Prasugrel hydrochloride, dronedarone, and saxagliptin hydrochloride

Antiplatelet agent Acute coronary syndrome (ACS), which includes unstable angina and myocardial infarction (MI), affects approximately 1.5 million Americans each year. Many of these individuals are candidates for percutaneous coronary intervention (PCI; angioplasty), a procedure in which a balloon device is used to open coronary arteries that are narrowed and clogged by atherosclerotic plaque. Often, a stent is inserted into the blood vessel to help keep the artery open following the procedure. Although the benefit of these procedures is well documented, aggregation of platelets around the procedure site is possible, potentially resulting in the formation of clots that can lead to heart attack, stroke, and death. Clopidogrel (Plavix) has been widely used to reduce the risk of clot formation following PCI. Prasugrel hydrochloride (Effient— Daiichi Sankyo; Lilly) is a thienopyridine derivative that is structurally and pharmacologically related to clopidogrel and ticlopidine (e.g., Ticlid). Like these agents, prasugrel is a prodrug and is converted to an active metabolite that inhibits platelet activation and aggregation by binding to the P2Y 12 class of adenosine 5’ diphosphate receptors on platelets. Following oral administration, prasugrel undergoes rapid hydrolysis and subsequent conversion to its active metabolite by a cytochrome P450 (CYP)-mediated step. Clopidogrel undergoes biotransformation via two competing metabolic pathways, with the major pathway producing an inactive metabolite and the minor pathway producing the active metabolite after it goes through two sequential CYP-dependent steps. Prasugrel is specifically indicated to reduce the rate of thrombotic cardiovascular events (including stent thrombosis) in patients with ACS who are to be managed with PCI, including patients with unstable angina or non-STelevation MI (NSTEMI) and patients with ST-elevation MI when managed with primary or delayed PCI. The effectiveness of the new drug was demonstrated in studies in which it was used in conjunction with aspirin and compared with a regimen of clopidogrel plus aspirin. The primary outcome measure was the composite of cardiovascular death, nonfatal MI, and nonfatal stroke. When compared with the clopidogrel/aspirin regimen, the prasugrel/aspirin regimen provided a 19% relative risk reduction with respect to the composite endpoint, although the benefit was almost entirely attributable to a reduction in nonfatal MI. Fewer stent-related clots (i.e., stent thrombosis) were also observed in patients treated with prasugrel/aspirin, with a relative risk reduction of approximately 50%. The greater effectiveness of prasugrel reported in these studies must be considered in the context of a greater risk of bleeding, including life-threatening and fatal bleeding. One analysis of the reduction in cardiovascular events and the risk of bleeding has reported an overall benefit favoring prasugrel compared with clopidogrel. For every 1,000 patients treated with prasugrel, as compared with clopidogrel, 23 fewer patients had nonfatal heart attacks and 6 more had major bleeding events. Different opinions exist regarding the results of the studies in which prasugrel was compared with clopidogrel. Some have proposed that if a lower dosage of prasugrel had been used in the clinical studies, there might be little or no difference in the efficacy of the two agents and the risk of bleeding. In the labeling for prasugrel, an “alternative explanation” is included for the differences reported in the comparison of the two drugs. The labeling notes that the pharmacokinetic properties of the active metabolite of clopidogrel were affected by the CYP2C19 genotype and that approximately 30% of whites are reduced metabolizers. It is further noted that a proton pump inhibitor is often used by patients with ACS and that certain of these agents (i.e., omeprazole [e.g., Prilosec]) inhibit CYP2C19, thereby decreasing the formation of the active metabolite of clopidogrel. The extent to which these two factors may have influenced the comparison of clopidogrel and prasugrel was not evaluated. The indications for prasugrel are more limited than those for clopidogrel. The indications for clopidogrel also include use in patients with NSTEMI who are to be managed medically (as well as in those to be managed with PCI) and patients who are to be managed with coronary artery bypass graft (CABG) surgery. Clopidogrel is also indicated for reducing atherothrombotic events in patients with a history of recent MI, recent stroke, or established peripheral arterial disease. However, these are not labeled indications for prasugrel at the present time. The risk of bleeding is the most important concern with the use of prasugrel and is the subject of a boxed warning in its labeling. The new drug is contraindicated in patients with active pathological bleeding (e.g., peptic ulcer, intracranial hemorrhage) and in patients with a history of previous transient ischemic attack (TIA) or stroke. In the largest comparative study, patients with a history of TIA or ischemic stroke had a higher incidence of stroke when treated