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importance of fibrate trials
- Michael D Feher, Robert S. Elkeles (28 November 2002)
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LEADER follows other fibrate trials
- Anthony S. Wierzbicki, Timothy mM. Reynolds, Dimitri P. Mikhailidis (30 December 2002)
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Michael D Feher, consultant physician in diabetes & clinical pharmacology Chelsea & Westminster Hospital, 369 Fulham rd, London SW10 9NH, Robert S. Elkeles
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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 Dr RS Elkeles 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 |
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Anthony S. Wierzbicki, Senior lecturer in chemical pathology St. Thomas Hospital, London SE1 7EH, Timothy mM. Reynolds, Dimitri P. Mikhailidis
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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 |
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