Abstract: We included 13 trials involving a total of 16,112 participants. Eleven trials recruited participants with history of coronary heart disease, two trials recruited participants with history of stroke, and one trial recruited participants with a mix of people with CVD. We judged overall risk of bias to be moderate. The meta-analysis (including all fibrate trials) showed evidence for a protective effect of fibrates primarily compared to placebo for the primary composite outcome of non-fatal stroke, non-fatal myocardial infarction (MI), and vascular death (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.83 to 0.94; participants = 16,064; studies = 12; I2 = 45%, fixed effect). Fibrates were moderately effective for preventing MI occurrence (RR 0.86, 95% CI 0.80 to 0.93; participants = 13,942; studies = 10; I2 = 24%, fixed effect). Fibrates were not effective against all-cause mortality (RR 0.98, 95% CI 0.91 to 1.06; participants = 13,653; studies = 10; I2 = 23%), death from vascular causes (RR 0.95, 95% CI 0.86 to 1.05; participants = 13,653; studies = 10; I2 = 11%, fixed effect), and stroke events (RR 1.03, 95% CI 0.91 to 1.16; participants = 11,719; studies = 6; I2 = 11%, fixed effect). Excluding clofibrate trials, as the use of clofibrate was discontinued in 2002 due to safety concerns, the remaining class of fibrates were no longer effective in preventing the primary composite outcome (RR 0.90, 95% CI 0.79 to 1.03; participants = 10,320; studies = 7; I2 = 50%, random effects). However, without clofibrate data, fibrates remained effective in preventing MI (RR 0.85, 95% CI 0.76 to 0.94; participants = 8304; studies = 6; I2 = 47%, fixed effect). There was no increase in adverse events with fibrates compared to control. Subgroup analyses showed the benefit of fibrates on the primary composite outcome to be consistent irrespective of age, gender, and diabetes mellitus. Moderate evidence showed that the fibrate class can be effective in the secondary prevention of composite outcome of non-fatal stroke, non-fatal MI, and vascular death. However, this beneficial effect relies on the inclusion of clofibrate data, a drug that was discontinued in 2002 due to its unacceptably large adverse effects. Further trials of the use of fibrates in populations with previous stroke and also against a background treatment with statins (standard of care) are required.

Plain-language summary: The duration of fibrates ranged from 12 months to 8 years. We included 13 trials in this review with a total of 16,112 participants with a history of coronary heart disease or stroke. This review includes evidence identified up to October 2014. Our analysis showed that when compared primarily to placebo, fibrates can be effective for prevention of composite outcome of non-fatal stroke, non-fatal heart attack (myocardial infarction), and death due to circulatory disease. However, this beneficial effect relies on the inclusion on data from clofibrates, a drug that was discontinued in 2002 because of safety concerns. In other words, there is no good evidence to support the use of currently available fibrates in the prevention of future heart attacks, strokes, and circulatory disease death in people with existing circulatory disease. In combination with clofibrate data, quality of evidence was moderate for the composite (non-fatal stroke, non-fatal myocardial infarction (MI), and vascular death) and MI (non-fatal or fatal) outcomes and low for stroke (ischaemic or haemorrhagic, non-fatal or fatal) and death from vascular or any cause during the treatment and scheduled follow-up period. The quality of evidence without clofibrate data was moderate for MI (non-fatal or fatal) outcome and low for the composite (non-fatal stroke, non-fatal MI, and vascular death), stroke (ischaemic or haemorrhagic, non-fatal or fatal), and death from vascular or any cause outcomes during the treatment and scheduled follow-up period.