FOCUS: Adjunctive Pharmacotherapy Part II

Medical Director The Christ Hospital Heart & Vascular Center and The Lindner Center for Research and Education Professor of Clinical Medicine Ohio State University Welcome to part two of our focus issue on adjunctive pharmacotherapy. This issue includes timely and comprehensive reviews on topics of considerable current interest. In the context of our aging population, the potential for concurrent disease processes which require concomitant anticoagulation and antiplatelet therapies has become commonplace. The prospect of “triple therapy” involving warfarin (administered for atrial fibrillation, prosthetic heart valves, deep vein thrombosis, etc.), in combination with “dual” antiplatelet therapy (aspirin plus a thienopyridine) administered following drug-eluting stent deployment, raises real concern regarding bleeding risks. Valuable insights into appropriate indications, as well as guidelines for prescription of triple therapy are provided in this issue by Drs. Henkel and Holmes. In addition, Drs. Gurbel et al examine the topic of platelet response variability and the role of platelet function testing. Specifically, the prevalence, pathogenesis and clinical ramifications of hyporesponsiveness to the platelet-inhibiting effects of clopidogrel are discussed. Specific strategies to address clopidogrel “resistance” are provided and include increasing clopidogrel dose, tailored therapy with the addition of platelet glycoprotein (GP) IIb/IIIa receptor blockade, as well as the advent of prasugrel, a novel third-generation thienopyridine. Interestingly, clopidogrel nonresponders are almost invariably responsive to prasugrel, as the pathways for metabolic activation differ. Additional strategies which have been successfully employed to enhance platelet inhibition in clopidogrel-“resistant” individuals have included CYP isoenzyme induction with rifampin or St. John’s Wort,1,2 adding a third agent, cilostazol (in addition to aspirin and a thienopyridine),3,4 and switching to ticlopidine therapy, which has different pathways for metabolic activation.5 Approximately 80% of patients who are resistant to clopidogrel will be responsive to ticlopidine.5 Dr. Richard Becker provides valuable insights into the next generation of antithrombin agents and the rationale for their development through a biology-based model of coagulation. Specific targets and strategies (active site-blocked competitive antagonists, monoclonal antibodies, small-molecule inhibitors and RNA aptamers) are discussed. The intracoronary administration of reduced drug doses offers the promise of regional benefit with reduced systemic bleeding hazard. Such a strategy is employed in the treatment of large intracoronary thrombus burden by Dr. Cortese and colleagues. The targeted intracoronary administration of a reduced-dose combination of fibrinolytic (urokinase) and abciximab through a novel coronary infusion catheter successfully reduced intracoronary thrombus burden and safely expedited patient care. Lastly, a novel strategy for bridging patients with eptifibatide GP IIb/IIIa receptor blocked following late stent thrombosis who subsequently require noncardiac surgery is explored by Drs. Ben-dor and Waksman. The transient substitution of a rapidly reversible platelet GP IIb/IIIa blocker (eptifibatide) for an irreversible platelet P2Y12 receptor blocker (clopidogrel) appeared to successfully prevent recurrent stent thrombosis. An intuitively more attractive agent for this purpose, which is not as yet U.S. FDA-approved for use, would be cangrelor. Currently, under evaluation in the CHAMPION trial,6 cangrelor provides rapid, reliable and reversible P2Y12 receptor inhibition.7,8 Platelet function rapidly returns to normal (t ½ 3.3 minutes) within 1 hour of drug discontinuation. Thus, as the field of adjunctive pharmacotherapy continues to evolve, the tenuous balance between anti-ischemic efficacy and bleeding risks (safety) must be maintained so that patient net clinical benefit is at least preserved or, more ideally, improved. Hopefully, this focus on adjunctive pharmacotherapy will provide you with information that is useful for the care of your patients.