New advances in intracranial or extracranial stents, stent grafts, flow diverters, and pCONUS have changed the way in which patients are treated in the field of neurointervention. The endovascular use of these devices requires dual antiplatelet therapy due to the inherent risk of platelet-rich in-stent thrombus formation [1-3]. The importance of dual antiplatelet therapy with aspirin and a P2Y12 receptor antagonist (such as clopidogrel, prasugrel, or ticagrelor) during stenting has been documented in numerous studies [4-6]. The combination of aspirin and clopidogrel has been documented to be safe and efficacious as compared to other antiplatelet combinations [7-10]. While aspirin resistance is less common, clopidogrel resistance may be more challenging, as it is reported to be as high as 30–35% and is reported to increase thromboembolic complications, even with escalating dosing of clopidogrel [11-14].

In recent years, a few studies on patients after neurovascular stent placement have revealed similar rates of resistance for aspirin and clopidogrel compared with rates in the cardiovascular literature [13,15-17]. This necessitates the need to look for a safe and efficacious antiplatelet regimen that not only minimizes the risk of neurosurgical thromboembolism after stenting but also reduces risk of perioperative intracranial hemorrhage due to potent P2Y12 receptor over-inhibition.

Unlike clopidogrel, ticagrelor is a reversible allosteric binder that does not need hepatic activation. Ticagrelor and its equipotent metabolite are absorbed quickly and reach peak concentration after about 1.5 hours [18]. Moreover, the extremely low number of non-responders makes it particularly advantageous for neurological stenting procedures [19-22].

The purpose of this paper is to present our experience using ticagrelor in combination with aspirin in a limited cohort of Indian patients with clopidogrel resistance who underwent elective neuroendovascular procedures at the NH Institute of Neurosciences (Narayana Health City, Bangalore).

From July 2015 to May 2017, of the total 127 patients who underwent a neuroendovascular procedure, 32 patients (25%) were identified as non-responders to clopidogrel and were started on a ticagrelor and aspirin regimen. There were 22 men (69%) and 10 women (31%), with a median age of 54 years (range, 20–75). All procedures were elective. Twenty patients (63%) underwent endovascular intervention for intracranial aneurysm (three bled and 17 unbled), two (6%) for dissecting aneurysms, nine (28%) patients for stenotic lesions, and one (3%) patient for carotico-cavernous fistula (CCF). Of the 20 patients with aneurysms, 11 patients (55%) were treated with flow diverters and nine patients (45%) had stent-assisted coiling. All stenotic lesions were stented, and CCF lesions underwent stent grafting. These results are summarized in Tables 1, 2.

There were no thromboembolic phenomena (stroke or myocardial infarction) during follow up. There was no incidence of major, minor, or life-threatening bleeding. No patient had dyspnea, diarrhea, dizziness, bradyarrhythmia, or increased serum creatinine. Follow-up angiography revealed no in-stent thrombosis or stenosis.

A clopidogrel and aspirin dual antiplatelet regimen has been routinely used for coronary intervention, and off-label use of this drug combination has been standard for neuroendovascular procedures. Because of the complex pathophysiology of cerebrovascular thromboembolic events involving thrombosis, inflammation, vascular biology, and hemodynamics, no single agent can be expected to completely stop ischemic events.

Clopidogrel resistance is defined as the failure of a molecule to inhibit the target of its action; it has been observed in approximately one-third of patients. It is best demonstrated by the evidence of residual post treatment P2Y12 activity by measuring adenosine diphosphate (ADP)-induced platelet aggregation before and after treatment. No single receptor signalling pathway is responsible for its activity. Therefore, a single treatment strategy may not be sufficient to overcome clopidogrel resistance [24]. A limited number of studies on clopidogrel resistance in India have been carried out on patients with acute coronary syndrome and coronary artery disease; they indicate that prevalence of clopidogrel resistance in India is aligned with the global incidence [25,26]. Observational studies from the cardiovascular literature have demonstrated a relationship between clopidogrel resistance and the development of cardiovascular events after percutaneous coronary intervention [27,28]. Fifi et al. [11] reported increased peri-procedural thromboembolic complications from neurovascular stent-placement procedures in their patients with clopidogrel resistance.

Ticagrelor is the first reversibly binding, oral, direct-acting P2Y receptor antagonist. Clinical pharmacology and early dose-finding studies have suggested a faster onset and greater inhibition of platelet aggregation with ticagrelor than with clopidogrel [29,30]. In the ONSET-OFFSET trial, ticagrelor achieved a rapid and better platelet inhibition compared to clopidogrel [31]. Unlike clopidogrel, ticagrelor and its metabolite are primarily metabolized via the CYP34A enzyme and, hence, do not require hepatic activation. Also, the extremely low number of non-responders makes it particularly advantageous for neurological stenting procedures [19-22]. In the PLATO trial and its sub-analyses, use of ticagrelor achieved platelet inhibition in almost all cases of clopidogrel resistance, had lower incidences of in-stent thrombosis, and had similar rates of major and fatal bleeding [32-34]. However, there is limited data documenting the use of ticagrelor in patients undergoing neurointerventional procedures. Hanel et al. [35] documented the safety and efficacy of ticagrelor when used in conjunction with aspirin as a dual treatment in their patients with clopidogrel resistance.

We present our experience using ticagrelor in Indian patients undergoing neurointerventional procedures who were non-responders to clopidogrel. At the NH Institute of Neurosciences, we have seen a few in-stent thromboses arise from aspirin and clopidogrel dual antiplatelet therapy. Since we started testing patients for clopidogrel resistance and moved non-responders to ticagrelor in conjunction with aspirin, we have not encountered any complications to date. All our patients tolerated ticagrelor well with no incidence of any adverse event including hemorrhage. Our study is, however, limited by having a small number of patients and a retrospective nature. A future prospective, randomized, and larger patient population study is warranted to support the safety of ticagrelor in neurointerventional procedures, especially as newer technology with interventional devices is evolving so quickly.

In summary, we report the safety and efficacy of ticagrelor when used in conjunction with aspirin in a small group of Indian patients who were non-responders to clopidogrel for neuroendovascular procedures at our center. The drawbacks of ticagrelor, including its cost and its risk of faster platelet aggregation activation after discontinuation, should be taken into consideration prior to its utilization.