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Thrombin potently activates platelets through the protease-activated receptor PAR-1. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of PAR-1.
We randomly assigned 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease to recei...
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Context 1
... September 26, 2007, through November 13, 2009, a total of 26,449 patients were enrolled in the trial. Of these, 13,225 were randomly assigned to receive vorapaxar, and 13,244 to receive placebo ( Fig. S1 in the Supplementary ...
Context 2
... 3 years, the primary end point of cardiovascular death, myocardial infarction, or stroke had oc- curred in 1028 patients (9.3%) in the vorapaxar group, as compared with 1176 patients (10.5%) in the placebo group (hazard ratio, 0.87; 95% confi- dence interval [CI], 0.80 to 0.94; P<0.001) ( Table 2 and Fig. 1A). The major secondary end point of cardiovascular death, myocardial infarction, stroke, or urgent coronary revascularization occurred in 1259 patients (11.2%) in the vorapaxar group, as compared with 1417 patients (12.4%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.82 to 0.95; P = 0.001) ( Table 2 and Fig. 1B). The rate of ...
Context 3
... 0.94; P<0.001) ( Table 2 and Fig. 1A). The major secondary end point of cardiovascular death, myocardial infarction, stroke, or urgent coronary revascularization occurred in 1259 patients (11.2%) in the vorapaxar group, as compared with 1417 patients (12.4%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.82 to 0.95; P = 0.001) ( Table 2 and Fig. 1B). The rate of cardio- vascular death or myocardial infarction was re- duced from 8.2% among patients in the placebo group to 7.3% among patients in the vorapaxar group (P = 0.002) ( Table 2, and Fig. S2 in the Sup- plementary Appendix). Individual components of these composite end points are also shown in Table 2. The rate of death from ...
Citations
... Vorapaxar specifically targets and inhibits PAR-1 on platelets, effectively inhibiting thrombin-induced platelet aggregation. The Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients with Atherosclerosis (TRAP 2P-TIMI 50) study randomized 26,449 patients with a history of MI, ischemic stroke, or peripheral artery disease to receive either vorapaxar 2.5 mg daily or a placebo, in addition to standard aspirin therapy [47]. Over an average follow-up period of three years, those who were administered vorapaxar experienced a lower incidence of ischemic events or cardiovascular death compared to those who received the placebo. ...
... Over an average follow-up period of three years, those who were administered vorapaxar experienced a lower incidence of ischemic events or cardiovascular death compared to those who received the placebo. However, the vorapaxar group exhibited a higher occurrence of major and intracranial bleeding [47]. ...
Purpose of Review
To summarize the recent evidence and guideline recommendations on aspirin or P2Y12 inhibitor monotherapy in patients with stable ischemic heart disease and provide insights into future directions on this topic, which involves transition to a personalized assessment of bleeding and thrombotic risks.
Recent Findings
It has been questioned whether the evidence for aspirin as the foundational component of secondary prevention in patients with coronary artery disease aligns with contemporary pharmaco-invasive strategies. The recent HOST-EXAM study randomized patients who had received dual antiplatelet therapy for 6 to 18 months without ischemic or major bleeding events to either clopidogrel or aspirin for a further 24 months, and demonstrated that the patients in the clopidogrel arm had significantly lower rates of both thrombotic and bleeding complications compared to those in the aspirin arm. The patient-level PANTHER meta-analysis showed that in patients with established coronary artery disease, P2Y12 inhibitor monotherapy was associated with lower rates of myocardial infarction, stent thrombosis as well as gastrointestinal bleeding and hemorrhagic stroke compared to aspirin monotherapy, albeit with similar rates of all-cause mortality, cardiovascular mortality and major bleeding.
Summary
Long-term low-dose aspirin is recommended for secondary prevention in patients with stable ischemic heart disease, with clopidogrel monotherapy being acknowledged as a feasible alternative. Dual antiplatelet therapy for six months after percutaneous coronary intervention remains the standard recommendation for patients with stable ischemic heart disease. However, the duration of dual antiplatelet therapy may be shortened and followed by P2Y12 inhibitor monotherapy or prolonged based on individualized evaluation of the patient’s risk profile.
... Vorapaxar blocks protease-activated receptor 1 (PAR1) (encoded by F2R gene) activation on platelet membrane through reversible antagonism and inhibits thrombin-induced platelet aggregation and thrombin receptor agonist peptide (TRAP)-induced platelet aggregation. 1 May et al. (2023) showed that podocyte-specific activation of PAR1 leads to early severe nephrotic syndrome in mice and there might be unknown circulating factors in patients with NS that cause relapsing focal segmental glomerulosclerosis (FSGS) after kidney transplantation. 2 Anti-PAR1 treatments have also been studied in clinical trials for NS. ...
... clinicaltrials.gov ID: NCT03207451 and NCT02545933), vorapaxar protected against the primary endpoint of cardiovascular mortality, MI, or stroke compared to the placebo (Hazard ratio = 0.87, p < 0.001).1 However, to our knowledge, there is currently no available GWAS of thrombotic cardiovascular events in individuals with prior MI or PAD. ...
In clinical trials, the anti-protease-activated receptor-1 (PAR1) therapy, vorapaxar, has been tested as a treatment for nephrotic syndrome (NS). This study aimed to investigate the causal relationship of PAR1 (encoded by the gene F2R) with renal phenotypes using drug-target Mendelian Randomization (MR).
First, we performed colocalization analyses to confirm whether PAR1/F2R expression instruments were shared between plasma/blood and kidney tissue. We selected PAR1/F2R expression instruments from the UK Biobank-Pharma Proteomics Project (UKB-PPP), eQTLGen, and Genotype-Tissue Expression (GTEx). Kidney F2R expression data were obtained from NephQTL2. Second, given the known experimental evidence of the vorapaxar effect on PAR1 inhibition, we conducted drug-target MR to investigate the causal effects of genetically lower PAR1 protein levels or F2R expression levels on thrombotic diseases as positive controls from FinnGen, including venous thromboembolism (VTE), deep venous thrombosis (DVT), and arterial thromboembolism (AET). Finally, we performed drug-target MR to investigate the causal relationship of genetically lower PAR1 protein or F2R expression levels from plasma/blood and kidney tissues on renal diseases and function. We included five renal phenotypes as our main outcomes: CKD, microalbuminuria (MA), NS, estimated GFR (eGFR), and urinary albumin-to-creatinine ratio (uACR). Renal genome-wide association studies (GWAS) data were obtained from the CKDGen consortium, except for NS, which was obtained by meta-analysing FinnGen and a novel GWAS in the UKB. In addition, we also used serum albumin from UKB as a further outcome in a sensitivity analysis.
Colocalization analyses identified shared genetic variants between blood and tubulointerstitial F2R expression (posterior probabilities are 89.1% for eQTLGen and 95.4% for GTEx) but not between plasma PAR1 and tubulointerstitial F2R expression. We present MR findings as β or odds ratios (ORs) with 95% confidence intervals (CIs) per unit decrease in plasma protein or gene expression, or per effect allele, consistent with the direction of effect when taking vorapaxar. Genetically- proxied lower PAR1 and F2R expression reduced risk of VTE with ORs of 0.84 [95% CI 0.71 to 1.00] (UKB-PPP), 0.94 [0.88 to 1.01] (eQTLGen) and 0.89 [0.75 to 1.06] (GTEx), indicating that genetically-instrumented lower PAR1 is directionally consistent with the effect of vorapaxar. Genetically-proxied lower PAR1 and F2R expression increased the risk of developing CKD (UKB- PPP: OR=1.17 [0.99 to 1.38]; eQTLGen: OR=1.12 [1.02 to 1.23]; GTEx: OR=1.24 [1.05 to 1.46]), but may decrease eGFR (eQTLGen: β=-0.02 [-0.06 to 0.01], GTEx: β=-0.04 [-0.08 to 0.01], UKB-PPP: β =-0.01, [-0.05, 0.04]). The effect of genetically-proxied PAR1 on NS was inconclusive due to lack of power.
Our study suggests that genetically-proxied lower PAR1 and F2R expression reduces VTE risk, and increases CKD risk, but provides less evidence on reducing eGFR or increasing uACR. Evidence regarding NS was inconclusive. For NS patients, the decision to use anti-PAR1 treatment should be made with caution, given the potential renal implications and the current lack of conclusive evidence of its impact on NS.
... Vorapaxar is the first PAR-1 antagonist to receive FDA approval as an oral antiplatelet agent. Although vorapaxar reduces the risk of cardiovascular death and ischemic events in patients with atherosclerosis, it also increases the risk of moderate or severe bleeding, including intracranial hemorrhage (Morrow et al., 2012). These results also suggest that drugs that induce excessive PAR1 activity in platelets have the potential to induce thrombosis. ...
Background: Protease-activated receptor 1 (PAR1) is expressed in human platelets and can be activated by low concentrations of thrombin. Vorapaxar, a selective antagonist of PAR1, inhibits thrombin-induced calcium mobilization in human platelet, which is associated with an increased risk of bleeding. Conversely, the administration of a positive allosteric modulator (PAM) of PAR1 may pose a substantial risk of thrombosis due to inducing excessive platelet activation. In this study, we discovered a novel PAM of PAR1 and investigated the effect of enhanced PAR1 activation by PAM of PAR1 on platelet activation.
Methods: To find PAMs of PAR1, a cell-based screen was performed in HT29 cells, and finally, gestodene, an oral contraceptive drug (OC), was identified as a novel PAM of PAR1. The mechanism of action of gestodene and its effects on platelet activation were investigated in human megakaryocytic leukemia cell line MEG-01 cells and human platelet.
Results: Gestodene enhanced both thrombin- and PAR1-activating peptide (AP)-induced intracellular calcium levels in a dose-dependent manner without altering PAR2 and PAR4 activity. Gestodene significantly increased PAR1-AP-induced internalization of PAR1 and phosphorylation of ERK1/2, and the enhancing effects were significantly blocked by vorapaxar. Furthermore, gestodene potently increased PAR1-AP induced morphological changes in MEG-01 cells. Remarkably, in human blood, gestodene exerted a robust augmentation of PAR1-AP-induced platelet aggregation, and vorapaxar effectively attenuated the gestodene-induced enhancement of platelet aggregation mediated by PAR1.
Conclusion: Gestodene is a selective PAM of PAR1 and suggest one possible mechanism for the increased risk of venous thromboembolism associated with OCs containing gestodene.
... Finally, another antiplatelet agent used for secondary prevention was the protease-activated receptor inhibitor vorapaxar, being able to prevent thrombin-induced platelet activation [59]. The drug was compared with placebo in 26,449 patients with established cardiovascular disease in the TRA 2P -TIMI 50 trial, but, while a significant reduction in MACE was found in patients receiving vorapaxar (9.3% vs 10.5%; HR: 0.87; 95% CI: 0.80-0.94), the drug failed to significantly reduce ischemic stroke (2.2% vs 2.6%; HR: 0.85; 95% CI: 0.72-1.01) ...
... and was associated with significant bleeding harm (4.2% vs 2.5%; HR: 1.66; 95% CI: 1.43-1.93) at 30 months, outweighing the potential ischemic benefits [59]. ...
Introduction: Ischemic etiology accounts for two thirds of all strokes in which platelet activation and
aggregation play a major role. A variety of antiplatelet therapies have been tested for primary, secondary,
and tertiary prevention, with certain patient subtypes benefiting more than others from a specific regimen.
Areas covered: This review aims at synthetizing current evidence on pharmacology of antiplatelet
agents approved for primary, secondary, and tertiary stroke prevention and their application among
possible patient subtypes that may benefit more from their administration.
Expert opinion: Management of ischemic stroke has largely evolved over the past decades. A better
understanding of stroke pathophysiology has allowed to identify patients who can benefit most from
antiplatelet therapies, with varying degrees of benefit depending on whether these agents are being used
for primary, secondary, or tertiary prevention. Importantly, the antiplatelet treatment regimens currently
available have expanded and no longer limited to aspirin but include other drugs such as P2Y12 and
phosphodiesterase inhibitors, also used in combination, as well as precision medicine approaches using
genetic testing aiming at optimizing the safety and efficacy in this population
... The FDA-approved small-molecule antagonist, vorapaxar, effectively and irreversibly inhibits various downstream signaling pathways of PAR1; however, its usage is limited due to the increased risk of bleeding and intracranial hemorrhage. [18][19][20][21] To avoid the disadvantage of the orthosteric antagonist, an increasing number of allosteric modulators, including parmodulins and pepducins, are designed to target the intracellular domain of PAR1, [22][23][24][25] with the aim of disrupting or inhibiting G protein binding. Ligands that possess the ability to selectively inhibit particular signaling pathways are of particular necessity, yet the unknown mechanisms of G protein coupling selectivity of PAR1 have posed significant challenges for drug development. ...
Protease-activated receptors (PARs) are a unique group within the G protein-coupled receptor superfamily, orchestrating cellular responses to extracellular proteases via enzymatic cleavage, which triggers intracellular signaling pathways. Protease-activated receptor 1 (PAR1) is a key member of this family and is recognized as a critical pharmacological target for managing thrombotic disorders. In this study, we present cryo-electron microscopy structures of PAR1 in its activated state, induced by its natural tethered agonist (TA), in complex with two distinct downstream proteins, the G q and G i heterotrimers, respectively. The TA peptide is positioned within a surface pocket, prompting PAR1 activation through notable conformational shifts. Contrary to the typical receptor activation that involves the outward movement of transmembrane helix 6 (TM6), PAR1 activation is characterized by the simultaneous downward shift of TM6 and TM7, coupled with the rotation of a group of aromatic residues. This results in the displacement of an intracellular anion, creating space for downstream G protein binding. Our findings delineate the TA recognition pattern and highlight a distinct role of the second extracellular loop in forming β-sheets with TA within the PAR family, a feature not observed in other TA-activated receptors. Moreover, the nuanced differences in the interactions between intracellular loops 2/3 and the Gα subunit of different G proteins are crucial for determining the specificity of G protein coupling. These insights contribute to our understanding of the ligand binding and activation mechanisms of PARs, illuminating the basis for PAR1’s versatility in G protein coupling.
... Thrombin is an extremely potent agonist that activates human platelets by proteolytic cleavage of PAR1 and PAR4, which are high-and low-affinity receptors, respectively. Two PAR1-specific antagonists have been licensed: vorapaxar and atopaxar [95,96]. The latest studies have examined the impact of triple antiplatelet therapy on cardiovascular death by combining vorapaxar with standard antiplatelet therapy (aspirin and clopidogrel). ...
... The latest studies have examined the impact of triple antiplatelet therapy on cardiovascular death by combining vorapaxar with standard antiplatelet therapy (aspirin and clopidogrel). Patients undergoing triple therapy exhibited lower rates of cardiovascular death, but also experienced an uptick in intracranial hemorrhage [95,97,98]. Despite these findings, vorapaxar has been cleared for use in patients with a history of cardiovascular disease and no history of stroke. ...
... It is thought that they may generate a variety of active signaling molecules. 12-LOX, named for the ability of this family member to oxidize arachidonic acid at carbon 12, is found in both megakaryocytes and platelets, according to the latest evidence [95,102]. ...
Platelets play a significant role in hemostasis, forming plugs at sites of vascular injury to limit blood loss. However, if platelet activation is not controlled, it can lead to thrombotic events, such as myocardial infarction and stroke. To prevent this, antiplatelet agents are used in clinical settings to limit platelet activation in patients at risk of arterial thrombotic events. However, their use can be associated with a significant risk of bleeding. An enhanced comprehension of platelet signaling mechanisms should facilitate the identification of safer targets for antiplatelet therapy. Over the past decade, our comprehension of the breadth and intricacy of signaling pathways that orchestrate platelet activation has expanded exponentially. Several recent studies have provided further insight into the regulation of platelet signaling events and identified novel targets against which to develop novel antiplatelet agents. Antiplatelet drugs are essential in managing atherothrombotic vascular disease. The current antiplatelet therapy in clinical practice is limited in terms of safety and efficacy. Novel compounds have been developed in response to patient variability and resistance to aspirin and/or clopidogrel. Recent studies based on randomized controlled trials and systematic reviews have definitively demonstrated the role of antiplatelet therapy in reducing the risk of cardiovascular events. Antiplatelet therapy is the recommended course of action for patients with established atherosclerosis. These studies compared monotherapy with a P2Y12 inhibitor versus aspirin for secondary prevention. However, in patients undergoing percutaneous coronary intervention, it is still unclear whether the efficacy of P2Y12 inhibitor monotherapy after a short course of dual antiplatelet therapy depends on the type of P2Y12 inhibitor. This paper focuses on the advanced-stage evaluation of several promising antiplatelet drugs.
... It has been demonstrated to lower the chance of heart-related incidents. when used in conjunction with standard antiplatelet treatment in individuals with previous experiences of peripheral arterial disease or myocardial infarction [17]. Although antiplatelet therapy is efficient in lowering heart attacks, it is not without risk. ...
Cardiovascular diseases (CVDs) continue to be a worldwide health concern, requiring effective strategies for risk reduction. This article explores the extensive collaboration between medical therapy and lifestyle modifications in the management of CVDs, aiming to interpret whether a single approach holds the key to reducing major cardiovascular events. In the realm of pharmaceutical therapy, statins, beta-blockers, angiotensin-converting-enzyme (ACE) inhibitors, and antiplatelet agents have shown significant effectiveness, as evidenced by landmark trials such as Scandinavian Simvastatin Survival Study (4S) and Heart Outcomes Prevention Evaluation (HOPE). Concurrently, lifestyle adjustments, encompassing physical activity, dietary changes, and management of stress, emerge as indispensable elements in cardiovascular care. The article discusses the pivotal role of patient adherence, tailored approaches, and the synergistic impact of combining medical therapy and lifestyle modifications. Challenges, such as socioeconomic disparities and uncertainties in lipid management, underscore the need for ongoing research and precision medicine. Digital health interventions offer novel avenues for personalized care. Despite advancements, uncertainties persist regarding the optimal balance between medical and lifestyle interventions in lowering major cardiovascular event risks. This article emphasizes the ongoing evolution of cardiovascular care, highlighting the imperative need for evidence-based guidelines tailored to individual patient needs.
... Vorapaxar was approved by the FDA in 2014 as an antiplatelet agent to treat patients with a history of myocardial infarction or with peripheral artery disease ( Figure 1) [52,53]. In clinical trials, effects of vorapaxar were also assessed in patients with a history of ischemic stroke, but it was terminated early due to a significant increase in intracranial hemorrhage among patients treated with vorapaxar [53]. ...
... Vorapaxar was approved by the FDA in 2014 as an antiplatelet agent to treat patients with a history of myocardial infarction or with peripheral artery disease ( Figure 1) [52,53]. In clinical trials, effects of vorapaxar were also assessed in patients with a history of ischemic stroke, but it was terminated early due to a significant increase in intracranial hemorrhage among patients treated with vorapaxar [53]. ...
... It is approved to be used as a single antiplatelet therapy or in combination with aspirin and/or clopidogrel [56]. However, consideration of the bleeding potential associated with vorapaxar should be taken into account prior to its administration, as the bleeding risk observed with vorapaxar may be aggravated when used in combination with another antiplatelet drug [52,53]. ...
... However, targeting PAR1 comes with a significant risk of bleeding, which outweighs its clinical benefits in preventing cardiovascular events. [14,15] In recent years, PAR4 has become a rising star as a safer antiplatelet and antithrombotic target for a number of reasons. First, targeting PAR4 signaling without inhibiting PAR1 allows platelets to continue to respond to low levels of thrombin and preserves normal hemostasis. ...
Background: Protease activated receptor 4 (PAR4) mediates thrombin signaling on platelets and other cells. Our recent structural studies demonstrated a single nucleotide polymorphism in extracellular loop 3 (ECL3), PAR4-P310L (rs2227376) leads to a hypo-reactive receptor. Objectives:
The goal of this study was to determine how the hypo-reactive PAR4 variant in ECL3 impacts platelet function in vivo using a novel knock-in mouse model (PAR4-322L). Methods: A point mutation was introduced into the PAR4 gene, F2rl3, via CRISPR/Cas9 to create PAR4-P322L, the mouse homolog to human PAR4-P310L. Platelet response to PAR4 activation peptide (AYPGKF), thrombin, ADP, and convulxin was monitored by αIIbβ3 integrin activation and P-selectin translocation using flow cytometry or platelet aggregation. In vivo responses were determined by the tail bleeding assay and the ferric chloride-induced carotid artery injury model. Results:
PAR4-P/L and PAR4-L/L platelets had a reduced response to AYPGKF and thrombin measured by P-selectin translocation or αIIbβ3 activation. The response to ADP and convulxin was unchanged among genotypes. In addition, both PAR4-P/L and PAR4-L/L platelets showed a reduced response to thrombin in aggregation studies. There was an increase in the tail bleeding time for PAR4-L/L mice. The PAR4-P/L and PAR4-L/L mice both showed an extended time to arterial thrombosis. Conclusions: PAR4-322L significantly reduced platelet responsiveness to AYPGKF and thrombin, which is in agreement with our previous structural and cell signaling studies. In addition, PAR4-322L had prolonged arterial thrombosis time. Our mouse model provides a foundation to further evaluate the role of PAR4 in other pathophysiological contexts.
... in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2P)-Thrombolysis in MI (TIMI) 50 trial revealed a reduction in MACE but at the expense of significantly increased risk of bleeding, especially intracranial hemorrhage [21]. ...
... However, moderate or severe bleeding occurred in 4.2% of patients in the vorapaxar group versus 2.5% in the placebo group (HR 1.66, 95% CI: 1.43-1.93). The intracranial hemorrhage rate in the vorapaxar group was 1.0% versus 0.5% in the placebo group [21]. ...
Purpose of review
Peripheral arterial disease (PAD) is a complex atherosclerotic arterial disease with significant morbidity and mortality. Hence, the role of evidence-based medical therapy in PAD is critical, especially the use of antithrombotic therapy.
Recent findings
Multiple randomized controlled trials, especially those from the last few years, including but not limited to the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial and the Vascular Outcomes Study of Aspirin along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD (VOYAGER PAD) trial, have shown the utility of the use of various antiplatelet and oral anticoagulant therapies, especially the combination of low-dose rivaroxaban and aspirin, in patients with PAD both with and without revascularization.
Summary
In this review, we will (i) summarize the current guidelines outlining the evidence-based use of various antithrombotic agents in PAD, (ii) summarize the current available trials supporting such guidelines, and (iii) discuss future trial designs.
