Cochrane Database of Systematic Reviews

Fibrates for secondary prevention of cardiovascular disease

and stroke (Review)

Wang D, Liu B, Tao W, Hao Z, Liu M

Wang D, Liu B, Tao W, Hao Z, Liu M.

Fibrates for secondary prevention of cardiovascular disease and stroke.
Cochrane Database of Systematic Reviews 2015, Issue 10. Art. No.: CD009580.
DOI: 10.1002/14651858.CD009580.pub2.

www.cochranelibrary.com

Fibrates for secondary prevention of cardiovascular disease and stroke (Review)

Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Review]

Fibrates for secondary prevention of cardiovascular disease

and stroke

Deren Wang1 , Bian Liu1 , Wendan Tao1 , Zilong Hao1 , Ming Liu1

1 Department of Neurology, West China Hospital, Sichuan University, Chengdu, China

Contact address: Ming Liu, Department of Neurology, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu,
Sichuan, 610041, China. wyplmh@hotmail.com.

Editorial group: Cochrane Heart Group.

Publication status and date: New, published in Issue 10, 2015.
Review content assessed as up-to-date: 13 October 2014.

Citation: Wang D, Liu B, Tao W, Hao Z, Liu M. Fibrates for secondary prevention of cardiovascular disease and stroke. Cochrane
Database of Systematic Reviews 2015, Issue 10. Art. No.: CD009580. DOI: 10.1002/14651858.CD009580.pub2.

Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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 methods

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.
Fibrates for secondary prevention of cardiovascular disease and stroke (Review)
Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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; I
2 = 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.
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.

PLAIN LANGUAGE SUMMARY

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
Fibrates for secondary prevention of cardiovascular disease and stroke (Review)
Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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.

Fibrates for secondary prevention of cardiovascular disease and stroke (Review)

Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.