Evolution of endovascular therapy trials for basilar artery occlusion

Abstract

Basilar artery occlusion (BAO) is an uncommon event, and leads to poor outcome in an estimated 60 to 80% of patients. Two early randomized trials, BASICS and BEST demonstrated equivocal benefit of endovascular therapy (EVT) compared to medical management. These trials helped in forming the design, sample size and eligibility criteria for the subsequent two trials, ATTENTION and BAOCHE which demonstrated superiority of EVT over medical management. In this commentary, we look at the evolution of how early BAO studies formed the building blocks for successive BAO trials, review lessons learned, and opportunities for future research.

Commentary

Basilar artery occlusion (BAO) stroke is an uncommon event, and comprises up to 10% of large vessel occlusion stroke. ¹ Its clinical presentation can be diverse, with a range of symptoms from mild vertigo with ataxia, isolated cranial nerve palsy, dysphagia, to quadriparesis, locked-in syndrome and coma. An estimated 60 to 80% of patients with basilar artery occlusion may be disabled or die with medical management.^2,3 Early reports of poor outcome in patients with BAO with anticoagulation treatment inspired reports of intra-arterial thrombolysis for basilar artery occlusion in Germany. In this commentary, we look at how early studies influenced subsequent design of the BAO trials, the challenges encountered, and then review two trials that proved the benefit of endovascular therapy (EVT) for basilar artery occlusion.

The Basilar Artery International Cooperation study (BASICS) registry was a seminal prospective study conducted between 2002 to 2007 that formed our understanding of the natural history of medical management compared to EVT for patients with BAO. ² No treatment strategy was found superior between antithrombotic treatment, intravenous thrombolysis (IVT), or intra-arterial therapy (IAT), leading to the rationale to conduct a randomized trial for BAO. Notably, patients with mild to moderate deficits had worse outcomes after IAT compared to IVT (aRR 1.49, 95% CI 0.97–1.72) in the BASICS registry and hence were initially excluded in the BASICS randomized trial. In essence, the results of the BASICS registry defined eligibility criteria and primary outcomes unique to BAO disease that led to the design of the BASICS randomized trial.

The BASICS (2011–2019) and Basilar Artery Occlusion Endovascular Intervention Versus Standard Medical Treatment (BEST, 2015–2017) randomized clinical trials (RCT) compared EVT versus medical management in patients with BAO.^3,4 Both trials were neutral in demonstrating superiority of EVT, likely related to formidable challenges in recruiting consecutive patients with BAO amidst the 2015 trials that had proven efficacy of EVT for anterior circulation LVO. ⁵ The high rate of IVT in the BASICS RCT likely accounts for better than expected outcomes in the control group with 38% of patients achieving the primary endpoint of a good outcome (mRS 0–3), hence narrowing the EVT treatment effect size. The widening of BASICS trial eligibility criteria to later include patients with mild stroke defined as NIHSS < 10 has been subject to criticism. However, including these patients with mild BAO in BASICS helped gain insight into the outcomes of this important subgroup, in which medical therapy compared well with EVT, although this analysis was underpowered.^3,6 The NIHSS has also been criticized as not being a reliable indicator for predicting disability in patients with BAO, whereas a dedicated posterior circulation scale may be informative.

Neutral results from the BEST and BASICS trial likely reinforced the concept of equipoise for investigators to randomize consecutive patients into the subsequent two BAO trials conducted in China. ⁷ The Endovascular Treatment for Acute Basilar Artery Occlusion (ATTENTION, 2021–2022) trial enrolled patients with moderate to severe deficit (NIHSS ≥ 10) in the 12 hour window of estimated symptom onset ⁸ and Basilar Artery Occlusion Chinese Endovascular (BAOCHE, 2016–2021) included patients with NIHSS ≥6 in the 6–24 hour window. ⁹ With extension of the time window, the rate of IVT pretreatment was lower in ATTENTION (one third of patients) and BAOCHE (18%), as were the proportion of patients with good outcome in the medical management group. These trials were unique in that a posterior circulation imaging scale, PC-ASPECTS, was utilized to select patients, ¹⁰ and advanced imaging was not required for patient selection. ATTENTION and BAOCHE demonstrated a greater proportion of patients in the EVT group achieving the primary outcome (mRS 0–3) compared to medical management with an effect size of 23% and 22%, respectively. These findings were concordant with two other prospective registries, the BASILAR and ATTENTION registries, indicating favorable outcomes with thrombectomy for BAO.^11,12

The generalizability of these trials to countries outside of China has been raised, considering the high proportion of patients with intracranial atherosclerotic disease in Asia. Nonetheless, in both ATTENTION and BAOCHE, no heterogeneity of treatment effect was observed in the intracranial atherosclerotic disease (ICAD) subgroup, or in patients who were treated with intracranial angioplasty and stenting.^8,9

The investigators of all four BAO trials are to be commended and congratulated for their seminal work in proving the benefit of EVT for BAO in patients with moderate to severe stroke. The results from the BAOCHE trial now align patients with large vessel occlusion of the anterior or posterior circulation to a 24-hour therapeutic time window.

Future research looking at EVT for patients with mild deficit (NIHSS < 10), ⁶ IVT paradigms for patients with BAO in extended time window with intravenous tenecteplase (NCT05105633), and improved imaging selection are of interest. As an estimated half of LVO patients who reperfuse do not achieve functional independence, ¹³ study of the no-reflow phenomenon may be of interest, ¹⁴ potentially via pharmacological adjuvant therapy. Optimal endovascular technique in the treatment of patients with BAO with or without ICAD ¹⁵ are other lingering questions. Altogether, more BAO trials examining these gaps are needed, and they should involve patients and clinicians from all over the world.^6,7