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Review
. 2016 Nov 16;11(11):CD009753.
doi: 10.1002/14651858.CD009753.pub2.

Fibrates for Primary Prevention of Cardiovascular Disease Events

Affiliations
Free PMC article
Review

Fibrates for Primary Prevention of Cardiovascular Disease Events

Tobias Jakob et al. Cochrane Database Syst Rev. .
Free PMC article

Abstract

Background: Fibrates are effective for modifying atherogenic dyslipidaemia, and particularly for lowering serum triglycerides. However, evidence that fibrates reduce mortality and morbidity associated with cardiovascular disease (CVD), or overall mortality and morbidity, in the primary prevention of CVD is lacking.

Objectives: This Cochrane Review and meta-analysis aimed to evaluate the clinical benefits and harms of fibrates versus placebo or usual care or fibrates plus other lipid-modifying drugs versus other lipid-modifying drugs alone for the primary prevention of cardiovascular disease (CVD) morbidity and mortality.

Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid), Embase (Ovid), CINAHL (EBSCO), and Web of Science (all from inception to 19 May 2016). We searched four clinical trial registers (last searched on 3 August 2016) with the help of an experienced professional librarian. We searched the databases to identify randomised controlled trials (RCTs) evaluating the clinical effects of fibrate therapy in the primary prevention of CVD events. We did not impose any language restrictions.

Selection criteria: We aimed to include all RCTs comparing the effects of fibrate monotherapy versus placebo or usual care, or fibrates plus other lipid-modifying drugs versus other lipid-modifying drugs alone. Included studies had a follow-up of at least six months for the primary prevention of CVD events. We excluded trials with clofibrate, because it was withdrawn from the market in 2002.

Data collection and analysis: Two review authors independently screened titles and abstracts for potential study inclusion. Two review authors independently retrieved the full-text papers and extracted data. Disagreements were resolved by consensus. We calculated risk ratios (RRs) and accompanying 95% confidence intervals (CIs) for aggregate data on primary and secondary outcomes. We tested for heterogeneity with the Cochrane Q-test and used the I2 statistic to measure inconsistency of treatment effects across studies. Using the GRADE approach, we assessed the quality of the evidence and used the GRADE profiler software (GRADEpro GDT) to import data from Review Manager 5 to create 'Summary of findings' tables.

Main results: We identified six eligible trials including 16,135 individuals. The mean age of trial populations varied across trials; between 47.3 and 62.3 years. Four trials included individuals with diabetes mellitus type 2 only. The mean treatment duration and follow-up of participants across trials was 4.8 years. We judged the risks of selection and performance bias to be low; risks of detection bias, attrition bias, and reporting bias were unclear. Reporting of adverse effects by included trials was very limited; that is why we used discontinuation of therapy due to adverse effects as a proxy for adverse effects. Patients treated with fibrates had a reduced risk for the combined primary outcome of CVD death, non-fatal myocardial infarction, or non-fatal stroke compared to patients on placebo (risk ratio (RR) 0.84, 95% confidence interval (CI) 0.74 to 0.96; participants = 16,135; studies = 6; moderate-quality of evidence). For secondary outcomes we found RRs for fibrate therapy compared with placebo of 0.79 for combined coronary heart disease death or non-fatal myocardial infarction (95% CI 0.68 to 0.92; participants = 16,135; studies = 6; moderate-quality of evidence); 1.01 for overall mortality (95% CI 0.81 to 1.26; participants = 8471; studies = 5; low-quality of evidence); 1.01 for non-CVD mortality (95% CI 0.76 to 1.35; participants = 8471; studies = 5; low-quality of evidence); and 1.38 for discontinuation of therapy due to adverse effects (95% CI 0.71 to 2.68; participants = 4805; studies = 3; I2 = 74%; very low-quality of evidence). Data on quality of life were not available from any trial. Trials that evaluated fibrates in the background of statins (2 studies) showed no benefits in preventing cardiovascular events.

Authors' conclusions: Moderate-quality evidence suggests that fibrates lower the risk for cardiovascular and coronary events in primary prevention, but the absolute treatment effects in the primary prevention setting are modest (absolute risk reductions < 1%). There is low-quality evidence that fibrates have no effect on overall or non-CVD mortality. Very low-quality evidence suggests that fibrates are not associated with increased risk for adverse effects.

Conflict of interest statement

TJ has no conflict of interest to declare.

AJN has no conflict of interest to declare.

SS has no conflict of interest to declare.

IFG has no conflict of interest to declare.

MB has no conflict of interest to declare.

Figures

Figure 1
Figure 1
Study flow diagram.
Figure 2
Figure 2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figure 3
Figure 3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figure 4
Figure 4
Funnel plot of comparison: 1 Outcomes/adverse effects, outcome: 1.1 Combined CVD death, non‐fatal MI, or non‐fatal stroke.
Figure 5
Figure 5
Funnel plot of comparison: 1 Outcomes/adverse effects primary prevention trials, outcome: 1.3 Overall mortality.
Figure 6
Figure 6
Funnel plot of comparison: 1 Outcomes/adverse effects primary prevention trials, outcome: 1.4 Non‐CVD mortality.
Analysis 1.1
Analysis 1.1
Comparison 1 Fibrates versus placebo, Outcome 1 Combined CVD death, non‐fatal MI, or non‐fatal stroke.
Analysis 1.2
Analysis 1.2
Comparison 1 Fibrates versus placebo, Outcome 2 Overall mortality.
Analysis 1.3
Analysis 1.3
Comparison 1 Fibrates versus placebo, Outcome 3 Combined coronary heart disease death or non‐fatal MI.
Analysis 1.4
Analysis 1.4
Comparison 1 Fibrates versus placebo, Outcome 4 Non‐CVD mortality.
Analysis 1.5
Analysis 1.5
Comparison 1 Fibrates versus placebo, Outcome 5 Progression of pre‐existing diabetic retinopathy.
Analysis 1.6
Analysis 1.6
Comparison 1 Fibrates versus placebo, Outcome 6 Development of new diabetic retinopathy.
Analysis 1.7
Analysis 1.7
Comparison 1 Fibrates versus placebo, Outcome 7 Incidence of macroalbuminuria (>= 300 ratio mg albumine/g creatinine).
Analysis 1.8
Analysis 1.8
Comparison 1 Fibrates versus placebo, Outcome 8 Incidence of micro‐ or macroalbuminuria (>= 30 ratio mg albumine/g creatinine).
Analysis 1.9
Analysis 1.9
Comparison 1 Fibrates versus placebo, Outcome 9 Raised serum creatinine.
Analysis 1.10
Analysis 1.10
Comparison 1 Fibrates versus placebo, Outcome 10 Raised serum transaminases.
Analysis 1.11
Analysis 1.11
Comparison 1 Fibrates versus placebo, Outcome 11 Pancreatitis.
Analysis 1.12
Analysis 1.12
Comparison 1 Fibrates versus placebo, Outcome 12 Venous thrombotic events.
Analysis 1.13
Analysis 1.13
Comparison 1 Fibrates versus placebo, Outcome 13 Gallbladder disease.
Analysis 1.14
Analysis 1.14
Comparison 1 Fibrates versus placebo, Outcome 14 Discontinuation of therapy due to side effects.

Update of

  • Fibrates for primary prevention of cardiovascular disease events.
    Nordmann AJ, Ferreira-González I, Kasenda B, Saccilotto R, Bassler D, Bhatnagar N, Briel M. Nordmann AJ, et al. Cochrane Database Syst Rev. 2012;(3):CD009753. doi: 10.1002/14651858.CD009753. Cochrane Database Syst Rev. 2012. PMID: 25267898 Free PMC article. Updated.

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