Overcoming limitations of current antiplatelet drugs: A concerted effort for more profitable strategies of intervention

Abstract

Platelets play a central role in the pathophysiology of atherothrombosis, an inappropriate platelet activation leading to acute ischemic complications (acute myocardial infarction, ischemic stroke). In view of this, platelets are a major target for pharmacotherapy. Presently, the main classes of antiplatelet agents approved for the use in such complications are aspirin and thienopyridines. Although antiplatelet treatment with these two types of drugs, alone or in combination, leads to a significant reduction of non-fatal myocardial infarction (−32%), non-fatal stroke (−25%), and of cardiovascular death (−17%), a residual risk persists.

Newer antiplatelet agents have addressed some, but not all, these limitations. Vis-à-vis their net clinical benefit, the higher potency of some of them is associated with a rise in bleeding complications. Moreover, newer thienopyridines do not show advantages over and above the older ones as to reduction of stroke. A concerted effort that takes into consideration clinical, genetic, and laboratory information is increasingly recognized as a major direction to be pursued in the area. The well-established road signs of clinical epidemiology will provide major information to define newer potentially useful targets for platelet pharmacology.

Key words::

• Aspirin failure
• cardiovascular prevention
• clopidogrel failure
• new antiplatelet drugs

Acknowledgements

Supported by a grant of the Italian Government: Ministero dell'Istruzione, dell'Università e della Ricerca. PRIN 2008: ‘Farmacogenetica degli antiaggreganti: identificazione di varianti geniche comuni quali alleli di suscettibilità per una farmacoterapia su base individuale’.

Declaration of interest: All the authors have revised and approved the present manuscript. Professor Giovanni Di Minno, Professor Elena Tremoli, Professor Marina Camera, and Professor Susanna Colli did not receive specific funding for the preparation of this manuscript. During the last 5 years they served on advisory boards and received honoraria and grants for research unrelated to this study. The other authors have nothing to declare.

Note

While this manuscript was under revision, results from LANCELOT-CAD were published (Circulation. 2011;123:1854–1863). In this study patients with a history of high-risk CAD were randomized to receive 50, 100, or 200 mg daily atopaxar or matching placebo for 24 weeks and followed up for an additional 4 weeks. Although no difference was found as to major bleeding events, overall bleeding incidence (key safety end point) showed a dose-dependent trend in the atopaxar arm as compared with placebo by CURE criteria (p for trend = 0.01) but not by TIMI criteria (p for trend = 0.07). As to the major adverse cardiac events occurrence (secondary end points), no significant difference was found between the atopaxar treatment arms and placebo (2.6% vs 4.6%; p = 0.20). In addition, a transient elevation in liver transaminases and dose-dependent QTc prolongation without apparent complications were observed in higher-dose atopaxar treatment groups.