Fibrates for secondary prevention of cardiovascular disease and stroke

Review question

The aim of this study was to assess the effect of fibrates for the prevention of major events including heart attacks, strokes, and circulatory disease death in people with existing circulatory disease.

Background

Fibrates have been used for many years as a treatment to prevent further heart attacks and strokes in people who already have disease of their circulatory system. Fibrates are a class of drugs that work by positively influencing fats in the the blood, that is lowering triglyceride, raising high-density lipoprotein ('good') cholesterol and lowering the small dense fraction of low-density lipoprotein ('bad') cholesterol. The drug class includes clofibrate, gemfibrozil, fenofibrate, bezafibrate, and ciprofibrate. Successful adjustment of the blood fats in people with disease of their circulatory system could mean these individuals are less likely to have heart attacks, stroke, and die from their circulatory disease. There is currently no clear evidence for benefit of fibrates in such people.

Study characteristics

The duration of fibrates ranged from 12 months to 8 years.

Key results

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.

Quality of the evidence

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.

Authors' conclusions: 

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.

Read the full abstract...
Background: 

Fibrates are a class of drugs characterised by mainly lowering high triglyceride, raising high-density lipoprotein (HDL) cholesterol, and lowering the small dense fraction of low-density lipoprotein (LDL) cholesterol. Their efficacy for secondary prevention of serious vascular events is unclear, and to date no systematic review focusing on secondary prevention has been undertaken.

Objectives: 

To assess the efficacy and safety of fibrates for the prevention of serious vascular events in people with previous cardiovascular disease (CVD), including coronary heart disease and stroke.

Search strategy: 

We searched the Cochrane Central Register of Controlled Trials (CENTRAL; Issue 9, 2014) on the Cochrane Library, MEDLINE (OVID, 1946 to October week 1 2014), EMBASE (OVID, 1980 to 2014 week 41), the China Biological Medicine Database (CBM) (1978 to 2014), the Chinese National Knowledge Infrastructure (CNKI) (1979 to 2014), Chinese Science and Technique Journals Database (VIP) (1989 to 2014). We also searched other resources, such as ongoing trials registers and databases of conference abstracts, to identify further published, unpublished, and ongoing studies.

Selection criteria: 

We included randomised controlled trials (RCTs) in which a fibrate (for example gemfibrozil, fenofibrate) was compared with placebo or no treatment. We excluded RCTs with only laboratory outcomes. We also excluded trials comparing two different fibrates without a placebo or no-treatment control.

Data collection and analysis: 

Two review authors independently selected trials for inclusion, assessed risk of bias, and extracted the data. We contacted authors of trials for missing data.

Main results: 

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 2012 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.

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