Refractory Stroke Thrombectomy: Prevalence, Etiology, and Adjunctive Treatment in a North American Cohort

DISCUSSION

Our study indicates that refractory stroke thrombectomy occurs in approximately 8–9% of cases of a representative North American population, a lower prevalence than in previously reported Asian studies.⁴ Patients with cerebrovascular risk factors including diabetes and hyperlipidemia may be prone to refractory thrombectomy due to underlying vessel wall pathology such as ICAD and/or IAD versus the less common etiology of recalcitrant emboli.⁵ Antiplatelet GPI, intracranial angioplasty and/or stenting are safe and effective adjunctive treatments for vessel salvage, resulting in equivalent clinical outcomes compared with patients undergoing standard thrombectomy.^8,18

ICAD is a common cause of AIS, accounting for nearly 15%–20% of ELVOs in Asian populations, and it often requires adjunctive treatment to obtain successful recanalization or maintain vessel patency in cases refractory to mechanical thrombectomy.^8,19,20 Lee et al⁵ reported a series of patients having undergone thrombectomy, including 24 patients with underlying ICAD, and identified independent predictors of male sex, hypercholesterolemia, and posterior circulation occlusions. In a smaller series of 14 patients with ELVO related to ICAD, Suh et al²⁰ also showed a predilection for younger patients, male sex, smoking, and involvement of the M1 segment of the MCA in 93% of cases. Our study supports these statistical trends for younger patients; cerebrovascular risk factors, especially diabetes as an independent predictor of refractory thrombectomy; and an inverse correlation with atrial fibrillation consistent with the nonembolic stroke etiology of in situ vessel wall pathologies (ICAD or IAD). Although there were no significant differences in the prevalence of anterior-versus-posterior circulation occlusions, the MCA remained the most commonly affected vessel in 76% of refractory cases.

Despite extracranial cervical dissections being responsible for 10%–25% of strokes in young and middle-aged patients,²¹ IAD is a rare diagnosis accounting for <2% of all AIS.^22,23 However, IAD is an important consideration in cases of refractory thrombectomy secondary to spontaneous or iatrogenic/traumatic etiologies and is probably under-recognized when superimposed in the setting of an acutely ruptured atherosclerotic plaque. Differentiating IAD from ICAD is not always possible during emergent thrombectomy, with significant imaging overlap of both vessel wall pathologies. In a French study, spontaneous IAD was observed in 3% of all mechanical thrombectomy cases; the authors described complete normalization of vessel caliber after stent retriever deployment without irregular clot visualization or extraction as an imaging feature suggestive of IAD pathology.⁹ In contrast, Suh et al²⁰ reported the need for angioplasty and/or stent placement to achieve vessel recanalization, persistent residual stenosis (>70%), and the absence of a dissection (intimal) flap on final angiography as imaging criteria indicative of ICAD. While these paradigms may differentiate uncomplicated cases, not all refractory thrombectomy cases conform to a binary classification. In our study, we developed comprehensive criteria, including patient demographics, clinical risk factors, and additional imaging criteria, to improve the assessment and diagnosis of refractory thrombectomy etiologies, including recalcitrant emboli. Cases with overlapping findings were deemed superimposed IAD in the setting of ICAD. Twenty of 25 (80%) refractory thrombectomy cases were attributable to either IAD or ICAD; 6 were diagnosed as combined IAD/ICAD pathology.

Two large cohort Korean studies by Baek et al¹⁸ and Kang et al²⁴ studied the management of refractory thrombectomy secondary to ICAD, demonstrating that >70% of patients initially fail stent retriever thrombectomy and require adjunctive treatment. Both antiplatelet GPI and intracranial angioplasty/stenting were shown to be safe and effective with equivalent rates of successful reperfusion, functional clinical outcomes, sICH, and mortality in comparison with patients negative for ICAD undergoing standard thrombectomy. Patients treated with GPI required rescue stenting in 9%–46% of cases, and angioplasty and/or stenting groups underwent permanent stenting in 64%–94% of cases. Balloon angioplasty alone in the treatment of symptomatic ICAD is controversial, with some studies suggesting that it is a safe and effective alternative that obviates the need for dual-antiplatelet therapy in the immediate postthrombectomy period of intracranial hemorrhage risk.^25,26 Other studies compared the durability of endovascular treatment strategies for symptomatic ICAD and identified higher rates of immediate lesion recoil, delayed restenosis (50% versus 7.5%), and iatrogenic dissections with angioplasty alone versus angioplasty in conjunction with stenting.²⁷ In our cohort, 14 patients experiencing refractory thrombectomy with underlying ICAD (including 6 patients with superimposed IAD) were equivocally salvaged with either GPI or angioplasty and/or stenting. However, in 3 patients who underwent angioplasty alone, 2 required rescue stent placement for immediate or delayed restenosis/occlusion.

Few studies have evaluated treatment options for spontaneous IAD in the setting of ELVO, and suggest the superiority of intracranial stenting over mechanical thrombectomy alone.^9,28,29 Labeyrie et al⁹ demonstrated improved recanalization rates and lower rates of residual dissection–related stenosis with intracranial stenting, but >50% rescue recanalization in patients managed conservatively. In our study, 9 patients with IAD (6 with underlying ICAD, 2 iatrogenic, and 1 spontaneous) were managed equivocally with antiplatelet GPI or intracranial stenting and no patients treated with GPI required rescue stenting.

Another less common cause of intracranial ELVO and refractory thrombectomy is recalcitrant/calcified emboli that may be spontaneous or iatrogenic with increasing cardiovascular catheterization procedures in patients with calcified aortic/cervical atherosclerotic plaques or cardiac valves.³⁰ In a large multicenter European retrospective study, Maurer et al³¹ reported a 1.3% (40/2969) prevalence for calcified emboli and noted worse angiographic TICI ≥ 2b reperfusion rates (57.5%), functional outcomes (mRS 0–2, 26.5%), and mortality (55.9%) at 90 days. These recalcitrant/calcified emboli are less likely to respond to standard mechanical thrombectomy techniques and often require adjunctive intracranial stenting for successful revascularization.^10,11 In fact, all 4 patients who were eligible for salvage interventions in our cohort of 5 patients with recalcitrant emboli etiologies required intracranial stenting. We suspect that the prevalence of recalcitrant emboli causing refractory thrombectomy may continue to decline with advancements in the technology of flexible distal guide sheaths, large-bore aspiration catheters, and clot-retrieval devices.³²

Using GPI or thienopyridine P2Y12 inhibitors during or after stroke thrombolysis/thrombectomy is concerning, with a risk of intracranial hemorrhagic complications from reperfusion or core infarct transformation. However, single (aspirin) and often dual-antiplatelet loading (for intracranial stenting) are mandatory after adjunctive interventions for refractory thrombectomy to maintain vessel recanalization and prevent in-stent thrombosis or reocclusion via platelet aggregation across an acutely ruptured atherosclerotic plaque or dissection flap. In our study, 2/12 patients treated with intracranial stents reoccluded, possibly due to in-stent thrombosis complications from inadequate or delayed antiplatelet loading. This is consistent with previously published literature suggesting an 87% patency rate for rescue stenting after failed mechanical thrombectomy.³³ Immediate and adequate antiplatelet loading should be initiated in refractory thrombectomy interventions, with early P2Y12 testing recommended to confirm antiplatelet efficacy. Furthermore, novel intravenous P2Y12 inhibitors such as cangrelor may offer improved therapeutic transition to oral antiplatelet loading agents and safety over GPI. Several studies have shown no increased incidence of sICH after intracranial stenting and suggest that the benefit of recanalization outweighs the risk of hemorrhage.^8,12,34 Although no patients in our refractory thrombectomy cohort developed sICH complications, the risk should not be underestimated. This may have been partly due to our patient or imaging selection of small-core infarct volumes, intraprocedural cone beam CT scanning to exclude hemorrhagic complications prior to adjunctive interventions with GPI or intracranial angioplasty and/or stenting, and strict hemodynamic control afterwards to limit reperfusion complications.

Our study had several limitations, due to the inherent methodologic weaknesses of retrospective and small sample size studies, to assess rare pathologies such as ICAD, IAD, and recalcitrant/calcified emboli presenting with ELVO. Furthermore, patients experiencing refractory thrombectomy were managed at the discretion of treating neurointerventionalists without a formal protocol or randomization to adjunctive interventions of GPI versus intracranial angioplasty and/or stenting. Hence, we deferred direct comparisons of either underlying etiologies or treatment protocols for refractory thrombectomy. We limited our aims to assessing the prevalence of refractory thrombectomy in a North American population not previously described in the literature and identifying specific etiologies using a comprehensive diagnostic clinical and imaging evaluation. Finally, we compared the safety and efficacy of adjunctive interventions for vessel salvage in patients experiencing refractory thrombectomy with the standard thrombectomy cohort.