Thrombin Receptor Antagonist Research Articles

Abstract 10315: The Effect of Protease-Activated Receptor-1 Inhibition With Vorapaxar in Post-mi and Nstemi Patients on Selected Biomarkers Reflecting Endothelial Function

Introduction: Biomarker research related to protease-activated receptor-1 (PAR-1) inhibition with vorapaxar in humans has essentially focused on platelets. Follow-up (FU) time has been short, whereas in the current study, focus has been on endothelial function during both short- and long-term PAR-1 inhibition. Aim: To assess short- and long-term effects of vorapaxar (V) as compared to Placebo (PL) on the following biomarkers: Angiopoietin-2 (ANGPT2), Angiopoietin-like 4 (ANGPTL4), VEGF, ICAM-1, VCAM-1, E-Selectin (ESEL), von Willebrand Factor (VWF), Thrombomodulin (TM), PAI-1 and PAI-2. Methods: In an independent collective subproject performed in Norway, post-MI patients at steady state were recruited from the “Trial to Assess the Effects of Vorapaxar in Preventing Heart Attack and Stroke in Patients with Atherosclerosis” (TRA2ᵒP-TIMI 50) and NSTEMI patients were recruited from the “Thrombin Receptor Antagonist for Clinical Event Reduction in acute coronary syndrome” (TRACER) trial. Biomarkers were measured in duplicate by enzyme immunoassays (EIA) in citrated plasma at one month follow-up and at study completion (median 2.3 years) for subjects recruited from both trials. Results: Biomarkers were measured in 265 consecutive patients [age median 62.0 years (Q1-Q3: 55.0-68.0 years), males 83%] with at least one change from baseline value. Among these, biomarkers were available at both short- and long-term follow-up in 221 subjects. ANGPT2 increased significantly in V as compared to PL at 1-month follow-up in the total population (p=0.034), and in males in both post-MI (p=0.031) and NSTEMI subjects (p=0.012), respectively. ANGPTL4 increased (p=0.028) and PAI-2 decreased (p=0.025) significantly in the total population in favor of V at final FU. In the total post-MI subgroup and among males of that group, a short-term significant increase in ESEL in favor of V was observed, p=0.029 and p=0.018, respectively. Also, a transient significant increase in VWF (p=0.032) in favor of V was seen at one month in NSTEMI patients. Conclusions: Significant changes suggesting potential harmful effects in some biomarkers were observed during 1-month and long-term PAR-1 inhibition as compared to placebo in post-MI and acute coronary syndrome patients.

Biomarker-Based Prediction of Recurrent Ischemic Events in Patients With Acute Coronary Syndromes

BackgroundIn patients with acute coronary syndrome (ACS), there is residual and variable risk of recurrent ischemic events. ObjectivesThis study aimed to develop biomarker-based prediction models for 1-year risk of cardiovascular (CV) death and myocardial infarction (MI) in patients with ACS undergoing percutaneous coronary intervention. MethodsWe included 10,713 patients from the PLATO (A Comparison of Ticagrelor [AZD6140] and Clopidogrel in Patients With Acute Coronary Syndrome) trial in the development cohort and externally validated in 3,508 patients from the TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) trial. Variables contributing to risk of CV death/MI were assessed using Cox regression models, and a score was derived using subsets of variables approximating the full model. ResultsThere were 632 and 190 episodes of CV death/MI in the development and validation cohorts. The most important predictors of CV death/MI were the biomarkers, growth differentiation factor 15, and N-terminal pro–B-type natriuretic peptide, which had greater prognostic value than all candidate variables. The final model included 8 items: age (A), biomarkers (B) (growth differentiation factor 15 and N-terminal pro–B-type natriuretic peptide), and clinical variables (C) (extent of coronary artery disease, previous vascular disease, Killip class, ACS type, P2Y12 inhibitor). The model, named ABC-ACS ischemia, was well calibrated and showed good discriminatory ability for 1-year risk of CV death/MI with C-indices of 0.71 and 0.72 in the development and validation cohorts, respectively. For CV death, the score performed better, with C-indices of 0.80 and 0.84 in the development and validation cohorts, respectively. ConclusionsAn 8-item score for the prediction of CV death/MI was developed and validated for patients with ACS undergoing percutaneous coronary intervention. The ABC-ACS ischemia score showed good calibration and discrimination and might be useful for risk prediction and decision support in patients with ACS. (A Comparison of Ticagrelor [AZD6140] and Clopidogrel in Patients With Acute Coronary Syndrome [PLATO]; NCT00391872; Trial to Assess the Effects of Vorapaxar [SCH 530348; MK-5348] in Preventing Heart Attack and Stroke in Participants With Acute Coronary Syndrome [TRACER]; NCT00527943)

Induction of endothelial barrier dysfunction by serum factors in rats subjected to traumatic brain injury and hemorrhagic shock.

Traumatic brain injury (TBI) has been associated with the development of indirect acute respiratory distress syndrome (ARDS). However, the causative relationship between TBI and lung injury remains unclear. To explore potential mechanisms linking TBI with the development of ARDS, we characterized the effects of serum factors released following TBI and hemorrhagic shock (HS) in a rat model on the pulmonary endothelial cell (EC) barrier dysfunction, a key feature of ARDS. We found that serum samples from animals exposed to both controlled cortical impact (CCI) and HS, but not from sham‐operated rats induced significant barrier dysfunction in human pulmonary artery EC monolayers at 2 days post injury. Thrombin inhibitor and thrombin receptor antagonist attenuated the acute phase of the serum‐induced trans‐endothelial resistance (TER) decline caused by CCI‐HS serum, but not in later time points. However, both the early and late phases of CCI‐HS‐induced EC permeability were inhibited by heparin. The barrier disruptive effects of CCI‐HS serum were also prevented by serum preincubation with heparin‐sepharose. Pulmonary EC treated for 3 h with serum from CCI‐HS rats demonstrated a significant decline in expression of EC junctional protein, VE‐Cadherin, and disassembly of peripheral EC adherens junction complexes monitored by immunostaining with VE‐cadherin antibody. These results suggest that exposure to CCI‐HS causes early and late‐phase barrier disruptive effects in vascular endothelium. While thrombin‐PAR1 signaling has been identified as a mechanism of acute EC permeability increase by CCI‐HS serum, the factor(s) defining long‐term EC barrier disruption in CCI‐HS model remains to be determined.

Serum from rats subjected to traumatic brain injury and hemorrhagic shock induces profound endothelial barrier dysfunction

IntroductionTraumatic brain injury (TBI) has been associated with development of indirect acute respiratory distress syndrome (ARDS). However, the causative relationship between TBI and lung injury remains unclear. To explore potential mechanism linking TBI with development of ARDS, we characterized effects of serum factors released during TBI and hemorrhagic shock (HS) in a rat model on the pulmonary endothelial cell (EC) barrier dysfunction, a key feature of ARDS.MethodsThe adult male rat polytrauma model consisted of controlled cortical impact (CCI)–induced TBI followed by 30 minutes of hemorrhage shock (HS) induced by blood withdrawal. The HS phase was followed by a 1‐hour “prehospital” Hextend fluid resuscitation phase and then a 1‐hour “hospital phase” when shed blood was reinfused. 48 hours after the TBI, blood was drawn from right ventricle and serum samples were obtained. Serum was collected from the TBI or sham rats, and its effects on barrier properties of pulmonary endothelial cell culture were assessed by measurements of transendothelial electrical resistance (TER) using the electrical cell impedance sensor and visualization of fluorescent tracer penetration through EC monolayer using XPerT assay.ResultsWe found pronounced barrier‐disruptive effects of serum samples from animals exposed to controlled cortical impact (CCI) and HS, but not from sham operated rats. Rapid and sustained decrease in EC monolayer transendothelial resistance was observed within minutes after serum addition and remained below basal TER levels after incubation with CCI‐HS sera. Thrombin has been implicated in the early‐phase barrier disruptive activity of CCI‐HS serum, as both thrombin inhibitor and thrombin receptor antagonist attenuated the acute phase of serum‐induced TER decline, but did not affect TER decline at later time points. These findings suggest that thrombin elevation may play a role in early‐phase barrier disruptive activity of CCI‐HS serum. However, both the early and late phases of CCI‐HS‐induced EC permeability were inhibited by heparin. The late phase barrier disruptive effect of CCI‐HS was also prevented by serum preincubation with heparin‐sepharose. Pulmonary EC treated with serum from CCI‐HS rats for 3 hours have demonstrated significant decline in expression of EC junctional protein, VE‐Cadherin, and disassembly of peripheral EC adherens junction complexes monitored by immunostaining with VE‐cadherin antibody.ConclusionThese results suggest that exposure to CCI‐HS leads to production of humoral factors causing early and late‐phase barrier disruptive effects in lung vascular endothelium. While thrombin‐PAR1 signaling has been identified as mechanism of acute EC permeability increase by CCI‐HS serum, the factor(s) defining long‐term EC barrier disruption in CCI‐HS model remain to be determined.

Abstract 10426: Worse Clinical Outcomes in Patients with Acute Coronary Syndrome and Prior or New Onset Heart Failure: Insights from 47,474 Patients in a Pooled Analysis of Randomized Clinical Trials

Introduction: Heart failure (HF) frequently complicates acute coronary syndrome (ACS). Despite known associated high rates of mortality, there are only limited data regarding recurrent ischemic events and re-hospitalization for HF (HHF) in those with HF and ACS. Methods: We used a pooled dataset of four randomized clinical ACS trials (Platelet Inhibition and Patient Outcomes [PLATO], Apixaban for Prevention of Acute Ischemic Events 2 [APPRAISE-2], Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome [TRA-CER], and Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndrome [TRILOGY ACS]). We assessed the association between HF status (history of HF, de novo HF, no HF) at presentation for ACS on death, future ischemic events, and HHF at one year following hospital discharge using Cox proportional hazards analysis and estimated cumulative event rates using cumulative incidence function. Results: Of 47,474 patients presenting with ACS, 11.1% showed evidence of acute HF, 55.0% of whom had no previous history of HF. Patients with prior/chronic HF were more likely to present with acute HF than those with no previous HF (40.3% vs 6.9%). Compared to those without HF, patients with prior and de novo HF were at a significantly increased risk at one year of all-cause mortality (adjusted HR (aHR) 2.10, 95% Confidence Interval [CI] 1.80-2.45, and aHR 1.51, CI 1.18-1.93, respectively), MACE (aHR 1.50, CI 1.34-1.69, and aHR 1.40, CI 1.14-1.72), recurrent MI (aHR 1.58, CI 1.41-1.78, and aHR 1.40, CI 1.15-1.70), stroke (aHR 1.93, CI 1.67-2.32, and aHR 1.38, CI 1.09-1.75), and HHF (aHR 2.38, CI 2.09-2.71, and aHR 1.53, CI 1.24-1.88). Conclusion: Following an ACS event, both prior and de novo HF were found to be major predictors of death, recurrent ischemic events, and HHF by one year. These findings highlight the need for improved strategies to prevent and manage adverse outcomes in this high-risk population.

Abstract 1122‐000043: Vorapaxar as An Alternative for Ticagrelor Resistance in Neuroendovascular Intervention

Introduction : Perioperative dual‐antiplatelet therapy (DAPT) for flow diversion (FD) limits thromboembolic complications. Practice of DAPT varies across the neuroendovascular field but typically includes aspirin and an ADP receptor antagonist such as clopidogrel, prasugrel, or ticagrelor. Unfortunately, resistance to DAPT medications remains a concern for neuroendovascular intervention, and there is a current lack of standard alternatives for such resistance. The main goal of this abstract is to discuss ticagrelor resistance and to inform possible therapeutic options. Methods : We report a case of vorapaxar treated FD for an intracranial aneurysm in a patient with ticagrelor resistance. FD was deployed for a left internal carotid artery (ICA) blister aneurysm and bilateral ICA dissecting pseudoaneurysms (Figure 1). We also provide a narrative review on previous reports of ticagrelor resistance and associated treatment responses. We used the keywords: “ticagrelor,” “resistance,” “hypo‐response,” “stent thrombosis,” and “aneurysm.” These were implemented in various combinations with Boolean operators in three databases: PubMed, Ovid MEDLINE, and Ovid EMBASE. Results : During a complicated clinical course, the patient had three thromboembolic complications while on DAPT with ticagrelor or prasugrel leading to transition of antiplatelet therapy to vorapaxar. Thromboelastography with platelet mapping (TEG‐PM) routinely demonstrated inadequate platelet inhibition, which was confirmed with platelet function analyzer‐100. Initial TEG‐PM results were 0.0% ADP receptor inhibition and MA‐ADP of 62.2 mm. Repeat angiograms also indicated thromboembolic formation after each of the three events (Figure 1). After introduction of vorapaxar, the patient had adequate platelet inhibition with TEG‐PM results of 49.1% ADP receptor inhibition and MA‐ADP of 48.3 mm. At 84 days follow‐up, the patient was fully recovered with complete occlusion of the aneurysms. In a narrative review of the literature, there were ten previously reported cases of ticagrelor resistance or hypo‐response: three cases in the neuroendovascular literature and seven cases in the cardiovascular literature. Among all of the cases, there was a variability in protocol for treating patients with suggested ticagrelor resistance. All three neuroendovascular cases either employed another ADP receptor antagonist in hopes that the resistance would not generalize or eliminated DAPT altogether and settled for aspirin alone. In some of the cardiovascular cases, ticagrelor was even continued after patients exhibited laboratory evidence of resistance or hypo‐response. Conclusions : Given the paucity of cases describing ticagrelor resistance or hypo‐response in the neuroendovascular and cardiovascular literature, management of DAPT should remain a multifactorial decision depending on the clinical situation. Moreover, we need to consider therapeutic alternatives for cases of resistance such as thrombin receptor antagonists, specifically PAR1 receptor antagonists like vorapaxar. High quality randomized controlled trials are needed to elucidate the safety and efficacy of vorapaxar in neuroendovascular procedures.

Efficacy and Safety of Vorapaxar by Intensity of Background Lipid-Lowering Therapy in Patients With Peripheral Artery Disease: Insights From the TRA2P-TIMI 50 Trial.

BackgroundPatients with peripheral artery disease are at increased risk of both major adverse cardiovascular events (MACEs) and limb events. The pathobiology of limb events is likely multifactorial. Observational studies suggest a benefit of statin therapy for reducing the risk of limb ischemic events while randomized trials demonstrate a benefit with more potent antithrombotic therapies, particularly those targeting thrombin. Whether the effects of these therapeutic pathways are independent and complementary is not known.Methods and ResultsThe TRA 2°P‐TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events–Thrombolysis in Myocardial Infarction 50) trial demonstrated that vorapaxar significantly reduced MACEs and limb events. The purpose of the current analysis was to evaluate the association of statin use and intensity and the occurrence of MACEs and limb events in 5845 patients with symptomatic peripheral artery disease randomized in TRA 2°P‐TIMI 50 and then to understand whether statin use modified the benefits of vorapaxar for MACEs or limb ischemic events. We found that statin therapy was associated with significantly lower risk of MACEs (hazard ratio [HR], 0.77; 95% CI, 0.66–0.89; P<0.001) and limb ischemic events (HR, 0.73; 95% CI, 0.60–0.89; P=0.002). The benefit of vorapaxar for reducing MACEs and limb events was consistent regardless of background statin (P‐interaction=0.715 and 0.073, respectively). Event rates were lowest in patients receiving the combination of statin therapy and vorapaxar.ConclusionsIn conclusion, statin use and intensity is associated with significantly lower rates of MACEs and limb ischemic events. Thrombin inhibition with vorapaxar is effective regardless of background statin therapy. These results suggest that targeting both lipid and thrombotic risk in peripheral artery disease is necessary in order to optimize outcomes.

Cardiovascular Biomarkers and Heart Failure Risk in Stable Patients With Atherothrombotic Disease: A Nested Biomarker Study From TRA 2°P-TIMI 50.

BackgroundPatients with stable atherothrombotic disease vary in their risk of developing heart failure (HF). Circulating cardiovascular biomarkers may improve HF risk assessment and identify patients who may benefit from emerging HF preventive therapies.Methods and ResultsWe measured high‐sensitivity cardiac troponin I and BNP (B‐type natriuretic peptide) in 15 833 patients with prior myocardial infarction, ischemic stroke, or peripheral artery disease from the TRA 2°P‐TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events‐Thrombolysis in Myocardial Infarction 50) trial, excluding patients with recent myocardial infarction (<30 days). Biomarkers were categorized using a priori cut points. Hospitalization for HF (HHF) end points were adjudicated with blinded structured review of serious adverse events. Associations between biomarkers and HHF outcomes were adjusted for sex and independent clinical risk predictors of HHF in our cohort (age ≥75, prior HF, type 2 diabetes mellitus, polyvascular disease, body mass index, anemia, chronic kidney disease, hypertension). Baseline high‐sensitivity cardiac troponin I and BNP each identified a significant graded risk of HHF independent of clinical risk predictors, including in the subgroups of patients with and without type 2 diabetes mellitus and with and without prior HF. Patients with both high‐sensitivity cardiac troponin I ≥5 ng/L and BNP ≥100 pg/mL had the highest HHF event rates. When added to a multivariable Cox regression model with clinical risk predictors (C‐index 0.88; 95% CI, 0.85–0.90), BNP (C ‐index 0.92; 95% CI, 0.90–0.93), and high‐sensitivity cardiac troponin I (C‐index 0.90; 95% CI, 0.88–0.92) each significantly improved the prognostic performance of the model (both P LRT<0.001).ConclusionsBiomarkers of myocardial injury and hemodynamic stress are independent predictors of HHF risk in patients with stable atherothrombotic disease, with and without prior HF and/or type 2 diabetes mellitus.RegistrationURL: https://www.clinicaltrials.gov; Unique identifier: NCT00526474.

Favorable therapeutic index of an orally-active small-molecule antagonist of the platelet protease-activated receptor-4, BMS-986141, compared with the P2Y12 antagonist ticagrelor in cynomolgus monkeys

Abstract Introduction BMS-986141 is an orally-active small-molecule platelet thrombin receptor antagonist selective for the protease-activated receptor-4 (PAR4), a human platelet thrombin receptor. Purpose This study assessed effects of BMS-986141 vs. the P2Y12 antagonist ticagrelor, a standard of care antiplatelet agent, on arterial thrombosis (AT), mesenteric bleeding time (MBT) and platelet aggregation in monkeys. Methods Studies were conducted in models of electrically-mediated carotid artery thrombosis and MBT in anesthetized monkeys. Monkeys were given a single oral dose of BMS-986141 (0.05, 0.1, 0.5 mg/kg) or vehicle (n=8/group). At 2 hr post-dose, in vivo AT, MBT as well as ex vivo platelet aggregation were monitored in the same animal. Ticagrelor was studied as a comparator and given as IV bolus plus infusion at 0.0023+0.017 to 0.075+0.6 (mg/kg+mg/kg/h) (n=5–6/group). Thrombus weight reduction, MBT increase over vehicle, and platelet aggregation inhibition were determined. Peak platelet aggregation responses to activation peptides selective for PAR4 (PAR4-AP, 12.5 μM) and PAR1 (PAR1-AP, 18 μM), to collagen (5 μg/ml) and to ADP (20 μM) were determined by whole blood aggregometry. Results BMS-986141 inhibited platelet aggregation induced by PAR4-AP in human and monkey blood in vitro with comparable IC50 of 1.8±0.3 and 1.2±0.3 nM, respectively. BMS-986141 at 0.5 mg/kg completely inhibited platelet aggregation induced by PAR4-AP but not PAR1-AP, ADP and collagen, suggesting PAR4 receptor selectivity. In the AT model, BMS-986141 at 0.05, 0.1 and 0.5 mg/kg reduced thrombus weight by 36±7*, 63±8*, and 88±3%*, respectively (*P&amp;lt;0.05 vs. vehicle). BMS-986141 increased MBT by up to 1.2-fold. In a separate study, ticagrelor at 0.0023+0.017, 0.0068+0.055, 0.0255+0.18 and 0.075+0.6 (mg/kg+mg/kg/h IV) reduced thrombus weight by 19±8, 36±5*, 76±6* and 89±1%*, and increased MBT by respectively by 1.7-, 6.4-*, &amp;gt;10-*, and &amp;gt;10-fold*, respectively (*P&amp;lt;0.05 vs. vehicle). Conclusion Comparable antithrombotic efficacy was observed between BMS-986141 and ticagrelor in monkeys. BMS-986141 exhibited lower MBT compared with ticagrelor at equivalent antithrombotic doses. This study suggests that PAR4 antagonism provides a potentially safer antiplatelet therapy. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Research was supported by Bristol-Myers Squibb

Enantioselective synthesis of a chiral intermediate of himbacine analogs by Burkholderia cepacia lipase A.

The enantiomers of (4R/S)-4-hydroxy-N, N-diphenyl-2-pentynamide are key chiral synthons for the synthesis of thrombin receptor antagonists such as vorapaxar. In this paper, we report the enzymatic preparation of enantiomerically enriched (4R)-4-hydroxy-N, N-diphenyl-2-pentynamide using lipase A from Burkholderia cepacia ATCC 25416 as the catalyst. First, the lipase gene (lipA) and its chaperone gene (lipB) was cloned and expressed in Escherichia coli system. After purification, lipase A activation was performed with the assistance of foldase lipase B. Enzyme assay revealed that the activated lipase A showed the optimal catalytic activity at 60ºC and pH 7. The effects of various metals on the activity were investigated and results demonstrated that most of the metals inhibited the activity. To further improve the catalytic outcome, two-phase reaction was studied, and n-hexane proved to be a good organic solvent for the combination system. Using the optimize conditions, (4R)-4-hydroxy-N, N-diphenyl-2-pentynamide with 94.5% ee value and 48.93% conversion ratio was achieved. Our investigation on this lipase reveals lipase A as a promising biocatalyst for producing chiral propargyl alcohol for preparation of novel himbacine analogs.

Post-Discharge Bleeding and Mortality Following Acute Coronary Syndromes With or Without PCI

BackgroundThe long-term prognostic impact of post-discharge bleeding in the unique population of patients with acute coronary syndrome (ACS) treated without percutaneous coronary intervention (PCI) remains unexplored. ObjectivesThe aim of this study was to assess the association between post-discharge bleeding and subsequent mortality after ACS according to index strategy (PCI or no PCI) and to contrast with the association between post-discharge myocardial infarction (MI) and subsequent mortality. MethodsIn a harmonized dataset of 4 multicenter randomized trials (APPRAISE-2 [Apixaban for Prevention of Acute Ischemic Events-2], PLATO [Study of Platelet Inhibition and Patient Outcomes], TRACER [Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome], and TRILOGY ACS [Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes]), the association between post-discharge noncoronary artery bypass graft–related GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) moderate, severe, or life-threatening bleeding (landmark 7 days post-ACS) and subsequent all-cause mortality was evaluated in a time-updated Cox proportional hazards analysis. Interaction with index treatment strategy was assessed. Results were contrasted with risk for mortality following post-discharge MI. ResultsAmong 45,011 participants, 1,133 experienced post-discharge bleeding events (2.6 per 100 patient-years), and 2,149 died during follow-up. The risk for mortality was significantly higher <30 days (adjusted hazard ratio: 15.7; 95% confidence interval: 12.3 to 20.0) and 30 days to 12 months (adjusted hazard ratio: 2.7; 95% confidence interval: 2.1 to 3.4) after bleeding, and this association was consistent in participants treated with or without PCI for their index ACS (p for interaction = 0.240). The time-related association between post-discharge bleeding and mortality was similar to the association between MI and subsequent mortality in participants treated with and without PCI (p for interaction = 0.696). ConclusionsPost-discharge bleeding after ACS is associated with a similar increase in subsequent all-cause mortality in participants treated with or without PCI and has an equivalent prognostic impact as post-discharge MI.

Long-Term Risk Stratification of Patients Undergoing Coronary Angiography According to the Thrombolysis in Myocardial InfarctionRisk Score for Secondary Prevention.

BackgroundA risk score for secondary prevention after myocardial infarction (Thrombolysis in Myocardial Infarction Risk Score for Secondary Prevention [TRS2P]), based on 9 established clinical factors, was recently developed from the TRA2°P‐TIMI50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events) trial. We aimed to evaluate the performance of TRS2P for predicting long‐term outcomes in real‐world patients presenting for coronary angiography.Methods and ResultsA retrospective analysis of 13 593 patients referred to angiography for the assessment or treatment of coronary disease was performed. Risk stratification for 10‐year major adverse cardiovascular events was performed using the TRS2P, divided into 6 categories (0 to ≥5 points), and in relation to the presenting coronary syndrome. All clinical variables, except prior coronary artery bypass grafting, were independent risk predictors. The annualized incidence rate of major adverse cardiovascular events increased in a graded manner with increasing TRS2P, ranging from 1.65 to 16.6 per 100 person‐years (P trend<0.001). Compared with the lowest‐risk group (risk indicators=0), the hazard ratios (95% CIs) for 10‐year major adverse cardiovascular events were 1.60 (95% CI, 1.36–1.89), 2.58 (95% CI, 2.21–3.02), 4.31 (95% CI, 3.69–5.05), 6.43 (95% CI, 5.47–7.56), and 10.03 (95% CI, 8.52–11.81), in those with 1, 2, 3, 4 and ≥5 risk indicators, respectively. Risk gradation was consistent among individual clinical end points. TRS2P showed reasonable discrimination with C‐statistics of 0.693 for major adverse cardiovascular events and 0.758 for mortality. The graded relationship between the risk score and event rates was observed in both patients presenting with acute and nonacute coronary syndromes.ConclusionsThe use of TRS2P, a simple risk score based on routinely collected variables, enables risk stratification in patients undergoing coronary angiography. Its predictive value was demonstrated in a real‐world setting with long‐term follow‐up and regardless of the acuity of coronary presentation.

Stroke Outcomes With Vorapaxar Versus Placebo in Patients With Acute Coronary Syndromes: Insights From the TRACER Trial.

BackgroundVorapaxar, a protease‐activated receptor‐1 antagonist, is approved for secondary prevention of cardiovascular events but is associated with increased intracranial hemorrhage.Methods and Results TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) was a trial of vorapaxar versus placebo among patients with acute coronary syndrome. Strokes were adjudicated by a central events committee. Of 12 944 patients, 199 (1.5%) had ≥1 stroke during the study period (median follow‐up, 477 days). Four patients had a single stroke of unknown type; 195 patients had ≥1 stroke classified as hemorrhagic or nonhemorrhagic (165 nonhemorrhagic, 28 hemorrhagic, and 2 both). Strokes occurred in 96 of 6473 patients (1.5%) assigned vorapaxar and 103 of 6471 patients (1.6%) assigned placebo. Kaplan‐Meier incidence of stroke for vorapaxar versus placebo was higher for hemorrhagic stroke (0.45% versus 0.14% [hazard ratio, 2.74; 95% confidence interval, 1.22–6.15]), lower but not significantly different for nonhemorrhagic stroke (1.53% versus 1.98% at 2 years [hazard ratio, 0.79; 95% confidence interval, 0.58–1.07]), and similar for stroke overall (1.93% versus 2.13% at 2 years [hazard ratio, 0.94; 95% confidence interval, 0.71–1.24]).ConclusionsStroke occurred in <2% of patients. Vorapaxar‐assigned patients had increased hemorrhagic stroke but a nonsignificant trend toward lower nonhemorrhagic stroke. Overall stroke frequency was similar with vorapaxar versus placebo.

Prognostic and Practical Validation of Current Definitions of Myocardial Infarction Associated With Percutaneous Coronary Intervention

ObjectivesIn 13,038 patients with non–ST-segment elevation acute coronary syndrome undergoing index percutaneous coronary intervention (PCI) in the EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Non–ST-Segment Elevation Acute Coronary Syndrome) and TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) trials, the relationship between PCI-related myocardial infarction (MI) and 1-year mortality was assessed. BackgroundThe definition of PCI-related MI is controversial. The third universal definition of PCI-related MI requires cardiac troponin >5 times the 99th percentile of the normal reference limit from a stable or falling baseline and PCI-related clinical or angiographic complications. The definition from the Society for Cardiovascular Angiography and Interventions (SCAI) requires creatine kinase–MB elevation >10 times the upper limit of normal (or 5 times if new electrocardiographic Q waves are present). Implications of these definitions on prognosis, prevalence, and implementation are not established. MethodsIn our cohort of patients undergoing PCI, PCI-related MIs were classified using the third universal type 4a MI definition and SCAI criteria. In the subgroup of patients included in the angiographic core laboratory (ACL) substudy of EARLY ACS (n = 1,401) local investigator– versus ACL-reported angiographic complications were compared. ResultsAltogether, 2.0% of patients met third universal definition of PCI-related MI criteria, and 1.2% met SCAI criteria. One-year mortality was 3.3% with the third universal definition (hazard ratio: 1.96; 95% confidence interval: 1.24 to 3.10) and 5.3% with SCAI criteria (hazard ratio: 2.79; 95% confidence interval: 1.69 to 4.58; p < 0.001). Agreement between ACL and local investigators in detecting angiographic complications during PCI was overall moderate (κ = 0.53). ConclusionsThe third universal definition of MI and the SCAI definition were both associated with significant risk for mortality at 1 year. Suboptimal concordance was observed between ACL and local investigators in identifying patients with PCI complications detected on angiography. (Trial to Assess the Effects of Vorapaxar [SCH 530348; MK-5348] in Preventing Heart Attack and Stroke in Participants With Acute Coronary Syndrome [TRA·CER] [Study P04736]; NCT00527943; EARLY ACS: Early Glycoprotein IIb/IIIa Inhibition in Patients With Non–ST-Segment Elevation Acute Coronary Syndrome [Study P03684AM2]; NCT00089895)

Nexilin Regulates Oligodendrocyte Progenitor Cell Migration and Remyelination and Is Negatively Regulated by Protease-Activated Receptor 1/Ras-Proximate-1 Signaling Following Subarachnoid Hemorrhage.

Progressive white matter (WM) impairments caused by subarachnoid hemorrhage (SAH) contribute to cognitive deficits and poor clinical prognoses; however, their pathogenetic mechanisms are poorly understood. We investigated the role of nexilin and oligodendrocyte progenitor cell (OPC)-mediated repair in a mouse model of experimental SAH generated via left endovascular perforation. Nexilin expression was enhanced by the elevated migration of OPCs after SAH. Knocking down nexilin by siRNA reduced OPC migration both in vitro and in vivo and abridged WM repair. In contrast, the protease-activated receptor 1 (PAR1), Ras-proximate-1 (RAP1) and phosphorylated RAP1 (pRAP1) levels in WM were elevated after SAH. The genetic inhibition of PAR1 reduced RAP1 and pRAP1 expression, further enhancing nexilin expression. When delivered at an early stage at a concentration of 25 µg/kg, thrombin receptor antagonist peptide along with PAR1 knockdown rescued the down-regulation of myelin basic protein and improved remyelination at the later stage of SAH. Our results suggest that nexilin is required for OPC migration and remyelination following SAH, as it negatively regulates PAR1/RAP1 signaling, thus providing a promising therapeutic target in WM repair and functional recovery.

Antithrombotic treatment in peripheral artery disease.

This review treats antithrombotic use for peripheral arterial disease (PAD). In asymptomatic patients, there are no scientific data to support single antiplatelet therapy (SAPT) for primary prophylaxis. In symptomatic PAD, SAPT with aspirin or clopidogrel is indicated. The efficacy of aspirin is controversial. Clopidogrel may be preferred over aspirin. Ticagrelor is not superior to clopidogrel in reducing major adverse cardiovascular events and major adverse limb events, but lowers the risk of ischaemic stroke. In symptomatic PAD, dual antiplatelet therapy (DAPT) with clopidogrel and aspirin does not provide benefit over SAPT with aspirin alone and is associated with increased risk of major bleeding. DAPT with ticagrelor 60 mg b. i. d. and aspirin provides a significant major adverse cardiovascular events reduction in symptomatic PAD patients and may be considered in PAD patients with prior myocardial infarction. The use of a new thrombin receptor antagonist, vorapaxar, on top of SAPT or DAPT with aspirin and/or clopidogrel, reduces the risk of acute limb ischaemia and peripheral artery revascularization in patients with symptomatic PAD, at the cost of an increased risk for bleeding. Rivaroxaban (2.5 mg b. i. d.) plus aspirin (100 mg daily) is the first antithrombotic association that proved significant benefit for PAD patients, in terms of strong endpoints - total mortality and cardiovascular mortality. Therefore, this association shows the strongest evidence for secondary prevention of symptomatic PAD patients. In PAD patients undergoing percutaneous peripheral interventions, at least four weeks of DAPT with aspirin and clopidogrel is recommended after infrainguinal stent implantation. Stenting below-the-knee arteries is often followed by a longer period of DAPT, but no specific evidence is available. Anticoagulation is mandatory to prevent arterial occlusion during radial or brachial invasive procedures. The strategy includes use of unfractioned heparin, bivalirudin or enoxaparin. Vitamin K antagonists may be considered after autologous vein infrainguinal bypass.

Frequency, Predictors, and Impact of Combined Antiplatelet Therapy on Venous Thromboembolism in Patients With Symptomatic Atherosclerosis.

Observational studies suggest that symptomatic atherosclerosis may be associated with risk of venous thromboembolism (VTE). Prior randomized studies have demonstrated a significant reduction in recurrent VTE with aspirin monotherapy. Whether VTE risk is associated with more severe symptomatic atherosclerosis and more intensive antiplatelet therapy reduces VTE risk beyond aspirin monotherapy is unknown. TRA2P-TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-Thrombolysis in Myocardial Infarction) (vorapaxar) and PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54) (ticagrelor) were blinded, randomized placebo-controlled trials of antiplatelet therapy for the prevention of ischemic events in stable patients with symptomatic atherosclerosis. Two blinded vascular specialists systematically identified symptomatic venous thromboembolic events in both trials. Of 47 611 patients with stable vascular disease followed for 3 years in both studies there were 343 VTE events in 301 patients (Kaplan-Meier rate at 3 years, 0.9% for placebo). The risk of VTE was independently associated with age, body mass index, polyvascular disease, chronic obstructive pulmonary disease, and malignancy. The burden of atherosclerosis manifested as an increasing number of symptomatic vascular territories was associated with a graded increase in the 3-year rates of VTE (0.76% for 1, 1.53% for 2, and 2.45% for 3 territories). More intensive antiplatelet therapy (vorapaxar and ticagrelor pooled) significantly reduced the risk of VTE by 29% compared with background antiplatelet therapy, from 0.93% to 0.64% at 3 years (hazard ratio, 0.71; 95% confidence interval, 0.56-0.89; P=0.003). The rate of VTE in patients with atherosclerosis is ≈0.3% per year while on treatment with ≥1 antiplatelet agent, with increased risk independently associated with the number of symptomatic vascular territories. More intensive antiplatelet therapy reduces the risk of VTE. These data suggest a relationship between atherosclerosis burden and VTE risk, and they support inclusion of VTE as a prospective end point in long-term secondary prevention trials evaluating the risks and benefits of antiplatelet therapies in patients with atherosclerosis. URL: https://www.clinicaltrials.gov. Unique identifier: NCT01225562.

Clinical features and outcomes of patients with type 2 myocardial infarction: Insights from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial

Type 2 myocardial infarction (MI) is characterized by an imbalance between myocardial blood supply and demand, leading to myocardial ischemia without coronary plaque rupture, but its diagnosis is challenging. In the TRACER trial, patients with non-ST-segment elevation acute coronary syndromes were included. We aimed to describe provoking factors, cardiac biomarker profiles, treatment patterns, and clinical outcomes of patients with type 2 MIs. MI events during trial follow-up were adjudicated by an independent clinical events classification committee (CEC) and were classified according to the Third Universal Definition of MI. Using available source documents retrieved as part of the CEC process, we performed a retrospective chart abstraction to collect details on the type 2 MIs. Cox regression models were used to explore the association between MI type (type 1 or type 2) and cardiovascular death. Overall, 10.3% (n=1327) of TRACER participants had a total of 1579 adjudicated MIs during a median follow-up of 502 days (25th and 75th percentiles [IQR] 349-667). Of all MIs, 5.2% (n=82) were CEC-adjudicated type 2 MIs, occurring in 76 patients. The incidence of type 2 MI was higher in the first month following randomization, after which the distribution became more scattered. The most frequent potential provoking factors for type 2 MIs were tachyarrhythmias (38.2%), anemia/bleeding (21.1%), hypotension/shock (14.5%), and hypertensive emergencies (11.8%). Overall, 36.3% had a troponin increase >10× the upper limit of normal. Coronary angiography was performed in 22.4% (n=17) of patients during hospitalizations due to type 2 MIs. The hazard of cardiovascular death was numerically higher following type 2 MI (vs. no MI, adj. HR 11.82, 95% CI 5.71-24.46; P<.0001) than that of type 1 MI (vs. no MI, adj. HR 8.90, 95% CI 6.93-11.43; P<.0001). Type 2 MIs were more prevalent in the first month after ACS, were characterized by the presence of triggers and infrequent use of an invasive strategy, and were associated with a high risk of death. Further efforts are needed to better define the role and implications of type 2 MI in both clinical practice and research.

Vorapaxar: The Current Role and Future Directions of a Novel Protease-Activated Receptor Antagonist for Risk Reduction in Atherosclerotic Disease.

IntroductionDespite the current standard of care, patients with cardiovascular disease remain at a high risk for recurrent events. Inhibition of thrombin-mediated platelet activation through protease-activated receptor-1 antagonism may provide reductions in atherosclerotic disease beyond those achievable with the current standard of care.ObjectiveOur primary objective is to evaluate the clinical literature regarding the role of vorapaxar (Zontivity™) in the reduction of cardiovascular events in patients with a history of myocardial infarction and peripheral artery disease. In particular, we focus on the potential future directions for protease-activating receptor antagonists in the treatment of a broad range of atherosclerotic diseases.Data SourcesA literature search of PubMed and EBSCO was conducted to identify randomized clinical trials from August 2005 to June 2016 using the search terms: ‘vorapaxar’, ‘SCH 530348’, ‘protease-activated receptor-1 antagonist’, and ‘Zontivity™’. Bibliographies were searched and additional resources were obtained.ResultsVorapaxar is a first-in-class, protease-activated receptor-1 antagonist. The Thrombin Receptor Antagonist for Clinical Event Reduction (TRACER) trial did not demonstrate a significant reduction in a broad primary composite endpoint. However, the Thrombin-Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2°P-TIMI 50) trial examined a more traditional composite endpoint and found a significant benefit with vorapaxar. Vorapaxar significantly increased bleeding compared with standard care. Ongoing trials will help define the role of vorapaxar in patients with peripheral arterial disease, patients with diabetes mellitus, and other important subgroups. The use of multivariate modeling may enable the identification of subgroups with maximal benefit and minimal harm from vorapaxar.ConclusionVorapaxar provides clinicians with a novel mechanism of action to further reduce the burden of ischemic heart disease. Identification of patients with a high ischemic risk and low bleeding risk would enable clinicians to maximize the utility of this unique agent.Electronic supplementary materialThe online version of this article (doi:10.1007/s40268-016-0158-4) contains supplementary material, which is available to authorized users.

High-Sensitivity Troponin I in Stable Patients with Atherosclerotic Disease in the TRA 2°P - TIMI 50 Trial.

Cardiac troponin I, measured with a high-sensitivity assay (hs-TnI), is well-established for risk prediction in acute coronary syndromes. However, its prognostic role in stable atherosclerotic disease, particularly for future myocardial infarction (MI), is less well defined. We measured hs-TnI (Abbott ARCHITECT) in 15833 patients with prior MI, ischemic stroke, or peripheral arterial disease from the placebo-controlled Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2°P)-Thrombolysis in Myocardial Infarction (TIMI) 50 trial of the platelet inhibitor vorapaxar, excluding patients with recent MI (<30 days). hs-TnI was categorized into 5 groups based on the detection limit (1.9 ng/L), 99th percentile reference limit (26 ng/L), and tertiles in between (1.9-26 ng/L), as well as sex-specific reference limits. Higher hs-TnI concentration was associated with older age, male sex, and increased atherosclerosis burden. hs-TnI identified a graded 3-year risk of cardiovascular death, MI, or stroke from 5.0% to 18.6% (P < 0.001), driven by cardiovascular death and MI (P < 0.001). This risk was independent of established clinical risk indicators, B-type natriuretic peptide and C-reactive protein [adjusted hazard ratio 2.70 (95% CI, 1.96-3.71), P < 0.001 for hs-TnI >26 ng/L vs <1.9 ng/L]. In patients with prior MI, there was a pattern of greater absolute benefit with vorapaxar in patients with an increased hs-TnI (absolute risk difference 1.9% with hs-TnI >26 ng/L vs 0.3% with hs-TnI <1.9 ng/L; P interaction = 0.82). In stable patients with established atherosclerosis, hs-TnI concentrations effectively stratified the risk of new or recurrent cardiovascular (CV) events, in particular CV death and MI. High-risk patients with prior MI identified by increased hs-TnI had a substantial absolute improvement in net clinical outcome with vorapaxar.