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J Am Coll Cardiol, 2007; 49:1035-1042, doi:10.1016/j.jacc.2006.10.064 (Published online 23 February 2007). © 2007 by the American College of Cardiology Foundation

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CLINICAL RESEARCH: PHARMACOLOGIC STUDY

Treatment With Ezetimibe Plus Low-Dose Atorvastatin Compared With Higher-Dose Atorvastatin Alone

Is Sufficient Cholesterol-Lowering Enough to Inhibit Platelets?

Michael Piorkowski, MD^_*, Sabine Fischer, MD^_*, Caroline Stellbaum, MD^_*, Markus Jaster, MD^_*, Peter Martus, PhD, Andreas J. Morguet, MD^_*, Heinz-Peter Schultheiss, MD^_* and Ursula Rauch, MD^_*,_*

^_* Department of Internal Medicine/Cardiology, Campus Benjamin Franklin, Charité Universitätsmedizin Berlin, Berlin, Germany
Institute for Biostatistics and Clinical Epidemiology, Campus Benjamin Franklin, Charité Universitätsmedizin Berlin, Berlin, Germany.

Manuscript received April 19, 2006; revised manuscript received October 20, 2006, accepted October 23, 2006.

^_* Reprint requests and correspondence: Dr. Ursula Rauch, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Department of Internal Medicine/Cardiology, Hindenburgdamm 30, 12200 Berlin, Germany. (Email: ursula.rauch{at}charite.de).

Objectives: We sought to test the platelet inhibitory and anti-inflammatory effects of a higher statin dosage compared with combined treatment with ezetimibe plus a low statin dose.

Background: Reducing the level of low-density lipoprotein cholesterol (LDL-C) with statins induces important pleiotropic effects such as platelet inhibition. An insufficient LDL-C reduction often is treated with ezetimibe, an intestinal cholesterol absorption inhibitor, in combination with a low statin dose. It is not known whether this combination therapy has the same pleiotropic effects as a statin monotherapy.

Methods: Fifty-six patients with coronary artery disease were assigned randomly to receive either 40 mg/day of atorvastatin or 10 mg/day of ezetimibe plus 10 mg/day of atorvastatin for 4 weeks. The levels of LDL-C, platelet activation markers after stimulation, platelet aggregation, and plasma chemokine levels (i.e., regulated on activation normally T-cell expressed and secreted [RANTES]) were measured before and after changing lipid-lowering medication.

Results: Platelet activation markers (P-selectin) after stimulation (adenosine diphosphate) were reduced by 40 mg/day of atorvastatin (–5.2 ± 1.6 arbitrary units) but not by ezetimibe plus low-dose atorvastatin (2.1 ± 1.8 arbitrary units; p < 0.005) despite a similar reduction of LDL-C (atorvastatin –1.01 ± 0.18 mmol/l vs. ezetimibe plus atorvastatin –1.36 ± 0.22 mmol/l, p = NS). Thrombin receptor-activating peptide-induced platelet aggregation as well as plasma RANTES levels were reduced by 40 mg/day of atorvastatin but not by ezetimibe plus low-dose atorvastatin.

Conclusions: Platelet reactivity and a proinflammatory chemokine were reduced more by the higher atorvastatin dose than by ezetimibe plus low-dose atorvastatin. In patients with coronary artery disease, it might be important to combine ezetimibe with higher statin dosages to benefit from cholesterol-independent pleiotropic effects.

Abbreviations and Acronyms   ADP = adenosine diphosphate   AU = arbitrary units   CAD = coronary artery disease   HDL-C = high-density lipoprotein cholesterol   LDL-C = low-density lipoprotein cholesterol   MA = maximum aggregation   MFI = median immunofluorescence intensity   RANTES = regulated on activation normally T-cell expressed and secreted   SL = maximum slope of aggregation   TG = triglycerides   TRAP = thrombin receptor-activating peptide

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