Managing residual risk in patients receiving statin therapy
Author: Ian R Hamilton-Craig
Published online: 20 September 2010
In reply: I agree with Montgomery that cardiovascular disease (CVD) outcomes are required to determine the role of ezetimibe. The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial (in which patients with aortic stenosis were treated for 52.2 months with statin plus ezetimibe or statin plus placebo) showed a 4.7% reduction in ischaemic CVD events in the ezetimibe group (P = 0.02; number needed to treat, 23), driven by a reduced need for coronary artery bypass grafting.1 In contrast to previous trials showing regression of atherosclerosis in response to statin therapy, baseline carotid intima media thickness (CIMT) levels in the ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) trial were normal, due to previous statin therapy. This is likely to account for the lack of change in CIMT with ezetimibe treatment in the ENHANCE trial.2 As no placebo group was included, neither lack of benefit nor harm from ezetimibe therapy can be inferred.2
Data from animal studies have shown atherosclerosis regression after ezetimibe treatment through multiple mechanisms.3-5 Prospective randomised controlled trials with statins, resins or surgery have independently shown an approximate 1% reduction in CVD per 1% reduction in low-density lipoprotein cholesterol (LDL-C) level. Evidence for the benefits of lowering LDL-C is among the most robust in medicine. Pending the outcomes of IMPROVE-IT (the Improved Reduction of Outcomes: Vytorin Efficacy International Trial, a multicentre study of ezetimibe plus simvastatin versus simvastatin treatment of patients with acute coronary syndrome [http://clinicaltrials.gov/ct2/show/NCT00202878]), or clinical outcome data confirming those of the ARBITER 6-HALTS (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6 — HDL and LDL Treatment Strategies in Atherosclerosis) trial,6 it seems reasonable to continue to use ezetimibe to lower LDL-C levels in patients who are not achieving LDL-C targets despite statin therapy or who are intolerant to statins. Extended-release nicotinic acid (Niaspan [Abbott Laboratories, Chicago, Ill, USA]) may be an appropriate alternative to statins as second-line therapy, and should be made available under the Pharmaceutical Benefits Scheme for treating patients with dyslipidaemia. (Niaspan has approval from the Therapeutic Goods Administration for marketing in Australia, but is not being imported into Australia at this stage.)
Competing interests
References
- Hamilton-Craig I, Kostner K, Colquhoun D, Woodhouse S. At sea with SEAS: the first clinical endpoint trial for ezetimibe, treatment of patients with mild to moderate aortic stenosis, ends with mixed results and more controversy. Heart Lung Circ 2009; 18: 343-346. BABDHJFI
- Stein EA. Low-density lipoprotein cholesterol reduction and prevention of cardiovascular disease. Mayo Clin Proc 2009; 84: 307-309. BABBHGJB
- Kuhlencordt PJ, Padmapriya P, Rützel S, et al. Ezetimibe potently reduces vascular inflammation and arteriosclerosis in eNOS-deficient ApoE ko mice. Atherosclerosis 2009; 202: 48-57. i1095408
- Gómez-Garre D, Muñoz-Pacheco P, González-Rubio ML, et al. Ezetimibe reduces plaque inflammation in a rabbit model of atherosclerosis and inhibits monocyte migration in addition to its lipid-lowering effect. Br J Pharmacol 2009; 156: 1218-1227.
- Dietrich T, Hucko T, Bourayou R, et al. High resolution magnetic resonance imaging in atherosclerotic mice treated with ezetimibe. Int J Cardiovasc Imaging 2009; 25: 827-836. BABGCHCI
- Villines TC, Stanek EJ, Devine PJ, et al. The ARBITER 6-HALTS Trial (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6 — HDL and LDL Treatment Strategies in Atherosclerosis). Final results and the impact of medication adherence, dose, and treatment duration. J Am Coll Cardiol 2010; 55: 2721-2726. BABHJBAH
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