Introduction Although platelet response testing is controversial, up to one-third of neuroendovascular patients are ‘resistant’ to clopidogrel and are at risk for in stent thrombotic complications and may require alternative antiplatelet therapy. Ticagrelor is a new reversible ADP P2Y12 platelet receptor inhibitor with no known resistance. We describe the clinical experience with ticagrelor for neuroendovascular procedures as an alternative in clopidogrel P2Y12 platelet resistant patients.
Methods We reviewed our cerebrovascular database for all patients who were non-responders to clopidogrel, defined as P2Y12% inhibition <30%, despite repeat clopidogrel loading dose of at least 600 mg, and who were then administered ticagrelor.
Results 18 patients were non-responders to clopidogrel; 10 (56%) were men, eight (44%) were women, with a median age of 61 years (range 38–84). All patients received loading doses of at least 600 mg of clopidogrel and showed P2Y12 levels below 20% prior to ticagrelor administration. Patients were loaded with 180 mg of ticagrelor, and all but one patient showed an initial P2Y12 response above 60%. 11 patients underwent stenting, two underwent coiling, and five underwent treatment by pipeline embolization device. No patient experienced any adverse effects in the postoperative period related to the use of ticagrelor.
Conclusions Ticagrelor offers an effective alternative to clopidogrel non-responders. All of our patients showed immediate platelet inhibition after a loading dose of 180 mg of ticagrelor, with no adverse effects. The cost of medication, patient compliance (twice a day doses), and reversible inhibition should be taken into consideration when using ticagrelor.
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The endovascular use of intracranial and extracranial stents requires dual antiplatelet therapy due to the risk of platelet rich thrombus formation in response to stenting.1–4 Numerous studies have shown the importance of dual antiplatelet therapy in the presence of intracranial or extracranial stenting.5–7 The use of aspirin and clopidogrel has been shown to exhibit an optimal safety and efficacy profile compared with other antiplatelet regimens.8–11 However, about one-third of patients appear to be non-responders to clopidogrel, as tested by P2Y12 response, and this patient group needs alternative treatment.12–15
Due to the potential catastrophic consequences of neurosurgical thromboembolism after cervical and intracranial stenting procedures, the need for a safe and efficacious antiplatelet regimen is particularly important. Ticagrelor is a new nucleoside analog indicated for the prevention of thrombotic events in patients with acute coronary syndrome or myocardial infarction with ST elevation.16 Ticagrelor and its equipotent metabolite (AR-C124910XX) interact reversibly with ADP receptors of the subtype P2Y(12), making this drug an allosteric antagonist with a reversible effect. Clopidogrel is a prodrug, which has to be metabolized in the liver to produce an active metabolite. The metabolite covalently binds the P2Y12 platelet ADP receptor and inhibits binding of ADP and activation of the receptor. Therefore, as ticagrelor and its metabolite do not need hepatic activation and are primarily metabolized via the CYP34A enzyme, this drug can be advantageous in patients with genetic mutations of the CYP2C19 enzyme. Also, the extremely low number of non-responders makes it particularly advantageous for neurological stenting procedures.17–20
In this study, we analyzed our experience with ticagrelor in combination with aspirin for the use of intracranial and extracranial stenting in both elective and emergency procedures. Special emphasis was put on the safety and efficacy of the use of ticagrelor in this context.
According to our protocol, all patients undergoing stenting are treated prior to the procedure with dual antiplatelet therapy using aspirin and clopidogrel. The efficacy of antiplatelet function is then analyzed, and patients are considered on adequate anticoagulation based on percentage P2Y12 inhibition (eg, >30%) and aspirin function tests. P2Y12 inhibition of >30% was adopted from VerifyNow-P2Y12 literature review.21 ,22 In elective cases, patients are usually loaded with 300 mg of clopidogrel and 650 mg of aspirin 7 days prior and maintained on 75 mg of clopidogrel and 325 mg of aspirin daily. In the cases of semi-urgent interventions, patients are administered 600 mg of clopidogrel and 650 mg of aspirin and the response tests are checked 4–6 h later. Inadequate response to clopidogrel is defined as inhibition <30%, and patients are considered as clopidogrel non-responders. While our regimen for similar cases has changed significantly over the past few years, we recently started using ticagrelor for clopidogrel non-responsive patients and we used a loading dose of 180 mg of ticagrelor. P2Y12 inhibition was then repeated within 120 min after administration of ticagrelor.
In this study, we performed a retrospective analysis of our cerebrovascular database and all patients who received medical preparation with a dual antiplatelet regimen were identified. From October 2011 to August 2012, 18 patients were identified as non-responders to clopidogrel, according to testing for P2Y12 inhibition levels. There were 10 men (56%) and eight women (44%), with a median age of 61 years (range 38–84). All patients initially received a loading dose of 600 mg of clopidogrel, and 4 h later their P2Y12 inhibition levels were below 20%. Then, this group received a loading dose of ticagrelor 180 mg by mouth. All but one patient showed initial P2Y12 inhibition >60%. Eleven patients underwent extracranial or intracranial stenting (six carotid artery stents (four extracranial and two intracranial), three vertebral artery stents, one basilar artery stent, and one middle cerebral artery stent), two patients underwent coiling, and five patients had placement of a pipeline embolization device for treatment of intracranial aneurysms. Sixteen procedures were done electively and two procedures were emergent. Following administration of ticagrelor, no patient experienced adverse effects during or following the postoperative period that could be related to ticagrelor.
Despite the impressive and consistent effects of aspirin in reducing adverse events in a variety of ischemic cerebrovascular disorders, a significant rate of such events persists, and more potent antiplatelet agents, especially glycoprotein IIb/IIIa inhibitors, have been developed. Clopidogrel has been routinely used in conjunction with aspirin as a dual antiplatelet regimen for coronary intervention, and off-label use of this drug has been standard for neuroendovascular procedures. Because of the complex pathophysiology of cerebrovascular thromboembolic events, involving thrombosis, inflammation, vascular biology, hemodynamics and others, no single agent can be expected to abolish ischemic events.
The issue of platelet function testing and the need for alternative medical options in cardiac procedures remain very controversial, with extrapolation of these results to neurointervention, even more so.
Resistance to clopidogrel has been observed in approximately one-third of patients and can be measured by genetic testing and a variety of platelet assays. Due to the potentially devastating consequences of thromboembolic complications, there has been increasing awareness of this resistance, with recent studies analyzing the efficacy of ticagrelor compared with clopidogrel in patients with coronary artery disease. In the RESPOND study,23 ticagrelor was associated with a greater platelet inhibition rate in both clopidogrel responders and non-responders, and ticagrelor therapy overcame clopidogrel resistance. Compared with clopidogrel, ticagrelor has comparable efficacy with no significant adverse effects.24
The ONSET/OFFSET study25 also showed that ticagrelor achieved faster and greater platelet inhibition than a high loading dose of clopidogrel. This was sustained during the maintenance phase and was faster in offset after drug discontinuation. The faster offset of ticagrelor after drug discontinuation could potentially decrease the mortality and morbidity associated with the adverse effects of antiplatelet treatment, which could result in overall improvement in outcomes.
Although many studies failed to show benefit of testing and correcting antiplatelet regimens based on clopidogrel resistance findings, cardiology results may not be readily applicable to neurointervention patients. Factors such as end organ result response to a thromboembolic event (heart muscle vs neurons), amount of metal implanted, among others, can be invoked as rationale to not simply apply cardiac literature to cervical and intracranial stenting.
The efficacy of ticagrelor has been shown in several reports from the cardiology literature; there are no reports documenting the use of ticagrelor in patients undergoing cerebrovascular interventions. Our study demonstrates the safety and efficacy of ticagrelor as an alternative antiplatelet agent to clopidogrel in non-responders when used in conjunction with aspirin as a dual treatment. Our data show that in clopidogrel resistant patients, adequate P2Y12 inhibition is achieved consistently with ticagrelor, and this hopefully serves as adequate protection from thromboembolic complications.
Several studies have shown the occurrence of intracranial hemorrhage in patients on a dual antiplatelet regimen after neuroendovascular procedures, including stenting for atherosclerotic disease, aneurysm embolization with coils, and new flow diverter devices.26 ,27 All of our patients tolerated ticagrelor well, and there were no cases of intracranial hemorrhage. However, the number of patients in the current study is small; future review of a larger pool of data would be beneficial to support the safety of ticagrelor in endovascular procedures, including new flow diverter devices. Of note, one patient who was a non-responder to clopidogrel and was placed on ticagrelor after pipeline embolization device placement, suffered from a stroke as a result of partial thrombosis of the device after ticagrelor was switched to clopidogrel at the rehabilitation center due to ticagrelor non-availability. Therefore, it is advisable to use ticagrelor in clopidogrel non-responders as an alternative treatment in order to prevent devastating adverse outcomes.
Compared with other agents such as clopidogrel and prasugrel, the need for twice a day administration and reversible ligation to P2Y12 receptors (with faster platelet aggregation activation after drug discontinuation) are potential drawbacks for ticagrelor utilization, and should be discussed on a case by case basis prior to utilization. The cost of ticagrelor compared with clopidogrel is also higher and should be taken into consideration when prescribing the drug.
In this report, we have presented our initial experience with the use of ticagrelor as an alternative for clopidogrel resistant patients undergoing cerebrovascular interventions. Ticagrelor appears to be safe and effective in preventing platelet thrombus formation. Ticagrelor administration in this subclass of patients who are clopidogrel non-responders might be beneficial as an alternative antiplatelet agent. It is possible and likely that most of the benefits, efficacy, and safety of ticagrelor that are described in the cardiac literature can be extrapolated and applied to cerebrovascular endovascular interventions. Although the initial results of our study are favorable, our numbers are limited. Further investigation is needed to assess the impact of platelet function testing with regards to neurointervention outcomes and use of ticagrelor (and other agents) as an alternative antiplatelet treatment in those cases.
Contributors All individuals listed as authors of this manuscript have participated in conceptualizing the research or content of the manuscript, in writing or critically editing the manuscript, and/or in analysis of the data presented in the manuscript.
Competing interests None.
Ethics approval The study was approved by the Mayo Clinic Institutional Review Board.
Provenance and peer review Not commissioned; externally peer reviewed.
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