Thrombin Receptor Antagonist Research Articles

Toward a guided approach to platelet activation in diabetes

Diabetes is associated with substantially poorer cardiovascular outcomes. Furthermore, people with diabetes are at greatly increased risk of not responding to standard antiplatelet therapy for acute coronary syndromes, leading to higher mortality and stent thrombosis [1]. Poor glucose control likely contributes to these cardiovascular events through changes in platelet membrane fluidity and signalling, increased production of platelets leading to a greater fraction of younger and more reactive platelets not yet exposed to antiplatelet therapy, and increased triggering of platelet activation arising from an underlying thromboinflammatory milieu [2]. While patients with higher thrombotic risk may be prospectively identified through laboratory identification of elevated blood glucose or HbA1c [3], the approach to treatment for diabetic platelet hyper-responsiveness remains unclear. Options such as increasing frequency of antiplatelet therapy, additional and more aggressive antiplatelet therapy or more intensive glucose control have been suggested (Fig. 1). However, the data to support these are limited and, particularly where more aggressive antiplatelet therapy is proposed, must be measured against the potential for increased bleeding risk in patients with hyperglycemia. In patients with type-2 diabetes, Capodanno et al. [4] demonstrated enhanced inhibition of platelet function when patients took 81 mg of aspirin twice per day compared with 81 mg daily. Spectre et al. [5] showed greater inhibition of platelet function with 75 mg twice per day when compared to 75 mg daily in patients with type-2 diabetes and vascular complications. In a recent study Rocca et al. [6] showed that increasing frequency of dose better attenuated platelet activation over 24 h in both diabetic and non-diabetic patients. Therefore increasing the frequency of antiplatelet therapy dosing represents an appealing strategy in patients with diabetes and poor glycemic control. However, the clinical effectiveness of this approach on cardiovascular outcome, as well as the net benefit against increased bleeding risk remains to be investigated. Similarly, the addition of more aggressive antiplatelet therapy, such as newer ADP receptor antagonists with greater potency and bioavailability, or emerging thrombin receptor antagonists have been suggested [2]. The use of these must be weighed against the potentially increased risk of bleeding. While altering antiplatelet therapy strategies in patients with diabetes and poor glycemic control is an appealing avenue for further clinical investigation, a potential alternative or complimentary approach might be to achieve improved glycemic control in order to attenuate platelet activation. Several studies have assessed the ability of infused insulin in patients with diabetes to attenuate platelet function and improve cardiovascular outcome in acute coronary syndromes [7]. While evidence of improvement in cardiovascular outcome is variable, intensive treatment with insulin in patients with diabetes may attenuate platelet activation relative to conventional approaches to glycemic control [8]. In this issue of the Journal of Thrombosis and Thrombolysis, Vivas et al. [9] explore whether tight glycemic control with insulin infusion attenuates platelet reactivity in patients with an acute coronary syndrome and hyperglycemia at admission. In a post hoc analysis of the prospective, randomized, open-label CHIPs study, 67 patients with poor glycemic control (as measured by HbA1c [ 6.5 %) were M. D. Linden (&) Centre for Microscopy, Characterisation and Analysis, M510, University of Western Australia, 35 Stirling Highway, Nedlands, WA 6009, Australia e-mail: matthew.linden@uwa.edu.au

Abstract 9964: Vorapaxar, a Platelet Thrombin-Receptor Antagonist, in Medically Managed Patients with Non-ST-Segment Elevation Acute Coronary Syndrome: Results from the TRACER Trial

Purpose: This is a prespecified post-randomization subgroup analysis to evaluate efficacy and safety outcomes of vorapaxar in the TRACER trial in patients that were medically managed without revascularization procedures during index hospitalization. Methods: Vorapaxar, a novel platelet-protease-activated receptor-1 antagonist, was randomized with placebo in 12,944 patients with NSTE ACS. We explored the effect of vorapaxar vs placebo among medically managed patients at discharge (n=4194; 32.4 %) vs those undergoing revascularization (n=8750; 67.6%) from discharge to end of follow-up, with adjustments for baseline differences. Events rates are provided as 2-yr Kaplan-Meier estimates. Results: The medically managed patients were more likely to be older and female and have prior MI, prior CABG, and decreased renal function. The 2-yr event rate of the primary outcome (CV death, MI, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization) was 16.9% with vorapaxar and 17.3% with placebo (HR 0.95; 95% CI 0.81-1.14), with no interaction between study drug and management strategy (p=0.63). The rate of the key secondary endpoint (CV death, MI, and stroke) was 13.9% with vorapaxar and 15.1% with placebo (HR 0.88; 95% CI 0.73-1.07), with no interaction (p=0.86). Lower MI rates were observed in medically managed patients treated with vorapaxar (9.3% vs 11.1% [HR 0.79; 95% CI 0.63-0.99). Vorapaxar significantly increased GUSTO moderate or severe bleeding in medically managed patients (HR 1.52; 95% CI 1.04-2.22) and in patients undergoing revascularization (HR 1.32; 95% CI 0.99-1.76). In the medical group, intracranial hemorrhage (ICH) occurred in 18 patients with vorapaxar and in 1 patient with placebo, whereas ICH occurred in 17 vorapaxar patients and 9 placebo patients treated with revascularization, with no significant interaction (p=0.056). Conclusion: In patients with NSTE ACS treated medically, the efficacy of vorapaxar was consistent with the main findings of the TRACER trial. Bleeding hazard with vorapaxar tended to be higher in medically treated patients, possibly due to patient selection factors.

Abstract 18805: Vorapaxar, A Platelet Thrombin-Receptor Antagonist, in Patients with Non-ST-Segment Elevation Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention: Results from the TRACER Trial

Objectives: Evaluate the effects of protease-activated-receptor 1 antagonist vorapaxar in NSTE ACS pts undergoing PCI during index hospitalization. Methods: This prespecified analysis of a post-randomization subgroup evaluated the effects of vorapaxar compared with placebo among TRACER pts undergoing PCI, focusing on implanted stent type (drug-eluting stent [DES] vs bare metal stent [BMS]). Results: Among 12,944 TRACER pts, 7479 (58%) underwent PCI during index hospitalization; 1576 (44.4%) of vorapaxar pts and 1484 (42.1%) of placebo pts received exclusively BMS implantation. During the treatment period with vorapaxar, the median duration of thienopyridine therapy was 133 (47-246) days with BMS and 221 (88-341) days with DES. At 1 yr, the primary endpoint (CV death, MI, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization) occurred in 10.4% of pts with vorapaxar vs 10.6% of pts with placebo (HR 0.96; 95% CI 0.83-1.10). The key secondary endpoint (CV death, MI, stroke) occurred in 6.8% with vorapaxar and 7.3% with placebo (HR 0.89; 95% CI 0.75-1.05). A trend of interaction was noted on CV death, MI, and stroke between treatment and type of implanted stent, with pts receiving BMS showing a relatively greater effect from vorapaxar (Figure). GUSTO moderate/severe bleeding was overall increased with vorapaxar with no statistical interaction, although the relative increase appeared less with BMS (HR 1.27; 95% CI 0.85-1.90) than with DES (HR 1.70; 95% CI 1.14-2.53). Conclusions: In this post-randomization subgroup analysis, the efficacy of vorapaxar among PCI pts is consistent with the overall TRACER results. The duration of dual antiplatelet therapy was shorter with BMS than with DES, and a noteworthy signal of increased efficacy and less bleeding liability was noted in BMS pts. These results point to further research opportunities to evaluate the potential clinical role of vorapaxar.

Protease-Activated Receptor-1 Antagonists

Currently available antiplatelet agents have shown improved short- and long-term clinical outcomes but are associated with increased bleeding risk, and the rates of recurrent ischemic events still remain high. Selective inhibition of protease-activated receptor-1 for thrombin represents a potential novel strategy to reduce ischemic events without increasing the risk of bleeding. Two protease-activated receptor-1 antagonists are currently being evaluated in clinical trials: SCH 530348 and E5555. Results of phase II trials have shown that SCH 530348, when added to standard antiplatelet therapy, was well tolerated and not associated with increased bleeding risk. Two large-scale phase III trials assessing the efficacy of SCH 530348 in addition to the standard of care are currently ongoing. This review provides an outline of the current status of understanding on platelet thrombin-receptor antagonist SCH 530348, focusing on its pharmacologic properties and clinical development.

TRA 2 P-TIMI 50 Results

For patients with a history of myocardial infarction (MI) who are stable, the addition of vorapaxar to the standard of care reduced the long-term risk of cardiovascular death or ischemic events and increased the risk of moderate or severe bleeding. The efficacy and safety of the drug were evaluated for secondary prevention in a broad group of patients with prior MI, prior stroke, or peripheral artery disease in the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-Thrombolysis in Myocardial Infarction 50 [TRA 2°P-TIMI 50] trial.

Safety and efficacy of protease‐activated receptor‐1 antagonists in patients with coronary artery disease: a meta‐analysis of randomized clinical trials

Thrombin receptor antagonists blocking protease-activated receptor-1 (PAR-1) on platelets represent a new class of oral antiplatelet agents for patients with atherothrombotic disease manifestations. We investigated the safety and efficacy of PAR-1 antagonists in patients with coronary artery disease (CAD). Randomized, placebo-controlled trials of the PAR-1 antagonists atopaxar or vorapaxar in CAD patients were identified. The primary safety endpoint was the composite of Thrombolysis In Myocardial Infarction (TIMI) clinically significant bleeding. The primary efficacy endpoint was the composite of death, myocardial infarction (MI) or stroke. A total of 41 647 patients from eight trials were included. PAR-1 antagonists were associated with higher risks of TIMI clinically significant (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.39-1.57, P < 0.001), major (OR 1.46, 95% CI 1.28-1.67, P < 0.001) and minor (OR 1.67, 95% CI 1.40-2.00, P < 0.001) bleeding than placebo in the fixed-effects model. PAR-1 antagonists reduced the composite of death, MI or stroke as compared with placebo (OR 0.87, 95% CI 0.81-0.92, P < 0.001), driven by a lower risk of MI (OR 0.85, 95% CI 0.78-0.92, P < 0.001). Conversely, PAR-1 antagonists and placebo did not differ in terms of risk of death (OR 0.99, 95% CI 0.90-1.09, P = 0.81) or stroke (OR 0.96, 95% CI 0.84-1.10, P = 0.59). PAR-1 antagonists decrease ischemic events in patients with CAD as compared with placebo, mainly driven by a reduction in MI, at the cost of an increased risk of clinically significant bleeding.

Vorapaxar for secondary prevention of thrombotic events for patients with previous myocardial infarction: a prespecified subgroup analysis of the TRA 2°P-TIMI 50 trial

Vorapaxar inhibits platelet activation by antagonising thrombin-mediated activation of the protease-activated receptor 1 on human platelets. The effect of adding other antiplatelet drugs to aspirin for long-term secondary prevention of thrombotic events in stable patients with previous myocardial infarction is uncertain. We tested this effect in a subgroup of patients from the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2°P)-TIMI 50 trial. In TRA 2°P-TIMI 50--a randomised, placebo-controlled, parallel trial--we randomly assigned patients with a history of atherothrombosis to receive vorapaxar (2·5 mg daily) or matching placebo in a 1:1 ratio. Patients, and those giving treatment, assessing outcomes, and analysing results were masked to treatment allocation. Patients with a qualifying myocardial infarction within the previous 2 weeks to 12 months were analysed as a pre-defined subgroup. The primary efficacy endpoint was cardiovascular death, myocardial infarction, or stroke, analysed by intention to treat. We analysed events by Kaplan-Meier analysis and compared groups with a Cox proportional hazard model. TRA 2°P-TIMI 50 is registered at ClinicalTrials.gov (NCT00526474). 17,779 of 26,449 patients had a qualifying myocardial infarction and were assigned treatment (8898 to vorapaxar and 8881 to placebo). Median follow-up was 2·5 years (IQR 2·0-2·9). Cardiovascular death, myocardial infarction, or stroke occurred in 610 of 8898 patients in the vorapaxar group and 750 of 8881 in the placebo group (3-year Kaplan-Meier estimates 8·1%vs 9·7%, HR 0·80, 95% CI 0·72-0·89; p<0·0001). Moderate or severe bleeding was more common in the vorapaxar group versus the placebo group (241/8880 [3·4%, 3-year Kaplan-Meier estimate] vs 151/8849 [2·1%, 3-year Kaplan-Meier estimate], HR 1·61, 95% CI 1·31-1·97; p<0·0001). Intracranial haemorrhage occurred in 43 of 8880 patients (0·6%, 3-year Kaplan-Meier estimate) with vorapaxar versus 28 of 8849 (0·4%, 3-year Kaplan-Meier estimate) with placebo (p=0·076). Other serious adverse events were equally distributed between groups. For patients with a history of myocardial infarction, inhibition of protease-activated receptor 1 with vorapaxar reduces the risk of cardiovascular death or ischaemic events when added to standard antiplatelet treatment, including aspirin, and increases the risk of moderate or severe bleeding. Merck.

Novel Antiplatelet Therapy in Acute Coronary Syndromes: What is New in the Pipeline?

Acute coronary syndromes (ACS) are triggered by enhanced platelet activation and aggregation. Hence, a cornerstone of successful secondary prevention in ACS is an effective platelet inhibition. Additionally, coronary interventions (PCI) lead to even increased artherothrombotic risks, another challenge in preventing recurrent events including stent thrombosis. Promising platelet targets were characterized and novel molecules were developed that are currently under investigation. Intensified antiplatelet therapy includes the risk of major bleeding which itself increases the mortality rate. Previous strategies of antiplatelet therapy were based on an "one-size fits all" concept. However, there has been evidence that variability of drug response exists and represents a clinically relevant issue. This observation is in line with results of randomized clinical trials that standard-of-care antiplatelet therapy is not sufficient to reduce cardiovascular (CV) risk in certain subgroups of ACS patients. In the last years, novel antiplatelet substances have entered the clinical arena and others are currently under investigation in phase II and III clinical trials. These include 3rd generation thienopyridine (prasugrel, elinogrel), ATP analogs (Ticagrelor, cangrelor), and non-ADP-receptor blocking antiplatelet substances like thrombin receptor antagonists. These agents have shown promising results in pilot studies and recent randomized trials. As the prevention of atherothrombotic risk is at the expense of bleeding risk, it will be a future task to clearly define patients' groups and subsets of ACS for the best net clinical benefit. This article focuses on the role of novel antiplatelet substances to reduce CV risk in ACS, discuss clinical implications and their potential future role.

Atopaxar and its effects on markers of platelet activation and inflammation: results from the LANCELOT CAD program

Atopaxar is a reversible protease activated receptor (PAR)-1 thrombin receptor antagonist that interferes with platelet signaling. The effects of PAR-1 antagonists on biomarkers remain unknown. The primary objective was to assess the effects of atopaxar on biomarkers of inflammation and platelet activation. The LANCELOT-CAD trial randomized 720 subjects to atopaxar (50, 100, or 200 mg daily) or matching placebo for 24 weeks. Biomarkers were assessed at serial time points. A linear mixed model to account for repeated measures was used to evaluate the change in biomarker concentration from randomization across time to week 24. Least square means were determined from the linear mixed models. The concentration of sCD40L decreased on average over time by -553 (95 % CI -677, -429) ng/L in the combined atopaxar group versus -30.3 (-249 to 189) ng/L fall in the placebo arm (P < 0.001) and a dose-dependent trend was seen across treatment groups (P < 0.001 for trend). In contrast, Lp-PLA(2) mass rose on average over time by 12.6 (95 % CI 10.0, 15.3) ng/ml in the combined atopaxar group as compared with 2.6 (95 % CI -2.1, 7.3) ng/ml in the placebo arm (P < 0.001). Similarly, the concentration of IL-18 rose by 17.5 (95 % CI 12.4, 22.6) pg/ml in the atopaxar group versus a -1.2 (95 % CI -10.2, 7.8) pg/ml fall in the placebo group (P < 0.001). The effects of atopaxar on Lp-PLA(2) and IL-18 appeared to be dose-dependent (P < 0.001 for trend) and were observed in J-LANCELOT. Atopaxar did not have a significant effect on other inflammatory markers. In conclusion, atopaxar appeared to decrease sCD40L, but did not demonstrate an anti-inflammatory effect in patients with stable CAD. Although atopaxar increased the concentration of Lp-PLA(2) and IL-18, the clinical relevance of these findings remains unknown and warrants further investigation and validation.

Beware of Novel Antiplatelet Therapy in Acute Coronary Syndrome Patients With Previous Stroke

Dual antiplatelet therapy with aspirin and the platelet P2Y12 receptor antagonist clopidogrel has become the cornerstone of the treatment of patients undergoing coronary stenting and of those with acute coronary syndromes (ACS) with or without stent implantation.1 Consequently, many patients in the cardiology practice in 2012 are on dual antiplatelet therapy, mainly aspirin and clopidogrel. The only important side effect of dual antiplatelet therapy is increased bleeding in comparison with aspirin alone. This has been established in the large trials with clopidogrel in acute coronary syndromes2,3 and thereafter,4 as well as in atrial fibrillation.5 Especially in the latter, dual antiplatelet therapy has been shown to be as hazardous as oral anticoagulation.6 The novel platelet P2Y12 receptor antagonists prasugrel and ticagrelor are more effective than clopidogrel in patients but show more noncoronary artery bypass graft–related thrombolysis in myocardial infarction major bleeding than clopidogrel.7,8 In the latter trial it became clear that patients with a previous stroke had significantly more bleeding with prasugrel, especially intracranial bleeding, than those without a history of stroke. Triple antiplatelet therapy with aspirin, clopidogrel, and the oral platelet thrombin receptor antagonist vorapaxar was …

Evaluation of a Novel Antiplatelet Agent for Secondary Prevention in Patients with Atherosclerotic Disease: Results from the TRA 2P-TIMI 50 Trial

In stable patients with a history of atherosclerosis, the investigational protease-activated receptor (PAR)-1 antagonist vorapaxar was effective at reducing further atherothrombotic events. This article presents data from the Thrombin Receptor Antagonist in Secondary Prevention-TIMI 50 Trial [TRA 2P; NCT00526474] which showed that vorapaxar significantly reduced the risk of deaths from cardiovascular disease, myocardial infarction, or stroke compared with placebo.

Clinical Trial Educator program – a novel approach to accelerate enrollment in a phase III International Acute Coronary Syndrome Trial

The conduct of current cardiovascular outcome trials requires investigation of thousands of patients at hundreds of investigator sites. Such large trials are clinically and logistically highly demanding and often tend to finish with significant delays, consequently delaying patient access to new medicines. To address this issue, we designed and implemented a novel approach - a Clinical Trial Educator (CTE) program - to accelerate enrollment in the Thrombin-Receptor Antagonist for Clinical Event Reduction (TRA•CER) trial. This article analyzes the effect of this approach on the study milestones: patient recruitment, site start-up time, and recruitment rate. Scientifically qualified and specifically trained CTEs regularly visited TRA•CER investigator sites in 18 European countries where they trained and educated investigators and site personnel to support them address recruitment challenges. Patient recruitment was assessed in absolute numbers and as recruitment rates, both in relation to CTE site visits. CTEs performed 2184 visits at 373 European TRA•CER sites (out of 921 global sites). Of sites visited by a CTE, significantly less remained without enrolling any patient than of sites not visited by a CTE (5.9% vs. 15.3%; p < 0.001). Sites visited within 30 days after initiation showed a significantly shortened median time to recruitment of the first patient (28 vs. 59 days with visits ≤30 or >30 days after initiation; p < 0.001). Mean patient recruitment rates were significantly higher at visited than at not-visited sites (1.13 vs. 0.89 patients per site per month, p < 0.001) and significantly increased after the first CTE site visit (from 0.70 to 1.17 patients per site per month; p < 0.001). Finally, there were fewer low-recruiting sites and more high-recruiting sites among the CTE-visited sites compared to the not-visited sites, and the mean recruitment rate at high-recruiting sites visited by CTEs was significantly higher than at high-recruiting sites without CTE visits (2.07 vs. 1.64 patients per site per month; p < 0.01). The possibility for selection bias is inherent to this post hoc analysis of a nonrandomized data set. The European focus of the CTE program described here might add some geographical bias. Also, other activities such as investigator meetings conducted in parallel with CTE activities might have partly masked the results of our analysis. Finally, the analysis is limited to recruitment-related parameters, and the aspect of cost-effectiveness has not been quantitatively assessed. We found a significant positive association between CTE site visits and the assessed recruitment-related study milestones in the TRA•CER trial, and enrollment finished ahead of plan. We propose that a CTE program could efficiently accelerate enrollment in other clinical trials and therapeutic areas and could contribute to shortening patient access time to novel and potential lifesaving treatments in cardiovascular medicine and beyond.

Antiplatelet and antithrombotic effect of F 16618, a new thrombin proteinase‐activated receptor‐1 (PAR1) antagonist

New antithrombotic agents with the potential to prevent atherothrombotic complications are being developed to target receptors on platelets and other cells involved in plaque growth. The aim of this study was to investigate the antiplatelet effects of F 16618, a new non-peptidic PAR1 (thrombin receptor) antagonist. We investigated the inhibitory effect of F 16618 on human platelet aggregation ex vivo, in whole blood and washed platelets, by using a multiple-electrode platelet aggregometer based on impedance and an optical aggregometer, respectively. Its effects on whole-blood haemostasis (clot parameters) were analysed with the ROTEM thromboelastometry device and the platelet function analyser PFA-100. A guinea-pig model of arterial thrombosis was used to investigate its effects on thrombus formation in vivo. F 16618 inhibited PAR1 agonist peptide (SFLLR-peptide)-induced washed platelet aggregation ex vivo. This effect was concentration-dependent and exhibited a competitive inhibition profile. Washed platelet aggregation, as well as P-selectin expression induced by thrombin, were significantly inhibited by 10 µM F 16618. In whole-blood experiments, 20 µM F 16618 inhibited SFLLR-induced platelet aggregation by 49%. In contrast, it had no effect on whole-blood haemostasis. In the guinea-pig model of carotid thrombosis, 0.32 mg·kg(-1) F 16618 doubled the occlusion time. F 16618 was shown to have strong antithrombotic activity in vivo and moderate antiplatelet effects ex vivo. As these effects were not associated with major effects on physiological haemostasis, this molecule is a good antiplatelet drug candidate for use either alone or in combination with current treatments.

Discovery of nor-seco himbacine analogs as thrombin receptor antagonists

Discovery of a novel nor-seco himbacine analog as potent thrombin receptor (PAR-1) antagonist is described. Despite low plasma level, these new analogs showed excellent ex vivo efficacy in the monkey platelet aggregation assay. A potent hydroxy metabolite generated in vivo was identified as the agent responsible for the ex vivo efficacy. Following this discovery, the metabolite series was optimized to obtain analogs that showed very good ex vivo efficacy along with excellent pharmacokinetic profile in c. monkey.

Recent Development in Thrombin Receptor Antagonist as Novel Antithrombotic Agent

Significant progress was achieved in the search of a thrombin receptor antagonist as a novel antithrombotic treatment since the thrombin receptor (protease-activated receptor-1, PAR-1) was cloned 20 years ago. Previous works have shown that it is possible to develop potent thrombin receptor antagonists to compete effectively with the receptor’s internal “tethered” ligand to block platelet activation. Vorapaxar (SCH 530348) from Schering-Plough (now Merck) and atopaxar (E5555) from Eisai have been advanced to human clinical trials. Recently, the pivotal phase III clinical trial results for vorapaxar were published. In this article we review these results plus the phase II results from atopaxar. Several newly described thrombin receptor antagonists from the literature will also be discussed. The phase III results from vorapaxar demonstrated that a thrombin receptor antagonist can achieve efficacy in addition to current standard- of-care in treating atherothrombotic patients, especially those with previous myocardial infarction (MI). However, the increased moderate and severe bleeding, especially intracranial bleeding, point to the limitations of current thrombin receptor antagonists. Future thrombin receptor antagonists that can improve on the efficacy and bleeding profile of current ones should have a promising place in meeting the unmet medical need in treating atherothrombotic patients using current standard therapy.

Atopaxar.

Atopaxar, also known as E 5555 is a novel reversible protease-activated receptor-1 (PAR-1) thrombin receptor antagonist. To date, Atopaxar has been investigated in phase II trials with focus on safety and tolerability in patients with acute coronary syndromes or stable coronary artery disease on top of standard antiplatelet therapy. Atopaxar was generally well tolerated, however a rise in liver enzymes and prolongation of the QTcF interval were observed. The data suggest, that atopaxar administration may promote some minor bleeding complications, but does not seem to significantly increase the risk of major bleeding. Although not powered for efficacy, the currently available data suggest potential benefits in patients at high risk for recurrent ischemic events on top of standard antiplatelet therapy. In conclusion, more studies (e.g. phase III) are needed to evaluate efficacy and safety of atopaxar.

AHA 2011 Scientific Sessions highlight key studies

AHA 2011 Scientific Sessions highlight key studies

Results from the TRA*CER Trial

The results of the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome [TRA•CER] trial showed that vorapaxar does not significantly improve outcomes in high-risk patients with non-ST-segment elevation acute coronary syndrome and significantly increases the risk of major bleeding, including intracranial hemorrhage.

Novel Antiplatelet Therapies

Advances in antiplatelet therapy have significantly improved outcomes in patients with ischemic heart disease. Thienopyridines remain a cornerstone of therapy along with aspirin. Recently, concerns have been raised about the use of clopidogrel due to its pharmacokinetic and pharmacogenetic interpatient variability. A third-generation thienopyridine, prasugrel, overcomes some of these problems by improving inhibition of platelet aggregation, but increasing the risk of peri-procedural bleeding. Other novel antiplatelet agents, such as ticagrelor, have shown improved efficacy in recent trials and require further investigations. The field of pharmacotherapy continues to rapidly evolve as newer agents, such as thrombin receptor antagonists, along with older agents, such as cilostazol and glycoprotein IIb/IIIa inhibitors, are being explored.

Coagulation Cofactor Presentation and Complex Assembly on Platelets by Protease Activated Receptors (PARs): PAR4 Stimulation Leads to More FV and FVIII and More Thrombin Generation Than PAR1

Abstract 1135Protease activated receptor (PAR) stimulation induces procoagulant phenotypes on platelets leading to thrombin generation; however, the efficacy of PAR1 versus PAR4 in the presentation of coagulation cofactors and assembly of coagulation complexes on platelet membranes have not been compared. We used immunocytochemistry and flow cytometry techniques to measure PAR mediated binding of coagulation cofactors to the platelet surface. The maximal response for PAR4-activating peptide (PAR4-AP) mediated Factor (F) Va release and association with the platelet membrane was 1.61 fold greater than PAR1-AP (Fig. 1A, *p=0.0069). To monitor platelet provision of coagulation cofactors and assembly of individual coagulation complexes (prothrombinase, extrinsic Xase, intrinsic Xase), we developed a novel thrombin generation assay. Conditions were established in which the targeted cofactors were withheld and thrombin generation was triggered by platelet stimulation and provision of the missing cofactor. Thrombin generation targeting provision of FVa and assembly of the prothrombinase complex (FII+FXa+Antithrombin [AT]) yielded 1.5 fold higher peak thrombin levels for PAR4 versus PAR1 stimulation (Fig 1B, *p=0.0129). A similar difference between PAR1 and PAR4 was observed for FVIII binding, in which PAR4-stimulated platelets displayed 1.7 fold greater levels. Consistent with FVIII expression, thrombin generation targeting the intrinsic Xase complex (FII+FX+FIXa+AT) was 2.0 fold higher for PAR4 versus PAR1. Peak thrombin levels in thrombin generation experiments targeting intrinsic Xase complex assembly were significantly higher than experiments targeting the isolated prothrombinase complex, demonstrating the ability of the intrinsic Xase complex to amplify thrombin generation. We also observed a rapid mobilization of tissue factor (TF) to the cell surface following PAR stimulation, and activity in thrombin generation assays targeting the extrinsic Xase complex (FII+FX+FVIIa+TFPI+AT), but no significant difference between PAR1 and PAR4. Although thrombin generation was observed under conditions targeting extrinsic Xase complex assembly, peak thrombin levels were negligible compared to thrombin generation conducted under conditions targeting the prothrombinase and intrinsic Xase complexes. In conclusion, we have shown that platelets can assemble prothrombinase, intrinsic Xase, and extrinsic Xase complexes, but the prothrombinase and intrinsic Xase complexes are responsible for the majority of thrombin generated on the platelet. Moreover, PAR4 stimulation induces the provision of more FV and FVIII, consistently yielding higher peak thrombin levels than PAR1 stimulation. These data have important clinical impact in light of recent efforts to develop thrombin receptor antagonists as agents to treat thrombotic disorders, and suggest that a PAR4 antagonist would be a more effective strategy to control pathologic thrombosis. [Display omitted] Disclosures:No relevant conflicts of interest to declare.