Antidotes for antiplatelets – why, what and when?

Friday, 13 March 2015

Recently, specific antidotes for anticoagulants have been described and are undergoing clinical trials. These include a specific antibody fragment for the thrombin inhibitor dabigatran, idarucizumab1, a recombinant catalytically inactive FXa, andexanet alfa, which should reverse all the FXa inhibitors2 and a small molecule, PER977, that is proposed to reverse all the FXa inhibitors, dabigatran and heparins3.

But what about antidotes for antiplatelets? Dual antiplatelet therapy, consisting of aspirin and a P2Y12 antagonist, is critical for the treatment of ACS, the most common cause of cardiovascular mortality and morbidity worldwide.4 However, like anticoagulants, antiplatelet therapies are known to increase the risk of bleeding complications5, which is why specific antidotes are desired also for antiplatelet agents.

So why have no antidotes for antiplatelets been developed? One obvious reason is the fact that aspirin as well as the thienopyridines (ticlopidine, clopidogrel and prasugrel) are all irreversible inhibitors of their respective targets, COX-1 and P2Y12. However this has changed since the arrival of a reversibly binding antagonist belonging to a new chemical class (cyclo-pentyl-triazolo-pyrimidine (CPTP)).6

Two sides of a coin

Currently, if severe bleeding occurs in a patient on antiplatelet treatment, transfusion of platelets is often used in an attempt to restore platelet function and haemostasis. However, the efficacy of platelet transfusions in patients on anti-platelet therapy is not well documented. Although platelet transfusions restore platelet function in patients on aspirin7, they have shown no or minimal ability to reverse the effect of clopidogrel (healthy volunteers7,8) or a reversibly binding antagonist (patient case reports9,10). Thienopyridines are prodrugs that are transformed to an active metabolite binding irreversibly to platelet P2Y12 and thus inhibiting the receptor for the lifetime of the platelet. Platelets transfused after elimination of active metabolites (detectable for only about 4h post dose in the circulation) remain unaffected and should, in theory, be un-inhibited. A direct acting reversibly binding antagonist persists in the circulation and is reversibly bound to platelets, potentially negating the haemostatic effect of the new platelet introduced by a platelet transfusion.

On the other hand, the unique reversibly binding mode of action provides an opportunity for developing a specific reversal agent not possible for the thienopyridines or aspirin. The first data for a specific neutralising antibody fragment (Fab) was presented at ACC.The mode of action of the Fab is to bind up all free drug in the circulation and thereby preventing its interaction with and inhibition of the platelet P2Y12 receptor. The availability of an antidote may provide additional confidence for prescribing physicians and ultimately added benefits to patients.

References:

  1. Schiele F, van Ryn J, Canada K, et al. A specific antidote for dabigatran: functional and structural characterization. Blood. 2013;121:3554-3562.
  2. Lu G, DeGuzman FR, Hollenbach SJ, et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med. 2013;19:446-451.
  3. Ansell JE, Bakhru SH, Laulicht BE, et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med. 2014;371:2141-2142.
  4. Turpee, A. Burden of Disease:Medical and Economic Impact of Acute Coronary Syndromes. The American Journal of managed care. 2006.
  5. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–1057.
  6. Van Giezen JJ, Nilsson L, Berntsson P, et al. Ticagrelor binds to human P2Y(12) independently from ADP but antagonizes ADP-induced receptor signalling and platelet aggregation. J Thromb Haemost. 2009;7:1556-1565
  7. Taylor G, Osinski D, Thevenin A, et al. Is platelet transfusion efficient to restore platelet reactivity in patients who are responders to aspirin and/or clopidogrel before emergency surgery? J Trauma Acute Care Surg. 2013;74:1367-1369.
  8. Prüller F, Drexler C, Archan S, Macher S, Raggam RB, Mahla E. Low platelet reactivity is recovered by transfusion of stored platelets: a healthy volunteer in vivo study. J Thromb Haemost. 2011;9:1670-1673.
  9. Godier A, Taylor G, Gaussem P. Inefficacy of Platelet Transfusion to Reverse Ticagrelor. N Engl J Med. 2015;372:196-197.
  10. Dalén M, Ivert T, Lindvall G, et al. Ticagrelor-associated bleeding in a patient undergoing surgery for acute type A aortic dissection. J Cardiothorac Vasc Anesth. 2013;27:e55-57.