Association Between Time to Treatment With Endovascular Reperfusion Therapy and Outcomes in Patients With Acute Ischemic Stroke Treated in Clinical Practice

Abstract

Importance: Randomized clinical trials suggest benefit of endovascular-reperfusion therapy for large vessel occlusion in acute ischemic stroke (AIS) is time dependent, but the extent to which it influences outcome and generalizability to routine clinical practice remains uncertain.

Objective: To characterize the association of speed of treatment with outcome among patients with AIS undergoing endovascular-reperfusion therapy.

Design, setting, and participants: Retrospective cohort study using data prospectively collected from January 2015 to December 2016 in the Get With The Guidelines-Stroke nationwide US quality registry, with final follow-up through April 15, 2017. Participants were 6756 patients with anterior circulation large vessel occlusion AIS treated with endovascular-reperfusion therapy with onset-to-puncture time of 8 hours or less.

Exposures: Onset (last-known well time) to arterial puncture, and hospital arrival to arterial puncture (door-to-puncture time).

Main outcomes and measures: Substantial reperfusion (modified Thrombolysis in Cerebral Infarction score 2b-3), ambulatory status, global disability (modified Rankin Scale [mRS]) and destination at discharge, symptomatic intracranial hemorrhage (sICH), and in-hospital mortality/hospice discharge.

Results: Among 6756 patients, the mean (SD) age was 69.5 (14.8) years, 51.2% (3460/6756) were women, and median pretreatment score on the National Institutes of Health Stroke Scale was 17 (IQR, 12-22). Median onset-to-puncture time was 230 minutes (IQR, 170-305) and median door-to-puncture time was 87 minutes (IQR, 62-116), with substantial reperfusion in 85.9% (5433/6324) of patients. Adverse events were sICH in 6.7% (449/6693) of patients and in-hospital mortality/hospice discharge in 19.6% (1326/6756) of patients. At discharge, 36.9% (2132/5783) ambulated independently and 23.0% (1225/5334) had functional independence (mRS 0-2). In onset-to-puncture adjusted analysis, time-outcome relationships were nonlinear with steeper slopes between 30 to 270 minutes than 271 to 480 minutes. In the 30- to 270-minute time frame, faster onset to puncture in 15-minute increments was associated with higher likelihood of achieving independent ambulation at discharge (absolute increase, 1.14% [95% CI, 0.75%-1.53%]), lower in-hospital mortality/hospice discharge (absolute decrease, -0.77% [95% CI, -1.07% to -0.47%]), and lower risk of sICH (absolute decrease, -0.22% [95% CI, -0.40% to -0.03%]). Faster door-to-puncture times were similarly associated with improved outcomes, including in the 30- to 120-minute window, higher likelihood of achieving discharge to home (absolute increase, 2.13% [95% CI, 0.81%-3.44%]) and lower in-hospital mortality/hospice discharge (absolute decrease, -1.48% [95% CI, -2.60% to -0.36%]) for each 15-minute increment.

Conclusions and relevance: Among patients with AIS due to large vessel occlusion treated in routine clinical practice, shorter time to endovascular-reperfusion therapy was significantly associated with better outcomes. These findings support efforts to reduce time to hospital and endovascular treatment in patients with stroke.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Jahan reports being a consultant for Medtronic Neurovascular, Balt USA, BlackSwan Vascular Inc, and Viz.ai outside the submitted work. Dr Saver reports being an employee of the University of California, which has patent rights in retrieval devices for stroke. Dr Saver reports serving as an unpaid site investigator in multicenter trials sponsored by Medtronic, Stryker, Johnson & Johnson, and Boehringer Ingelheim (prevention only), for which the University of California Regents received payments on the basis of clinical trial contracts for the number of patients enrolled; receipt of contracted hourly payments for services as a scientific consultant advising on rigorous trial design and conduct to Medtronic, Stryker, Johnson & Johnson, and Boehringer Ingelheim (prevention only); and contracted stock options for services as a scientific consultant advising on rigorous trial design and conduct to Rapid Medical. Dr Schwamm reports serving as chair of the stroke clinical work group of Get With The Guidelines-Stroke (GWTG-Stroke) and as a stroke system consultant to the Massachusetts Department of Public Health for the Paul Coverdell National Acute Stroke Registry; and receipt of research support from the Patient-Centered Outcome Research Institute, National Institute of Neurological Disorders and Stroke, and Genentech; and serving as a scientific consultant regarding trial design and conduct to Penumbra (data and safety monitoring committee [Separator 3D and MIND trial]), Genentech (steering committee [TIMELESS trial]), and Medtronic (Victory AF, REACT AF and Stroke AF trials). Dr Fonarow reported serving on the GWTG steering committee; receiving grant funding from the Patient-Centered Outcome Research Institute; being an employee of the University of California, which has a patent on an endovascular therapy device; and serving as a consultant for Janssen. Dr Xian reported receipt of grants from Genentech during the conduct of the study and grants from Genentech outside the submitted work. Dr Peterson reported receipt of grants from Genentech and Regeneron; and grants and personal fees from Sanofi, AstraZenica, Amarin, and Amgen outside the submitted work. Dr Yavagal reported receipt of personal fees from Medtronic, Cerenovus/Johnson & Johnson, Rapid Medical, and Neuralanalytics outside the submitted work. Dr Smith reports serving as consultant for Alnylam Pharmaceuticals and Portola Pharmaceuticals; being a member of the GWTG steering committee; and serving on a data and safety monitoring board for Massachusetts General Hospital. No additional disclosures were reported.

Figures

Figure 1.. Flow Diagram Showing Study Population Screening, Eligibility, and Inclusion

aData were for patients with ischemic stroke receiving care between January 1, 2015, and December 31, 2016, with at least 75% of medical history field completion. bCriteria are listed in the order in which applied.

Figure 2.. Changes in Main Clinical Outcomes and Adverse Events With Continuous Variation in Onset-to-Puncture Time, Adjusted Analysis

Onset time was defined as last-known well time. Relationships between onset-to-puncture times and the binary outcomes were assessed using logistic regression models with restricted cubic splines with knots at the 5th, 35th, 65th, and 95th percentiles. Curves (blue shading indicates 95% CIs) show the adjusted predicted outcome rate for a hypothetical patient with mean values for baseline characteristics, for symptom onset to arterial puncture times as a continuous variable, and 6 main clinical outcomes: (A), independent ambulation at discharge; (B), discharge to home; (C), functional independence (mRS, 0-2) at discharge; (D), freedom from disability (mRS, 0-1) at discharge; (E), in-hospital mortality; and (F), symptomatic intracranial hemorrhage.

Figure 3.. Changes in Main Clinical Outcomes and Adverse Events With Continuous Variation in Door-to-Puncture Time, Adjusted Analysis

Relationships between door-to-puncture times and the binary outcomes were assessed using logistic regression models with restricted cubic splines with knots at the 5th, 35th, 65th, and 95th percentiles. These door-to-puncture analyses indicate patients who arrived direct via emergency medical services transport, not interfacility transfer. Curves (blue shading indicates 95% CIs) show the adjusted predicted outcome rate for a hypothetical patient with mean values for baseline characteristics, for door-to-puncture times as a continuous variable, and 6 main clinical outcomes: (A), independent ambulation at discharge; (B), discharge to home; (C), functional independence (mRS, 0-2) at discharge; (D), freedom from disability (mRS, 0-1) at discharge; (E), in-hospital mortality; and (F), symptomatic intracranial hemorrhage.