Treatment with ezetimibe plus low-dose atorvastatin compared with higher-dose atorvastatin alone: is sufficient cholesterol-lowering enough to inhibit platelets?

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.