The “polypill concept” of fixed-dose combinations of inexpensive generic cardiovascular (CV) drugs, whether or not in a single pill, is perhaps most controversial in the arena of primary prevention. But a new patient-level analysis of three large, randomized trials seems to strengthen the case for the idea at the population level, at least for older adults with CV risk factors.
The meta-analysis encompassed more than 18,000 participants, arguably enough to also examine whether adding aspirin to a mix of at least two hypertension meds and a statin made any difference to clinical outcomes across the trials, which were TIPS-3, HOPE-3, and PolyIran.
Together, the trials suggest a highly significant 38% drop in risk for the meta-analysis primary endpoint, a composite of CV death, myocardial infarction (MI), stroke, or arterial revascularization, in participants on the fixed-dose regimens, for a number-needed-to-treat (NNT) of 52.
Moreover, “The largest effects were with fixed-dose combination strategies that included aspirin,” with a 47% drop in the primary endpoint and a smaller NNT of 37, said Philip Joseph, MD, Population Health Research Institute, Hamilton, Canada, when presenting the study during the all-virtual European Society of Cardiology (ESC) Congress 2021.
Risk reductions for the individual parts of the composite endpoint were also significant on combination therapy, and dropped further when aspirin was in the mix, further suggesting that “aspirin is an important component of these fixed-dose combination strategies if the goal is to maximally reduce cardiovascular disease risk.”
On the other hand, fixed-dose combination drug therapy also produced a significant primary endpoint benefit when aspirin wasn’t included, observed Joseph, who is lead author on the study’s report published August 29 in The Lancet.
Aspirin wasn’t associated with significantly more important bleeding in the analysis, and dizziness was the only adverse effect to be more common on the fixed-dose strategy, he reported.
Such regimens are “widely applicable and low-cost,” have been shown to “substantially reduce cardiovascular disease in the population,” and because the trials took place in high-, middle-, and low-income countries, are “globally applicable,” Joseph said.
“Therefore, a fixed-dose combination treatment strategy, either as separate components or in combination as a polypill,” he said, “could be a key strategy to assist achieving UN [United Nations] sustainable development goals to reduce premature deaths from noncommunicable disease by one third by 2030.”
The Lancet report “convincingly demonstrates that the polypill is better than placebo in reducing cardiovascular events,” but it’s far less convincing in its claims about aspirin, to which it even refers in its title, John J. McNeil, MBBS, PhD, Monash University, Melbourne, Australia, told theheart.org | Medscape Cardiology.
That’s especially so given recent publication of three large randomized, controlled trials of aspirin in the primary prevention setting, said McNeil, who was a lead investigator on one of them, ASPREE.
That trial, which showed no primary preventive advantage to aspirin but did show an increased risk of major bleeding, was largely consistent with two other major studies, ARRIVE and ASCEND.
The current report’s conclusion that aspirin adds to the efficacy of fixed-dose combination therapy “is drawn from the fact that the hazard ratios were reduced somewhat more in cross-study comparisons in which the trials with aspirin were compared to those without,” he observed. The “usual approach” would be “a meta-analysis of studies randomized to polypill plus or minus aspirin,” he said.
“It is hard to see how this fragile design supports the statement that aspirin is an important component in primary prevention, and is safe, McNeil said. “To provide advice on such a controversial topic requires a strong research design involving a randomized comparison of polypill plus aspirin vs polypill minus aspirin.”
The meta-analysis covered 18,162 participants across the three trials, which all compared fixed-dose combination therapy to either a placebo or standard care for primary or secondary prevention; only cohorts treated for primary prevention were included. They averaged 63 years in age, 49.8% were women, 23.4% had diabetes, and 63.4% had a history of hypertension, Joseph reported.
Their mean systolic blood pressure (BP) was 137.7 mm Hg and LDL cholesterol was 121.7 mg/dL. The mean estimated 10-year CV risk was 17.7% by Framingham criteria, suggesting they were an intermediate-risk primary-prevention population, the report states.
LDL cholesterol fell by an average of 22.6 mg/dL in the fixed-dose therapy group compared with the controls after a mean of 2.1 years. Mean systolic BP declined in both the active-therapy and control group throughout a total 5-year follow-up, but on average it was 4.7 mm Hg lower in the fixed-dose therapy group. The differences for both markers were significant at P < .0001.
Despite “modest differences in blood pressure and LDL between randomized groups, fixed-dose combination treatment substantially reduced fatal and nonfatal CV events,” Joseph said.
Indeed, the hazard ratio (HR) for the primary composite outcome over a median of 5 years, fixed-dose regimen vs control, was 0.62 (95% CI, 0.53 – 0.73, P < .0001). Reductions for the individual endpoint components were consistent and similarly significant.
In an analysis that included 8951 participants, the primary endpoint HR for aspirin-containing, fixed-dose regimens vs controls was 0.53 (95% CI, 0.41 – 0.67, P < .0001).
A similar analysis of fix-dose regimens not containing aspirin compared with controls, conducted for 12,061 participants, put the HR at 0.68 (95% CI, 0.57 – 0.81, P < .0001).
There was a trend for greater primary endpoint risk reductions with older age overall for the fixed-dose combination group vs controls, and a suggestion of benefit in the 61-66 and older-than-66 years age group. But the interaction between age and treatment effect fell short of significance at P = .06.
On the other hand, that interaction reached significance (P = .03) in an analysis limited to aspirin-containing fixed-dose combination therapy vs controls. No significant benefit for the intervention was seen among participants 57 years of age or younger, but the risk-reductions reached 45% for the 58-63 age group and 58% for the older-than-63 age groups.
Dizziness was more common with fixed-dose combination therapy, 11.7% compared with 9.2% for controls (P < .0001). Muscle pain and dyspepsia were observed at rates of 7.8% and 34.4%, respectively, with no significant differences by group assignment.
Nor were there significant differences in rate of hemorrhagic stroke (0.2% for fixed-dose combination therapy vs 0.3% for controls), gastrointestinal bleeding (0.4% vs 0.2%, respectively) or fatal bleeding (less than 0.1% vs 0.1%, respectively).
The meta-analysis suggests the results “would be most applicable to populations at intermediate or greater cardiovascular disease risk,” and point to “broad applicability of a fixed-dose combination treatment strategy across a range of cardiometabolic risk factor profiles, rather than in a specific at-risk group,” the authors write.
The results also support prior evidence that “fixed-dose combination treatment strategies could be of particular benefit in older populations.”
Joseph discloses receiving institutional grants from the Wellcome Trust, Canadian Institutes of Health Research, Heart and Stroke Foundation of Ontario, Cadila Pharmaceuticals, and AstraZeneca related to TIPS-3, HOPE-3, or both studies. Disclosures for the other authors are in the original report.
Lancet. Published online August 29, 2021. Full text
European Society of Cardiology Congress 2021, Late Breaking Science in Prevention. Presented August 29, 2021.