Leukoaraiosis, Cerebral Hemorrhage, and Outcome After Intravenous Thrombolysis for Acute Ischemic Stroke

The effectiveness and benefit of intravenous (IV) thrombolysis using recombinant tissue-type plasminogen activator (r-tPA) within 4.5 hours for acute ischemic stroke (AIS) have been clearly demonstrated. However, early symptomatic intracranial hemorrhage (sICH) remains the most serious complication after IV thrombolysis. Given the increasing number of patients eligible for IV thrombolysis, especially elderly individuals with chronic comorbidities, it is crucial to understand the association between not only acute, but also preexisting signs of brain injury and the risk of early symptomatic sICH and poor outcome. Along with clinical variables (such as age, early ischemic computed tomography [CT] changes, high blood pressure, hyperglycemia, baseline stroke severity, and large infarct volume), neuroimaging markers of diffuse cerebral small vessel disease might be a risk factor for thrombolysis-related sICH and poor poststroke functional outcome. Leukoaraiosis, an established cerebral microangiopathy marker, is associated with cognitive impairment, triples the risk of future stroke, and doubles the risk of death. Moreover, leukoaraiosis presence is independently associated with the risk of spontaneous Background and Purpose—We performed a meta-analysis to assess whether leukoaraiosis on brain computed tomographic scans of acute ischemic stroke patients treated with intravenous thrombolysis is associated with an increased risk of symptomatic intracerebral hemorrhage (sICH) or poor functional outcome at 3 to 6 months after stroke, or both. Methods—We searched PubMed and pooled relevant data in meta-analyses using random effects models. Using odds ratios (OR), we quantified the strength of association between the presence and severity of leukoaraiosis and post-thrombolysis sICH or 3to 6-month modified Rankin Score >2. Results—Eleven eligible studies (n=7194) were pooled in meta-analysis. The risk of sICH was higher in patients with leukoaraiosis (OR, 1.55; 95% confidence interval [CI], 1.17–2.06; P=0.002) and severe leukoaraiosis (OR, 2.53; 95% CI, 1.92–3.34; P<0.0001) compared with patients without leukoaraiosis. Leukoaraiosis was an independent predictor of sICH in 6 included studies (n=4976; adjusted OR, 1.75; 95% CI, 1.35–2.27; P<0.0001). OR for leukoaraiosis and poor 3to 6-month outcome was 2.02 (95% CI, 1.54–2.65; P<0.0001), with significant statistical heterogeneity (I, 75.7%; P=0.002). In adjusted analyses, leukoaraiosis was an independent predictor of poor outcome (n=3688; adjusted OR, 1.61; 95% CI, 1.44–1.79; P<0.0001). In post hoc analyses, including only leukoaraiosis patients in randomized controlled trials (IST-3 [third International Stroke Trial], NINDS [National Institute of Neurological Disorders and Stroke], ECASS-1–2 [European Cooperative Acute Stroke Study]; n=2234), tissue-type plasminogen activator versus control was associated with higher sICH risk (OR, 5.50; 95% CI, 2.49–12.13), but lower poor outcome risk (OR, 0.75; 95% CI, 0.60–0.95). Conclusions—Leukoaraiosis might increase post-intravenous thrombolysis sICH risk and poor outcome poststroke. Despite increased sICH risk, intravenous tissue-type plasminogen activator treatment has net clinical benefit in patients with leukoaraiosis. Given the risk of bias/confounding, these results should be considered hypothesis-generating and do not justify withholding intravenous thrombolysis. (Stroke. 2016;47:2364-2372. DOI: 10.1161/STROKEAHA.116.014096.)