Thrombotic Cardiovascular Events In Patients Research Articles

EE81 The Budget Impact of Cangrelor for the Treatment of Patients Undergoing Percutaneous Coronary Intervention When Oral P2Y12 Inhibitors Are Not Feasible or Desirable in the UK

Cangrelor is an intravenous, direct-acting, reversible P2Y12 inhibitor indicated for the reduction of thrombotic cardiovascular events in patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI) who have not received an oral P2Y12 inhibitor prior to the PCI procedure, and in whom oral therapy with P2Y12 inhibitors is not feasible or desirable. The objective of this analysis is to estimate the UK budget impact of introducing cangrelor, for the ST-elevation myocardial infarction (STEMI) population in whom oral P2Y12 inhibitors are not feasible or desirable.

Lead Optimization to Advance Protease-Activated Receptor-1 Antagonists in Early Discovery

Vorapaxar is an approved drug for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction or with peripheral arterial disease. Subsequent to the discovery of Vorapaxar, medicinal chemistry efforts were continued to identify structurally differentiated leads. Toward this goal, extensive structure-activity relationship studies using a C-ring-truncated version of Vorapaxar culminated in the discovery of three leads, represented as 13, 14, and 23. Among these leads, compound 14 possessed favorable pharmacokinetic properties and an off-target profile, which supported additional profiling in an exploratory rat toxicology study.

Budget impact analysis of antiplatelet therapy with cangrelor in patients with acute coronary artery disease undergoing percutaneous coronary intervention in Portugal

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Ferrer, Barcelona, Spain Background Cangrelor is a novel, intravenous, potent, fast onset, direct-acting, P2Y12 receptor antagonist that blocks adenosine diphosphate-induced platelet activation and aggregation with a half-life of 3-6 min. Co-administered with acetylsalicylic acid, it is indicated for reducing thrombotic cardiovascular events in patients with coronary artery disease (CAD) (ST-elevation myocardial infarction (STEMI), non-STEMI, stable CAD) undergoing percutaneous coronary intervention (PCI) who have not received an oral P2Y12 inhibitor (clopidogrel, prasugrel or ticagrelor) prior to PCI procedure and in whom oral therapy with P2Y12 inhibitors is not feasible or desirable. Purpose To assess the economic implications of incorporating cangrelor into the hospital formulary for the acute care of CAD patients undergoing PCI in Portugal. Methods A budget impact model (BIM) was developed. The 3-year pharmacological and clinical event costs of two hypothetical scenarios, without and with cangrelor in the formulary for the total PCI population (base case) in Portugal were compared. Also, the primary PCI (STEMI) and a PCI population with special needs (ie. unable to swallow) were assessed as complementary setups. Epidemiological, efficacy (stent thrombosis, myocardial infarction (MI), ischaemia-driven revascularization, death), safety (Thrombolysis in Myocardial Infarction (TIMI) bleeding criteria) and costs (€, 2019) data were based on clinical trials, meta-analyses and on Portuguese registries. Only the costs of pre-treatment with oral P2Y12 inhibitors and glycoprotein IIb-IIIa inhibitors (GPI) for bail-out were considered. One-way sensitivity analysis established the effect of uncertainty on BIM results. Results The model assumes that the total PCI population grows from 13,422 to 14,370 adults (age 65 years, mean) over three years in Portugal. Pre-treatment with oral P2Y12 inhibitors increases from 9,932 to 10,634 patients, and uptake of cangrelor rises from 0.80% to 1.40% in the same period. The number of total PCI patients receiving cangrelor grows from 79 to 149. At current usage of antithrombotics and at existing pharmacological and management costs, adding cangrelor into the hospital formulary represents 115 thousand € over 3 years in Portugal. Results are most sensible to the percentage of patients on GPI bail-out. Conclusions Under BIM assumptions, introducing cangrelor for the acute care of CAD patients undergoing PCI represents a safe and affordable option in Portugal, particularly when the required control of thrombosis is not certain with oral pre-treatment.

Budget impact analysis of antiplatelet therapy with cangrelor in patients with acute coronary artery disease undergoing percutaneous coronary intervention in Belgium

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Ferrer, Barcelona, Spain Background Cangrelor is a novel, intravenous, potent, fast onset, direct-acting, P2Y12 receptor antagonist that blocks adenosine diphosphate-induced platelet activation and aggregation with a half-life of 3-6 min. Co-administered with acetylsalicylic acid, it is indicated for reducing thrombotic cardiovascular events in patients with coronary artery disease (CAD) (ST-elevation myocardial infarction (STEMI), non-STEMI, stable CAD) undergoing percutaneous coronary intervention (PCI) who have not received an oral P2Y12 inhibitor (clopidogrel, prasugrel or ticagrelor) prior to PCI procedure and in whom oral therapy with P2Y12 inhibitors is not feasible or desirable. Purpose To assess the economic implications of incorporating cangrelor into the hospital formulary for the acute care of CAD patients undergoing PCI in Belgium. Methods A budget impact model (BIM) was developed. The 3-year pharmacological and clinical event costs of two hypothetical scenarios, without and with cangrelor in the formulary for the total PCI population (base case) in Belgium were compared. Also, the primary PCI (STEMI) and a PCI population with special needs (e.g., unable to swallow) were assessed as complementary setups. Epidemiological, efficacy (stent thrombosis, myocardial infarction (MI), ischaemia-driven revascularization, death), safety (Thrombolysis in Myocardial Infarction (TIMI) bleeding criteria) and costs (€, 2019) data were based on clinical trials, meta-analyses and on Belgian registries. Only the pharmacological costs of pre-treatment (preload) with oral P2Y12 inhibitors and glycoprotein IIb-IIIa inhibitors (GPI) for bail-out were considered. One-way sensitivity analysis established the effect of uncertainty on BIM results. Results The model assumes that the primary PCI population grows from 4,790 to 4,935 adults (age 68 years, mean) over three years in Belgium. Pre-treatment with oral P2Y12 inhibitors increases from 3,544 to 3,652 patients, and uptake of cangrelor rises from 20.60% to 38.30% in the same period. The number of primary PCI patients receiving cangrelor grows from 730 to 1,399. At current usage of antithrombotics and at existing pharmacological and management costs, adding cangrelor into the hospital formulary represents 1.1 million euros over 3 years in Belgium. 6 additional stent thromboses, 3 ischaemia-driven revascularisations and 2 cardiovascular related deaths are avoided while three extra minor bleedings occur over 3 years. Similar pharmacoeconomic findings emerge in the base case and complementary setups. Results are most sensible to the percentage of patients on GPI bail-out. Conclusions Under BIM assumptions, introducing cangrelor for the acute care of CAD patients undergoing primary PCI represents a safe and affordable option in Belgium, particularly when the required control of thrombosis is not certain with oral pre-treatment.

Improving Outcomes in Cardiovascular Diseases: A Review on Vorapaxar.

Antiplatelet agents are the standard of practice in the management of atherosclerosis and acute coronary syndrome. In contrast to the available antiplatelet agents, vorapaxar represents a novel mechanism of action. It is an antagonist of the platelet protease-activated receptor-1 and inhibits thrombin-induced and thrombin receptor agonist peptide-induced platelet aggregation. The Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-Thrombolysis in Myocardial Infarction 50 (TRA 2°P-TIMI 50) trial led to the approval of vorapaxar by the Food and Drug Administration and European Medicines Agency for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or peripheral arterial disease. TRA 2°P-TIMI 50 trial showed that the use of vorapaxar (2.5 mg once/daily) in addition to standard dual antiplatelet therapy with aspirin and a P2Y12 receptor inhibitor was effective in the secondary prevention of recurrent thrombotic events among patients with previous atherothrombosis, particularly in patients with prior MI; at the expense of an increase in major bleeding. Another recently published Vorapaxar Therapy in Patients With Prior Myocardial Infarction Treated With Newer Generation P2Y12 Receptor Inhibitors Prasugrel and Ticagrelor (VORA-PRATIC) study showed that among post-MI patients treated with potent P2Y12 inhibitors (prasugrel or ticagrelor), vorapaxar reduced platelet-driven global thrombogenicity, an effect that persisted, albeit attenuated, in the absence of aspirin. The current review summarizes an up-to-date literature on pharmacokinetics, pharmacodynamics, and clinical efficacy of vorapaxar and proposes future directions of research.

Analysis of the Financial Impact of Using Cangrelor on the Safety and Efficacy Outcomes in Patients Undergoing Percutaneous Coronary Intervention in Whom Oral Therapy with P2Y12 Inhibitors is Not Feasible or Desirable, in Spain.

PurposeCangrelor is an intravenous, direct-acting, reversible P2Y12 inhibitor indicated for the reduction of thrombotic cardiovascular events in patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI) in whom oral P2Y12 inhibitors are not feasible or desirable. The objective was to assess the financial impact of introducing cangrelor into the hospital formulary in Spain.Patients and MethodsA budget impact model was developed to calculate the cost difference between two scenarios (without and with cangrelor) to treat CAD patients undergoing PCI in whom oral P2Y12 inhibitors are not feasible or desirable, over 3 years. Intravenous P2Y12 inhibitor (cangrelor), oral P2Y12 inhibitors (clopidogrel, prasugrel, and ticagrelor), and glycoprotein IIb-IIIa inhibitors (GPIs) for bail-out use were considered. Epidemiological, efficacy (thrombotic events including cardiac death), safety (bleeding events), and costs (€, 2019) data were based on Spanish registries, clinical trials, and meta-analyses. One-way sensitivity analysis established the effect of uncertainty on results.ResultsFor years 1, 2, and 3, the target population to receive cangrelor was 607, 1,822, and 3,340 patients, and cangrelor uptake was 23.70%, 58.30%, and 51.30%, respectively. The 3-year budget impact was 1,021,717€ varying from 50,245€ in year 1 to 599,272€ in year 3. The results were sensitive to the number of patients treated with GPIs in Spanish hospitals.ConclusionBased on our results, the financial effort needed to introduce the use of cangrelor in patients undergoing PCI in whom antiplatelet therapy with oral P2Y12 inhibitors is not feasible or desirable barely exceeds one million € over three years, in Spain.

PCV26 Budget IMPACT Analysis of Antiplatelet Therapy with Cangrelor in Patients with ACUTE Coronary Artery Disease Undergoing Percutaneous Coronary Intervention in Germany

Cangrelor is a novel, potent, intravenous, fast onset P2Y12 receptor antagonist that blocks adenosine diphosphate-induced platelet activation and aggregation. Co-administered with acetylsalicylic acid, it is indicated for reducing thrombotic cardiovascular events in patients with coronary artery disease (CAD) undergoing PCI who have not received an oral P2Y12 inhibitor (clopidogrel, prasugrel or ticagrelor) prior to PCI and in whom oral therapy is not feasible or desirable. Our purpose was to assess the economic consequences of incorporating cangrelor into the hospital formulary for the acute care of CAD patients undergoing PCI in Germany. A budget impact model (BIM) was developed. The 3-year pharmacological and clinical event costs of two hypothetical scenarios, without and with cangrelor for the primary PCI population in Germany were compared. Epidemiological, efficacy (stent thrombosis, myocardial infarction (MI), ischaemia-driven revascularization, death), safety (Thrombolysis in Myocardial Infarction (TIMI) bleeding criteria) and costs (€, 2019) data were based on clinical trials, meta-analyses and on German registries. Only the costs of pre-treatment (pre-loading) with oral P2Y12 inhibitors and bail-out with glycoprotein IIb-IIIa inhibitors (GPI) were considered. One-way sensitivity analysis established the effect of uncertainty on BIM results. The model assumes that the three-year primary PCI population is 240,539 (85% are STEMI patients). The uptake of cangrelor changes from 0.40% to 0.90% in the same period. Considering current antithrombotics use and PCI management costs in Germany, the three-year budget impact of adding cangrelor into the hospital formulary for the primary PCI population represents less than 5 hundred thousand €. Results are most sensible to GPI bail-out use. Under BIM assumptions, introducing cangrelor for the acute care of CAD patients undergoing primary PCI represents a consistently affordable option in Germany. Cangrelor is particularly valuable when oral pre-treatment and adequate control of thrombosis cannot be guaranteed.

Vorapaxar in the Treatment of Cardiovascular Diseases

Vorapaxar specifically and effectively inhibits protease activated receptor-1 and may reduce thrombin-mediated ischemic events without interfering primary hemostasis. In the TRA-2P-TIMI 50 trial, vorapaxar reduced the risk of primary ischemic outcome but with increased bleeding risk. In the post hoc analysis, in patients with a history of myocardial infarction, peripheral artery disease, the net clinical outcome favored vorapaxar therapy with 10% reduction in cardiovascular death, myocardial infarction, stroke, urgent coronary revascularization and moderate or severe bleeding. Based on these favorable results, vorapaxar was approved for the reduction of thrombotic cardiovascular events in patients with prior myocardial infarction or with peripheral artery disease on top of standard antiplatelet therapy. A careful patient selection is needed to balance efficacy versus safety.

2350Evaluation of the pharmacodynamics of a ticagrelor reversal agent PB2452

Abstract Background Ticagrelor is a P2Y12 antagonist used in combination with aspirin to reduce the risk of recurrent thrombotic cardiovascular events in patients with acute coronary syndrome. Ticagrelor is associated with a risk for spontaneous major bleeding or bleeding associated with invasive procedures, particularly cardiac surgery. A rapid-acting reversal agent for ticagrelor would be advantageous. The pharmacodynamic effects of ticagrelor and a ticagrelor reversal agent are best evaluated using a panel of platelet function tests that have different sensitivities and methodologies and using a variety of agonists at different concentrations. Purpose In a first-in-human randomized, double-blind, placebo-controlled, healthy volunteer Phase 1 study, intravenous (IV) PB2452, a monoclonal antibody fragment that binds ticagrelor with high affinity, was evaluated as a ticagrelor reversal agent. Methods Platelet function was assessed using light transmission aggregometry (LTA) and 5 and 20 μM adenosine diphosphate (ADP), 1.6 mM arachidonic acid (AA), and 15 μM thrombin receptor agonist peptide (TRAP-6) as agonists. The VerifyNow P2Y12 cartridges, which assess whole blood platelet function, were evaluated as a point-of-care test. A modified vasodilator-stimulated phosphoprotein (VASP) ELISA was used to assess the extent of P2Y12 signaling. These assessments were performed 48 h prior to ticagrelor administration and at multiple time points up to 48 h after administration of PB2452 or placebo. Results 64 subjects were randomized; 48 received PB2452 and 16 received placebo. After ticagrelor administration, LTA response to 20 μM ADP was inhibited by 87% compared to the pre-ticagrelor values. Platelet function as measured by the VerifyNow P2Y12 cartridge was completely inhibited (<10 platelet reactivity units [PRU]). The VASP platelet reactivity index (PRI) was inhibited by 82%. Ticagrelor reduced TRAP-6 induced LTA by 30% reflecting the effect of ADP on platelet aggregate stability. PB2452 administered as a 10 min IV bolus followed by 16 h infusion, significantly restored platelet function to >80% and >90% of baseline as measured by LTA using ADP and TRAP-6, respectively, to >180 PRU using VerifyNow, and to >90% PRI as measured by VASP. The VASP assay enabled batch analyses in a central laboratory, eliminating the need for special equipment on-site and reducing operator variability. When platelet function was assessed by VASP, PB2452 administration produced rapid ticagrelor reversal within 5 min consistent with restoration of P2Y12 signaling. Onset of reversal by all measurements occurred within 15 min of PB2452 administration and was sustained for 20–24 h. Conclusions PB2452 is a specific reversal agent for ticagrelor and produces a rapid and sustained reversal of ticagrelor inhibition of platelets. Utilizing multiple platelet function assays provided a broader understanding of the PB2452 pharmacodynamics in this first-in-human Phase 1 study. Acknowledgement/Funding PhaseBio Pharmaceuticals

Pharmacokinetic drug evaluation of vorapaxar for secondary prevention after acute coronary syndrome

ABSTRACTIntroduction: 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.

Trans-fused 5-[(tert-Butoxtycarbonyl)amino]octahydroindenes as a protease activated receptor-1 (PAR1) antagonist.

Protease activated receptor 1 (PAR1) has been considered as a promising antiplatelet target to prevent thrombotic cardiovascular events in patients with prior myocardial infarction or peripheral arterial diseases. Previously, we found a series of octahydroindene analogues to have high potency on PAR1 and no significant cytotoxicity but poor metabolic stability in human and rat liver microsomes. We designed and synthesized substituted analogues of octahydroindenes at C5 or C6 aiming to improvement of metabolic stability, and identified that trans-fused 5-[(tert-butoxtycarbonyl)amino]octahydroindene analogues showed improved metabolic stability with maintaining good activity on PAR1. Especially, 2-methanesulfonate 57 (IC50=0.006 μM; R50=126.3min in human, 83.3min in rat), sulfamate 58 (IC50=0.020 μM; R50=52.8min in human, 106.0min in rat), and N-(cyclopropyl)methylsufonamide 63 (IC50=0.010 μM; R50=51.4min in human, 90.5min in rat) exhibited excellent activity and metabolic stability both on human and rat liver microsomes, comparable to those obtained for varapaxar (IC50=0.0015 μM; R50=83.2min in human, 32.4min in rat). Additionally, these compounds (57, 58, and 63) represented significant efficacy (IC50=0.0022, 0.0062, and 0.015 μM, each) in human washed platelet aggregation (WPA) assay without cytotoxicity and CYP3A4 inhibitory activity.

ASPIRIN DOSING IN PATIENTS WITH ACUTE MYOCARDIAL INFARCTION TREATED WITH TICAGRELOR: INSIGHT FROM THE NATIONAL CARDIOVASCULAR DATA REGISTRY (NCDR)

Ticagrelor reduces thrombotic cardiovascular events in patients with acute myocardial infarction (AMI). High-dose aspirin (>100 mg daily, HiASA) reduces the effectiveness of ticagrelor and should be avoided. We studied the contemporary patterns of aspirin dosing at discharge in patients treated with

Protease-activated receptor 4: from structure to function and back again.

Protease-activated receptors are a family of four GPCRs (PAR1-PAR4) with a number of unique attributes. Nearly two and a half decades after the discovery of the first PAR, an antagonist targeting this receptor has been approved for human use. The first-in-class PAR1 antagonist, vorapaxar, was approved for use in the USA in 2014 for the prevention of thrombotic cardiovascular events in patients with a history of myocardial infarction or with peripheral arterial disease. These recent developments indicate the clinical potential of manipulating PAR function. While much work has been aimed at uncovering the function of PAR1 and, to a lesser extent, PAR2, comparatively little is known regarding the pharmacology and physiology of PAR3 and PAR4. Recent studies have begun to develop the pharmacological and genetic tools required to study PAR4 function in detail, and there is now emerging evidence for the function of PAR4 in disease settings. In this review, we detail the discovery, structure, pharmacology, physiological significance and therapeutic potential of PAR4. Linked Articles This article is part of a themed section on Molecular Pharmacology of G Protein-Coupled Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.20/issuetoc.

Abstract 138: Contemporary Patterns of Use of Antiplatelet Agents in Patients With Acute Myocardial Infarction: Insight From the National Cardiovascular Data Registry (NCDR)

Background: Compared with clopidogrel, ticagrelor and prasugrel are more potent and faster-acting antiplatelet agents that have been associated with a greater reduction in thrombotic cardiovascular events in patients with acute myocardial infarction (AMI). We examined contemporary patterns of P2Y12 inhibitor selection both early (within 24 h of admission) and at discharge among AMI patients captured by a large national registry. Methods: Patients in the ACTION Registry® -GWTG™ who presented with AMI from October 2013 through December 2014 were included in the study (167,455 patients from 622 sites). Among these patients, we evaluated the temporal trends in early use (within 24 h of admission) and discharge prescription of antiplatelet agents and used logistic regression to identify factors associated with P2Y12 inhibitor selection at discharge. Results: Early ticagrelor use increased significantly over time from 11.8% to 16.4% (STEMI 19.6% to 27.6%; NSTEMI 6.8% to 9.5%; p<0.0001 for all). Similarly, ticagrelor prescription at discharge increased significantly from 12% to 16.7% (STEMI 17.5% to 24.6%; NSTEMI 8.7 to 11.9%; p<0.0001 for all). During the same time period, we observed a significant decrease in the early use of prasugrel and clopidogrel (13.3% to 11.9% and 43.4% to 39.5%, respectively, p<0.0001 for all) and their prescription at discharge (15.7% to 13.9% and 54.2% to 51.1%, respectively, p<0.0001 for all) (Figure 1). Independent factors associated with ticagrelor prescription at discharge over clopidogrel included younger age, white race, HMO/private insurance, home ticagrelor use, invasive management and in-hospital re-infarction and CVA (p<0.0001 for all), whereas prior CVA, atrial fibrillation and CABG favored clopidogrel prescription at discharge. Independent factors associated with ticagrelor prescription at discharge over prasugrel included older age, female gender, prior stroke, home ticagrelor use and in-hospital CVA (p<0.001 for all), whereas prior diabetes (p<0.001) and home prasugrel use (p<0.0001) were associated with prasugrel prescription at discharge. Conclusions: Our contemporary dataset shows a modest but significant increase in use of ticagrelor early and at discharge, with simultaneous decline in the use of clopidogrel and prasugrel in patients presenting with AMI.

Vorapaxar in the secondary prevention of atherothrombosis

Dual antiplatelet therapy with aspirin, a platelet cyclooxygenase-1 inhibitor and P2Y12 receptor blockers, remains the major drug strategy to prevent ischemic event occurrence in patients with acute coronary syndromes and in patients undergoing coronary stenting, but there some limitations that can be overcome by targeting novel targets. Unlike direct thrombin inhibitors that bind directly to thrombin, targeting the platelet thrombin receptor, protease activated receptor (PAR)-1, may offer a better choice for the attenuation of atherosclerosis progression, thrombus-mediated ischemic events and restenosis without interfering with primary hemostasis. Vorapaxar – a synthetic analogue of himbacine, is a high affinity and highly selective PAR-1 antagonist that can effectively inhibit thrombin-induced platelet aggregation. In the TRACER trial, the addition of vorapaxar to standard therapy in patients with non-stent thrombosis-elevation- acute coronary syndromes did not significantly reduce the primary composite end point occurrence of cardiovascular (CV) death, myocardial infarction (MI), stroke, hospitalization for ischemia, or urgent revascularization, but significantly increased the GUSTO moderate and severe bleeding (p < 0.001) and intracranial hemorrhage (ICH). In the TRA 2°P-TIMI 50 trial, in patients with a history of MI and peripheral arterial disease (PAD) (67% of the total population), the end point of CV death, MI, or stroke was significantly (20%) reduced with vorapaxar whereas GUSTO moderate or severe bleeding was increased (1.5-fold), but not ICH or fatal bleeding and the net clinical outcome favoring the vorapaxar therapy. Based on these favorable results, the FDA approved vorapaxar for the reduction of thrombotic cardiovascular events in patients with prior MI or with PAD for long term therapy. A careful patient selection is needed to balance efficacy versus safety. At this time, patients with high risk for recurrent ischemic event occurrence such as patients with diabetes mellitus and previous MI can be safely treated with vorapaxar for long-term therapy.

Vorapaxar: A Protease-Activated Receptor Antagonist for the Prevention of Thrombotic Events.

Antiplatelet therapy reduces the risks for cardiovascular morbidity and mortality in patients with atherosclerotic disease, and it is also beneficial in managing peripheral arterial disease (PAD). These agents work through various therapeutic pathways to achieve antithrombotic effects. Although single- or two-drug regimens have been deployed to prevent vascular events, approximately 10% of the patients with acute coronary syndrome remain at risk for recurrent thrombotic events and may need a more aggressive preventative strategy. Vorapaxar offers a unique mechanism for platelet inhibition via the antagonism of protease-activated receptor-1. It is approved for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or PAD. This new drug approval was mainly based on the results from subgroup analyses from a large landmark trial (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-Thrombolysis in Myocardial Infarction 50), which found that vorapaxar reduces the rate of the combined end point of cardiovascular death, MI, stroke, and urgent coronary revascularization when used in addition to aspirin and/or clopidogrel in patients without a history of stroke. In this study, vorapaxar was discontinued in patients with a history of stroke due to excessive risk for intracranial hemorrhage after 2 years of therapy. As an adjunctive therapy to standard regimens, vorapaxar provides a greater net clinical benefit in MI patients who are at a lower risk for bleeding. In patients with PAD, it reduces the rates of recurrent acute limb ischemia with rehospitalization or peripheral revascularization. The most concerning adverse effect is bleeding. Vorapaxar should not be used in patients with a history of stroke, transient ischemic attack, intracranial hemorrhage, or active pathological bleeding. The risks and benefits of adding vorapaxar to intensify antiplatelet regimens should be assessed in individual patients to aim for additional therapeutic outcomes with minimal bleeding risks.

Vorapaxar, a Protease-Activated Receptor-1 Antagonist, a Double-Edged Sword!

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.

In vitro pharmacological characterization of vorapaxar, a novel platelet thrombin receptor antagonist

Vorapaxar is a novel protease-activated receptor-1 (PAR1) antagonist recently approved for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction or with peripheral arterial disease. The present study provides a comprehensive in vitro pharmacological characterization of vorapaxar interaction with the PAR1 receptor on human platelets. Similar studies were performed with a metabolite of vorapaxar (M20). Vorapaxar and M20 were competitive PAR1 antagonists that demonstrated concentration-dependent, saturable, specific, and slowly reversible binding to the receptor present on intact human platelets. The affinities of vorapaxar and M20 for the PAR1 receptor were in the low nanomolar range, as determined by saturation-, kinetic- and competitive binding studies. The calculated Kd and Ki values for vorapaxar increased in the presence of plasma, indicating a decrease in the free fraction available for binding to the PAR1 receptor on human platelets. Vorapaxar was also evaluated in functional assays using thrombin or a PAR1 agonist peptide (SFLLRN). Vorapaxar and M20 completely blocked thrombin-stimulated PAR1/β-arrestin association in recombinant cells and abolished thrombin-stimulated calcium influx in washed human platelets and vascular smooth muscle cells. Moreover, vorapaxar and M20 inhibited PAR1 agonist peptide-mediated platelet aggregation in human platelet rich plasma with a steep concentration response relationship. Vorapaxar exhibited high selectivity for inhibition of PAR1 over other platelet GPCRs. In conclusion, vorapaxar is a potent PAR1 antagonist exhibiting saturable, reversible, selective binding with slow off-rate kinetics and effectively inhibits thrombin’s PAR1-mediated actions on human platelets.

Platelet transfusion reverses bleeding evoked by triple anti-platelet therapy including vorapaxar, a novel platelet thrombin receptor antagonist

Vorapaxar is a novel protease-activated receptor-1 (PAR-1) antagonist recently approved for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction or with peripheral arterial disease. Patients who received vorapaxar in addition to standard of care antiplatelet therapy had an increased incidence of major bleeding events compared with placebo. To assess whether platelet transfusion can restore hemostasis in primates on triple antiplatelet therapy, template bleeding times were assessed concurrently in the buccal mucosa, finger pad, and distolateral tail of anesthetized cynomolgus macaques to evaluate bleeding with vorapaxar as either monotherapy or in combination with aspirin or aspirin and clopidogrel. Aspirin (5mg/kg, IV) or vorapaxar (1mg/kg, PO) alone had no significant effect on bleeding times in the three vascular beds examined. A modest (<2-fold) increase in bleeding time was achieved in the three beds with the dual combination of aspirin and vorapaxar. Major increases in bleeding time were achieved in the three beds with the triple combination of aspirin (5mg/kg, IV), vorapaxar (1mg/kg, PO), and clopidogrel (1mg/kg, PO). Transfusion of fresh human platelet rich plasma, but not platelet poor plasma, reversed the increase in bleeding time in the triple therapy group. Transfusion of human platelets may be a viable approach in situations requiring a rapid reversal of platelet function in individuals treated with triple anti-platelet therapy that includes vorapaxar.

Economic Analysis of Ticagrelor Therapy From a U.S. Perspective: Results From the PLATO Study

BackgroundBased on results of the PLATO (Platelet Inhibition and Patient Outcomes) trial comparing ticagrelor with clopidogrel therapy, the U.S. Food and Drug Administration approved ticagrelor in 2011 for reducing thrombotic cardiovascular events in patients with acute coronary syndrome (ACS) with the proviso that it be taken with low-dose aspirin. ObjectivesThis study sought to assess the cost and cost effectiveness of ticagrelor therapy relative to clopidogrel in treating ACS patients from the perspective of the U.S. health care system. MethodsWe estimated within-trial resource use and costs using U.S. low-dose aspirin patients in PLATO (n = 547). Quality-adjusted life expectancy was estimated using the total PLATO population (n = 18,624), combined with baseline risk and long-term survival data from an external ACS patient cohort. Study drugs were valued at current costs. Cost effectiveness was assessed, as was the sensitivity of results to sampling and methodological uncertainties. ResultsOne year of ticagrelor therapy, relative to that of generic clopidogrel, cost $29,665/quality-adjusted life-year gained, with 99% of bootstrap estimates falling under a $100,000 willingness-to-pay threshold. Results were robust to extensive sensitivity analyses, including variations in clopidogrel cost, exclusion of costs in extended years of life, and a recalibrated estimate of survival reflecting a lower underlying mortality risk in the United States. ConclusionsFor PLATO-eligible ACS patients, a U.S. perspective comparison of the current standard of dual antiplatelet therapy of aspirin with clopidogrel versus aspirin plus ticagrelor showed that the ticagrelor regimen increased life expectancy at an incremental cost well within accepted benchmarks of good value for money. (A Comparison of Ticagrelor [AZD6140] and Clopidogrel in Patients With Acute Coronary Syndrome [PLATO]; NCT00391872)