Editorial
August 9, 2022
Therapeutic Strategies for Intracranial Atherosclerosis
Craig S. Anderson, Lili Song, Jianmin Liu
JAMA. 2022;328(6):529-531. doi:10.1001/jama.2022.11525
Intracranial atherosclerosis (ICAS) is a major cause of stroke worldwide. Although approximately 12% of White patients with a history of acute ischemic stroke or transient ischemic attack (TIA) have some form of ICAS detected on routine screening in predominantly older adults, ICAS accounts for an estimated up to one-third of ischemic strokes in Black, Asian, and Hispanic populations at comparatively younger ages.1 The reasons for these differences are not clear, because risk factor profiles are broadly similar across racial and ethnic groups.2 ICAS presents diagnostic challenges, not just in differentiating this condition from other causes of stroke or TIA (including nonatherosclerotic conditions such as moyamoya disease, arterial dissection, and intracranial vasculitis), but also in defining underlying mechanisms of ischemia in those with ICAS (eg, artery-to-artery embolism, in situ thrombotic occlusion of large vessels, local branch occlusion of small perforating vessels, hemodynamic insufficiency), which influence prognosis and treatment.3 Considering the need to balance potential benefits with the risks of reperfusion treatment (both for the acute ischemic stroke event and in elective stenting for secondary prevention) along with appropriate use of antiplatelet therapy, the treatment of patients with ICAS can be complex. These complexities have been reiterated by the neutral results of 2 investigator-initiated and -conducted, multicenter clinical trials undertaken in China, published in this issue of JAMA.
The Endovascular Treatment With vs Without Tirofiban for Patients with Large Vessel Occlusion Stroke (RESCUE BT) trial was undertaken to assess the effect of adding a standard dose of intravenous tirofiban to endovascular thrombectomy in patients with acute ischemic stroke in the anterior circulation undergoing thrombectomy between 4.5 hours and 24 hours after the onset of symptoms and without preceding thrombolysis.4 Tirofiban is a highly selective, fast- and short-acting nonpeptide glycoprotein IIb/IIIa platelet receptor antagonist that is approved for the treatment of acute coronary syndromes, but has mixed results in largely observational studies of patients with acute ischemic stroke to date.5
Although modern thrombectomy with stent retrievers and direct aspiration systems have enabled high levels of reperfusion to be achieved in acute ischemic stroke from large vessel occlusion, more than half of patients still do not survive free of disability6 due to rapid evolution of cerebral infarction and periprocedural complications. It has been hypothesized that intravenous tirofiban could enhance thrombectomy, especially when significant stenosis is present, as in ICAS, which is often only differentiated from embolism-related occlusion at the time the procedure. The use of tirofiban might also reduce the need for multiple passes of a device or rescue therapy with balloon angioplasty and/or stenting for early reocclusion, which can increase the likelihood of endothelial damage and occlusion of smaller perforator vessels.
In the RESCUE BT trial, 948 patients (mean age, 67 years; 41.2% women) with moderate to severe neurological deficit (median National Institutes of Health Stroke Scale score of 16) were randomized to receive either intravenous tirofiban or placebo beginning immediately before and continued for 20 hours after endovascular thrombectomy across 55 hospitals from 2018 to 2021. At 90 days, there was no significant difference in the level of functional recovery between the groups according to a shift in the distribution of scores on the modified Rankin Scale (adjusted common odds ratio [OR] for a lower level of disability with tirofiban, 1.08 [95% CI, 0.86-1.36]).
However, there was a suggestion of possible benefit for tirofiban vs placebo in the subgroup of 435 patients with large artery atherosclerosis (with most having ICAS), although the test for interaction yielded a P value for interaction of .09. In the tirofiban group vs the placebo group, the risk of symptomatic intracranial hemorrhage was 9.7% vs 6.4% (adjusted OR, 1.56 [95% CI, 0.97-2.56]) and the risk of any intracranial hemorrhage was 34.9% vs 28.0% (adjusted OR, 1.40 [95% CI, 1.06-1.86]). In the as-treated analysis that accounted for crossover use of rescue drug allowed in the protocol, and in which 58 patients were given intravenous tirofiban in the placebo group (vs 38 patients given placebo infusion in tirofiban group), the between-group difference in symptomatic intracranial hemorrhage was enhanced (adjusted OR, 1.64 [95% CI 1.01-2.74]) and 90-day mortality rates were 19.0% vs 15.7% (adjusted OR, 1.39 [95% CI, 0.97-1.99]).
These results do not support the routine use of intravenous tirofiban as an adjuvant to thrombectomy in a “late” time window (beyond guideline-recommended use of thrombolysis treatment within 4.5 hours after symptom onset) after acute ischemic stroke. Given that any delay in symptom onset to treatment time7 reduces the likelihood of a good outcome from large vessel occlusion, it is reassuring that both randomized groups achieved high rates of recanalization (>90%) with a single-pass application of a range of approaches and devices. Any potential modest benefit of tirofiban in the large artery atherosclerosis subgroup was counterbalanced by the overall risk of serious bleeding as the single major complication of thrombectomy.
Recently, periprocedural use of intravenous aspirin and unfractionated heparin during thrombectomy was shown to increase the risk of symptomatic intracranial hemorrhage without any beneficial effects on functional outcome.8 Thus, any further investigation of targeted approaches with tirofiban, or other potent antiplatelet agent(s), in ICAS would benefit from a better understanding of the interactions between atherosclerosis and thrombosis, the importance of thrombus composition (“harder” fibrin-rich and red blood cell–rich thrombi vs “softer” platelet-rich thrombi), and the relation of blood flow to vascular occlusion in the progression of large vessel occlusion in acute ischemic stroke.9
In scenarios in which balloon angioplasty and stenting may be required to maintain recanalization in ICAS, interventionalists often postpone intervening in patients who present with TIA or minor ischemic stroke to allow sufficient time for clinical stability and the effect of loading with dual antiplatelet therapy (generally aspirin plus clopidogrel) to reduce the risk of early vessel reocclusion. However, the Stenting and Aggressive Medical Management for Prevention of Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial showed no benefit of the Wingspan stent compared with aggressive medical therapy for clinically stable patients with ICAS, due to an unexpectedly high 30-day rate of stroke or death of 14.7% vs 5.8% in the medically managed group.10 Postmarket surveillance of the Wingspan stent11 in the US and registry series in China12 have suggested that a lower periprocedural complication rate could be obtained if patients received a stent several weeks after an ischemic event as opposed to a median (IQR) of 7 (4-16) days in the SAMMPRIS trial. Moreover, among the 19 patients with periprocedural ischemic complications in the SAMMPRIS trial, 12 had perforating vessel occlusions and 2 had mixed perforator and embolic occlusions.13 These data led to the hypothesis that intracranial angioplasty and stenting, if performed in carefully selected patients expected to have a low rate of periprocedural complications, might result in long-term benefit and protection from subsequent disabling stroke and death compared with medical therapy alone.
The China Angioplasty and Stenting for Symptomatic Intracranial Severe Stenosis (CASSISS) trial,14 also reported in this issue of JAMA, was undertaken with special care to address perceived shortcomings of previous studies and allow an assessment of the effectiveness of the Wingspan stent combined with standard medical therapy vs standard medical therapy alone. The medical therapy included dual antiplatelet therapy, commenced 3 to 5 days prior to the procedure and continued for 90 days after, and guideline-recommended use of statins and antihypertensive therapy to manage stroke risk factors. Participating sites were carefully selected and narrow inclusion criteria were used to identify a potential “responder group” at low procedural risk: patients with TIA or nondisabling, nonperforator territory, ischemic stroke from severe isolated intracranial stenosis (70%-99%) that occurred between 3 weeks and 12 months prior to randomization. Rigorous performance, training, and quality control procedures were used, and efforts were made toward achieving a high level of patient follow-up, with blinded and objective outcome assessments over 3 years.
Among 1152 patients screened at 8 hospitals between 2014 and 2019, a total of 380 were randomized, but 22 were excluded from analysis because of ineligibility due to a recent cerebrovascular event less than or equal to 3 weeks prior to randomization or vascular pathology that met exclusion criteria. Of the 358 patients (mean age, 56.3 years; 26.5% women) included in the analysis, 343 (95.8%) completed the trial. There was no significant difference in the primary outcome—stroke or death within 30 days or stroke in the qualifying artery territory between 30 days to 1 year—between patients who received stenting and medical therapy compared with those who received medical therapy alone (8.0% vs 7.2%; hazard ratio, 1.10 [95% CI, 0.52-2.35]). In a post hoc analysis, stroke or death at 30 days occurred in 9 patients (5.1%) in the stenting group (5 with ischemic stroke and 4 with hemorrhagic stroke) and in 4 patients (2.2%) in the medical therapy group (4 with ischemic stroke). There was no significant between-group difference across any of 5 prespecified secondary end points, including various combinations of cardiovascular events. Mortality at 3 years was 4.4% in the stenting group compared with 1.3% in the medical therapy group (hazard ratio, 3.75 [95% CI, 0.77-18.13]).
Despite the efforts to improve patient selection and operator experience, the CASSISS trial redemonstrated that any potential benefit of stenting for ICAS in terms of long-term stroke prevention appears to be at least counterbalanced by the short-term procedural risk, which includes both ischemic and hemorrhagic events. Although arguments can be made that the restrictive inclusion criteria inevitably led to a biased, stable, “lower-risk” patient group, the trial further highlights the importance of best medical management of cardiovascular risk factors, in particular, use of statins and blood pressure–lowering agents to achieve guideline recommended targets in this patient population.
Comparisons of these 2 studies published in JAMA with other published literature are complicated by differences in criteria and methods for selecting patients, in defining ICAS, and in the approaches taken to assess outcomes. Despite relatively long workflow times and low use of intravenous thrombolysis, outcomes from endovascular procedures in China are comparable to Western countries.15 Although the prognosis from ICAS will vary according to age, background risk factors, and the effectiveness of medical management, the evidence generated from these 2 trials are broadly generalizable. Moreover, these studies demonstrate the substantial advances being made by investigators in China, with input from experts in the US, in the conduct of multicenter randomized clinical trials and strengthen the importance of such evidence in guiding health policy and practice in this vast country where stroke has an enormous health, economic, and social toll.
