Review question
What are the benefits and harms of using fibrate treatment compared to placebo or usual care for preventing cardiovascular disease in people at increased risk of developing cardiovascular disease?
Background
Cardiovascular disease is the most common cause of death, illness, disability, and reduced quality of life in industrialised countries. One of the major risk factors for cardiovascular disease is elevated low-density lipoprotein cholesterol (LDL-C, 'bad' cholesterol). In addition, persons with elevated serum triglycerides and low levels of high-density lipoprotein cholesterol (HDL-C, 'good' cholesterol) are also at increased risk for cardiovascular disease events such as heart attacks or strokes. Fibrates lower serum triglycerides, modestly raise HDL-C, and modestly lower LDL-C. Therefore, long-term therapy with fibrates may help prevent cardiovascular disease events, in particular in combination with statins, for which it has been shown that they substantially lower LDL-C and reduce the risk of heart attack, stroke, and overall mortality.
Study characteristics
The evidence is current to May 2016. We identified six eligible primary prevention trials including 16,135 individuals without established cardiovascular disease that compared fibrate therapy with placebo or usual care. The mean age of the trial populations varied between 47.3 and 62.3 years; the majority of included individuals had diabetes mellitus type 2. The mean treatment duration and follow-up of participants across trials was 4.8 years.
Key results and quality of the evidence
Moderate-quality evidence suggests a risk reduction of 16% with fibrate therapy for the combined outcome of death due to cardiovascular disease, heart attack, or stroke. In absolute terms, the risk for this combined outcome in patients with cardiovascular risk factors but without established cardiovascular disease was on average reduced from 5.0% to 4.3% over five years. Moderate-quality evidence also suggests a risk reduction for fatal and non-fatal heart attacks with fibrates, but there is low-quality evidence for no risk reduction for overall mortality or death from non-CVD with fibrates. Very-low quality evidence suggests that there is no increased risk for adverse effects with fibrate treatment. The reporting of adverse effects by identified trials was very limited. Data on quality of life were not available from any included study. Trials that evaluated fibrates in the background of statin treatment showed no benefits in preventing cardiovascular events.
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.
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.
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.
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.
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.
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.
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.