vorapaxar and Acute-Coronary-Syndrome

Acute Coronary Syndrome (ACS) is a term that describes pathologies related to myocardial ischemia, and is comprised of unstable angina, non-ST elevation myocardial infarction, and ST elevation myocardial infarction. Urgent management of ACS is typically necessary to prevent future morbidity and mortality. Current medical recommendations of ACS management involve use of dual antiplatelet therapy, typically with aspirin and clopidogrel. However, newer therapies are being designed and researched to improve outcomes for patients with ACS. Vorapaxar is a novel antiplatelet therapy that inhibits thrombin-mediated platelet aggregation to prevent recurrence of ischemic events. It has been Food and Drug Administration approved for reduction of thrombotic cardiovascular events in patients with a history of MI or peripheral arterial disease with concomitant use of clopidogrel and/or aspirin, based upon the findings of the TRA 2°P-TIMI 50 trial. However, Vorapaxar was also found to have a significantly increased risk of bleeding, which must be considered when administering this drug. Based upon further subgroup analysis of both the TRA 2°P-TIMI 50 trial and TRACER trial, Vorapaxar was found to be potentially beneficial in patients with peripheral artery disease, coronary artery bypass grafting, and ischemic stroke. There are current trials in progress that are further evaluating the use of Vorapaxar in those conditions, and future research and trials are necessary to fully determine the utility of this drug.

Topics: Acute Coronary Syndrome; Aspirin; Clopidogrel; Humans; Myocardial Infarction; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Receptors, Proteinase-Activated; Stroke; Treatment Outcome

Vorapaxar is the first protease-activated receptor-1 inhibitor approved for clinical use. Its main indication is the reduction in thrombotic cardiovascular events in patients with previous myocardial infarction or symptomatic peripheral artery disease. Areas covered: This article reviews the pharmacokinetics of vorapaxar and its potential use in secondary prevention after an acute coronary syndrome. Expert opinion: Vorapaxar inhibits platelet aggregation mediated by thrombin. This effect is carried out without affecting to coagulation parameters and bleeding times. This drug has showed a significant reduction of cardiovascular events in patients with chronic atherosclerosis but not during the admission for an acute coronary syndrome. The rate of major bleeding found in patients treated with vorapaxar in randomized trials was consistently higher than placebo in most of the analyzed subgroups. For this reason, cautious evaluation of risk-benefit profiles should be required before prescribing this drug.

Topics: Acute Coronary Syndrome; Animals; Hemorrhage; Humans; Lactones; Platelet Aggregation Inhibitors; Pyridines; Randomized Controlled Trials as Topic; Receptor, PAR-1; Secondary Prevention

Atherosclerosis is frequently caused by clot blockage of the coronary or peripheral arteries, and may lead to myocardial infarction (MI) or peripheral arterial disease (PAD). Despite advancements in management of atherosclerosis, mortality and ischemic rates remain high. Vorapaxar is a protease activated receptor-1 (PAR-1) antagonist, and prevents thrombin activation of PAR-1 receptors on platelets.. Vorapaxar was studied in 2 landmark trials in patients with acute coronary syndrome (ACS) and in those with history of atherosclerosis. For patients with ACS, vorapaxar did not significantly reduce rates of the primary efficacy outcome as compared to placebo. For patients with a history of atherosclerosis, vorapaxar significantly reduced rates of primacy outcome. However, in both landmark trials, vorapaxar significantly increased risks of bleeding, and significantly increases risks of intracranial hemorrhage in patients with a history of stroke. Vorapaxar was approved in 2014 in the US for patients with a history of MI or PAD, and in the European Union for patients with a history of MI.. Use of vorapaxar may be limited due to its high potential for causing bleeding. Efficacy of vorapaxar in addition to aspirin and prasugrel or ticagrelor for the management of ACS should be studied in the future.

Topics: Acute Coronary Syndrome; Animals; Atherosclerosis; Hemorrhage; Humans; Lactones; Platelet Aggregation Inhibitors; Pyridines; Randomized Controlled Trials as Topic; Receptor, PAR-1; Risk; Stroke; Thrombosis

The optimal utilization of antiplatelet therapy in patients with renal impairment (RI) following acute coronary syndromes (ACS) represents an urgent, unmet and yet unsolved need with regards to the choice of agents, duration of treatment and potential dose/regimen adjustment. The lack of any large randomized trials designed and powered specifically in such high-risk patients, absence of the uniformed efficacy and safety data reporting policy to the FDA and endless overoptimistic publications based on post hoc analyses of primary trials sometimes exaggerating benefits and hiding risks, clouds reality. In addition, triaging RI patients is problematic due to ongoing kidney deterioration and the fact that such patients are prone to both vascular occlusions and bleeding. The authors summarize available FDA-confirmed evidence from the latest trials with approved antiplatelet agents, namely clopidogrel (CAPRIE, CURE, CREDO, CLARITY, CHARISMA); prasugrel (TRITON, TRILOGY); ticagrelor (PLATO, and PEGASUS); and vorapaxar (TRACER and TRA2P) in RI patient cohorts on top of aspirin as part of dual antiplatelet therapy (DAPT). We deliberately avoided any results unless they were verified by the FDA, with the exception of the recent PEGASUS, since Agency reviews are not yet available. Despite differences among the trials and DAPT choices, RI patients universally experience much higher (HR = 1.3-3.1) rates of primary endpoint events, and bleeding risks (HR = 1.7-3.6). However, only ticagrelor increases creatinine and uric acid levels above that of clopidogrel; has the worst incidence of serious adverse events, more adverse events, and inferior outcomes in patients with severe (eGFR <30 ml/min), especially in the lowest (eGFR <15 ml/min) RI subsets. Clopidogrel, prasugrel and vorapaxar appear safer. Moreover, less aggressive half dose (5 mg/daily) prasugrel and strict DAPT, are well justified in RI, but not predominantly triple strategies with vorapaxar as tested in TRA2P and especially in TRACER. In conclusion, data from clinical trials, their sub-studies and affiliated FDA reviews indicate that RI cause more vascular occlusions and bleeding in ACS patients treated with DAPT. Among the novel antiplatelet agents, prasugrel and vorapaxar, but probably not ticagrelor, offer advantage in RI patients.

Topics: Acute Coronary Syndrome; Adenosine; Clinical Trials as Topic; Clopidogrel; Comparative Effectiveness Research; Glomerular Filtration Rate; Hemorrhage; Humans; Lactones; Patient Selection; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Pyridines; Renal Insufficiency; Ticagrelor; Ticlopidine

Patients with acute coronary syndrome (ACS) usually receive acetylsalicylic acid plus an adenosine diphosphate (ADP) receptor inhibitor to reduce the long-term risk of recurrent events. However, patients receiving standard antiplatelet prophylaxis still face a substantial risk of recurrent events. Strategies involving 3 antithrombotic agents with different modes of action have now been tested. In Thrombin Receptor Antagonists for Clinical Event Reduction (TRA-CER), compared with standard care alone, bleeding complications including intracranial hemorrhage (ICH) were increased with the addition of vorapaxar, without efficacy benefit. In Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients With Atherosclerosis (TRA 2°P-TIMI 50), the addition of vorapaxar reduced recurrent events compared with standard care in stable patients with prior myocardial infarction. This study was terminated early in patients with prior stroke owing to excess ICH, though an increased risk of ICH or fatal bleeding was not detected in patients with prior myocardial infarction. The Apixaban for Prevention of Acute Ischemic and Safety Events 2 (APPRAISE-2) trial of standard-dose apixaban added to standard care in patients with ACS was also stopped early owing to excess serious bleeding. However, in Rivaroxaban in Combination With Aspirin Alone or With Aspirin and a Thienopyridine in Patients With Acute Coronary Syndromes (ATLAS ACS 2 TIMI 51), fatal bleeding or fatal ICH did not increase with low-dose rivaroxaban added to low-dose acetylsalicylic acid-based standard care compared with standard care alone. In that trial, a significant reduction of recurrent vascular events was shown with 3 antithrombotic regimens compared with standard care. Therefore, depending on drug dose and patient population, further reductions in recurrent vascular events after ACS may be possible in future clinical practice, with a favorable benefit-risk profile.

Topics: Acute Coronary Syndrome; Anticoagulants; Benzimidazoles; beta-Alanine; Clinical Trials as Topic; Coronary Thrombosis; Dabigatran; Hemorrhage; Humans; Imines; Lactones; Morpholines; Platelet Activation; Platelet Aggregation Inhibitors; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Secondary Prevention; Thiophenes; Thrombin

Mortality and morbidity in acute coronary syndromes (ACSs), caused principally by plaque erosion or rupture leading to thrombus formation and myocardial ischemia, have been reduced by a combination of antithrombotic agents (antiplatelet drugs and anticoagulants) and early revascularization. Aspirin is the foundation antiplatelet agent. New P2Y12 receptor inhibitors (prasugrel and ticagrelor) have clear benefits compared with clopidogrel for dual antiplatelet therapy, and cangrelor or vorapaxar, a thrombin receptor inhibitor, may be of value in specific settings. Anticoagulation uses 1 of 4 choices: bivalirudin, unfractionated heparin, enoxaparin, and fondaparinux. Moreover, some patients (such as those who have chronic atrial fibrillation) require triple therapy with aspirin, clopidogrel, plus an anticoagulant, frequently a vitamin K antagonist. New oral anticoagulants have been shown to be at least as effective as vitamin K antagonists in atrial fibrillation and led to fewer bleeding complications. Finally, the combination of aspirin, clopidogrel, and low-dose rivaroxaban has recently been approved by the European Medicines Agency (but not the Food and Drug Administration) for secondary prevention after ACS. Several strategies have been developed to balance the potential benefit of antithrombotic therapy against the risk of bleeding complications, for example, radial access in coronary angiography or restricted use of combination therapy, and others are under investigation, such as discontinuation of aspirin. This overview summarizes the current status of antithrombotic therapy in ACS and describes strategies currently explored to optimize its benefit/risk ratio.

Topics: Acute Coronary Syndrome; Adenosine; Adenosine Monophosphate; Anticoagulants; Aspirin; Drug Therapy, Combination; Enoxaparin; Eptifibatide; Fondaparinux; Heparin; Hirudins; Humans; Lactones; Peptide Fragments; Peptides; Piperazines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Polysaccharides; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Pyridines; Receptors, Thrombin; Recombinant Proteins; Thiophenes; Ticagrelor; Tirofiban; Tyrosine; Warfarin

Acute coronary syndrome (ACS) constitutes a group of pathophysiological entities resulting from reduced blood flow in the coronary arteries leading to decreased or improper functioning or death of heart muscle. Such patients are usually prescribed combination antiplatelet drug therapy, containing acetylsalicylic acid (aspirin) and an adenosine diphosphate receptor inhibitor to prevent recurrence of ischemic events. The combination prophylactic therapy to certain extend has been successful in preventing secondary complications including ischemic/thrombotic events in these patients. However, research is still on for newer advances in anti-thrombotic therapy that can further prevent secondary complications of Acute Coronary Syndrome. Vorapaxar is a newer drug recommended along with aspirin or clopidogril for prevention of recurrence of cardiac events. Vorapaxar, a thrombin receptor antagonist acts by reversible inhibition of the protease-activated receptor-1 (PAR-1). PAR-1 is expressed on platelets, and it inhibits platelet aggregation, both thrombin-induced and thrombin receptor agonist peptide (TRAP)-induced. Various trials world -wide have documented its efficacy as an anti-platelet agent for preventing recurrent cardiovascular ischemic events but at the expense of increased bleeding complications including intracranial haemorrhage (ICH), when compared to standard therapy alone. For the same reason, vorapaxar is contraindicated in patients with prior stroke, transient ischemic attack and ICH. U.S. Food and Drug Administration (FDA) approved vorapaxar in May 2014 as an antiplatelet agent along with standard anti-platelet therapy for the reduction of recurring thrombotic cardiovascular events in patients with a history of myocardial infarction or with peripheral arterial disease. Vorapaxar is developed and marketed by Merck Sharp Dohme and is available by the brand name 'Zontivity' as 2.5 mg oral tablet equivalent to 2.08 mg of vorapaxar sulfate. There are two patents protecting this drug.

Topics: Acute Coronary Syndrome; Animals; Blood Platelets; Drug Therapy, Combination; Hemorrhage; Humans; Lactones; Patient Selection; Platelet Aggregation Inhibitors; Pyridines; Receptor, PAR-1; Risk Factors; Signal Transduction; Treatment Outcome

Acute coronary syndrome (ACS) encompasses acute myocardial infarction (MI) and unstable angina. Activation of platelets and coagulation cascade plays a central role in the development of ACS. Over the past decade, there have been substantial improvements in the strategies for secondary prevention of ACS, including the development of more potent oral antiplatelet agents such as prasugrel and ticagrelor. However, therapies with even better efficacy and safety profiles and more rapid onset and offset of action would be desirable.. This review discusses the advantages and disadvantages of the currently available antithrombotic agents and describes the findings from recent clinical trials of three novel agents; cangrelor (an intravenous P2Y12 receptor antagonist), vorapaxar (protease-activated receptor-1 inhibitor) and rivaroxaban (an oral factor Xa inhibitor).. Cangrelor appears more promising than clopidogrel when a very rapid onset and reversal of antiplatelet effect is needed. Vorapaxar in addition to standard oral antiplatelet therapy was effective in patients with prior MI, but was not safe in patients with a prior stroke. Low dose rivaroxaban decreased cardiovascular events and mortality in patients post-ACS compared to placebo, although bleeding was increased.

Topics: Acute Coronary Syndrome; Adenosine Monophosphate; Fibrinolytic Agents; Humans; Lactones; Morpholines; Platelet Aggregation Inhibitors; Pyridines; Rivaroxaban; Thiophenes

Platelet activation is a key process in the pathogenesis of acute coronary syndromes (ACS). Of the many triggers involved in this process, three are presumed to be critical: thromboxane A(2) (TBXA(2)) via the TBXA(2) receptor, adenosine diphosphate via the P2Y(12) receptor, and thrombin via the protease-activated receptor (PAR)-1. Despite the effective inhibition of the first two pathways with aspirin and an expanding family of P2Y(12) inhibitors, the incidence of recurrent ischemic events remains high after ACS. PAR-1 inhibitors are a novel class of antiplatelet agents that inhibit thrombin-mediated platelet activation. Preclinical data and phase 2 clinical trials in patients with stable and unstable coronary disease support the potential of these compounds to improve clinical outcome. In this review we discuss the rationale for developing this novel class of agents with a focus on the two compounds in most advanced clinical development, vorapaxar (SCH 530348) and atopaxar (E5555).

Topics: Acute Coronary Syndrome; Aspirin; Female; Humans; Imines; Lactones; Male; Myocardial Ischemia; Platelet Activation; Platelet Aggregation Inhibitors; Pyridines; Randomized Controlled Trials as Topic; Receptor, PAR-1; Recurrence; Treatment Outcome

Ischemic heart disease remains the number one cause of death in the world despite advances in invasive and pharmacologic therapies. An ongoing area of research is the central role of platelets in atherothrombosis. Many therapeutic strategies have been developed over the last few decades affecting different platelet receptors to alter platelet-mediated thrombosis including targeting the receptors for thromboxane A(2), adenosine diphosphate, and fibrinogen. However, despite the use of pharmacologic agents directed at these pathways, residual morbidity and mortality still exist. Therefore, identifying agents that more favorably balance a reduction in ischemic events while minimizing bleeding events is an ongoing mission. Thrombin is known to be the most potent stimulant of platelet-mediated thrombosis whose action on the platelet is through a family of receptors known as the protease-activated receptors (PARs). Activation through the PAR-1 receptor, in particular, results in an early and intense response by the platelet to thrombin, and it is the primary thrombin receptor on platelets, thus making it a potentially desirable target for therapy. Most recently, two PAR-1 antagonists, atopaxar and vorapaxar, have been tested in clinical trials. Generally, the results show a reduction in ischemic event rates, but an increase in bleeding event rates. This article will summarize the current state of the literature and consider the role these drugs might play in the future for the prevention of ischemic heart disease events.

Topics: Acute Coronary Syndrome; Blood Platelets; Coronary Artery Disease; Hemorrhage; Humans; Imines; Lactones; Myocardial Infarction; Platelet Activation; Platelet Aggregation Inhibitors; Pyridines; Receptor, PAR-1; Thrombin; Treatment Outcome

The unifying basis of acute coronary syndrome (ACS) is the complication of a vulnerable coronary plaque, an event primarily mediated by platelet activation. Three major pathways are predominantly involved in this process: thromboxane A(2) via the thromboxane A(2) receptor, adenosine diphosphate via the P2Y(12) receptor, and thrombin via the protease-activated receptor (PAR)-1, with the latter being the most potent platelet activator. Despite the effective inhibition of the first two pathways with aspirin and an expanding family of P2Y(12) inhibitors, respectively, the recurrence of ischemic events in patients with ACS remains high. There is also a growing concern regarding the safety profile in terms of bleeding with more powerful antiplatelet agents, which has tempered expectations of newly developed compounds. PAR-1 inhibitors are a novel class of antiplatelet agents that inhibit thrombin-mediated platelet activation. Preliminary data indicate that these compounds have the potential to improve ischemic prognosis without increasing the bleeding risk. In this chapter we will discuss the rationale for developing this novel class of antiplatelet agents and specifically, the two compounds in most advanced clinical development, vorapaxar and atopaxar.

Topics: Acute Coronary Syndrome; Animals; Humans; Imines; Lactones; Myocardial Ischemia; Platelet Aggregation; Pyridines; Receptor, PAR-1; Receptors, Thrombin

Recent clinical trial data suggest that protease-activated receptor-1 (PAR-1) antagonists may increase the risk of intracranial hemorrhage. Our objective was to investigate the qualitative and quantitative risks of intracranial hemorrhage in patients receiving PAR-1 antagonist therapy.. Pubmed, EMBASE, Cochrane Central Register of Controlled Trials, and Clinicaltrials.gov from 1966 to May 2012, were searched to identify relevant studies. We included randomized controlled trials that included a comparison of PAR-1 antagonist with placebo and in which the total number of patients and intracranial hemorrhage events were reported separately for active treatment and control groups. Summary incidence rates, relative risks, and 95% confidence intervals (CIs) were calculated using random-effects models. Between-study heterogeneity was assessed using the I2 statistic.. In 9 PAR-1 antagonist trials with 42000 patients with a history of thrombotic vascular disease or acute coronary syndrome, PAR-1 antagonist treatment was associated with increased risk of intracranial hemorrhage (0.59% vs 0.30%; relative risk, 1.98; 95% CI, 1.46-2.68; P<0.00001; number needed to harm, 345). There was no heterogeneity across trials (P=0.84; I2=0%), PAR-1 antagonist agent (P=0.52), treatment duration (P=0.38), or trial-qualifying event (P=0.59). Risk of death from any cause or a cardiovascular cause did not differ between active treatment and control groups.. In a pooled analysis of data from 9 trials, PAR-1 antagonist therapy was associated with an increased risk for intracranial hemorrhage.

Topics: Acute Coronary Syndrome; Humans; Imines; Incidence; Intracranial Hemorrhages; Lactones; Placebos; Pyridines; Randomized Controlled Trials as Topic; Receptor, PAR-1; Risk Factors; Thrombosis

Merck & Co. is developing vorapaxar (SCH 530348), a thrombin receptor antagonist, for the prevention and treatment of arterial thrombosis. Vorapaxar is currently being evaluated in two large-scale multinational phase III trials (TRA*CER and TRA 2°P-TIMI 50) for the treatment and prevention of cardiac events in almost 30,000 patients with acute coronary syndromes and those with prior myocardial infarction or stroke, as well as patients with acute coronary syndrome and those with peripheral arterial disease. This review discusses the development history and scientific profile of this new compound.

Topics: Acute Coronary Syndrome; Animals; Clinical Trials, Phase III as Topic; Humans; Lactones; Pyridines; Receptors, Thrombin

Antiplatelet therapy is the cornerstone of management of acute coronary syndromes. Currently used antiplatelet drugs present several limitations that provoke new searches. These limitations include resistance, delay in the onset of action, risk for bleeding, variations in the individual response, and interaction with other medications (i.e. proton pump inhibitors, calcium channel blockers). New concepts and medications have emerged for the effective inhibition of platelets. Prasugrel, AZD6140 (ticagrelor), cangrelor, and SCH 530348 (thrombin receptor antagonist) are among some of the novel agents that survived randomized trials. In this review, we aimed to summarize novel concepts and agents in antiplatelet therapy.

Topics: Acute Coronary Syndrome; Adenosine; Adenosine Monophosphate; Aspirin; Clopidogrel; Humans; Lactones; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Pyridines; Receptors, Thrombin; Thiophenes; Ticagrelor; Ticlopidine

SCH 530348, a synthetic tricyclic 3-phenylpyridine, is an orally active fourth generation himbacine-based antagonist of the protease-activated receptor (PAR)-1, the primary receptor for thrombin on platelets in humans. SCH 530348 is the first in a new class of compounds that inhibit thrombin-mediated platelet aggregation without affecting the enzymatic activity of thrombin on fibrinogen. Preclinical and initial clinical studies have demonstrated this compound to be a highly potent inhibitor of thrombin-induced platelet activation, to have excellent oral bioavailability and to have a favorable safety profile. These data suggest that this compound has the potential to reduce the risk of ischemic events without significantly increasing the rate of bleeding. Two large Phase III clinical outcome trials are currently underway to evaluate the safety and efficacy of SCH 530348 for the management of acute coronary syndromes and the secondary prevention of atherothrombotic events.

Topics: Acute Coronary Syndrome; Coronary Thrombosis; Humans; Lactones; Platelet Aggregation; Pyridines; Receptor, PAR-1; Receptors, Thrombin; Thromboembolism

Despite recent advances in the treatment of acute coronary syndromes (ACS), including dual antiplatelet therapy with aspirin and a thienopyridine during the acute phase and for secondary prevention, this condition remains a leading cause of morbidity and mortality. The limitations of the currently available antiplatelet agents have triggered the development of newer drugs. In this review we summarize the mechanisms of actions and results of current clinical trials of novel antiplatelet agents. These include prasugrel, a thienopyridine prodrug which has a mechanism similar to that of clopidogrel but superior pharmacokinetic features; ticagrelor, a non-thienopyridine that binds reversibly to the platelet P2Y(12) receptor; cangrelor, an intravenously administered analog of ticagrelor; the thrombin receptor antagonist SCH 53048; and terutroban (S18886), a thromboxane A(2) receptor inhibitor.

Topics: Acute Coronary Syndrome; Adenosine; Adenosine Monophosphate; Humans; Lactones; Naphthalenes; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Prodrugs; Propionates; Pyridines; Thiophenes; Ticagrelor

Antiplatelet agents play an essential role in the treatment of acute coronary syndrome (ACS). Thienopyridines are a class of drugs that function via inhibition of the adenosine diphosphate (ADP) P2Y12 platelet receptors. Currently, clopidogrel, a second generation thienopyridine, is the main drug of choice and the combination of aspirin and clopidogrel is administered orally for the treatment of ACS. Clopidogrel, is a pro-drug that needs to be metabolized in the liver and intestines to form active metabolites. Prasugrel, a third generation thienopyridine, was approved for use in Europe in February 2009, and is currently available in the United Kingdom. All thienopyridines however, have pharmacological limitations that lead to a search for more effective non-thienopyridine P2Y12 inhibitors. Promising results have been reported with ticagrelor, an oral first reversible, direct-acting inhibitor of the P2Y12 receptor. Ticagrelor is the first oral P2Y12 receptor binding antagonist that does not require metabolic activation. Furthermore, ticagrelor has at last 1 active metabolite, which has very similar pharmacokinetics to the parent compound. Therefore, ticagrelor has more rapid onset and more pronounced platelet inhibition than other antiplatelet agents. The safety and efficacy of ticagrelor compared with clopidogrel in ACS patient has been recently evaluated by the PLATelet inhibition and patient Outcomes (PLATO) trial. Ticagrelor compared with clopidogrel had a significantly greater reduction in the death rate from vascular causes, myocardial infarction, or stroke without major bleeding. There was however, an increase in non-procedure related bleeding, dyspnoea and ventricular pauses in the first week of treatment. Further studies on new antiplatelet agents are needed to establish a new "gold standard" antiplatelet therapy.

Topics: Acute Coronary Syndrome; Adenosine; Adenosine Monophosphate; Biotransformation; Clinical Trials as Topic; Clopidogrel; Hemorrhage; Humans; Lactones; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Pyridines; Receptors, Purinergic P2; Receptors, Purinergic P2Y12; Thiophenes; Ticagrelor; Ticlopidine

The incidence of new coronary events in patients receiving dual antiplatelet therapy (e.g. cyclo-oxygenase inhibitors such as aspirin [acetylsalicylic acid; ASA]) and ADP receptor blockers (e.g. clopidogrel) is high. Therefore, it is critical to identify patients who require more intense treatment such as those with poor tolerance to existing drugs, those with genotypes that predict treatment resistance, diabetic patients, and smokers. The new ADP receptor blockers (prasugrel, cangrelor, Ticagrelor) can provide greater efficacy but it should not be associated with increased bleeding. Thrombin receptor antagonists (e.g. SCH530348) are another alternative that is currently being tested in randomized trials.

Topics: Acute Coronary Syndrome; Adenosine; Adenosine Diphosphate; Adenosine Monophosphate; Clopidogrel; Humans; Lactones; Piperazines; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Prasugrel Hydrochloride; Pyridines; Thiophenes; Ticagrelor; Ticlopidine

Three novel nonthienopyridine antiplatelet agents--cangrelor, ticagrelor (AZD6140), and SCH 530348--are in advanced clinical testing in patients with coronary artery disease. Cangrelor and ticagrelor are direct and reversible inhibitors of the platelet adenosine 5'-diphosphate P2Y12 receptor, whereas SCH 530348 is a thrombin receptor antagonist. Clinical data available to date for each of these compounds suggest that they have safety and efficacy profiles that will be advantageous to patients with acute coronary syndromes or undergoing percutaneous intervention. We review the clinical features of these new platelet inhibition therapies.

Topics: Acute Coronary Syndrome; Adenosine; Adenosine Monophosphate; Angioplasty, Balloon, Coronary; Aspirin; Clinical Trials as Topic; Coronary Disease; Drug Therapy, Combination; Humans; Lactones; Platelet Aggregation Inhibitors; Purinergic P2 Receptor Antagonists; Pyridines; Receptors, Thrombin; Ticagrelor

Platelet activation and thrombin formation play significant roles in the pathophysiology of acute coronary syndrome. To overcome this pathophysiology, antiplatelet agents are utilized to decrease platelet aggregation and anticoagulants to decrease thrombin formation. Current antiplatelet agents are designed to inhibit various mediators of platelet activation, such as thromboxane A2 and adenosine diphosphate, and platelet-surface receptors (e.g., glycoprotein IIb/IIIa receptors). The rationale for upstream versus deferred administration of antiplatelet therapy in patients scheduled for percutaneous intervention and the current ACC/AHA guidelines for the management of patients with unstable angina/non-ST-segment myocardial infarction are discussed. The next-generation antiplatelet drugs are in various stages of clinical development, with unique differentiating mechanistic and pharmacokinetic properties. The newer P2Y12 thienopyridine receptor antagonists and protease receptor inhibitor are also examined, in addition to the rationale of various outcome studies evaluating the efficacy and safety of the different agents.

Topics: Acute Coronary Syndrome; Adenosine Monophosphate; Angina, Unstable; Aspirin; Blood Platelets; Cardiac Catheterization; Fibrinolytic Agents; Humans; Lactones; Myocardial Infarction; Platelet Activation; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Pyridines; Treatment Outcome

Variation in platelet response to thrombin may affect the safety and efficacy of PAR antagonism. The Thr120 variant of the common single nucleotide polymorphism (SNP) rs773902 in the protease-activated receptor (PAR) 4 gene is associated with higher platelet aggregation compared to the Ala120 variant. We investigated the relationship between the rs773902 SNP with major bleeding and ischemic events, safety, and efficacy of PAR1 inhibition in 6177 NSTE ACS patients in the TRACER trial. There was a lower rate of GUSTO moderate/severe bleeding in patients with the Thr120 variant. The difference was driven by a lower rate in the smaller homozygous group (recessive model, HR 0.13 [0.02-0.92] P = 0.042). No significant differences were observed in the ischemic outcomes. The excess in bleeding observed with PAR1 inhibition was attenuated in patients with the Thr120 variant, but the interactions were not statistically significant. In summary, lower major bleeding rates were observed in the overall TRACER cohort with the hyperreactive PAR4 Thr120 variant. The increase in bleeding with vorapaxar was attenuated with the Thr120 variant, but we could not demonstrate an interaction with PAR1 inhibition. These findings warrant further exploration, including those of African ancestry where the A allele (Thr120) frequency is ~65%.

Topics: Acute Coronary Syndrome; Aged; Female; Genetic Variation; Genotype; Hemorrhage; Humans; Ischemia; Lactones; Male; Middle Aged; Platelet Aggregation Inhibitors; Polymorphism, Single Nucleotide; Pyridines; Randomized Controlled Trials as Topic; Receptor, PAR-1; Receptors, Thrombin

Dual antiplatelet therapy reduces non-fatal ischaemic events after acute coronary syndrome (ACS) but increases bleeding to a similar extent. We sought to determine the prognostic impact of myocardial infarction (MI) vs. bleeding during an extended follow-up period to gain insight into the trade-off between efficacy and safety among patients after ACS.. In 12 944 patients with non-ST-segment elevation ACS from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial, we investigated the relative impact of MI and bleeding occurring >30 days post-ACS and subsequent all-cause mortality. Bleeding was graded according to Bleeding Academic Research Consortium (BARC) criteria. MI was associated with a five-fold increase in mortality. BARC type 2 and 3, but not type 1, bleeding had a significant impact on mortality. MI was associated with a greater risk of mortality compared with BARC 2 [relative risk (RR) 3.5; 95% confidence interval (CI) 2.08-4.77; P < 0.001] and BARC 3a bleeding (RR 2.23; 95% CI 1.36-3.64; P = 0.001), and a risk similar to BARC 3b bleeding (RR 1.37; 95% CI 0.81-2.30; P = 0.242). Risk of death after MI was significantly lower than after BARC 3c bleeding (RR 0.22; 95% CI 0.13-0.36; P < 0.001). MI and bleeding had similar time-associations with mortality, which remained significant for several months, still being higher early after the event.. In patients treated with antiplatelet therapy after ACS, both MI and bleeding significantly impacted mortality with similar time-dependency. Although BARC 2 and 3a bleeding were less prognostic for death than MI, the risk of mortality was equivalent between BARC 3b bleeding and MI, and was higher following BARC 3c bleeding.

Topics: Acute Coronary Syndrome; Aged; Cause of Death; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Hemorrhage; Humans; Lactones; Male; Middle Aged; Non-ST Elevated Myocardial Infarction; Platelet Aggregation Inhibitors; Pyridines; Receptors, Thrombin

Vorapaxar is effective in the prevention of secondary atherothrombotic events, although the efficacy/safety balance appears less favorable in the treatment of patients with non-ST-segment elevation (NSTE) acute coronary syndrome (ACS). We hypothesized that patients with NSTE ACS already receiving thienopyridine prior to the ACS event may show differential efficacy/safety effects with vorapaxar vs. placebo added to their standard care.. We studied 12,944 patients from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial with respect to thienopyridine use before admission for the index NSTE ACS event. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, rehospitalization for ischemia, and urgent revascularization. The key secondary endpoint was a composite of cardiovascular death, myocardial infarction, and stroke. Safety endpoints were bleeding complications.. TRACER was largely conducted in thienopyridine-naïve patients with unknown tolerance to multiple antiplatelet treatments. Patients receiving thienopyridine before the index event may have had an attenuated increase in bleeding when adding vorapaxar, whereas concomitantly adding vorapaxar and thienopyridine in naïve patients may have uncovered a latent susceptibility to bleeding.

Topics: Acute Coronary Syndrome; Aged; Female; Hemorrhage; Humans; Lactones; Male; Middle Aged; Platelet Aggregation Inhibitors; Pyridines; Secondary Prevention; Treatment Outcome

We evaluated outcomes associated with transradial vs. transfemoral approaches and vorapaxar in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) in the TRACER trial.. Vorapaxar reduces ischemic events but increases the risk of major bleeding.. We compared 30-day and 2-year major adverse cardiac events (MACE: cardiovascular death, myocardial infarction, stroke, recurrent ischemia with rehospitalization, and urgent coronary revascularization) and noncoronary artery bypass graft (CABG)-related bleedings in 2,192 transradial and 4,880 transfemoral patients undergoing PCI after adjusting for confounding variables, including propensity for transradial access.. Overall, 30-day GUSTO moderate/severe and non-CABG TIMI major/minor bleeding occurred less frequently in transradial (0.9% vs. 2.0%, P = 0.001) vs. transfemoral (1.1% vs. 2.5%, P = 0.005) patients. A similar reduction was seen at 2 years (3.3% vs. 4.7%, P = 0.008; 3.3% vs. 4.9%, P < 0.001, respectively). Transradial was associated with an increased risk of ischemic events at 30 days (OR 1.38, 95% CI 1.11-1.72; P = 0.004), driven primarily by increased periprocedural myocardial infarctions. At 2 years, rates of MACE were comparable (HR 1.14, 95% CI 0.98-1.33; P = 0.096). Although bleeding rates were higher with vorapaxar in transfemoral vs. transradial patients, there was no significant treatment interaction. Also, the access site did not modulate the association between vorapaxar and MACE.. Transradial access was associated with lower bleeding rates and similar long-term ischemic outcomes, suggesting transradial access is safer than transfemoral access among ACS patients receiving potent antiplatelet therapies. Because of the nonrandomized allocation of arterial access, these results should be considered exploratory. © 2015 Wiley Periodicals, Inc.

Topics: Acute Coronary Syndrome; Aged; Catheterization, Peripheral; Female; Femoral Artery; Hemorrhage; Humans; Lactones; Male; Middle Aged; Myocardial Infarction; Patient Readmission; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Punctures; Pyridines; Radial Artery; Recurrence; Retreatment; Risk Factors; Stroke; Time Factors; Treatment Outcome

Vorapaxar is a first-in-class protease-activated receptor-1 antagonist indicated for secondary prevention in stable patients with previous myocardial infarction (MI) or peripheral artery disease and no cerebrovascular disease. Vorapaxar is not recommended for initiation in the acute phase of acute coronary syndromes (ACS) because of an unfavorable balance between bleeding and efficacy when started in that setting. The aim of this analysis was to investigate outcomes in patients who experienced a new ACS while receiving vorapaxar for long-term secondary prevention. Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic ischemic Events-Thrombolysis In Myocardial Infarction 50 was a randomized, double-blind, placebo-controlled trial of vorapaxar (n = 26,449). We evaluated bleeding and ischemic events during the acute care of patients with a new ACS during the trial. During a median follow-up of 30 months, 799 patients (8.9%) randomized to vorapaxar and 913 (10.0%) to placebo had a new ACS event (p = 0.003); 87% and 86%, respectively, were on study therapy at the time of the event. In a landmark analysis through 7 days after ACS, the rates of Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) severe bleeding were 0.8% versus 0.8% (hazard ratio [HR] 0.99, 95% CI 0.33 to 2.94) and GUSTO moderate/severe bleeding were 2.5% versus 1.6% (HR 1.59, 95% CI 0.78 to 3.24) with vorapaxar versus placebo. The effect of vorapaxar on cardiovascular death, MI, or stroke (2.4% vs 4.4%; HR 0.54, 95% CI 0.31 to 0.93; p = 0.027) was consistent with the overall trial result. In conclusion, in patients who experience a new ACS event while receiving vorapaxar for secondary prevention, continuing therapy was associated with favorable efficacy without excess severe bleeding during the period of acute ACS management.

Topics: Acute Coronary Syndrome; Aged; Double-Blind Method; Female; Fibrinolytic Agents; Follow-Up Studies; Humans; Lactones; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Pyridines; Secondary Prevention; Treatment Outcome

The Bleeding Academic Research Consortium (BARC) scale has been proposed to standardize bleeding endpoint definitions and reporting in cardiovascular trials. Validation in large cohorts of patients is needed.. This study sought to investigate the relationship between BARC-classified bleeding and mortality and compared its prognostic value against 2 validated bleeding scales: TIMI (Thrombolysis In Myocardial Infarction) and GUSTO (Global Use of Strategies to Open Occluded Arteries).. We analyzed bleeding in 12,944 patients with acute coronary syndromes without ST-segment elevation, with or without early invasive strategy. The main outcome measure was all-cause death.. During follow-up (median: 502 days), noncoronary artery bypass graft (CABG) bleeding occurred in 1,998 (15.4%) patients according to BARC (grades 2, 3, or 5), 484 (3.7%) patients according to TIMI minor/major, and 514 (4.0%) patients according to GUSTO moderate/severe criteria. CABG-related bleeding (BARC 4) occurred in 155 (1.2%) patients. Patients with BARC (2, 3, or 4) bleeding had a significant increase in risk of death versus patients without bleeding (BARC 0 or 1); the hazard was highest in the 30 days after bleeding (hazard ratio: 7.35; 95% confidence interval: 5.59 to 9.68; p < 0.0001) and remained significant up to 1 year. The hazard of mortality increased progressively with non-CABG BARC grades. BARC 4 bleeds were significantly associated with mortality within 30 days (hazard ratio: 10.05; 95% confidence interval: 5.41 to 18.69; p < 0.0001), but not thereafter. Inclusion of BARC (2, 3, or 4) bleeding in the 1-year mortality model with baseline characteristics improved it to an extent comparable to TIMI minor/major and GUSTO moderate/severe bleeding.. In patients with acute coronary syndromes without ST-segment elevation, bleeding assessed with the BARC scale was significantly associated with risk of subsequent death up to 1 year after the event and risk of mortality increased gradually with higher BARC grades. Our results support adoption of the BARC bleeding scale in ACS clinical trials. (Trial to Assess the Effects of Vorapaxar [SCH 530348; MK-5348] in Preventing Heart Attack and Stroke in Participants With Acute Coronary Syndrome [TRACER] [Study P04736]; NCT00527943).

Topics: Acute Coronary Syndrome; Aged; Coronary Artery Bypass; Double-Blind Method; Female; Hemorrhage; Humans; Lactones; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Prognosis; Pyridines; Risk Assessment; Severity of Illness Index; Stents; Stroke

Stent thrombosis (ST) is an important end point in cardiovascular clinical trials. Adjudication is traditionally based on clinical event committee (CEC) review of case report forms and source documentation rather than angiograms. However, the degree to which this method of adjudication is concordant with the review of independent angiographic core laboratories (ACLs) has not been studied. This report represents the first assessment of variability between local investigators (LIs), a CEC, and an ACL.. Serial angiograms of 329 patients with acute coronary syndrome without ST-segment-elevation who underwent percutaneous coronary intervention at entry in the Trial to Assess the Effects of Vorapaxar in Preventing Heart Attack and Stroke in Particpants With Acute Coronary Syndrome (TRACER) and who met criteria for possible ST subsequent to the index event were reviewed by an ACL. The ACL was blinded to the assessment by both LIs and the CEC regarding the presence or absence of ST. CEC adjudication was based on Academic Research Consortium definitions of ST, using case report form data and source documents, including catheterization laboratory reports. The ACL, CEC, and LIs agreed on the presence or absence of ST in 52.9% events (κ=0.32; 95% confidence interval, 0.26-0.39). The ACL and CEC agreed on 82.7% of events (κ=0.57; 95% confidence interval, 0.47-0.67); the ACL and LIs agreed on 61.1% of events (κ=0.25; 95% confidence interval, 0.16-0.34); and the CEC and LIs agreed on 62% of events (κ=0.28; 95% confidence interval, 0.21-0.36).. ST reporting by an ACL, a CEC, and LIs is discordant. The assessment of ST is more often detected by direct review of angiograms by an ACL.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00527943.

Topics: Acute Coronary Syndrome; Angiography; Animals; Blood Vessel Prosthesis Implantation; Chick Embryo; Clinical Laboratory Techniques; Drug-Eluting Stents; Electrocardiography; Female; Follow-Up Studies; Humans; Lactones; Male; Outcome Assessment, Health Care; Percutaneous Coronary Intervention; Postoperative Complications; Pyridines; Reproducibility of Results; Thrombosis

We evaluated the interaction between protease-activated receptor-1 antagonist vorapaxar and concomitant glycoprotein (GP) IIb/IIIa receptor inhibitors in patients with non-ST-segment elevation acute coronary syndromes who underwent PCI. In Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome trial, 12,944 patients with non-ST-segment elevation acute coronary syndromes were randomized to vorapaxar or placebo. Administration of GP IIb/IIIa receptor inhibitors was allowed at the treating physician's discretion. We investigated whether use of GP IIb/IIIa receptor inhibitors modified vorapaxar's effect on non-coronary artery bypass grafting (CABG)-related bleeding at 7 days and ischemic events at 30 days. In total, 7,455 patients underwent PCI during index hospitalization. Of these, 2,023 patients (27.1%) received inhibitors and 5,432 (72.9%) did not. Vorapaxar was associated with a numerically higher rate of non-CABG-related moderate/severe Global Use of Strategies to Open Occluded Arteries (GUSTO) bleeding at 7 days compared with placebo in those who did (1.3% vs 1.0%) and did not (0.6% vs 0.4%) receive GP IIb/IIIa receptor inhibitors. Ischemic end point rates at 30 days were not significantly lower with vorapaxar versus placebo. Increased rates of non-CABG GUSTO moderate/severe bleeding were observed in patients who received GP IIb/IIIa receptor inhibitors versus those who did not (adjusted hazard ratio [HR] 1.77, 95% confidence interval [CI] 0.43 to 7.35 in placebo arm; adjusted HR 2.02, 95% CI 0.62 to 6.61 in vorapaxar arm) and in those who received vorapaxar versus placebo (adjusted HR 1.54, 95% CI 0.36 to 6.56 in the GP IIb/IIIa group; adjusted HR 1.34, 95% CI 0.44 to 4.07 in the no-GP IIb/IIIa group). No interaction was found between vorapaxar and inhibitor use up to 7 days (P interaction = 0.89) nor at the end of the treatment (P interaction = 0.74); however, the event rate was low. Also, no interaction was observed for efficacy end points after PCI at 30 days or at the end of the treatment. In conclusion, GP IIb/IIIa receptor inhibitor use plus dual antiplatelet therapy in a population with non-ST-segment elevation myocardial infarction planned for PCI was frequent but did not interact with vorapaxar's efficacy or safety. Nonetheless, GP IIb/IIIa receptor inhibitors and vorapaxar were associated with increased bleeding risk, and their combined use may result in additive effects on bleeding rates.

Topics: Acute Coronary Syndrome; Aged; Cross-Over Studies; Dose-Response Relationship, Drug; Drug Therapy, Combination; Electrocardiography; Female; Follow-Up Studies; Humans; Lactones; Male; Middle Aged; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Pyridines; Receptors, Thrombin; Time Factors; Treatment Outcome

Perioperative antiplatelet agents potentially increase bleeding after non-ST-segment elevation (NSTE) acute coronary syndromes (ACS). The protease-activated receptor 1 antagonist vorapaxar reduced cardiovascular events and was associated with increased bleeding versus placebo in NSTE ACS, but its efficacy and safety in noncardiac surgery (NCS) remain unknown. We aimed to evaluate ischemic, bleeding, and long-term outcomes of vorapaxar in NCS after NSTE ACS.. In the TRACER trial, 2202 (17.0%) patients underwent major or minor NCS after NSTE ACS over 1.5 years (median); continuing study treatment perioperatively was recommended. The primary ischemic end point for this analysis was cardiovascular death, myocardial infarction, stent thrombosis, or urgent revascularization within 30 days of NCS. Safety outcomes included 30-day NCS bleeding and GUSTO moderate/severe bleeding. Overall, 1171 vorapaxar and 1031 placebo patients underwent NCS. Preoperative aspirin and thienopyridine use was 96.8% versus 97.7% (P=0.235) and 89.1% versus 86.1% (P=0.036) for vorapaxar versus placebo, respectively. Within 30 days of NCS, no differences were observed in the primary ischemic end point between vorapaxar and placebo groups (3.4% versus 3.9%; adjusted odds ratio 0.81, 95% CI 0.50 to 1.33, P=0.41). Similarly, no differences in NCS bleeding (3.9% versus 3.4%; adjusted odds ratio 1.41, 95% CI 0.87 to 2.31, P=0.17) or GUSTO moderate/severe bleeding (4.2% versus 3.7%; adjusted odds ratio 1.15, 95% CI, 0.72 to 1.83, P=0.55) were observed. In a 30-day landmarked analysis, NCS patients had a higher long-term risk of the ischemic end point (adjusted hazard ratio 1.62, 95% CI 1.33 to 1.97, P<0.001) and GUSTO moderate/severe bleeding (adjusted hazard ratio 5.63, 95% CI 3.98 to 7.97, P<0.001) versus patients who did not undergo NCS, independent of study treatment.. NCS after NSTE ACS is common and associated with more ischemic outcomes and bleeding. Vorapaxar after NSTE ACS was not associated with increased perioperative ischemic or bleeding events in patients undergoing NCS.

Topics: Acute Coronary Syndrome; Aged; Double-Blind Method; Female; Hemorrhage; Humans; Lactones; Male; Middle Aged; Pyridines; Receptor, PAR-1; Surgical Procedures, Operative; Treatment Outcome

This study evaluated effects of protease-activated receptor-1 antagonist vorapaxar (Merck, Whitehouse Station, New Jersey) versus placebo among the TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) study patients with non-ST-segment elevation acute coronary syndromes undergoing coronary artery bypass grafting (CABG).. Platelet activation may play a key role in graft occlusion, and antiplatelet therapies may reduce ischemic events, but perioperative bleeding risk remains a major concern. Although the TRACER study did not meet the primary quintuple composite outcome in the overall population with increased bleeding, an efficacy signal with vorapaxar was noted on major ischemic outcomes, and preliminary data suggest an acceptable surgical bleeding profile. We aimed to assess efficacy and safety of vorapaxar among CABG patients.. Associations between treatment and ischemic and bleeding outcomes were assessed using time-to-event analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using the Cox hazards model. Event rates were estimated using the Kaplan-Meier method.. Among 12,944 patients, 1,312 (10.1%) underwent CABG during index hospitalization, with 78% on the study drug at the time of surgery. Compared with placebo CABG patients, vorapaxar-treated patients had a 45% lower rate of the primary endpoint (i.e., a composite of death, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization during index hospitalization) (HR: 0.55; 95% CI: 0.36 to 0.83; p = 0.005), with a significant interaction (p = 0.012). The CABG-related Thrombolysis In Myocardial Infarction major bleeding was numerically higher with vorapaxar, but not significantly different between vorapaxar and placebo (9.7% vs. 7.3%; HR: 1.36; 95% CI: 0.92 to 2.02; p = 0.12), with no excess in fatal bleeding (0% vs. 0.3%) or need for reoperation (4.7% vs. 4.6%).. In non-ST-segment elevation acute coronary syndrome patients undergoing CABG, vorapaxar was associated with a significant reduction in ischemic events and no significant increase in major CABG-related bleeding. These data show promise for protease-activated receptor 1 antagonism in patients undergoing CABG and warrant confirmatory evidence in randomized trials. (Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients With Acute Coronary Syndrome [TRA·CER] [Study P04736AM3]; NCT00527943).

Topics: Acute Coronary Syndrome; Aged; Confidence Intervals; Coronary Artery Bypass; Electrocardiography; Female; Follow-Up Studies; Hospital Mortality; Humans; Kaplan-Meier Estimate; Lactones; Male; Middle Aged; Myocardial Ischemia; Postoperative Complications; Postoperative Hemorrhage; Proportional Hazards Models; Prospective Studies; Pyridines; Receptors, Thrombin; Reference Values; Risk Assessment; Severity of Illness Index; Stroke; Survival Analysis; Treatment Outcome

Vorapaxar is an antagonist of the protease activated receptor-1 (PAR-1), the principal platelet thrombin receptor. The Thrombin Receptor Antagonist for Clinical Event Reduction (TRACER) trial evaluated vorapaxar compared to placebo in non-ST-elevation (NSTE)-acute coronary syndrome (ACS) patients. It was the study's objective to assess the pharmacodynamic effects of vorapaxar versus placebo that included aspirin or a thienopyridine or, frequently, a combination of both agents in NSTE-ACS patients. In a substudy involving 249 patients, platelet aggregation was assessed by light transmittance aggregometry (LTA) in 85 subjects (41 placebo, 44 vorapaxar) using the agonists thrombin receptor activating peptide (TRAP, 15 μM), adenosine diphosphate (ADP, 20 μM), and the combination of collagen-related peptide (2.5 μg/ml) + ADP (5 μM) + TRAP (15 μM) (CAT). VerifyNow® IIb/IIIa and vasodilator-stimulated phosphoprotein (VASP) phosphorylation assays were performed, and platelet PAR-1 expression, plasma platelet/endothelial and inflammatory biomarkers were determined before and during treatment. LTA responses to TRAP and CAT and VerifyNow results were markedly inhibited by vorapaxar. Maximal LTA response to TRAP (median, interquartile range) 2 hours post loading dose: placebo 68% (53-75%) and vorapaxar 3% (2-6%), p<0.0001. ADP inhibition was greater in the vorapaxar group at 4 hours and one month (p<0.01). In contrast to the placebo group, PAR-1 receptor number in the vorapaxar group at one month was significantly lower than the baseline (179 vs 225; p=0.004). There were significant changes in selected biomarker levels between the two treatment groups. In conclusion, vorapaxar caused a potent inhibition of PAR-1-mediated platelet aggregation. Further studies are needed to explore vorapaxar effect on P2Y12 inhibition, PAR-1 expression and biomarkers and its contribution to clinical outcomes.

Topics: Acute Coronary Syndrome; Adenosine Diphosphate; Aged; Aspirin; Biomarkers; Blood Platelets; Cells, Cultured; Europe; Female; Follow-Up Studies; Humans; Inflammation Mediators; Lactones; Male; Middle Aged; North America; Platelet Aggregation; Pyridines; Receptor, PAR-1; Receptors, Thrombin

Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial compared vorapaxar and placebo in 12,944 high-risk patients with non-ST-segment elevation acute coronary syndrome. We explored aspirin (ASA) use and its association with outcomes. Kaplan-Meier event rates were compared in groups defined by ASA dose (low, medium, and high). Landmark analyses with covariate adjustment were performed for 0 to 30, 31 to 180, and 181 to 365 days. Of 12,515 participants, 7,523, 1,049, and 3,943 participants were treated with low-, medium-, and high-dose ASA at baseline, respectively. Participants enrolled in North America versus elsewhere were more often treated with a high dose at baseline (66% vs 19%) and discharge (60% vs 3%). Unadjusted cardiovascular death, myocardial infarction, stroke, hospitalization for ischemia, or urgent revascularization event rates tended to be higher with higher baseline ASA (18.45% low, 19.13% medium, and 20.27% high; p for trend = 0.15573). Unadjusted and adjusted hazard ratios (95% confidence intervals) for effect of vorapaxar on cardiovascular (unadjusted p for interaction = 0.065; adjusted p for interaction = 0.140) and bleeding (unadjusted p for interaction = 0.915; adjusted p for interaction = 0.954) outcomes were similar across groups. Landmark analyses showed similar safety and efficacy outcomes with vorapaxar and placebo by ASA dose at each time point except for 0 to 30 days, when vorapaxar tended to be worse for efficacy (hazard ratio 1.13, 95% confidence interval 0.89 to 1.44, p for interaction = 0.0157). In conclusion, most TRACER participants were treated with low-dose ASA, although a high dose was common in North America. High-dose participants tended to have higher rates of ischemic and bleeding outcomes. Although formal statistical testing did not reveal heterogeneity in vorapaxar's effect across dose subgroups, consistent trends support use of low-dose ASA with other antiplatelet therapies.

Topics: Acute Coronary Syndrome; Administration, Oral; Aged; Aspirin; Dose-Response Relationship, Drug; Double-Blind Method; Electrocardiography; Female; Follow-Up Studies; Humans; Lactones; Male; Middle Aged; Platelet Aggregation Inhibitors; Pyridines; Receptors, Thrombin; Treatment Outcome

This study characterized a medically managed population in a non-ST-segment elevation acute coronary syndrome (NSTEACS) cohort and evaluated prognosis and outcomes of vorapaxar vs. placebo.. In the TRACER study, 12,944 NSTEACS patients were treated with standard care and vorapaxar (a novel platelet protease-activated receptor-1 antagonist) or placebo. Of those, 4194 patients (32.4%) did not undergo revascularization during index hospitalization, and 8750 (67.6%) underwent percutaneous coronary intervention or coronary artery bypass grafting. Patients managed medically were heterogeneous with different risk profiles, including 1137 (27.1%) who did not undergo coronary angiography. Patients who underwent angiography but were selected for medical management included those without evidence of significant coronary artery disease (CAD), with prior CAD but no new significant lesions, and with significant lesions who were not treated with revascularization.. Cardiovascular event rates were highest among those without angiography and lowest in the group with angiography but without CAD. In the medically managed cohort, 2-year primary outcome (cardiovascular death, myocardial infarction, stroke, recurrent ischaemia with rehospitalization, urgent coronary revascularization) event rates were 16.3% with vorapaxar and 17.0% with placebo (HR 0.99, 95% CI 0.83-1.17), with no interaction between drug and management strategy (p=0.75). Key secondary endpoint (cardiovascular death, myocardial infarction, stroke) rates were 13.4% with vorapaxar and 14.9% with placebo (HR 0.89, 95% CI 0.74-1.07), with no interaction (p=0.58). Vorapaxar increased GUSTO moderate/severe bleeding numerically in medically managed patients (adjusted HR 1.46, 95% CI 0.99-2.15).. NSTEACS patients who were initially medically managed had a higher risk-factor burden, and one-third had normal coronary arteries. Outcome in the medically managed cohort was significantly related to degree of CAD, highlighting the importance of coronary angiography. Efficacy and safety of vorapaxar appeared consistent with the overall trial results.

Topics: Acute Coronary Syndrome; Aged; Double-Blind Method; Female; Hemorrhage; Humans; Lactones; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Pyridines; Recurrence; Risk Factors; Stroke; Treatment Outcome

Clinical trials traditionally use time-to-first-event analysis embedded within the composite endpoint of cardiovascular death (CVD), myocardial infarction (MI), or stroke. However, many patients have >1 event, and this approach may not reflect overall experience. We addressed this by analyzing all cardiovascular events in TRACER.. TRACER randomized 12 944 patients with non-ST-segment elevation acute coronary syndromes to placebo or to protease-activated receptor 1 antagonist vorapaxar with a median follow-up of 502 days (interquartile range, 349 to 667). Analysis of vorapaxar's effect on recurrent CVD, MI, or stroke was prespecified using the Wei, Lin, and Weissfeld approach. Vorapaxar did not reduce the first occurrence of the primary endpoint of CVD, MI, stroke, revascularization, or rehospitalization for recurrent ischemia, but reduced the secondary composite endpoint of CVD, MI, or stroke (14.7% vorapaxar vs. 16.4% placebo; hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.81 to 0.98; P=0.02; number needed to treat [NNT], 81). Recurrent secondary events occurred in 2.7% of patients. Vorapaxar reduced overall occurrences of ischemic events, first and subsequent (HR, 0.88; 95% CI, 0.80 to 0.98; P=0.02; NNT, 51). Also, there was a trend indicating that vorapaxar reduced the expanded endpoint, including revascularization and rehospitalization for recurrent ischemia (HR, 0.92; 95% CI, 0.84 to 1.01; P=0.09). Vorapaxar increased overall occurrences of moderate and severe Global Use of Strategies to Open Occluded Coronary Arteries bleeding (HR, 1.42; 95% CI, 1.21 to 1.66; P<0.001) and Thrombolysis in Myocardial Infarction clinically significant bleeding (HR, 1.550; 95% CI, 1.403 to 1.713; P<0.001).. Vorapaxar reduced overall occurrences of ischemic events, but increased bleeding. These exploratory findings broaden our understanding of vorapaxar's potential and expand our understanding of the value of capturing recurrent events.. ClinicalTrials.gov. Unique identifier: NCT00527943.

Topics: Acute Coronary Syndrome; Aged; Cardiovascular Diseases; Double-Blind Method; Female; Hemorrhage; Humans; Ischemia; Lactones; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Proportional Hazards Models; Pyridines; Recurrence; Secondary Prevention; Stroke; Treatment Outcome

The therapeutic potential of vorapaxar in patients with non-ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention (PCI) is unknown. This prespecified analysis of a postrandomization subgroup evaluated the effects of vorapaxar compared with placebo among Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) participants undergoing PCI, focusing on the implanted stent type (drug-eluting stent [DES] vs bare-metal stent [BMS]). Among 12,944 recruited patients, 7,479 (57.8%) underwent PCI during index hospitalization, and 3,060 (40.9%) of those patients received exclusively BMS, whereas 4,015 (53.7%) received DES. The median (twenty-fifth, seventy-fifth percentiles) duration of thienopyridine therapy was 133 days (47, 246) with BMS and 221 days (88, 341) with DES. At 2 years among patients undergoing PCI, the primary (cardiovascular death, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization) and secondary (cardiovascular death, myocardial infarction, or stroke) end points did not differ between vorapaxar and placebo groups, which was consistent with the treatment effect observed in the overall study population (p value for interaction = 0.540). However, the treatment effect trended greater (p value for interaction = 0.069) and the risk for bleeding in patients taking vorapaxar versus placebo appeared attenuated in BMS-only recipients. After adjustment for confounders, the interaction was no longer significant (p value = 0.301). The covariate that mostly explained the stent-type-by-treatment interaction was the duration of clopidogrel therapy. In conclusion, among patients with PCI, the effect of vorapaxar is consistent with the overall TRACER results. Patients who received a BMS underwent shorter courses of clopidogrel therapy and displayed trends toward greater ischemic benefit from vorapaxar and lesser bleeding risk, compared with patients who received a DES.

Topics: Acute Coronary Syndrome; Adult; Aged; Aged, 80 and over; Australia; Dose-Response Relationship, Drug; Double-Blind Method; Drug-Eluting Stents; Electrocardiography; Europe; Female; Follow-Up Studies; Humans; Incidence; Injections, Intravenous; Lactones; Male; Middle Aged; Percutaneous Coronary Intervention; Postoperative Complications; Prospective Studies; Pyridines; Receptors, Thrombin; Survival Rate; Treatment Outcome; United States

In the TRACER trial, vorapaxar, a protease-activated receptor-1 antagonist, plus standard care in non-ST-segment elevation acute coronary syndrome (NSTE ACS) patients did not significantly reduce the primary composite end point but reduced a key secondary end point and significantly increased bleeding. History of peripheral artery disease (PAD) was a risk-enrichment inclusion criterion. We investigated the efficacy and safety of vorapaxar in NSTE ACS patients with documented PAD.. TRACER was a double-blind, randomized trial comparing vorapaxar with placebo in 12,944 patients with NSTE ACS.. In total, 936 (7.2%) patients had a history of PAD. Ischemic events occurred more frequently among patients with PAD (25.3%) versus no PAD (12.2%, P < .001), and Global Use of Strategies to Open Occluded Coronary Arteries moderate/severe bleeding was more common in PAD (9.1%) versus no PAD (5.0%, P = .004). Similar rates of the composite end point (cardiovascular death, myocardial infarction, or stroke) occurred in patients with PAD treated with vorapaxar and placebo (21.7% vs 24.8%, P interaction = .787). Patients with PAD treated with vorapaxar, when compared with placebo, also had a numerical reduction in peripheral revascularization procedures (8.1% vs 9.0%, P = .158) and a lower extremity amputation rate (0.9% vs 1.5%, P = .107). Vorapaxar increased Global Use of Strategies to Open Occluded Coronary Arteries moderate/severe bleeding similarly in patients with PAD (hazard ratio 1.47, 95% CI 0.89-2.45) and without (hazard ratio 1.48, 95% CI 1.22-1.79; P interaction = .921).. Patients with NSTE ACS and PAD were at increased risk for ischemic events. Lower rates of ischemic end points, peripheral revascularization, and amputation with vorapaxar did not reach statistical significance but warrant further investigation. Vorapaxar increased bleeding in both patients with and without PAD at a similar magnitude of risk.

Topics: Acute Coronary Syndrome; Aged; Amputation, Surgical; Dose-Response Relationship, Drug; Double-Blind Method; Electrocardiography; Female; Follow-Up Studies; Humans; Lactones; Male; Middle Aged; Myocardial Revascularization; Peripheral Arterial Disease; Pyridines; Receptors, Thrombin; Retrospective Studies; Treatment Outcome

Protease-activated receptor 1 antagonism with vorapaxar represents a novel strategy for platelet inhibition. In TRACER, vorapaxar was compared with placebo plus standard of care among 12,944 patients with non-ST-segment elevation acute coronary syndromes. We anticipated that most patients would have received clopidogrel as part of standard care. We investigated the modification of vorapaxar's effect associated with clopidogrel use over time.. The marginal structural model method was used to estimate causal modification of vorapaxar effect by use of clopidogrel over time. The primary outcomes were the composite of cardiovascular death, myocardial infarction, or stroke and Global Use of Strategies to Open Occluded Coronary Arteries moderate or severe bleeding. The event accrual period excluded the time during which clopidogrel was clinically warranted.. Among 12,887 patients who received study medication, 11,117 (86.3%) received clopidogrel before randomization, of whom 38.5% stopped later in the trial (median time to stoppage 200 days with placebo; interquartile range [IQR] 14-367) (186 days with vorapaxar; IQR 17-366). In total, 1,770 (13.7%) patients were not on clopidogrel at randomization, of whom 47.8% started afterward (median time to start 2 days; IQR 2-4). During the period of event accrual, vorapaxar was associated with a 26% reduction in the composite of cardiovascular death, myocardial infarction, or stroke when used with clopidogrel (hazard ratio [HR] 0.74; 95% CI 0.60-0.91) and a 24% reduction when used without clopidogrel (HR 0.76; 95% CI 0.56-1.02) (interaction; P = .89). The hazard of Global Use of Strategies to Open Occluded Coronary Arteries bleeding with vorapaxar was not significantly different without clopidogrel (HR 1.33; 95% CI 0.81-2.20) or with clopidogrel (HR 1.09; 95% CI 0.76-1.56) (interaction; P = .53).. We observed no interaction between vorapaxar and clopidogrel after non-ST-segment elevation acute coronary syndromes on efficacy or safety outcomes, supporting a complementary role of protease-activated receptor 1 and P2Y12 antagonism.

Topics: Acute Coronary Syndrome; Aged; Clopidogrel; Drug Monitoring; Drug Therapy, Combination; Electrocardiography; Female; Hemorrhage; Humans; Lactones; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Pyridines; Secondary Prevention; Stroke; Survival Analysis; Ticlopidine; Treatment Outcome

The TRA·CER trial compared vorapaxar, a novel platelet protease-activated receptor (PAR)-1 antagonist, with placebo in 12 944 patients with high-risk non-ST-segment elevation acute coronary syndromes (NSTE ACS). In this analysis, we explored the effect of vorapaxar on myocardial infarction (MI).. A blinded, independent central endpoint adjudication committee prospectively defined and classified MI according to the universal MI definition, including peak cardiac marker value (creatine kinase-MB [CK-MB] and/or troponin). Because the trial failed to meet its primary endpoint, these analyses are considered exploratory. During a median follow-up of 502 days, 1580 MIs occurred in 1319 patients. The majority (n = 1025, 64.9%) were type 1 (spontaneous) MI, followed by type 4a [percutaneous coronary intervention (PCI)-related] MI (n = 352; 22.3%). Compared with placebo, vorapaxar reduced the hazard of a first MI of any type by 12% [hazard ratio (HR), 0.88; 95% confidence interval (CI), 0.79-0.98; P = 0.021] and the hazard of total number of MIs (first and subsequent) by 14% (HR, 0.86; 95% CI, 0.77-0.97; P = 0.014), an effect that was sustained over time. Vorapaxar reduced type 1 MI by 17% (HR, 0.83; 95% CI, 0.73-0.95; P = 0.007). Type 4a MIs were not significantly reduced by vorapaxar (HR, 0.90; 95% CI, 0.73-1.12; P = 0.35). Vorapaxar effect was consistent across MI sizes defined by peak cardiac marker elevations and across key clinical subgroups; however, in patients not treated with thienopyridine at baseline (HR, 0.65; 95% CI, 0.46-0.92) compared with patients who received thienopyridine (HR, 0.91; 95% CI, 0.81-1.02), there was a trend towards a higher effect (Pint = 0.077).. The PAR-1 antagonist vorapaxar was associated with a reduction of MI, including total number of infarctions. This reduction was sustained over time and was mostly evident in type 1 MI, the most common type of MI observed.

Topics: Acute Coronary Syndrome; Biomarkers; Creatine Kinase, MB Form; Double-Blind Method; Follow-Up Studies; Humans; Lactones; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Prospective Studies; Pyridines; Receptor, PAR-1; Troponin

Vorapaxar is a new oral protease-activated-receptor 1 (PAR-1) antagonist that inhibits thrombin-induced platelet activation.. In this multinational, double-blind, randomized trial, we compared vorapaxar with placebo in 12,944 patients who had acute coronary syndromes without ST-segment elevation. The primary end point was a composite of death from cardiovascular causes, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization.. Follow-up in the trial was terminated early after a safety review. After a median follow-up of 502 days (interquartile range, 349 to 667), the primary end point occurred in 1031 of 6473 patients receiving vorapaxar versus 1102 of 6471 patients receiving placebo (Kaplan-Meier 2-year rate, 18.5% vs. 19.9%; hazard ratio, 0.92; 95% confidence interval [CI], 0.85 to 1.01; P=0.07). A composite of death from cardiovascular causes, myocardial infarction, or stroke occurred in 822 patients in the vorapaxar group versus 910 in the placebo group (14.7% and 16.4%, respectively; hazard ratio, 0.89; 95% CI, 0.81 to 0.98; P=0.02). Rates of moderate and severe bleeding were 7.2% in the vorapaxar group and 5.2% in the placebo group (hazard ratio, 1.35; 95% CI, 1.16 to 1.58; P<0.001). Intracranial hemorrhage rates were 1.1% and 0.2%, respectively (hazard ratio, 3.39; 95% CI, 1.78 to 6.45; P<0.001). Rates of nonhemorrhagic adverse events were similar in the two groups.. In patients with acute coronary syndromes, the addition of vorapaxar to standard therapy did not significantly reduce the primary composite end point but significantly increased the risk of major bleeding, including intracranial hemorrhage. (Funded by Merck; TRACER ClinicalTrials.gov number, NCT00527943.).

Topics: Acute Coronary Syndrome; Aged; Angioplasty; Cardiovascular Diseases; Combined Modality Therapy; Coronary Artery Bypass; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Hemorrhage; Humans; Intracranial Hemorrhages; Kaplan-Meier Estimate; Lactones; Male; Middle Aged; Platelet Aggregation Inhibitors; Pyridines; Receptor, PAR-1

A previous phase 2 study of patients undergoing non-urgent PCI treated with SCH530348 plus aspirin and clopidogrel tended to reduce MACE without increased bleeding. This study evaluated the safety of SCH530348 in Japanese patients with NSTE ACS.. Subjects (117), in whom PCI was planned, received standard-of-care (aspirin, ticlopidine, and heparin) and were randomized 4:1 to receive either SCH530348 (20 or 40 mg loading dose followed by 1 mg/d or 2.5 mg/d for 60 days) or placebo. The key safety endpoint was TIMI major and minor bleeding in the PCI cohort (n=92). The key exploratory efficacy endpoint was MACE and death within 60 days. Addition of SCH530348 to standard-of-care did not significantly increase the rate of TIMI major and minor bleeding (or non-TIMI bleeding) in the primary cohort.. Incidence (non-MACE) and discontinuation of AEs were similar across groups. PCI subjects treated with SCH530348 plus standard-of-care experienced a significant reduction in periprocedural MI compared with standard-of-care alone (16.9% vs 42.9%, respectively; p=0.013). There were no deaths or any other MACE.. SCH530348 added to standard-of-care did not result in excess bleeding in Japanese subjects with NSTE ACS but significantly reduced the incidence of periprocedural MI in subjects undergoing urgent PCI.

Topics: Acute Coronary Syndrome; Aged; Aspirin; Blood Platelets; Clopidogrel; Cohort Studies; Double-Blind Method; Female; Heparin; Humans; Japan; Lactones; Male; Middle Aged; Placebos; Pyridines; Receptor, PAR-1; Ticlopidine

The protease-activated receptor 1 (PAR-1), the main platelet receptor for thrombin, represents a novel target for treatment of arterial thrombosis, and SCH 530348 is an orally active, selective, competitive PAR-1 antagonist. We designed TRA*CER to evaluate the efficacy and safety of SCH 530348 compared with placebo in addition to standard of care in patients with non-ST-segment elevation (NSTE) acute coronary syndromes (ACS) and high-risk features.. TRA*CER is a prospective, randomized, double-blind, multicenter, phase III trial with an original estimated sample size of 10,000 subjects. Our primary objective is to demonstrate that SCH 530348 in addition to standard of care will reduce the incidence of the composite of cardiovascular death, myocardial infarction (MI), stroke, recurrent ischemia with rehospitalization, and urgent coronary revascularization compared with standard of care alone. Our key secondary objective is to determine whether SCH 530348 will reduce the composite of cardiovascular death, MI, or stroke compared with standard of care alone. Secondary objectives related to safety are the composite of moderate and severe GUSTO bleeding and clinically significant TIMI bleeding. The trial will continue until a predetermined minimum number of centrally adjudicated primary and key secondary end point events have occurred and all subjects have participated in the study for at least 1 year. The TRA*CER trial is part of the large phase III SCH 530348 development program that includes a concomitant evaluation in secondary prevention.. TRA*CER will define efficacy and safety of the novel platelet PAR-1 inhibitor SCH 530348 in the treatment of high-risk patients with NSTE ACS in the setting of current treatment strategies.

Topics: Acute Coronary Syndrome; Adult; Blood Platelets; Double-Blind Method; Humans; Lactones; Platelet Aggregation Inhibitors; Prospective Studies; Pyridines; Receptor, PAR-1; Research Design

Background Vorapaxar, 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]). Conclusions Stroke 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.

Topics: Acute Coronary Syndrome; Aged; Clinical Trials, Phase III as Topic; Female; Humans; Incidence; Intracranial Hemorrhages; Lactones; Male; Middle Aged; Multicenter Studies as Topic; Platelet Aggregation Inhibitors; Pyridines; Randomized Controlled Trials as Topic; Recurrence; Risk Assessment; Risk Factors; Secondary Prevention; Stroke; Treatment Outcome

Antithrombotic therapy plays an important role in the treatment of non-ST-segment elevation acute coronary syndromes (NSTE ACS) but is associated with bleeding risk. Advanced age may modify the relationship between efficacy and safety.. Efficacy and safety of vorapaxar (a protease-activated receptor 1 antagonist) was analyzed across ages as a continuous and a categorical variable in the 12,944 patients with NSTE ACS enrolled in the TRACER trial. To evaluate the effect of age, Cox regression models were developed to estimate hazard ratios (HRs) with the adjustment of other baseline characteristics and randomized treatment for the primary efficacy composite of cardiovascular death, myocardial infarction (MI), stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization, and the primary safety composite of moderate or severe Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) bleeding.. The median age of the population was 64years (25th, 75th percentiles = 58, 71). Also, 1,791 patients (13.8%) were ≤54years of age, 4,968 (38.4%) were between 55 and 64 years, 3,979 (30.7%) were between 65 and 74 years, and 2,206 (17.1%) were 75years or older. Older patients had higher rates of hypertension, renal insufficiency, and previous stroke and worse Killip class. The oldest age group (≥75years) had substantially higher 2-year rates of the composite ischemic end point and moderate or severe GUSTO bleeding compared with the youngest age group (≤54years). The relationships between treatment assignment (vorapaxar vs placebo) and efficacy outcomes did not vary by age. For the primary efficacy end point, the HRs (95% CIs) comparing vorapaxar and placebo in the 4 age groups were as follows: 1.12 (0.88-1.43), 0.88 (0.76-1.02), 0.89 (0.76-1.04), and 0.88 (0.74-1.06), respectively (P value for interaction = .435). Similar to what was observed for efficacy outcomes, we did not observe any interaction between vorapaxar and age on bleeding outcomes. For the composite of moderate or severe bleeding according to the GUSTO classification, the HRs (95% CIs) comparing vorapaxar and placebo in the 4 age groups were 1.73 (0.89-3.34), 1.39 (1.04-1.86), 1.10 (0.85-1.42), and 1.73 (1.29-2.33), respectively (P value for interaction = .574).. Older patients had a greater risk for ischemic and bleeding events; however, the efficacy and safety of vorapaxar in NSTE ACS were not significantly influenced by age.

Topics: Acute Coronary Syndrome; Age Factors; Aged; Cardiovascular Diseases; Double-Blind Method; Female; Hemorrhage; Humans; Lactones; Male; Middle Aged; Myocardial Infarction; Myocardial Revascularization; Patient Readmission; Platelet Aggregation Inhibitors; Proportional Hazards Models; Pyridines; Randomized Controlled Trials as Topic; Recurrence; Stroke; Treatment Outcome

Designing of smart clinical trials is critical for regulatory approval and future drug utilization. Importantly, trial design should be reconsidered if the interim analyses suggest unexpected harm, or conflicting results were yielded from the other trials within the same therapeutic area. With regard to antiplatelet agents, the perfect example is redesigning of the ongoing PRoFESS trial by eliminating aspirin from clopidogrel arm after the earlier MATCH trial results became available. The goal was to aseess the unchanged TRACER trial design in light of the evidence yielded from the earlier completed TRITON trial. TRACER was designed as a triple versus dual antiplatelet trial in NSTEMI patients with no previous long-term outcome data supporting such aggressive strategy. TRITON data represented dual versus dual antiplatelet therapy, and became available before TRACER enrollment starts revealing prasugrel front-loaded early vascular benefit predominantly in STEMI patients with the growing over time bleeding and cancer risks. Moreover, large prasugrel NSTEMI TRITON cohort exhibited trend towards excess mortality in experimental arm warning against aggressive TRACER design. The long-term TRITON results in general, and especially in the NSTEMI patients challenge unchanged TRACER trial design. Applying dual, rather than triple antiplatelet therapy protocol modification should be considered in TRACER to minimize bleeding, cancer, and non-cardiovascular death risks.

Topics: Acute Coronary Syndrome; Aspirin; Clinical Trials as Topic; Clopidogrel; Drug Evaluation; Drug Therapy, Combination; Hemorrhage; Humans; Lactones; Neoplasms; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Pyridines; Research Design; Ticlopidine

There are consistent data suggesting that elderly patients benefit from less aggressive antiplatelet strategies following acute coronary syndromes. This observation is likely because advanced age is associated with greater bleeding and potentially less efficacy. Oral antiplatelet agents are often prescibed uniformly, without dose adjustments, representing a concerning reality for this patient population. Vorapaxar, a platelet thrombin PAR-1 inhibitor, has been evaluated in the TRA2P and TRACER trials, but drug efficacy and safety, with respect to age, were not discussed in detail. We sought to define the FDA-confirmed age-dependent clinical outcomes after vorapaxar. The mean and median ages in the TRA2P indicated population were about 60 years, with 33.4% greater than 65 years of age and 9.2% greater than 75 years of age. Vorapaxar efficacy was reduced in those aged 72 or older, while bleeding rates gradually increased with age for both arms. For patients aged 75 or older, efficacy numerically favored vorapaxar, but this interaction was not statistically significant (HR=1.18; 95% CI=0.95-1.46; p=0.132). In TRACER, the point estimates by age quintile for the primary endpoint also favored vorapaxar, except for the lowest age quintile ≤56 probably due to overtreatment. GUSTO moderate/severe bleeding was substantially higher with vorapaxar in both trials for the eldest age quintile (5.1% placebo vs. 7.0% vorapaxar in TRA2P; 8.4% placebo vs. 13% vorapaxar in TRACER). In conclusion, the FDA analyses reassure that vorapaxar efficacy is not reduced in the elderly. However, the bleeding risk after vorapaxar is definitely increased with advancing age.

Topics: Acute Coronary Syndrome; Aged; Female; Humans; Lactones; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Pyridines; Randomized Controlled Trials as Topic; Receptor, PAR-1; United States; United States Food and Drug Administration

Topics: Acute Coronary Syndrome; Coronary Artery Bypass; Female; Hospital Mortality; Humans; Lactones; Male; Pyridines

Topics: Acute Coronary Syndrome; Clinical Trials Data Monitoring Committees; Drug Approval; Hemorrhage; Humans; Lactones; Plaque, Atherosclerotic; Platelet Aggregation Inhibitors; Pyridines; Receptor, PAR-1; Risk Assessment; United States

Topics: Acute Coronary Syndrome; Humans; Lactones; Myocardial Infarction; Platelet Aggregation Inhibitors; Pyridines

Several key reports from the American Heart Association meeting, held in Orlando (FL, USA) in November 2011, are presented related to anti-thrombotic therapy in acute coronary syndrome and the use of dronedarone in permanent atrial fibrillation is discussed in this brief (and selective) overview of this meeting. A summary of the ATLAS-TIMI-51, TRACER and PALLAS trials is provided.

Topics: Acute Coronary Syndrome; American Heart Association; Amiodarone; Anti-Arrhythmia Agents; Anticoagulants; Atrial Fibrillation; Clinical Trials as Topic; Dronedarone; Fibrinolytic Agents; Humans; Lactones; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiophenes; Treatment Outcome; United States; Venous Thromboembolism

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.

Topics: Acute Coronary Syndrome; Clinical Trials, Phase III as Topic; Education; Europe; Humans; Lactones; Multicenter Studies as Topic; Patient Selection; Pyridines; Receptors, Thrombin; Research Design; Sample Size

Despite the proven efficacy of dual antiplatelet therapy with aspirin and one of the first-generation P2Y(12) antagonists (clopidogrel, prasugrel) in patients with atherothrombotic disease, residual ischemic risk remains substantial, and bleeding rates are increased. Incomplete protection against ischemic events can be attributed to the fact that these therapies each target a single platelet activation pathway, allowing continued platelet activation via other pathways, including the protease-activated receptor-1 (PAR-1) pathway stimulated by thrombin. Increased bleeding with dual antiplatelet therapy can be attributed to blockade of the thromboxane A(2) (by aspirin) and adenosine diphosphate (by P2Y(12) antagonist) platelet activation pathways that are essential to hemostasis. The second-generation P2Y(12) inhibitor ticagrelor plus aspirin demonstrated superior ischemic outcomes, including reduction in total mortality, versus clopidogrel plus aspirin, but event rates remain high, and major bleeding not related to coronary artery bypass grafting is increased. The novel P2Y(12) antagonist elinogrel, available in intravenous and oral formulations, may have a more favorable benefit-to-risk profile than existing agents in this class because of reversible and competitive binding to the P2Y(12) receptor. Inhibition of PAR-1 is an attractive, novel approach in antiplatelet therapy because it may provide incremental ischemic protection without increasing bleeding. The PAR-1 antagonist vorapaxar (SCH 530348) has been associated with favorable efficacy and safety in phase 2 trials. Two phase 3 trials are evaluating the efficacy and safety of vorapaxar in patients presenting with non-ST-segment elevation acute coronary syndromes and in patients with documented atherothrombotic disease.

Topics: Acute Coronary Syndrome; Adenosine; Angioplasty, Balloon, Coronary; Aspirin; Clopidogrel; Coronary Artery Disease; Coronary Thrombosis; Drug Therapy, Combination; Humans; Lactones; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Pyridines; Quinazolinones; Randomized Controlled Trials as Topic; Receptor, PAR-1; Sulfonamides; Ticagrelor; Ticlopidine

Emergency department physicians, along with hospitalists and interventional cardiologists, provide first-line care for patients experiencing symptoms potentially associated with acute coronary syndromes (ACS). Because these health care providers encounter and manage patients with varying degrees of risk, a clear understanding of the modes of action, benefits, and limitations of various therapeutic options is crucial for achieving optimal outcomes in the acute-care setting. Oral antiplatelet therapy has a major role in the acute care of patients with suspected ACS due to the critical role of platelets in the pathophysiology of disease. The current standard-of-care oral antiplatelet therapy for ACS is aspirin in combination with a P2Y12 adenosine diphosphate (ADP) receptor antagonist, most commonly clopidogrel. Aspirin and P2Y12 antagonists have both demonstrated efficacy in reducing morbidity and mortality in patients with ACS, but are also associated with increased bleeding risk compared with controls. Additionally, despite dual oral antiplatelet therapy, patients remain at substantial residual risk for ischemic events due to thrombotic episodes driven by platelet activation pathways that are not inhibited by these agents, including the protease-activated receptor (PAR)-1 platelet activation pathway, stimulated by thrombin. Novel oral antiplatelet agents in advanced clinical development include a direct and more readily reversible P2Y12 antagonist, ticagrelor, as well as a new class of PAR-1 antagonists, which includes vorapaxar and atopaxar. Ticagrelor has shown a significant ischemic benefit and an increase in non-surgical bleeding over clopidogrel in the large phase 3 Platelet Inhibition and Patient Outcomes trial. Results of phase 2 trials with PAR-1 antagonists suggest that these agents may provide incremental reduction in ischemic events without a bleeding liability. This hypothesis is being evaluated in 2 large ongoing phase 3 trials with vorapaxar, including the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRA*CER) trial in patients with non-ST-segment elevation ACS.

Topics: Acute Coronary Syndrome; Adenosine; Administration, Oral; Aspirin; Cardiology; Clopidogrel; Drug Therapy, Combination; Emergency Medicine; Hemorrhage; Hospitalists; Humans; Imines; Lactones; Patient Selection; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Purinergic P2Y Receptor Antagonists; Pyridines; Receptor, PAR-1; Risk Factors; Ticagrelor; Ticlopidine; Treatment Outcome