Bezafibrate in men with lower extremity arterial disease: randomised controlled trial
BMJ 2002; 325 doi: https://doi.org/10.1136/bmj.325.7373.1139 (Published 16 November 2002) Cite this as: BMJ 2002;325:1139All rapid responses
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Dear Dr Smith,
Re: Bezafibrate in men with lower extremity arterial disease:
randomised control trial
BMJ 2002: 325: 1139-
The 40% reduction in non-fatal myocardial infarction over 4.6 years
with bezafibrate therapy reported in the recent ‘Bezafibrate in men with
lower extremity arterial disease: randomised control trial’ (LEADER
study)1 is an important finding for the management of patients with
diffuse atherosclerotic disease. A similar clinical benefit of bezafibrate
has also been reported in the SENDCAP, a primary prevention lipid lowering
trial in type 2 diabetes. This compared treatment with a fibrate
(bezafibrate) to placebo in 164 type 2 diabetic patients followed
prospectively for at least three years. In those treated with
bezafibrate, there was a 68% reduction (p = 0.01, log-rank test) in the
prespecified secondary trial endpoint of clinical CHD (as determined by
the combined incidence of Minnesota-coded probable ischaemic change on the
resting ECG and of documented myocardial infarction)2 . Both these fibrate
studies have shown that despite modest reductions in total cholesterol (-
8% and -7% respectively) clinical CHD can be reduced.
The LEADER study is also an important addition to the list of fibrate
outcome trials which have shown that with relatively small cholesterol
lowering, CHD end-point reductions were similar to that of the statin
trials which reported greater cholesterol lowering treatment effects. As
fibrates have been shown to have greater triglyceride reduction compared
to statins, the potential improvement in LDL composition with the
triglyceride lowering -by a shift from the atherogenic small dense LDL to
a less atherogenic large LDL- combined with an increase in HDL cholesterol
may be key lipid factors modified by these drugs. The enhanced reduction
in new CHD events in relation to percentage fall in LDL cholesterol in the
triglyceride lowering drug trials compared to the LDL lowering drug trials
has been recognised 4 .
The lack of treatment benefit in the LEADER study in the primary endpoint
of stroke was also observed in SENDCAP where bezafibrate therapy did not
significantly alter the primary endpoint of change in carotid intima-media
-thickness. One possible explanation for the lack stroke benefit may be
the addition of specific antihypertensive therapies in particular
angiotensin converting enzyme inhibitors in the placebo and treatment
groups acting to offset any lipid lowering drug effect for this
cardiovascular end-point.
Another important feature of both the LEADER and other fibrate studies is
the good tolerability and lack of significant side-effects in long term
therapy.
Dr MD Feher
Consultant Physician in Diabetes and Clinical
Pharmacology
Beta Cell Diabetes Centre, Chelsea & Westminster
Hospital, London SW10
Dr RS Elkeles
Consultant Physician
Unit for Metabolic Medicine
St
Mary’s Hospital, London W2 1 NY
1. Tom Meade, Riaz Zuhrie, Claire Cook, Jackie Cooper, statistician,
on behalf of MRC General Practice Research Framework. Bezafibrate in men
with lower extremity arterial disease: randomised controlled trial. BMJ
2002;325:1139-48
2. Elkeles RS, Diamond JR, Poulter C, et al. Cardiovascular outcomes in
type 2 diabetes. A double-blind placebo-controlled study of bezafibrate:
the St. Mary's, Ealing, Northwick Park Diabetes Cardiovascular Disease
Prevention (SENDCAP) Study. Diabetes Care 1998; 21: 641-8.
3. Feher MD, Caslake M, Foxton J, Cox A, Packard CJ. Atherogenic
lipoprotein phenotype in type 2 diabetes: reversal with micronised
fenofibrate. Diabetes Metab Res Rev 1999; 15: 395-9.
4. Durrington PN, Illingworth DR. Lipid-lowering drug therapy: more
knowledge leads to more problems for composers of guidelines. Curr Opin
Lipidol 2000; 11: 345–9.
Competing interests:
None declared
Competing interests: No competing interests
LEADER follows other fibrate trials
The results of the Lower Extremity Arterial Disease Event Reduction
(LEADER) trial with bezafibrate [1] are not as negative as they seem. This
trial set the strictest criteria for showing benefits from fibrate therapy
and had design limitations[2]:
1. patients on or likely to receive a statin were excluded despite such
treatment being advised in some guideline statements
2. the average HDL-cholesterol was 1.19 ±0.36mmol/L (triglycerides
2.40±1.23mmol/L) compared with 0.82 ±0.13 mmol/L (triglycerides 1.70±
0.77mmol/L) in the Veterans Affairs HDL-intervention trial (VA-HIT)[3],
and the LDL–cholesterol was higher (3.40±0.86 vs. 2.87±0.56 mmol/L) thus
limiting the benefit on lipid profiles of a fibrate [3].
3.an event rate of 28% was expected and 20% was achieved
4.a 30% reduction in events was expected in contrast to other studies
where a 20-25% reduction was considered significant.
5.a 50% withdrawal rate driven largely by lack of wish to participate
compared with 25% in VA-HIT who died or withdrew.
6.a significant drop-in to therapy with statins in the placebo group
(13.9%) compared to the active treatment group (5.4%).
Despite these design limitations and hence the trial being under-sized (n=
1568) compared to other fibrate studies (VA-HIT; n=2531), it reported a
19% reduction in coronary heart disease counterbalanced by a 34% excess in
stroke resulting in a 4% overall benefit. The findings in respect to
coronary heart disease are in line with VA-HIT. However, LEADER showed no
benefit on stroke in contrast to bezafibrate in the bezafibrate infarct
prevention (BIP) study [4] and the results of VA-HIT [3]. Little benefit
was seen in the high triglyceride group in contrast to the results of the
BIP study but no data is presented on the low-HDL (<0.9mmol/L) subgroup
where most benefit would be expected. It is notable that the LEADER trial
group combines patients with high HDL and high triglycerides compared with
low HDL and moderate triglycerides (VA-HIT) or high HDL and moderate
triglycerides (BIP)[4].
Thus it is possible that LEADER is consistent with other fibrate data
given its limitations. Like BIP it shows that fibrates are likely to be
less effective in patients with high LDL[5]. It should not be viewed as
another reason for solely using statins in the treatment of
atherosclerotic disease. Decisions on the appropriate place for fibrate
therapy should await the results of large-scale studies (e.g. Fenofibrate
Intervention on Event Lowering in Diabetes; n=9000).
Reference List
1. Meade T, Zuhrie R, Cook C, Cooper J. Bezafibrate in men with lower
extremity arterial disease: randomised controlled trial. BMJ 2002;
325:1139.
2. Meade TW. Design and intermediate results of the Lower Extremity
Arterial Disease Event Reduction (LEADER)* trial of bezafibrate in men
with lower extremity arterial disease. Curr Control Trials Cardiovasc.Med
2001; 2:195-204.
3. Robins SJ, Collins D, Wittes JT et al. Relation of gemfibrozil
treatment and lipid levels with major coronary events: VA-HIT: a
randomized controlled trial. JAMA 2001; 285:1585-1591.
4. Tanne D, Koren-Morag N, Graff E, Goldbourt U. Blood lipids and first-
ever ischemic stroke/transient ischemic attack in the Bezafibrate
Infarction Prevention (BIP) Registry: high triglycerides constitute an
independent risk factor. Circulation 2001; 104:2892-2897.
5. Rizos E, Mikhailidis DP. Are high-density lipoprotein and triglyceride
levels important in secondary prevention: impressions from the BIP and VA-
HIT trials. Int.J Cardiol. 2002; 82:199-207.
Authors:
Anthony S. Wierzbicki, Senior Lecturer in Chemical Pathology
St. Thomas’ Hospital, London SE1 7EH
Timothy M. Reynolds, Professor of Chemical Pathology
Queen’s Hospital, Burton-on-Trent DE13 0RB
Dimitri P. Mikhailidis, Reader in Chemical Pathology
Royal Free Hospital, London NW3 2QG
Competing interests:
Lectue and grant upport from Merck, Sharp & Dohme, Bristol-Myers-Squibb, Astra-Zeneca, Bayer, Pfizer, Takeda and Fournier
Competing interests: No competing interests