Malignant stroke in a ticagrelor non-responder as a complication following aneurysm treatment with the Pipeline Embolization Device™

Abstract

The Pipeline Embolization Device™ (PED; Covidien Neurovascular Inc, Irvine, CA, USA) is a flow-diverting stent often used for the endovascular treatment of large or giant, wide-necked intracranial aneurysms of the internal carotid artery. Because of the inherent thrombogenicity of intracranial stents, dual-antiplatelet therapy is initiated after placement, which has been shown to decrease morbidity and mortality related to perioperative ischemic events in neurointerventional procedures. However, in some series, as much as 50% of patients demonstrate clopidogrel non-responsiveness. In these non-responders, alternate agents such as ticagrelor can be used to achieve adequate anticoagulation. Compared with clopidogrel, a prodrug requiring Cytochrome P450 enzymolysis for activation, ticagrelor directly and reversibly inhibits the P2Y12 ADP receptor. The absorption of the prodrug and the formation of its active metabolite is comparatively quicker (t_max 1.3–2 hours; 1.5–3 hours, respectively). To date, there have been no documented cases of ticagrelor non-responsiveness involving patients undergoing placement of flow-diverting stents or other endovascular neuro-interventional procedures.

Keywords

Dual-antiplatelet therapy aspirin clopidogrel ticagrelor nonresponse Pipeline Embolization Device pipeline flow diverter

Case presentation

We present the case of a 67-year-old female who was found to have a 15.8 × 14.7 mm right internal carotid artery (ICA) communicating segment aneurysm (Figure 1). Out of concern for potential rupture, the patient was counseled regarding treatment options for the lesion. The patient elected to undergo endovascular treatment of the aneurysm with use of the PED. She was started on aspirin 325 mg daily and clopidogrel 75 mg daily two weeks prior to the procedure.

Figure 1.

(a) Anteroposterior and (b) right anterior oblique angiogram views demonstrating supraclinoid right internal carotid artery aneurysm.

Aneurysmal treatment

On the morning of her treatment procedure, the patient was found to be a clopidogrel non-responder with P2Y12 reactivity units (PRU) of 249 as assessed by the VerifyNow PRUTest (Accriva Diagnostics, San Diego, CA, USA). She was then administered 180 mg of ticagrelor as a loading dose. The patient then underwent aneurysm embolization with intrasaccular coil placement as well as deployment of a single 3.75 mm × 20 mm Pipeline™ Flex flow-diverting stent across the neck of the aneurysm. During the procedure, intravenous heparin was administered to maintain an activated clotting time at greater than 250 seconds. There was no evidence of thromboembolic complications or intraprocedural complications. Final angiography runs demonstrated excellent parent artery wall apposition by the PED (Figure 2). She was eventually discharged home on dual-antiplatelet therapy with 90 mg of ticagrelor twice daily and 81 mg aspirin daily.

Figure 2.

(a) and (b) Digital subtraction angiogram demonstrating appropriate placement of the Pipeline Embolization Device.

Post-procedural care

The patient was discharged to home on post-operative day 7, but on day 12, she was re-admitted with acute onset of left-sided paresis, dysarthria, and alteration of consciousness. A computed tomography (CT) angiogram demonstrated a right ICA occlusion (Figure 3), secondary to in-stent thrombosis. Despite patient compliance with her prescribed ticagrelor and aspirin, a subsequent VerifyNow PRUTest showed a PRU of 245. The patient ultimately expired on post-operative day 14 due to her stroke. After thorough review of her past medical history and her family history, there was no evidence of preoperative individual or familial predisposition to the prothrombotic state. A comprehensive review of her medications, including vitamins and herbal supplements, did not suggest any potential drug-drug interactions that would decrease the bioavailability of ticagrelor.

Figure 3.

(a) and (b) Absence of flow in the right cavernous internal carotid artery consistent with in-stent thrombosis.

Discussion

Herein, we describe a case of ticagrelor non-responsiveness leading to a post-procedural stroke after embolization of an intracranial aneurysm with the PED. To date, there have been no documented cases of ticagrelor non-responsiveness after any neurointerventional procedures.

Responsiveness to antiplatelet therapy is commonly measured in platelet reactivity units (PRU) by the VerifyNow PRU Test (Accriva Diagnostics, San Diego, CA, USA). In the cardiac literature, the Assessment of Dual Antiplatelet Therapy with Drug-Eluting Stents (ADAPT-DES) study identified PRU > 208 as hyporesponsiveness to clopidogrel, the P2Y12 receptor antagonist used in their trial.¹ In this prospective multicenter study, high on-treatment platelet reactivity (HTPR) was associated with a statistically significant increase in thrombotic complications in patients co-treated with aspirin and clopidogrel while receiving implantation of drug eluting stents. Studies in the neurointerventional literature have also demonstrated hyporesponsiveness to antiplatelet therapy in patients requiring aneurysmal treatment procedures. In a 2015 publication by Hwang and colleagues, this group demonstrated that patients who had HTPR, defined as PRU > 213, after five days of treatment with aspirin and clopidogrel benefited from the addition of cilostazol, a phosphodiesterase-3 inhibitor, to the standard aspirin and clopidogrel regimen. In their series, patients with HTPR who were kept on the standard dual-antiplatelet regimen experienced seven times more thromboembolic events within seven days after coil embolization of unruptured intracranial aneurysms without a significant increase in bleeding events.² Similarly, Delgado Almandoz et al. demonstrated that pre-procedural PRU < 60 and > 240 is a significant predictor of bleeding and thromboembolic complications, respectively, for up to six months after treatment of cerebral aneurysms with the PED.³ In turn, these studies illustrate the importance of establishing an antiplatelet regimen in which platelets are inhibited enough to decrease the risk of thromboembolic events after placement of the PED, but not enough to lead to post-procedural bleeding complications.

Though the benefit of dual-antiplatelet therapy has been established, it has been shown that upward of 25% of patients are clopidogrel non-responders.^4–6 In this sub-population, alternate antiplatelet agents such as ticagrelor or prasugrel are commonly used for a functional dual-antiplatelet regimen. Studies in the cardiac literature have demonstrated equivalence between ticagrelor and prasugrel in patients with HTPR in decreasing prothrombotic complications.⁷ Among clopidogrel non-responders, neurointerventionalists have similarly incorporated dual-antiplatelet therapy combining aspirin and new P2Y12 receptor antagonists in their periprocedural antiplatelet protocol. In a recent query of national practice patterns, Gupta and colleagues identified that more than 80% of respondents administered either aspirin and ticagrelor or aspirin and prasugrel to patients who were found to be hypo- or non-responders to clopidogrel based on platelet function testing.⁸ Interestingly, only 15.4% of respondents to Gupta’s study identified with the use of higher-dose aspirin in their treatment paradigms.⁸ Ultimately whether high- vs low-dose aspirin is more efficacious in patients with HTPR is yet to be studied.

There have been rarely reported cases of ticagrelor non-responsiveness in some patients; specifically, after acute coronary syndromes;, the etiology of this decreased responsiveness, however, is unknown. Sub-therapeutic response to ticagrelor has been documented in acute coronary syndrome patients requiring therapeutic hypothermia.⁹ While factors such as pro-inflammatory cytokines and the presence of cardiogenic shock may independently affect ticagrelor resistance, it is hypothesized that decreased absorption in the hypothermic state can also account for a relative hypofunction of the drug.⁹ A 2015 case report by Musallam and colleagues also documented a case of ticagrelor non-responsiveness resulting in in-stent thrombosis.¹⁰ In their case, the patient initially had good response to treatment (PRU 33) but developed HTPR three weeks later (PRU 349).

Other authors have hypothesized an adverse relationship between advanced age and the efficacy of newer P2Y12 receptor antagonists such as ticagrelor.^11,12 However, the full complement of variables that can affect ticagrelor responsiveness in these patients is not entirely known. One important consideration is the sensitivity of current P2Y12 assays for ticagrelor and other adenosine diphosphate antagonists. There have been varied perspectives in the literature on the equivalence of these tools. The VerifyNow^© and the vasodilator-associated stimulated phosphoprotein (VASP) phosphorylation assays are the two available assays widely used.^13,14 Both have been individually shown to predict clinical platelet inhibition for cardiovascular procedures, with cutoffs identified as >235 PRU¹⁵ and >50% platelet reactivity inhibition (PRI)¹⁶ in the VerifyNow^© and VASP assays, respectively. Authors, however, contend that while there is correlation between results of the two assays, there is not also concordance with the gold-standard test, light transmission aggregometry.¹⁷ Similarly, studies have suggested that these two widely used assays are not interchangeable in their assessment of treatment efficacy.¹⁸ The VerifyNow© assay is the institutional standard in our case. Whether the preoperative use of multiple assays would be beneficial in this patient population remains to be seen. What is evident, however, is the need for consistent assessments of P2Y12 inhibition with the use of these antagonists.

Historically, because of the drug’s mechanism of action and its maintained efficacy in the face of genetic polymorphisms, neither genetic testing nor monitoring of platelet reactivity has been indicated for patients on ticagrelor. To our knowledge, this is the first case of a malignant stroke despite compliance with therapeutic dosing of ticagrelor. This case demonstrates that ticagrelor non-response can occur, and further study is indicated to determine the risk factors that contribute to this phenomenon. Until then, it would be prudent to monitor the platelet reactivity of patients taking ticagrelor to monitor their response to the drug and to ensure appropriate antiplatelet effects.

Conclusion

While novel P2Y12 receptor inhibitors have shown overwhelmingly successful antiplatelet activity for peri-procedural endovascular interventions, it is prudent for clinicians to appreciate that non-responders to ticagrelor, though rare, exist with the potential for clinically significant thrombotic complications after neurointerventional procedures. It is not known whether pretreatment maintenance with such inhibitors can have a meaningful effect on clinical outcome in hyporesponders; nor is it known which antiplatelet regimen is most effective in this subpopulation. Additionally, medication interactions leading to potential for reduced efficacy and bioavailability of P2Y12 receptor inhibitors must be considered. Unfortunately, the burden of responsibility thus rests with the clinician to ensure appropriate efficacy of antiplatelet drugs prior to intervention, and in ticagrelor hypo- and non-responders, this has become increasingly more challenging.

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

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