Proximal Intracranial Arterial Occlusions: Does the Natural History Justify Further Interventional Trials?

Over thepast2decades, the treatmentofacute ischemicstroke has undergone significant changes. The National Institute of Neurological Disorders andStroke tissueplasminogen activator study1 in 1995 followed by the third European Cooperative Acute Stroke Study (ECASS III)2 in 2008heralded major breakthroughs in the hyperacute management of patientswith ischemicstroke. Yet despite the promise of these landmark studies, the overall use of intravenous tissue plasminogen activator remained meager, reaching less than5%ofall strokepatients in theUnited States through 2006.3 Furthermore, for certain stroke subtypes, such as thosewith proximal intracranial arterial occlusions, therateof recanalizationremained low,4 resulting inpoor outcomes when early recanalization was not achieved.5 Over the ensuing years, major excitement was generated in the stroke community about endovascular therapy for ischemic stroke, which logically targeted this population. The Prolyse inAcuteCerebralThromboembolism(PROACT) study6 showed that intra-arterial prourokinase was superior to placebo in achieving recanalization and improving outcomes of stroke patients who were treated within 6 hours of symptom onset. The subsequent advances of new devices and techniques with high recanalization rates resulted in a tide of enthusiasmaseachnewendovascular technologybroughtgreater promise and a better chance of direct, early recanalization for patients with proximal intracranial arterial occlusions. The strokecommunityembracedtheconceptofendovascular treatment because the idea of direct revascularization just made somuch sense. Yet the recanalization rates, which continued to increase asdevices and techniques improved, began tooutstrip clinical outcomes in some studies, bringing into question the assumptions about what the recanalization was ultimately capable of achieving.7 Theexcitementoverdirect recanalizationwasquelled furtherby the results of 3 recent randomizedclinical trials8-10 that failed to show improvedclinical benefit for strokepatientsundergoing endovascular therapy. The Interventional Management of Stroke III (IMS-III) trial8 was an open-label study that randomly assigned 656 patients with a National Institutes of Health Stroke Scale (NIHSS) score of 10 or higher or an NIHSS score of 8 or 9 with vascular imaging evidence of large artery occlusion to thrombolytic therapy alone or thrombolytic therapy plus endovascular therapy. This study8 was stopped earlybecause therewasnodifference inoutcomebetween the 2 arms, and the investigators concluded that the addition of endovascular therapy to intravenous thrombolytic therapydid not improve stroke outcome. The Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE) trial10 randomly assigned 118 patients with an anterior circulation large artery occlusionwithin 8hours of symptom onset to undergo mechanical thrombectomy (Merci Retriever or Penumbra System) or to receive the standard of care. This study10 showed no difference in reperfusion rates, and the outcomes between the 2 groups supported the nonsuperiorityofendovascular treatmentover thestandardofcare for acute ischemic stroke. The Endovascular Treatment for Acute Ischemic Stroke (SYNTHESIS) trial9 randomly assigned 362 patients within 4.5 hours of symptom onset to endovascular therapyvs intravenous thrombolytic therapy.This study9 showed that there was no difference in the 3-month outcomes between the 2 study arms, concluding also that endovascular therapy is not superior to intravenous thrombolytic therapy. The findings in these trials8-10 had a sobering effect on the field, limiting the use of endovascular treatment in the stroke community. Althoughallof those recent studieswerewelldesignedand well conducted, valid criticisms were brought to bear on the results.Most of the endovascular devicesusedwereolder and were associatedwith lower recanalization rates thanwere the newerdevices.11 Longer time to treatmentwaspresent in each of the studies compared with the standard treatment arms, with a post hoc analysis of the IMS III trial8 suggesting that thosewhogot earlier interventionshadgreater potential benefits. Could it be that these trialswere inadequate toprove the ultimate failure of endovascular interventions after all?Might there still be a rationale tomove aheadwith additional endovascular trials despite these compelling negative studies? In their article published in this issue of JAMANeurology, Lima et al12 retrospectively analyzed a prospective cohort of stroke patients with proximal intracranial arterial occlusions fromtheScreeningTechnologyandOutcomeProject inStroke (STOPStroke) study. The objective was to evaluate the natural history and outcome of this disease in patients who were not treatedwith intravenous thrombolysis or who did not receive endovascular therapy. In this study,12 the authors demonstrated that theoverallnaturalhistoryofpatientswithproximal intracranial arterial occlusions was poor, withmore than half (56%) not achieving functional independence and about a quarter (22%) dead at 6months. Furthermore, their study12 showed that older age, anNIHSS score of 10orhigher, andevidence of poor collaterals on computed tomography angioAuthor Audio Interview at jamaneurology.com