Time to angiographic reperfusion and clinical outcome after acute ischaemic stroke: an analysis of data from the Interventional Management of Stroke (IMS III) phase 3 trial

Abstract

Background: The IMS III trial did not show a clinical benefit of endovascular treatment compared with intravenous alteplase (recombinant tissue plasminogen activator) alone for moderate or severe ischaemic strokes. Late reperfusion of tissue that was no longer salvageable could be one explanation, as suggested by previous exploratory studies that showed an association between time to reperfusion and good clinical outcome. We sought to validate this association in a preplanned analysis of data from the IMS III trial.

Methods: We used data for patients with complete proximal arterial occlusions in the anterior circulation who received endovascular treatment and achieved angiographic reperfusion (score on Thrombolysis in Cerebral Infarction scale of grade 2-3) during the endovascular procedure (within 7 h of symptom onset). We used logistic regression to model good clinical outcome (defined as a modified Rankin Scale score of 0-2 at 3 months) as a function of the time to reperfusion. We prespecified variables to be considered for adjustment, including age, baseline National Institutes of Health Stroke Scale score, sex, and baseline blood glucose concentration.

Findings: Of 240 patients who were otherwise eligible for inclusion in our analysis, 182 (76%) achieved angiographic reperfusion. Mean time from symptom onset to reperfusion (ie, procedure end) was 325 min (SD 52). Increased time to reperfusion was associated with a decreased likelihood of good clinical outcome (unadjusted relative risk for every 30-min delay 0·85 [95% CI 0·77-0·94]; adjusted relative risk 0·88 [0·80-0·98]).

Interpretation: Delays in time to angiographic reperfusion lead to a decreased likelihood of good clinical outcome in patients after moderate to severe stroke. Rapid reperfusion could be crucial for the success of future acute endovascular trials.

Funding: US National Institutes of Health and National Institute of Neurological Disorders and Stroke.

FIGURE 1

Flow Chart

FIGURE 2

Time Points from Stroke Symptom Onset to Angiographic Reperfusion in IMS III Reperfusion Cohort (n=182)

FIGURE 3. Probability of Good Clinical Outcome Over Time as Predicted by Unadjusted Analysis (p=0·003)

The reperfusion cohort was divided into groups of approximately 20 subjects each. The dot reflects the observed good outcome proportion (y-axis) and the mean time to reperfusion (x-axis), whereas the dashed line depicts the range of time included in the corresponding group. The solid line shows the model results from the logistic regression analysis, and the shaded area defines the corresponding 95% confidence bands.

FIGURE 4

Distributions of 90-Day modified Rankin Scores Based on Time to Reperfusion (<300 vs 300–360 vs>360 Minutes)

FIGURE 5. Probability of Good Clinical Outcome Over Time as Predicted by Unadjusted Analysis for Reperfusion Cohorts Defined by TICI 2a/2b/3 Vs. 2b/3

The solid blue line shows the model results from the logistic regression analysis, and the associated shaded area indicate the corresponding 95% confidence bands, for the cohort with the more stringently defined threshold for angiographic reperfusion of TICI 2b/3. For comparison, the solid back line and associated shaded area shows the result for the broader definition of angiographic reperfusion of TICI 2/3 used in the original IMS pilot studies to generate the time hypothesis.

FIGURE 6. Theoretical Trial Scenarios for Demonstrating Superiority of the Endovascular Approach Based on Varying Only Time to Angiographic Reperfusion and Rates of Angiographic Reperfusion

Based on the association of time to reperfusion and clinical outcome observed in the IMS III trial endovascular cohort with proximal occlusions on baseline angiogram, we consider scenarios in which varying time to angiographic reperfusion and rates of angiographic reperfusion might influence final outcome in the endovascular arm of a trial. We assume that the medical arm will have a good outcome rate of 39% based on the observed rate in the IV rt-PA cohort of the IMS III with proximal occlusions on baseline CTA.