Vorapaxar in the secondary prevention of atherothrombotic events.

Thrombolysis in Myocardial Infarction (TIMI) Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
New England Journal of Medicine (Impact Factor: 55.87). 03/2012; 366(15):1404-13. DOI: 10.1056/NEJMoa1200933
Source: PubMed


Thrombin potently activates platelets through the protease-activated receptor PAR-1. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of PAR-1.
We randomly assigned 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease to receive vorapaxar (2.5 mg daily) or matching placebo and followed them for a median of 30 months. The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction, or stroke. After 2 years, the data and safety monitoring board recommended discontinuation of the study treatment in patients with a history of stroke owing to the risk of intracranial hemorrhage.
At 3 years, the primary end point had occurred in 1028 patients (9.3%) in the vorapaxar group and in 1176 patients (10.5%) in the placebo group (hazard ratio for the vorapaxar group, 0.87; 95% confidence interval [CI], 0.80 to 0.94; P<0.001). Cardiovascular death, myocardial infarction, stroke, or recurrent ischemia leading to revascularization occurred in 1259 patients (11.2%) in the vorapaxar group and 1417 patients (12.4%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.82 to 0.95; P=0.001). Moderate or severe bleeding occurred in 4.2% of patients who received vorapaxar and 2.5% of those who received placebo (hazard ratio, 1.66; 95% CI, 1.43 to 1.93; P<0.001). There was an increase in the rate of intracranial hemorrhage in the vorapaxar group (1.0%, vs. 0.5% in the placebo group; P<0.001).
Inhibition of PAR-1 with vorapaxar reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis who were receiving standard therapy. However, it increased the risk of moderate or severe bleeding, including intracranial hemorrhage. (Funded by Merck; TRA 2P-TIMI 50 number, NCT00526474.).

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Available from: Keith A A Fox, Dec 14, 2013
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    • "The percutaneous shuttling device can then be passed via percutaneous anteromedial,8 superior medial or posterior medial access points shown in Figure 2. The safety of these access points has been previously described.5-7,9-11 The posterior medial access point can be used for large tear with posteromedial retraction. "
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    ABSTRACT: Most arthroscopic rotator cuff repairs utilize suture passing devices placed through arthroscopic cannulas. These devices are limited by the size of the passing device where the suture is passed through the tendon. An alternative technique has been used in the senior author's practice for the past ten years, where sutures are placed through the rotator cuff tendon using percutaneous passing devices. This technique, dubbed the global percutaneous shuttling technique of rotator cuff repair, affords the placement of sutures from nearly any angle and location in the shoulder, and has the potential advantage of larger suture bites through the tendon edge. These advantages may increase the area of tendon available to compress to the rotator cuff footprint and improve tendon healing and outcomes. The aim of this study is to describe the global percutaneous shuttling (GPS) technique and report our results using this method. The GPS technique can be used for any full thickness rotator cuff tear and is particularly useful for massive cuff tears with poor tissue quality. We recently followed up 22 patients with an average follow up of 32 months to validate its usefulness. American Shoulder and Elbow Surgeons scores improved significantly from 37 preoperatively to 90 postoperatively (P<0.0001). This data supports the use of the GPS technique for arthroscopic rotator cuff repair. Further biomechanical studies are currently being performed to assess the improvements in tendon footprint area with this technique.
    Orthopedic Reviews 04/2014; 6(2):5279. DOI:10.4081/or.2014.5279
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    • "These findings clearly put selective PAR-1 inhibition on center stage as a promising target to interfere with atherosclerosis. Interestingly, while PAR-1 inhibition reduces the risk of cardiovascular death or ischemic events with stable atherosclerosis [50], such effects have not been witnessed so far for acute coronary syndromes [51]. Both studies revealed that PAR-1 inhibition leads to an increased risk of moderate and severe bleeding, including intracranial hemorrhage, thus highlighting the need to optimize the therapeutic regimen to specifically interfere with thrombin’s contribution to the initiation, formation, progression, and destabilization of atherosclerotic plaques. "
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    ABSTRACT: Thrombin is the protease involved in blood coagulation. Its deregulation can lead to hemostatic abnormalities, which range from subtle subclinical to serious life-threatening coagulopathies, i.e., during septicemia. Additionally, thrombin plays important roles in many (patho)physiological conditions that reach far beyond its well-established role in stemming blood loss and thrombosis, including embryonic development and angiogenesis but also extending to inflammatory processes, complement activation, and even tumor biology. In this review, we will address thrombin's broad roles in diverse (patho)physiological processes in an integrative way. We will also discuss thrombin as an emerging major target for novel therapies.
    Journal of Molecular Medicine 08/2013; 91(11). DOI:10.1007/s00109-013-1074-5 · 5.11 Impact Factor
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    • "To date many PAR1 antagonists have been synthesized and characterized [7]–[10] and the high affinity non-peptide PAR1 antagonist, Vorapaxar, completed phase III clinical trials. The Vorapaxar TRA-CER trial was terminated due to an association of treatment with an increased risk of bleeding including intracranial hemorrhage however, the TRA-2P-TIMI 50 trial, excluding patients presenting with previous stroke, was completed and showed that PAR1 antagonism is effective in reducing cardiovascular death and ischemic events [11]–[13]. PAR4 as the low affinity thrombin receptor is consequently engaged by high concentrations of thrombin and thus subject to differential temporal engagement by thrombin. Our lab and others have documented signaling differences between PAR1 and PAR4 indicating that although activated by the same endogenous agonist and purportedly couple to the same G-proteins, platelet thrombin receptor signaling is fundamentally distinct [14]–[19]. "
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    ABSTRACT: Protease activated receptor-4 (PAR4) is one of the thrombin receptors on human platelets and is a potential target for the management of thrombotic disorders. We sought to develop potent, selective, and novel PAR4 antagonists to test the role of PAR4 in thrombosis and hemostasis. Development of an expedient three-step synthetic route to access a novel series of indole-based PAR4 antagonists also necessitated the development of a platelet based high-throughput screening assay. Screening and subsequent structure activity relationship analysis yielded several selective PAR4 antagonists as well as possible new scaffolds for future antagonist development.
    PLoS ONE 06/2013; 8(6):e65528. DOI:10.1371/journal.pone.0065528 · 3.23 Impact Factor
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