Fixed-dose combination drug therapy for the prevention of heart disease and stroke

Review question: We reviewed the evidence about the effect of fixed-dose combination drug therapy on the prevention of heart attacks and strokes. We found 13 studies including 9059 participants.

Background: We wanted to discover whether using fixed-dose combination therapy was better or worse than other alternatives, such as usual care, placebo, or giving drugs separately, for the prevention of heart attacks and strokes. This report represents an update from a previous review published in 2014.

Study characteristics: The evidence is current to September 2016. Four studies included individuals with a prior heart attack or stroke or with a high predicted risk for having an initial heart attack and five studies had long-term (12 months or more) follow-up. The main risk of bias was related to lack of blinding of participants and personnel, which was inherent to the intervention. Most study participants were middle-aged men with moderate elevations in blood pressure or cholesterol. Two studies specifically included ethnic Aboriginal or Maori minorities in half of the study participants. The fixed-dose combinations ranged from two to five drugs; all studies included at least one blood pressure-lowering and one cholesterol-lowering drug.

Key results: The effects of fixed-dose combination drug therapy on all-cause mortality and fatal and non-fatal heart attacks and strokes are uncertain, primarily due to the low number of participants experiencing these events in these studies (fewer than 5% for both) and comparisons with usual care (low-quality evidence). Fixed-dose combination drug therapy leads to more adverse events than control (32% versus 27%), including placebo (moderate-quality evidence). This information is not surprising since aspirin, blood pressure-lowering drugs and cholesterol drugs are known to increase the risk for side effects compared with placebo. Fixed-dose combination therapy may modestly lower blood pressure (~6 mmHg) and cholesterol (-0.6 mmol/L in LDL cholesterol), but these effects were not consistent (moderate-quality evidence for blood pressure and LDL cholesterol but low-quality evidence of total cholesterol). Fixed-dose combination therapy appears to improve adherence to medications to prevent ASCVD (moderate-quality evidence).

Quality of the evidence: The quality of evidence from these studies generally ranged from moderate to low. Ongoing trials of fixed-dose combination drug therapy will likely inform clinical endpoints to guide decision-making.

Authors' conclusions: 

The effects of fixed-dose combination therapy on all-cause mortality or ASCVD events are uncertain. A limited number of trials reported these outcomes, and the included trials were primarily designed to observe changes in ASCVD risk factor levels rather than clinical events, which may partially explain the observed differences in risk factors that were not translated into differences in clinical outcomes among the included trials. Fixed-dose combination therapy is associated with modest increases in adverse events compared with placebo, active comparator, or usual care but may be associated with improved adherence to a multidrug regimen. Ongoing, longer-term trials of fixed-dose combination therapy will help demonstrate whether short-term changes in risk factors might be maintained and lead to expected differences in clinical events based on these changes.

Read the full abstract...

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death and disability worldwide, yet ASCVD risk factor control and secondary prevention rates remain low. A fixed-dose combination of blood pressure- and cholesterol-lowering and antiplatelet treatments into a single pill, or polypill, has been proposed as one strategy to reduce the global burden of ASCVD.


To determine the effect of fixed-dose combination therapy on all-cause mortality, fatal and non-fatal ASCVD events, and adverse events. We also sought to determine the effect of fixed-dose combination therapy on blood pressure, lipids, adherence, discontinuation rates, health-related quality of life, and costs.

Search strategy: 

We updated our previous searches in September 2016 of CENTRAL, MEDLINE, Embase, ISI Web of Science, and DARE, HTA, and HEED. We also searched two clinical trials registers in September 2016. We used no language restrictions.

Selection criteria: 

We included randomised controlled trials of a fixed-dose combination therapy including at least one blood pressure-lowering and one lipid-lowering component versus usual care, placebo, or an active drug comparator for any treatment duration in adults 18 years old or older, with no restrictions on presence or absence of pre-existing ASCVD.

Data collection and analysis: 

Three review authors independently selected studies for inclusion and extracted the data for this update. We evaluated risk of bias using the Cochrane 'Risk of bias' assessment tool. We calculated risk ratios (RR) for dichotomous data and mean differences (MD) for continuous data with 95% confidence intervals (CI) using fixed-effect models when heterogeneity was low (I2 < 50%) and random-effects models when heterogeneity was high (I2 ≥ 50%). We used the GRADE approach to evaluate the quality of evidence.

Main results: 

In the initial review, we identified nine randomised controlled trials with a total of 7047 participants and four additional trials (n = 2012 participants; mean age range 62 to 63 years; 30% to 37% women) were included in this update. Eight of the 13 trials evaluated the effects of fixed-dose combination (FDC) therapy in populations without prevalent ASCVD, and the median follow-up ranged from six weeks to 23 months. More recent trials were generally larger with longer follow-up and lower risk of bias. The main risk of bias was related to lack of blinding of participants and personnel, which was inherent to the intervention. Compared with the comparator groups (placebo, usual care, or active drug comparator), the effects of the fixed-dose combination treatment on mortality (FDC = 1.0% versus control = 1.0%, RR 1.10, 95% CI 0.64 to 1.89,  I2 = 0%, 5 studies, N = 5300) and fatal and non-fatal ASCVD events (FDC = 4.7% versus control = 3.7%, RR 1.26, 95% CI 0.95 to 1.66, I2 = 0%, 6 studies, N = 4517) were uncertain (low-quality evidence). The low event rates for these outcomes and indirectness of evidence for comparing fixed-dose combination to usual care versus individual drugs suggest that these results should be viewed with caution. Adverse events were common in both the intervention (32%) and comparator (27%) groups, with participants randomised to fixed-dose combination therapy being 16% (RR 1.16, 95% CI 1.09 to 1.25, 11 studies, 6906 participants, moderate-quality evidence) more likely to report an adverse event . The mean differences in systolic blood pressure between the intervention and control arms was -6.34 mmHg (95% CI -9.03 to -3.64, 13 trials, 7638 participants, moderate-quality evidence). The mean differences (95% CI) in total and LDL cholesterol between the intervention and control arms were -0.61 mmol/L (95% CI -0.88 to -0.35, 11 trials, 6565 participants, low-quality evidence) and -0.70 mmol/L (95% CI -0.98 to -0.41, 12 trials, 7153 participants, moderate-quality evidence), respectively. There was a high degree of statistical heterogeneity in comparisons of blood pressure and lipids (I2 ≥ 80% for all) that could not be explained, so these results should be viewed with caution. Fixed-dose combination therapy improved adherence to a multidrug strategy by 44% (26% to 65%) compared with usual care (4 trials, 3835 participants, moderate-quality evidence).