Fixed-Dose Combination Treatments Show Increased Reduction of CVD Outcomes


Data show substantially reductions in cardiovascular disease, myocardial infarction, stroke, revascularization, and cardiovascular death following fixed-dose combination treatment strategies.

Philip Joseph, MD

Philip Joseph, MD

Although fixed-dose combination treatments have shown reductions in cardiovascular disease outcomes in primary prevention, it is still unknown is aspirin should be included or not in the treatment combination.

Investigators, led by Philip Joseph, MD, Population Health Research Institute, Hamilton Health Sciences and McMaster University, found fixed-dose combinations showed substantial reductions in cardiovascular disease (CVD), myocardial infarction, stroke, revascularization, and cardiovascular death in primary CVD prevention.


The team performed a meta-analysis of large randomized controlled trials (RCTs) with ≥1000 participants and ≥2 years of follow-up of fixed-dose combination treatment strategy versus control in primary CVD prevention population.

Trials included in the study assessed a fixed-dose combination strategy of ≥2 blood pressure lowering agents, followed by a statin (with or without aspirin), in comparison with a control strategy which included placebo or usual care.

Primary outcomes included time to first occurrence of a composite of CVD, myocardial infarction, stroke, or arterial revascularization. In addition, secondary outcomes included individual cardiovascular outcomes and death from any cause.

Then, outcomes were evaluated in groups stratified by inclusion of aspirin in the treatment strategy, with effect sizes estimated in subgroups based on risk factors.

Furthermore, the study used Kaplain-Meier survival curves and Cox proportional hazard regression models to compare strategies.


The analysis included 3 large RCTs, including the TIPS-3, HOPE-3, and PolyIran, with a total of 18,162 participants.

Data show participants had a mean age of 63.0 years and 9038 participants (49.8%) were female, with an estimated 10-year CVD risk for the population at 17.7%.

After a median follow-up of 5 years, the primary outcome occurred in 276 participants (3.0%) in the fixed-dose combination strategy group, in comparison with 445 participants (4.9%) in the control group (HR 0.62; 95% CI, 0.53 - 0.73, P <.0001).

Investigators observed reductions in each component of the primary outcome, including myocardial infarction (HR 0.52; 95% CI, 0.38 - 0.70), revascularization (HR 0.54; 95% CI, 0.36 - 0.80), stroke (HR 0.59; 95% CI, 0.45 - 0.78), and CVD (HR 0.65; 95% CI, 0.52 - 0.81).

In addition, the team saw reductions in the primary outcome and its components with or without aspirin, showing greater reductions in combination strategies including aspirin.

More frequent gastrointestinal bleeding was observed in the fixed-dose combination strategy with the aspirin group compared to control (19 participants versus 11 participants, P = .15).

There were low frequencies of hemorrhagic stroke (10 [0.2%] versus 15 [0.3%]), fatal bleeding (2 [0.1%] versus 4 [0.1%]), and peptic ulcer disease (32 [0.7%] versus 34 [0.8%]), with no significant differences observed between each group.


“Fixed-dose combination treatment strategies substantially reduce cardiovascular disease, myocardial infarction, stroke, revascularization, and cardiovascular death in primary cardiovascular disease prevention,” investigators wrote. “These benefits are consistent irrespective of cardiometabolic risk factors.”

The study, “Fixed-dose combination therapies with and without aspirin for primary prevention of cardiovascular disease: an individual participant data meta-analysis,” was published online in The Lancet.

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