Cerebral Microbleeds and Treatment Effect of Intravenous Thrombolysis in Acute Stroke: An Analysis of the WAKE-UP Randomized Clinical Trial

Abstract

Background and objectives: Cerebral microbleeds (CMBs) are common in patients with acute ischemic stroke and are associated with increased risk of intracerebral hemorrhage (ICH) after intravenous thrombolysis. Whether CMBs modify the treatment effect of thrombolysis is unknown.

Methods: We performed a prespecified analysis of the prospective randomized controlled multicenter Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) trial including patients with acute ischemic stroke with unknown time of symptom onset and diffusion-weighted imaging-fluid-attenuated inversion recovery mismatch on MRI receiving alteplase or placebo. Patients were screened and enrolled between September 2012 and June 2017 (with final follow-up in September 2017). Patients were randomized to treatment with IV thrombolysis with alteplase at 0.9 mg/kg body weight or placebo. CMB status (presence, number, and distribution) was assessed after study completion by 3 raters blinded to clinical information following a standardized protocol. Outcome measures were excellent functional outcome at 90 days, defined by modified Rankin Scale (mRS) score ≤1, and symptomatic ICH according to National Institutes of Neurological Disease and Stroke trial criteria 22 to 36 hours after treatment.

Results: Of 503 patients enrolled in the WAKE-UP trial, 459 (91.3%; 288 [63%] men) were available for analysis. Ninety-eight (21.4%) had at least 1 CMB on baseline imaging; 45 (9.8%) had exactly 1 CMB; 37 (8.1%) had 2 to 4 CMBs; and 16 (3.5%) had ≥5 CMBs. Presence of CMBs was associated with a nonsignificant increased risk of symptomatic ICH (11.2% vs 4.2%; adjusted odds ratio [OR] 2.32, 95% confidence interval [CI] 0.99-5.43, p = 0.052) but had no effect on functional outcome at 90 days (mRS score ≤1: 45.8% vs 50.7%; adjusted OR 0.99, 95% CI 0.59-1.64, p = 0.955). Patients receiving alteplase had better functional outcome (mRS score ≤1: 54.6% vs 44.6%, adjusted OR 1.61, 95% CI 1.07-2.43, p = 0.022) without evidence of heterogeneity in relation to CMB presence (p of the interactive term = 0.546). Results were similar for subpopulations with strictly lobar (presumed cerebral amyloid angiopathy related) or not strictly lobar CMB distribution.

Discussion: In the randomized-controlled WAKE-UP trial, we saw no evidence of reduced treatment effect of alteplase in patients with acute ischemic stroke with ≥1 CMBs. Additional studies are needed to determine the treatment effect of alteplase and its benefit-harm ratio in patients with a larger number of CMBs.

Trial registration information: ClinicalTrials.gov identifier NCT01525290; ClinicalTrialsRegister.EU identifier 2011-005906-32.

Classification of evidence: This study provides Class II evidence that for patients with acute ischemic stroke with unknown time of onset and diffusion-weighted imaging-fluid-attenuated inversion recovery mismatch who received IV alteplase, CMBs are not significantly associated with functional outcome at 90 days.

Figure 1. Flow Diagram

CMB = cerebral microbleed.

Figure 2. Association Between Alteplase Treatment and Functional Outcome at 90 Days According to Presence and Spatial Distribution of CMBs

Point estimates >1 indicate better functional outcome with alteplase treatment. *First p value per group corresponds to the hypothesis that across patients with any number of cerebral microbleeds (CMBs), the odds ratio (OR) is equal to 1 (no effect); the second p value corresponds to the hypothesis that within strata of patients with no CMBs and ≥1 CMBs, the OR is identical (no interaction). CAA = cerebral amyloid angiopathy; CI = confidence interval; mRS = modified Rankin Scale.

Figure 3. Association Between Alteplase Treatment and Hemorrhagic Complications According to Presence and Spatial Distribution of CMBs

Point estimates >1 indicate higher risk of hemorrhage with alteplase treatment. *First p value per group corresponds to the hypothesis that across patients with any number of cerebral microbleeds (CMBs), the odds ratio (OR) is equal to 1 (no effect); the second p value corresponds to the hypothesis that within strata of patients with no CMBs and ≥1 CMBs, the OR is identical (no interaction). CAA = cerebral amyloid angiopathy; CI = confidence interval; HT = hemorrhagic transformation; sICH = symptomatic intracranial hemorrhage.

Figure 4. Relative Frequencies of Low-Frequency Safety Endpoints by Treatment Group and Presence of CMBs

CAA = cerebral amyloid angiopathy; CMB = cerebral microbleed; PH2 = parenchymal hematoma type 2.

Figure 5. Associations Between Number of CMBs and Functional and Safety Outcomes

The p values for linear association between cerebral microbleed (CMB) number and outcome measure (linear trend) are derived from Mantel-Haenszel tests for trend. mRS = modified Rankin Scale; PH2 = parenchymal hemorrhage; sICH = symptomatic intracranial hemorrhage.