lower-income countries.
Access and cost are not issues only in the developing world, she argued, pointing to the less-than-perfect adherence achieved in the polypill group in the high-risk population studied.
High scores for adherence were seen at six months in 71% of the polypill group and 62.7% of usual care patients (risk ratio [RR] 1.13, 95% CI 1.06-1.20) and at 24 months in 74.1% and 63.2%, respectively (RR 1.17, 95% CI 1.10-1.25).
“That’s so telling, because you’ve had something that could kill you and is a pretty serious medical event and then people don’t take their medication,” Gulati said. “A lot of patients with myocardial infarction… these are not the only drugs they’re on. They’re often on expensive anti-platelet agents, they may be on medications for diabetes, they might need more than just a statin eventually, they may need other lipid-lowering agents.
“We put a great burden on our patients and a financial burden as well with every copay. So making it easy is something we should be interested in,” she said. “Even the generic drugmakers should have some interest in making it available.”
It’s really a public health problem, Fuster agreed. “People do not have adherence to what we know.”
The SECURE (Secondary Prevention of Cardiovascular Disease in the Elderly) trial included 2 499 patients aged 75 and older (or at least 65 with an additional risk factor) who had type 1 MI in the previous six months.
They were randomised to treatment with a single daily pill containing aspirin (100mg), ramipril (2.5, 5, or 10mg), and atorvastatin (92% on 40mg, and the rest on 20mg based on patient history and blood test results) or usual care based on ESC guidelines.
Results were consistent across the countries where patients were enrolled (Spain, Italy, France, Germany, Poland, the Czech Republic and Hungary), age (mean 76), sex (31% women), diabetes and kidney disease status, and prior revascularisation.
“The trial results are broadly applicable to the general population,” Fuster’s group suggested, “especially considering that the average age at the time of a first myocardial infarction is now 65.6 for men and 72.0 for women, along with the high prevalence of diabetes mellitus, chronic kidney disease, and previous coronary artery disease in these patients.”
All patients were enrolled before the end of 2019 and followed for a median of 36 months, during which the COVID-19 pandemic possibly kept some people from trial visits.
Other limitations included a lack of adjustment for multiple comparisons of secondary outcomes, which made the lower cardiovascular death rate in the polypill group (3.9% vs 5.8%) only a hypothesis-generating finding.
Between COVID-19 and the 14% withdrawal rate, the trial enrolled fewer patients than planned and had a lower event rate than expected, dropping the statistical power for the primary endpoint below the anticipated 80% to a “rather limited” level, noted Louise Bowman, MBBS, of the University of Oxford in England.
Study details
Polypill Strategy in Secondary Cardiovascular Prevention
Jose M. Castellano, Stuart J. Pocock, Deepak L. Bhatt, Antonio J. Quesada, Ruth Owen, Antonio Fernandez-Ortiz, Pedro L. Sanchez, Francisco Marin Ortuño, Jose M. Vazquez Rodriguez, Alexandra Domingo-Fernández, Iñigo Lozano, Maria C. Roncaglioni, et al., for the SECURE Investigators*
Published in The New England Journal of Medicine on 26 August 2022
Abstract
Background
A polypill that includes key medications associated with improved outcomes (aspirin, angiotensin-converting–enzyme [ACE] inhibitor, and statin) has been proposed as a simple approach to the secondary prevention of cardiovascular death and complications after myocardial infarction.
Methods
In this phase 3, randomised, controlled clinical trial, we assigned patients with myocardial infarction within the previous 6 months to a polypill-based strategy or usual care. The polypill treatment consisted of aspirin (100 mg), ramipril (2.5, 5, or 10 mg), and atorvastatin (20 or 40 mg). The primary composite outcome was cardiovascular death, nonfatal type 1 myocardial infarction, nonfatal ischaemic stroke, or urgent revascularisation. The key secondary end point was a composite of cardiovascular death, nonfatal type 1 myocardial infarction, or nonfatal ischaemic stroke.
Results
A total of 2,499 patients underwent randomisation and were followed for a median of 36 months. A primary-outcome event occurred in 118 of 1,237 patients (9.5%) in the polypill group and in 156 of 1,229 (12.7%) in the usual-care group (hazard ratio, 0.76; 95% confidence interval [CI], 0.60 to 0.96; P=0.02). A key secondary-outcome event occurred in 101 patients (8.2%) in the polypill group and in 144 (11.7%) in the usual-care group (hazard ratio, 0.70; 95% CI, 0.54 to 0.90; P=0.005). The results were consistent across prespecified subgroups. Medication adherence as reported by the patients was higher in the polypill group than in the usual-care group. Adverse events were similar between groups.
Conclusions
Treatment with a polypill containing aspirin, ramipril, and atorvastatin within 6 months after myocardial infarction resulted in a significantly lower risk of major adverse cardiovascular events than usual care.
NEJM article – Polypill Strategy in Secondary Cardiovascular Prevention (Open access)
MedPage Today article – Polypill Proves Its Mettle for Heart Protection Post-MI (Open access)
See more from MedicalBrief archives:
Polypill plus aspirin reduces incidence of cardiovascular events by 31% — TIPS-3
Daily 4-in-1 polypill could cut CVD risk in low-income countries
Benefits of polypills include preventing heart attacks and strokes
Daily cocktail of four drugs reduces stroke risk and heart attack in half