title: Fixed-dose combination therapy for the prevention of cardiovascular disease.
abstract: BACKGROUND
  Cardiovascular disease (CVD) is the leading cause of death and disability worldwide, yet CVD 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 CVD by up to 80% given its potential for better adherence and lower costs.
  
  
  OBJECTIVE
  To determine the effectiveness of fixed-dose combination therapy on reducing fatal and non-fatal CVD events and on improving blood pressure and lipid CVD risk factors for both primary and secondary prevention of CVD. We also aimed to determine discontinuation rates, adverse events, health-related quality of life, and costs of fixed-dose combination therapy.
  
  
  METHODS
  We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2013, Issue 6), MEDLINE Ovid (1946 to week 2 July 2013), EMBASE Ovid (1980 to Week 28 2013), ISI Web of Science (1970 to 19 July 2013), and the Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment Database (HTA), and Health Economics Evaluations Database (HEED) (2011, Issue 4) in The Cochrane Library. We used no language restrictions.
  
  
  METHODS
  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 a single drug active component for any treatment duration in adults ≥ 18 years old with no restrictions on presence or absence of pre-existing cardiovascular disease.
  
  
  METHODS
  Three review authors independently selected studies for inclusion and extracted the data. We evaluated risk of bias using the Cochrane risk of bias assessment tool. We sought to include outcome data on all-cause mortality, fatal and non-fatal CVD events, adverse events, changes in systolic and diastolic blood pressure, total and low density lipoprotein (LDL) cholesterol concentrations, discontinuation rates, quality of life, and costs. We calculated risk ratios (RR) for dichotomous data and weighted mean differences (MD) for continuous data with 95% confidence intervals (CI) using fixed-effect models when heterogeneity was low (I(2) < 50%) and random-effects models when heterogeneity was high (I(2) > 50%).
  
  
  RESULTS
  We found nine randomised controlled trials with a total of 7047 participants. Seven of the nine trials evaluated the effects of fixed-dose combination therapy on primary CVD prevention, and the trial length ranged from six weeks to 15 months. We found a moderate to high risk of bias in the domains of selection, performance, detection, attrition, and other types of bias in five of the nine trials. Compared with the comparator groups, the effects of the fixed-dose combination treatment on mortality (1.2% versus 1.0%, RR 1.26, 95% CI 0.67 to 2.38,  N = 3465) and cardiovascular events (4.0% versus 2.9%, RR 1.38, 95% CI 0.91 to 2.10, N = 2479) were uncertain (low quality evidence). The low event rates for these outcomes, limited availability of data as only two out of nine trials reported on these outcomes, and a high risk of bias in at least one domain suggest that these results should not be viewed with confidence. Adverse events were common in both the intervention (30%) and comparator (24%) groups, with participants randomised to fixed-dose combination therapy being 20% (95% CI 9% to 30%) more likely to report an adverse event. Notably, no serious adverse events were reported. Compared with placebo, the rate of discontinuation among participants randomised to fixed-dose combination was higher (14% versus 11%, RR 1.26 95% CI 1.02 to 1.55). The weighted mean differences in systolic and diastolic blood pressure between the intervention and control arms were -7.05 mmHg (95% CI -10.18 to -3.87) and -3.65 mmHg (95% CI -5.44 to -1.85), respectively. The weighted mean differences (95% CI) in total and LDL cholesterol between the intervention and control arms were -0.75 mmol/L (95% CI -1.05 to -0.46) and -0.81 mmol/L (95% CI -1.09 to -0.53), respectively. There was a high degree of statistical heterogeneity in comparisons of blood pressure and lipids (I(2) ≥ 70% for all) that could not be explained, so these results should be viewed with caution. Fixed-dose combination therapy improved adherence to a multi-drug strategy by 33% (26% to 41%) compared with usual care, but this comparison was reported in only one study. The effects of fixed-dose combination therapy on quality of life are uncertain, though these results were reported in only one trial. No trials reported costs.
  
  
  CONCLUSIONS
  Compared with placebo, single drug active component, or usual care, the effects of fixed-dose combination therapy on all-cause mortality or CVD events are uncertain; only few trials report these outcomes and the included trials were primarily designed to observe changes in CVD risk factor levels rather than clinical events. Reductions in blood pressure and lipid parameters are generally lower than those previously projected, though substantial heterogeneity of results exists. Fixed-dose combination therapy is associated with modest increases in adverse events compared with placebo, single drug active component, or usual care but may be associated with improved adherence to a multidrug regimen. Ongoing trials of fixed-dose combination therapy will likely inform key outcomes.
authors.affiliation: Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK, CV4 7AL.
authors.forename: Angharad N
authors.initials: AN
authors.lastname: de Cates
authors.forename: Matthew R B
authors.initials: MR
authors.lastname: Farr
authors.forename: Nicola
authors.initials: N
authors.lastname: Wright
authors.forename: Morag C
authors.initials: MC
authors.lastname: Jarvis
authors.forename: Karen
authors.initials: K
authors.lastname: Rees
authors.forename: Shah
authors.initials: S
authors.lastname: Ebrahim
authors.forename: Mark D
authors.initials: MD
authors.lastname: Huffman
mesh_terms: D000924:Anticholesteremic Agents / Q000008:administration & dosage*; D000959:Antihypertensive Agents / Q000008:administration & dosage*; D001241:Aspirin / Q000008:administration & dosage*; D002318:Cardiovascular Diseases / Q000401:mortality / Q000517:prevention & control*; D004338:Drug Combinations; D006801:Humans; D015990:Placebo Effect; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage*; D016032:Randomized Controlled Trials as Topic
chemical_list: D000924:Anticholesteremic Agents; D000959:Antihypertensive Agents; D004338:Drug Combinations; D010975:Platelet Aggregation Inhibitors; D001241:Aspirin
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