Combination Antithrombotic Therapies

Sinai Center for Thrombosis Research, Cardiac Catheterization Laboratories, Sinai Hospital of Baltimore, 2401 W Belvedere Ave, Baltimore, MD 21215, USA.
Circulation (Impact Factor: 14.95). 02/2010; 121(4):569-83. DOI: 10.1161/CIRCULATIONAHA.109.853085
Source: PubMed
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: Despite well-documented efficacy, recurrent thrombotic event occurrences, particularly stent thrombosis, have been repeatedly demonstrated in stented patients treated with aspirin and clopidogrel. The latter observation stimulated the close scrutiny of the pharmacodynamic effects of clopidogrel and revealed the ‘wide variability’ and the phenomenon of ‘antiplatelet resistance’. High on-treatment platelet reactivity to ADP (HPR) during clopidogrel therapy is an independent risk factor for ischemic event occurrences in post-percutaneous coronary intervention (post-PCI) patients. Recent observational studies demonstrated a link between low on-treatment platelet reactivity to bleeding. The concept of a ‘therapeutic window’ of P2Y12 receptor reactivity associated with both ischemic event occurrence (upper threshold) and bleeding risk (lower threshold) has been proposed.Areas covered: An update on and a brief review of the current knowledge on antiplatelet resistance were presented. Evidence available from studies evaluating aspirin resistance and high and low on-treatment platelet reactivity to ADP during P2Y12 receptor blocker therapy was collected from a selective literature search.Expert opinion: The available evidence indicates that HPR is an independent risk factor for post-PCI ischemic event occurrences. The therapeutic window concept for the P2Y12 receptor blocker therapy may facilitate the balance between reducing ischemic events and avoiding bleeding events, thereby improving net clinical outcome.
    Expert Opinion on Pharmacotherapy 10/2014; DOI:10.1517/14656566.2014.968126 · 2.86 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Necrosis of skin flaps is considered as an important complication in reconstructive surgery. We conducted an experimental study to investigate the efficacy of low-molecular weight heparin, clopidogrel and their combination to improve the flap survival. Forty male, adult Sprague-Dawlay rats were divided randomly into 4 groups. Standard rectangular, distally based dorsal random pattern skin flap was elevated. To prevent the graft effect, a sterile sheet was put under the flap. No pharmacological agent was administered for the control group. In group 2, single subcutaneous dose of enoxaparin (3.2 mg/kg) was immediately administrated after surgery. In group 3, clopidogrel (25 mg/kg) was given orally for 7 days. In group 4, both enoxaparin and clopidogrel were administrated. The rats were evaluated on post-operative day 7 for viable and necrotic portions of flaps. The mean and SD of necrosis was 17.79+2.5 cm in the control group, 16.20±3.1 cm in low-molecular weight heparin, 15.25+3.8 cm in combined therapy group and 13.69+2.7 cm in clopidogrel group. Clopidogrel was the only pharmaceutical agent that produced a significant increase in the flap survival area. Clopidogrel may be an effective pharmaceutical agent that significantly increases viability of random skin flaps in rats, but low-molecular weight heparin and their combination did not have any significant beneficial effects.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Platelet G-protein-coupled receptors influence platelet function by mediating the response to various agonists, including ADP, thromboxane A2, and thrombin. Blockade of the ADP receptor, P2Y12, in combination with cyclooxygenase-1 inhibition by aspirin has been among the most widely used pharmacological strategies to reduce cardiovascular event occurrence in high-risk patients. The latter dual pathway blockade strategy is one of the greatest advances in the field of cardiovascular medicine. In addition to P2Y12, the platelet thrombin receptor, protease activated receptor-1, has also been recently targeted for inhibition. Blockade of protease activated receptor-1 has been associated with reduced thrombotic event occurrence when added to a strategy using P2Y12 and cyclooxygenase-1 inhibition. At this time, the relative contributions of these G-protein-coupled receptor signaling pathways to in vivo thrombosis remain incompletely defined. The observation of treatment failure in ≈10% of high-risk patients treated with aspirin and potent P2Y12 inhibitors provides the rationale for targeting novel pathways mediating platelet function. Targeting intracellular signaling downstream from G-protein-coupled receptor receptors with phosphotidylionisitol 3-kinase and Gq inhibitors are among the novel strategies under investigation to prevent arterial ischemic event occurrence. Greater understanding of the mechanisms of G-protein-coupled receptor-mediated signaling may allow the tailoring of antiplatelet therapy. © 2015 American Heart Association, Inc.
    Arteriosclerosis Thrombosis and Vascular Biology 01/2015; DOI:10.1161/ATVBAHA.114.303412 · 6.34 Impact Factor