Circulation Journal Oicial Journal of the Japanese Circulation Society http://www.j-circ.or.jp lipophilic compounds, but pravastatin and rosuvastatin are rela- tively hydrophilic and not signiicantly metabolized by cyto- chrome P(450) enzymes. 11 Lipophilic statins are more suscep- tible to metabolism by the cytochrome P(450) system, except for pitavastatin, which is mostly excreted unchanged in bile and undergoes minimal biotransformation through the cytochrome P450 system. 12–16 Editorial p ???? We reasoned that consideration of the differences among the lipophilic statins helps to provide a rational basis for their igh platelet reactivity in patients on dual antiplatelet therapy (DAPT) has been shown to be an independent risk factor for recurrent ischemic events. 1,2 Levels of platelet reactivity can be inluenced by concomitant treatment with medications (ie, statins) that might inhibit the CYP3A4 system involved in the activation of clopidogrel. 3,4 Although all statins share a common mechanism of action, they differ in terms of their chemical structures, pharmacokinetic proiles, and lipid-modifying eficacy. 5–9 The chemical structures of statins govern their water solubility, which in turn inluences their ab- sorption, distribution, metabolism and excretion. 10 Atorvastatin, simvastatin, lovastatin, luvastatin, and pitavastatin are relatively H Received October 6, 2013; revised manuscript received November 5, 2013; accepted November 25, 2013; released online December 27, 2013 Time for primary review: 23 days Department “Attilio Reale”, Sapienza University, Rome (F.P., M.P., C.Greco, C.Gaudio); Medical Science Departement, IRCCS San Raffaele Pisana, Rome (G.R., G.M., C.V., I.S.); Department of Internal Medicine, University of Pisa, Pisa (F.F.); Anthea Hospital, GVM Care & Research, ES Health Science Foundation, Bari (G.S.); Eleonora Lorillard Spencer Cenci Foundation, Rome (C.Gaudio), Italy; and Laboratory of Vascular Physiology, IRCCS San Raffaele, London (C.V.), UK Mailing address: Francesco Pelliccia, MD, PhD, Via Tommaso Inghirami 85, Rome 00179, Italy. E-mail: f.pelliccia@mclink.it ISSN-1346-9843 doi:10.1253/circj.CJ-13-1216 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: cj@j-circ.or.jp Pharmacodynamic Comparison of Pitavastatin Versus Atorvastatin on Platelet Reactivity in Patients With Coronary Artery Disease Treated With Dual Antiplatelet Therapy – The PORTO Trial – Francesco Pelliccia, MD, PhD; Giuseppe Rosano, MD, PhD; Giuseppe Marazzi, MD, PhD; Cristiana Vitale, MD, PhD; Ilaria Spoletini, MD; Ferdinando Franzoni, MD; Giuseppe Speziale, MD; Marina Polacco, MD; Cesare Greco, MD; Carlo Gaudio, MD Background: Levels of platelet reactivity in patients on dual antiplatelet therapy (DAPT) can be influenced by con- comitant treatment with statins. We verified if the pharmacodynamic effects of CYP3A4-metabolized statins (atorvas- tatin) and non-CYP3A4-metabolized statins (pitavastatin) differ in patients with coronary artery disease (CAD) treated with DAPT. Methods and Results: A total of 155 CAD patients receiving DAPT (clopidogrel 75 mg plus aspirin 100 mg) entered the PORTO trial. Patients were randomly assigned to atorvastatin (20 mg day) or pitavastatin (4 mg day) for 30 days, and then switched to the other drug for 30 days. Platelet reactivity was expressed as VerifyNow P2Y12 platelet response units (PRU) before and after each 30-day treatment period. High platelet reactivity was defined as PRU >208. As com- pared with pretreatment (192±49), PRU was significantly higher after 30-day atorvastatin (210±56; P=0.003), but was unchanged after 30-day pitavastatin (199±47 PRU, NS). In the 48 patients with PRU >208 at baseline (232±44), PRU increased significantly after 30-day atorvastatin (258±41, P=0.004), but not after 30-day pitavastatin (237±43, NS). In the 107 patients with PRU <208 at baseline (174±52), PRU did not change significantly with respect to baseline either after 30-day atorvastatin (188±61, NS) or after 30-day pitavastatin (181±59, NS). Conclusions: Pitavastatin, a non-CYP3A4-metabolized statin, does not affect clopidogrel’s response as compared with atorvastatin in patients who are borderline or poor responders to DAPT. Key Words: Clopidogrel; Coronary artery disease; Percutaneous coronary intervention; Platelet reactivity Advance Publication by-J-STAGE