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

Author(s):  
James C Mamaril‐Davis ◽  
Pedro Aguilar‐Salinas ◽  
Leonardo Brasiliense ◽  
Richard Cosgrove ◽  
Travis Dumont ◽  
...  

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

2009 ◽  
Vol 29 (04) ◽  
pp. 349-355 ◽  
Author(s):  
C. Bode ◽  
S. K. Hildemann

SummaryMorbidity and mortality in patients with atherothrombotic disease remain high despite the use of antiplatelet therapy with aspirin and an ADP receptor antagonist. Selective inhibition of the principal protease-activated receptor (PAR)-1 for thrombin, the most potent agonist for platelet activation, represents a promising novel strategy to reduce thrombosis and ischaemic events. SCH 530348, a potent thrombin receptor antagonist (TRA) selective for PAR-1, has been evaluated in preclinical studies, demonstrating complete and sustained inhibition of thrombin/TRAP-induced platelet aggregation without a concomitant increase in the risk of bleeding. Phase 2 studies in patients undergoing non-urgent or urgent PCI showed that treatment with SCH 530348 in addition to the standard of care (aspirin plus an ADP receptor antagonist) is not associated with an increased risk of TIMI bleeding and is well tolerated, with a rate of adverse events comparable to standard therapy alone. These studies also demonstrated that the use of SCH 530348 in combination with aspirin and an ADP receptor antagonist may reduce the incidence of major adverse cardiac events, specifically periprocedural myocardial infarction, vs aspirin plus an ADP receptor antagonist alone. On the basis of these encouraging results, 2 ongoing large phase 3 randomized trials are evaluating the efficacy and safety of SCH 530348 in combination with the standard-of-care therapy in ≈35 000 patients with NSTE ACS or established atherosclerosis.


Author(s):  
James C. Mamaril‐Davis ◽  
Pedro Aguilar‐Salinas ◽  
Leonardo B. Brasiliense ◽  
Richard Cosgrove ◽  
Judy Dawod ◽  
...  

Abstract BACKGROUND Perioperative dual‐antiplatelet therapy for flow diversion limits thromboembolic complications. However, resistance to dual‐antiplatelet therapy medications remains a concern for neuroendovascular intervention. To date, there is no standardized approach for resistance to ADP receptor antagonists. METHODS We report a case of ticagrelor resistance for flow diversion of an intracranial aneurysm treated with vorapaxar, as well as a narrative review of the literature for previous cases of ticagrelor resistance. RESULTS Flow diversion with the Pipeline embolization device was deployed for a left internal carotid artery blister aneurysm and bilateral internal carotid artery dissecting pseudoaneurysms. The patient had 3 thromboembolic complications while on dual‐antiplatelet therapy with ticagrelor or prasugrel, leading to transition of antiplatelet therapy to vorapaxar. At 84 days follow‐up, the patient was fully recovered with complete occlusion of the aneurysms. CONCLUSION Our case suggests that vorapaxar is a promising alternative for patients with ticagrelor resistance in flow diversion–treated intracranial aneurysms. High‐quality randomized controlled trials are needed to elucidate the safety and efficacy of vorapaxar in neuroendovascular procedures.


2013 ◽  
Vol 132 (1) ◽  
pp. e36-e41 ◽  
Author(s):  
Günter Christ ◽  
Thomas Hafner ◽  
Jolanta M. Siller-Matula ◽  
Marcel Francesconi ◽  
Katharina Grohs ◽  
...  

2016 ◽  
Vol 130 (6) ◽  
pp. 441-442 ◽  
Author(s):  
David W. Essex ◽  
A. Koneti Rao

Platelets play a major role in the complex interactions involved in blood coagulation via multiple mechanisms. As reported in this issue, Schoergenhofer et al. tested the hypothesis that platelet inhibition by prasugrel, a potent platelet P2Y12 ADP receptor antagonist, attenuates the effect of lipopolysaccharide (LPS) on the blood coagulation system in healthy human subjects. LPS, a bacterial product with potent pro-inflammatory and pro-thrombotic effects, plays a central role in sepsis. It activates monocytes and endothelial cells via Toll-like receptor (TLR) 4 and other TLRs to stimulate production of TF and other pro-coagulant molecules, chemokines and cytokines. Treatment with prasugrel did not decrease biomarkers of coagulaion. A better understanding of the relative roles of platelet and coagulation mechanisms in triggering the pro-thrombotic state may lead to more effective antithrombotic strategies.


1991 ◽  
Vol 65 (05) ◽  
pp. 573-577 ◽  
Author(s):  
Jean McPherson ◽  
Marjorie B Zucker ◽  
Evelyn A Mauss ◽  
Sandra Brownlea

SummaryRistocetin-induced platelet agglutination (RIPA) in EDTA-treated citrated platelet-rich plasma was reduced to 49 ± 11% by 1.25 ΜM ADP, 41 ± 14% by 1 ΜM A 23187, and 26 ± 7% by 0.1 Μg/ml platelet activating factor (PAF). The effect of 5-110 ΜM epinephrine was not dose-dependent, but varied between donors, with RIPA from 56-100% of the control. The inhibitory effects of these agonists were not altered by prior treatment of platelets with aspirin. Prior addition of 200 ΜM ATP (an ADP receptor antagonist acting at both high and low affinity ADP receptors) prevented the inhibitory action of ADP but not that of A 23187 or PAF, suggesting that the inhibitory actions of the latter are not mediated by released ADP. As 700 ΜM 8-bromoadenosine 5-diphosphate (an ADP receptor antagonist acting mainly at the high affinity receptor) did not prevent ADP-induced inhibition of RIPA, interaction of ADP with the low affinity receptor is presumably responsible for its inhibitory action. As A 23187, but not phorbol myristate acetate (0.1 ΜM) inhibited RIPA, an increase in intracellular calcium ions rather than direct stimulation of protein kinase C appears to mediate agonist-induced inhibition. Cytochalasin B (10.5-21 ΜM), dibucaine (0.5-1 mM), and prostaglandin E1 (25 nM), added before or after the agonist, prevented or reversed ADP-, A23187-, and PAF-induced inhibition of RIPA, suggesting that the state of the platelet cytoskeleton affects inhibition. N-ethylmaleimide (0.25-0.5 mM), an agent that can penetrate cell membranes and block sulphydryl groups, prevented or reversed ADP, A 23187- and PAF-induced inhibition of RIPA, but 0.5 mM dithionitrobisbenzoic acid, a non-penetrating sulphydryl blocker, had no effect. Diamide (0.1-0.5 mM), an agent that can crosslink cytoskeletal proteins by oxidation of sulphydryl groups, reduced RIPA. Thus an increase in intracellular calcium ions with resultant cytoskeletal changes and reorganisation of intracellular sulphydryl groups may mediate the inhibitory action of agonists on RIPA.


2020 ◽  
Vol 12 (11) ◽  
pp. 1113-1116 ◽  
Author(s):  
Mahmoud H Mohammaden ◽  
Stephen W English ◽  
Christopher J Stapleton ◽  
Eman Khedr ◽  
Ahmed Shoyb ◽  
...  

BackgroundFlow diversion (FD) is a common treatment modality for complex intracranial aneurysms. A major concern regarding the use of FD is thromboembolic events (TEE). There is debate surrounding the optimal antiplatelet regimen to prevent TEE. We aim to evaluate the safety and efficacy of ticagrelor as a single antiplatelet therapy (SAPT) for the prevention of TEE following FD for complex aneurysm treatment.MethodsA retrospective review of a prospectively maintained neuroendovascular database at three endovascular centers was performed. Patients were included if they had an intracranial aneurysm that was treated with FD between January 2018 and September 2019 and were treated with ticagrelor as SAPT. Primary outcomes included early (within 72 hours post-procedure) and late (within 6 months) ischemic events.ResultsA total of 24 patients (mean age 47.7 years) with 36 aneurysms were eligible for analysis, including 15 (62.5%) females. 14 (58.3%) patients presented with subarachnoid hemorrhage. 35 aneurysms arose from the anterior circulation and 1 from the posterior circulation. 23 aneurysms had a saccular morphology, whereas 7 were fusiform and 6 were blister. For the treatment of all 36 aneurysms, 30 procedures were performed with 32 FD devices. Procedural in-stent thrombosis occurred in 2 cases and was treated with intra-arterial tirofiban without complications. Aneurysm re-bleeding was reported in 1 (4.2%) patient. There were no reported early or late TEE. Three patients discontinued ticagrelor due to systemic side effects.ConclusionTicagrelor is a safe and effective SAPT for the prevention of TEE after FD. Large multicenter prospective studies are warranted to validate our findings.


Author(s):  
Suvro Sankha Datta ◽  
Dibyendu De ◽  
Nadeem Afroz Muslim

AbstractHigh on-treatment platelet reactivity (HPR) with P2Y12 receptor antagonists in patients treated with dual antiplatelet therapy (DAPT) is strongly associated with adverse ischemic events after percutaneous coronary intervention (PCI). This prospective study was conducted to assess individual platelet response and HPR to antiplatelet medications in post-PCI cases by thromboelastography platelet mapping (TEG-PM). Total 82 patients who were on aspirin and on either clopidogrel, prasugrel, or ticagrelor were evaluated. The percentage of platelet inhibition to arachidonic acid (AA) and adenosine disdiphosphate (ADP) was calculated by [100-{(MA ADP/AA–MA Fibrin) / (MA Thrombin–MA Fibrin) × 100}], taking 50% response as cut-off for HPR. HPR to clopidogrel and prasugrel was 14.29 and 12.5%, respectively. No HPR was detected to aspirin and ticagrelor. The mean percentage of platelet inhibition was significantly higher in patients with ticagrelor 82.99, 95% confidence interval (CI) of [77.3, 88.7] as compared with clopidogrel 72.21, 95% CI of [65.3, 79.1] and prasugrel 64.2, 95% CI of [52.5, 75.9] (p-value of 0.041 and 0.003, respectively). Aspirin along with ticagrelor is associated with a higher mean percentage of platelet inhibition, and lower HPR as compared with the usage of aspirin combined with clopidogrel or prasugrel. Additionally, it might also be concluded that TEG-PM could be used effectively to measure the individual platelet functions which would make oral antiplatelet therapy more personalized for cardiac patients.


2016 ◽  
Vol 202 ◽  
pp. 463-466 ◽  
Author(s):  
Jussi Mikkelsson ◽  
Tuomas Paana ◽  
Aino Lepantalo ◽  
Pasi P. Karjalainen

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