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: 14.43). 02/2010; 121(4):569-83. DOI: 10.1161/CIRCULATIONAHA.109.853085
Source: PubMed

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    • "It has been shown that the combination of aspirin and clopidogrel reduces the rate of major vascular events in patients with atrial fibrillation (Hankey et al., 2000) and in those with acute coronary syndromes without ST-segment elevation (Yusuf et al., 2001). However, several other works have demonstrated that this combination increased the risk of bleeding (Fisher & Loscalzo, 2011; Gurbel & Tantry, 2010; Hankey et al., 2000). Results of the present study showed that DLBS1033, when combined with aspirin and clopidogrel, caused gastric bleeding, whereas any combination of two among the drugs did not appear to have any gastric consequences. "
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    ABSTRACT: DLBS1033 is a bioactive protein extract containing Lumbricus rubellus and has been known to have antithrombotic/thrombolytic activity. The present study was aimed to assess the safety aspect of DLBS1033 in a preclinical setting, which included observation on toxic signs after acute and repeated administrations, and the drug’s effect on prenatal development and drug interaction. In acute toxicity study, a high dose level (16.2 g/kg) of DLBS1033 was well tolerated. In subchronic toxicity study, after the doses of 270, 540 and 1080 mg/kg of DLBS1033 per day, no mortality was observed and other parameters were all observed to be normal. In prenatal developmental toxicity, no observed adverse effect level (NOAEL) of DLBS1033 was observed at a moderate dose (540 mg/kg). Coadministration of DLBS1033 with clopidogrel or aspirin did not cause gastric lesions, except when all three drugs were coadministrated. Taken together, results of the present study suggested that DLBS1033 is safe for long-term administration, with a caution at a high dose used during pregnancy, and can be used in combination with one of the antiplatelet drugs.
    Full-text · Article · Jul 2013 · Drug and Chemical Toxicology
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    • "Additionally, multiple platelet activation pathways contribute to thrombosis. The redundancy of this process has provided the basis for combining antiplatelet agents (Gurbel and Tantry 2010). In a monkey model of thrombosis, the combined inhibition of the PAR-1 and P2Y 12 platelet activation with SCH 602539, an intravenous analog of vorapaxar, and cangrelor, a potent intravenous P2Y 12 receptor antagonist, had synergistic antithrombotic and antiplatelet effects (Chintala et al. 2010). "
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    ABSTRACT: Stroke and myocardial infarction are leading causes of death and disability worldwide. Typically, these events are triggered by the rupture or erosion of “vulnerable” atherosclerotic plaque, a phenomenon termed atherothrombosis. Three platelet activation pathways are presumed to be particularly important in the genesis of atherothrombosis and are triggered by 1) cyclo-oxygenase (COX)-1 mediated thromboxane A2 (TXA2) synthesis and activation via the TXA2 receptor, 2) adenosine diphosphate (ADP) via the P2Y12 receptor, and 3) thrombin via the protease activated receptor (PAR)-1. Despite the efficacy of aspirin and of a growing family of P2Y12 receptor antagonists on the first 2 pathways, major cardiovascular events continue to occur in patients with coronary and cerebrovascular disease, suggesting that thrombin-mediated platelet activation may contribute to these adverse events. Recently, a novel class of antiplatelet agents able to inhibit thrombin-mediated platelet activation has been developed, PAR-1 inhibitors. In this chapter, we will discuss the rationale underlying the development of this novel class of agents focus on the two drugs in the most advanced stages of development: vorapaxar (SCH530348) and atopaxar (E5555).
    Full-text · Article · Aug 2012 · Handbook of experimental pharmacology
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    ABSTRACT: Dual antiplatelet therapy (DAT) can decrease effectively the rate of major adverse cardiovascular events after drug-eluting stent (DES) implantation in high-risk coro-nary artery disease (CAD) patients, but its implementation is associated with excess in bleeding events compared with aspirin monotherapy and a considerable treatment failure rate, namely persistence of occurrence of ischemic events, despite the use of the recommended dosage of the standard DAT. All large-scale antiplatelet randomized controlled trials have shown that the prolonged administration of DAT after coronary stenting provides improved thrombotic prevention at a cost of increased bleedings. Newer antiplatelet regimens including higher maintenance doses of clopidogrel, or us-ing the newer agents, prasugrel or ticagrelor, can effectively reduce rates of myocardial infarction and stent thrombosis during follow-up of high-risk CAD patients undergo-ing an invasive therapy, but they are accompanied by an increase in bleeding rates and, except for ticagrelor plus aspirin, do not reduce mortality. Therefore, the chal-lenge remains to develop therapies that more effectively inhibit platelet activation and have a beneficial net effect on mortality without increasing bleeding complications. For patients receiving triple therapy, they are advised to keep the dose of aspirin as low as possible (75 to 81 mg); clopidogrel should be given at its standard dose of 75 mg/day, and warfarin should be administered under tight control to achieve a slightly lower target INR of 2.0 to 2.5. It is also suggested that proton-pump inhibitors (PPIs) should be considered as prophylaxis against gastric bleeds, tending to use pantopra-zole and esomeprazole, which have the least incriminating data regarding an inter-action with clopidogrel. In patients with mild or moderate bleeding while on triple therapy, every effort should be made to maintain the INR as close to 2.0 as possible, and the aspirin dose should be kept at <100 mg. If bleeding persists, it is advised that aspirin be discontinued first, as clopidogrel seems to be more important than aspirin in preventing stent thrombosis after PCI.
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