Abstracts From the Emerging Science Series, June 20, 2012
- Vorapaxar for Secondary Prevention in Patients With Peripheral Artery Disease: Results From the Peripheral Artery Disease Cohort of the TRA 2°P-TIMI 50 Trial
- Reversal of Apixaban Induced Alterations of Hemostasis By Different Coagulation Factor Concentrates: Studies In Vitro With Circulating Human Blood
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Vorapaxar for Secondary Prevention in Patients With Peripheral Artery Disease: Results From the Peripheral Artery Disease Cohort of the TRA 2°P-TIMI 50 Trial
Marc P Bonaca, David A Morrow, Eugene Braunwald, TIMI Study Group, Brigham and Women’s Hosp, Boston, MA
Vorapaxar is a novel platelet inhibitor that potently and selectively inhibits thrombin mediated platelet activation through antagonism of the platelet protease-activated receptor (PAR)-1. Patients with peripheral artery disease (PAD) are at high risk of atherothrombotic events and warrant new strategies for secondary prevention. Few medical therapies have been shown to reduce the risk of limb ischemia in patients with PAD.
Methods: The TRA2P-TIMI 50 trial was a randomized, double-blind, placebo controlled trial of vorapaxar 2.5 mg daily in addition to standard care in 26,449 patients with stable atherosclerotic vascular disease (History of myocardial infarction, stroke, or PAD). Eligible patients with PAD (N=3,787) had a history of symptoms of claudication and either an ABI of <0.85 or prior peripheral revascularization for limb ischemia. The first efficacy endpoint was a composite of cardiovascular death, MI, or stroke and the principal safety endpoint was GUSTO moderate or severe bleeding. All hospitalizations for limb ischemia were also reviewed and adjudicated by a blinded Clinical Events Committee. Results: In patients who qualified for the trial with PAD, the primary endpoint did not differ significantly between patients allocated to vorapaxar compared with placebo (11.3% vs 11.9%, HR 0.94, 95% CI 0.78–1.14, p=0.53, p-interaction=0.16 for PAD vs MI qualifying cohorts). In contrast, rates of hospitalization for acute limb ischemia (2.3% vs 3.9%, HR 0.58, 95% CI 0.39–0.86, p=0.006) and peripheral arterial revascularization (18.4% vs 22.2%, HR 0.84, 95% CI 0.73–0.97, p=0.017) were significantly lower in patients randomized to vorapaxar. Moderate or severe bleeding was increased with vorapaxar (7.4% vs 4.5%, HR 1.62, 95% CI 1.21–2.18, p=0.001) including ICH (0.9% vs 0.4%, HR 2.03, 95% CI 0.82–5.02, p=0.13). Conclusions: Vorapaxar did not significantly reduce the risk cardiovascular death, MI, or stroke in patients who qualified for the trial with PAD without a recent myocardial infarction, and increased the risk of moderate or severe bleeding. However, vorapaxar significantly reduced hospitalization for acute limb ischemia and arterial revascularization. These findings highlight a novel therapeutic approach to reduce limb ischemia in patients with PAD.
M.P. Bonaca: Research Grant; Significant; Merck & Co., Astra Zeneca, Abbott, Amgen, Bayer, Brisol-Myers Squibb, Daichii Sankyo/Eli Lilly, GaxoSmithKline, Novartis, Pfizer, Roche (Diagnostics), Sanofi Aventis, Johnson & Johnson. D.A. Morrow: Research Grant; Significant; Merck (SPRI), Abbott, AstraZeneca, Amgen, Bayer, Bristol-Myers Squibb, Daichii Sankyo/Eli LIlly, GlaxoSmithKline, Novartis, Pfizer, Roche (Diagnostics), Sanofi Aventis, Johnson & Johnson. Consultant/Advisory Board; Significant; Merck (SPRI), Boeringher Ingelheim, CV Therapeutics/Gilead, Genentech, Ikaria, Menarini, Novartis, Servier, Roche (diagnostics). Other; Significant; AztraZeneca. E. Braunwald: Research Grant; Significant; Merck & Co., Astra Zeneca, Johnson & Johnson, Beckman Coulter, Eli Lilly, Roche Diagnostics, Sanofi Aventis, Daiichi Sankyo, Glaxo Smith Kline, Bristol Myers Squibb. Speakers Bureau; Significant; Eli Lilly, Merck & Co., CVRx, CV Therapeutics-now Gilead, Daiichi Sankyo, MC Communications, Menarini International. Consultant/Advisory Board; Modest; Merck & Co., Consultant/Advisory Board; Significant; Genzyme, Amorcyte, Daiichi Sankyo, Medicines Co., MC Communications, Ikaria, CardioRentis, Sanofi Aventis, CVRx.
Reversal of Apixaban Induced Alterations of Hemostasis By Different Coagulation Factor Concentrates: Studies In Vitro With Circulating Human Blood
Gines Escolar, Eduardo Arellano-Rodrigo, Jaun Carlos Reverter, Jaume Villalta, Veronica Sanz, Patricia Molina, Maribel Diaz-Ricart, Ana Maria Galan, Hosp Clinic, Barcelona, Spain
Urgent reversal of the hemostatic alterations caused by newly developed oral anticoagulants in patients is a matter of concern. Apixaban is a new oral anticoagulant with inhibitory action on FXa. It has showed a very good efficacy/safety profile in studies in prophylaxis of thrombotic complications after mayor orthopaedic surgery and in atrial fibrillation. We have explored the effects of concentrations of apixaban in excess of those achieved after standard approved dosage, on platelet and coagulation mediated mechanisms of hemostasis. We also evaluated the effectiveness of different factor concentrates at reversing the alterations of hemostatic mechanism induced by apixaban.
Methods: Apixaban (200 ng/ml) was added in vitro to blood aliquots from healthy donors. Modifications in platelet reactivity towards surfaces were measured at elevated shear rates in a cone and plate analyzer (Impact R). Effects on thrombin generation (TG) and on thromboelastometry parameters (TEM) were also assessed. Changes in platelet adhesive, aggregating and procoagulant activities were additionally evaluated in perfusion studies through vascular surfaces in a system producing results that correlate with clinical situations (Transfus Med Rev 15:144, 2001). The potential action of prothrombin complex concentrates (PCCs) (50 IU/kg), activated PCCs (aPCCs) at 75 IU/kg, or rFVIIa at 270 μg/kg reversing the anticoagulant actions of apixaban were tested in the different assays. Results: Apixaban did not affect the reactivity of platelets in the Impact R studies, but caused a moderate reduction in TG parameters as confirmed by delayed lag phase, prolonged time to peak and reduced velocity index. Thrombin peak and velocity indexes in TG were improved by concentrates with the following order of efficacy PCC≥aPCC>rFVIIa. Apixaban prolonged clotting time (CT) and reduced maximal clot firmness (MCF) in TEM studies using tissue factor as activator. Alterations in these parameters were corrected by the different concentrates with the following order of efficacy rFVIIa≥aPCC>PCC. Apixaban quantitatively reduced fibrin and platelet interactions with damaged vascular surfaces (p<0.01 and p<0.05 respectively) in perfusion studies. These alterations were counteracted by the different concentrates with efficacy following this order rFVIIa>PCC>aPCC. Conclusions: Apixaban at 200 ng/ml did not show a direct antiplatelet effect in studies in the cone and plate analyzer, but demonstrated evident alterations in hemostasis related to its recognized anticoagulant action. These alterations were variably compensated or even reversed by the different factor concentrates. Effects of these concentrates were not homogeneous in all the tests, with PCCs showing more efficacy in TG and rFVIIa being more effective on TEM and perfusion studies.
G. Escolar: Research Grant; Modest; Bristol Myers Squibb. Honoraria; Modest; Bayer, Boehringer Ingelheim, Bristol Myers Squibb. E. Arellano-Rodrigo: None. J. Reverter: None. J. Villalta: None. V. Sanz: None. P. Molina: None. M. Diaz-Ricart: None. A. Galan: None.
- © 2012 American Heart Association, Inc.
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