Dual antiplatelet therapy is established for prevention of stent thrombosis in cardiac patients, and widely utilized in neurointerventional stent cases. Aspirin and clopidogrel are typically synergistic. We present a case of clopidogrel resistance due to genetic polymorphism resulting in acute stent thrombosis during elective stent-assisted coiling, with novel use of prasugrel as an alternative platelet inhibitor in the neurovascular setting.
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Dual antiplatelet therapy to prevent acute in-stent thrombosis is well established in the cardiology literature. The synergism of aspirin and clopidogrel has been proved to reduce acute in-stent thrombosis, and improve patient outcome.1 2 However, a reduced response to clopidogrel occurs in a significant proportion of patients, leading to worse cardiovascular outcomes.3 In the cerebral circulation, in-stent thrombosis can result in devastating stroke or death. We report a case of reduced clopidogrel response due to genetic polymorphism resulting in acute in-stent thrombosis during elective stent-assisted basilar apex aneurysm coiling, with the novel use of prasugrel to achieve a good clinical outcome.
A middle-aged patient had incidentally discovered anterior communicating artery and basilar apex aneurysms managed endovascularly in 2007. Despite premedication with 10 days of aspirin and clopidogrel, the basilar apex aneurysm coiling was complicated by local platelet aggregation in the right posterior cerebral artery requiring intra-arterial eptifibatide (figure 1A). The patient recovered without complication and was discharged neurologically intact.
Stent-assisted recoiling due to basilar apex aneurysm regrowth was performed electively in 2010. A Neuroform EZ stent (Boston Scientific Corporation, Natick, Massachusetts, USA) was deployed from the basilar artery to the P2 segment of the right posterior cerebral artery. Following coiling of the aneurysm regrowth, platelet aggregation at the P1 and P2 segments causing acute partially occlusive in-stent thrombosis was observed (figure 1B). This occurred in spite of 10 days of premedication with aspirin and clopidogrel and again was responsive to intra-arterial eptifibatide (figure 1C). As reduced clopidogrel response was suspected, a loading dose of 60 mg of prasugrel was administered urgently. An intravenous eptifibatide infusion was continued for 12 h in addition to prasugrel 10 mg daily maintenance with aspirin 325 mg. The patient had no deficits on extubation.
Recovery was complicated by a retroperitoneal hematoma requiring transfusion of three units of red blood cells, but at discharge 3 days after the procedure the patient was intact. Further investigation revealed a heterozygote cytochrome P450 2C19 phenotype, confirming the suspected reduced clopidogrel response.
Endovascular stent deployment elicits a vascular injury response, with immediate platelet aggregation and fibrin deposition on the stent. With neoendotheliazation of the stent, thrombogenicity decreases over weeks to months.4 Effective prestent platelet inhibition prevents platelet activation, the initial step leading to stent-related thrombosis.
Multiple factors contribute to clopidogrel response variability. These include clinical factors (compliance, elevated body mass index, underdosage, drug–drug interactions) and genetic factors (variable enzymatic metabolism, platelet receptor polymorphism).5 Studies estimate that up to 30% of patients may have a poor response to clopidogrel.6 7 Identifying these patients preprocedurally is complicated because rapid bedside assessment of platelet response is confounded by the wide range of analytical issues with available tests, with no accepted gold standard.8
Poor clopidogrel response has clear clinical implications. Cardiology data are available but there is no literature at the present time on prasugrel use in intracranial stents. A study of 804 patients revealed that the incidence of definite or probable cardiac stent thrombosis was 8.6% in clopidogrel hyporesponders, significantly higher than in responders (2.3%).9 Low response to clopidogrel may be the strongest predictor of stent thrombosis.10 Moreover, another prospective cardiology trial found that in 802 consecutive poststent patients, those with post-treatment platelet aggregation based on platelet functional assay higher than the median level had a 6.7-fold increase in the risk of a 30-day composite of death, myocardial infarction and target lesion revascularization.11 Our patient clinically demonstrated poor response to dual therapy clopidogrel 75 mg and aspirin 325 mg platelet inhibition confirmed by gene testing for enzymatic activators of clopidogrel. The heterozygote cytochrome P450 2C19 phenotype is associated with significantly lower levels of the active clopidogrel metabolite, diminished platelet inhibition and a higher rate of major adverse cardiovascular events, including stent thrombosis, compared with non-carriers.12 The wide range of possible reasons for thrombosis precluded our testing for poor clopidogrel response after the initial thrombotic event.
Prasugrel is a newer thienopyridine, irreversibly inhibiting the platelet P2Y12 receptor responsible for ADP-induced platelet aggregation.13 Compared with clopidogrel, prasugrel has a more rapid onset, higher potency, more consistent absorption and is unaffected by genetic variations in the cytochrome P450 system or interaction with proton pump inhibitors. At currently studied doses, prasugrel inhibits platelet aggregation more rapidly, more consistently and to a greater extent than do standard and higher doses of clopidogrel.14 15 In Wiviott et al's series of >13 000 cardiac patients,16 prasugrel therapy was associated with significantly reduced rates of ischemic events, including cardiac stent thrombosis, though major bleeding (particularly in patients with previous stroke or advanced age) was observed in 2.4% of patients receiving prasugrel compared with 1.8% of patients receiving clopidogrel (p=0.03). This higher hemorrhage risk may have contributed to our patient's retroperitoneal hematoma formation, and is the rationale behind the recommendation to avoid prasugrel use in patients with prior stroke.
The duration of therapy with dual antiplatelet agents after intracranial stenting is unclear. The American Heart Association has issued recommendations following coronary stenting: for bare metal stents, aspirin 325 mg (162–325 mg) daily is suggested for a month, followed by long-term therapy with 81 mg (75–162 mg) daily. Clopidogrel at 75 mg daily is suggested for a month, though treatment for a year is preferred if possible.17 Clearly, direct extrapolation from cardiac data for intracranial stenting is difficult as significant differences exist with respect to vascular architecture, disease processes and surface area of the implanted metal constructs.18 Our practice is typically 3 months of dual therapy and then long-term aspirin therapy, based on the histopathological understanding of stent incorporation into the vessel wall, and this was our practice in this case. Follow-up imaging adhered to our standard protocol, with an angiogram at 6 months being the first diagnostic study in the absence of new clinical findings.
This case demonstrates a potentially devastating procedural complication that responded to effective short-term and long-term measures, with novel use of prasugrel to produce adequate platelet inhibition. While the overall safety of this approach remains to be proved we hope this report will stimulate more rigorous assessment of the role of prasugrel in the neurointerventional setting, particularly in the subset of up to a third of patients who demonstrate a reduced response to clopidogrel.
Competing interests None to declare.
Provenance and peer review Not commissioned; externally peer reviewed.