Risk Factors for Intracranial Hemorrhage in Acute Ischemic Stroke Patients Treated With Recombinant Tissue Plasminogen Activator

Abstract

Background and Purpose— Recombinant tissue plasminogen activator (rtPA) is an effective treatment for acute ischemic stroke but is associated with an increased risk of intracranial hemorrhage (ICH). We sought to identify the risk factors for ICH with a systematic review of the published literature. Methods— We searched for studies of rtPA-treated stroke patients that reported an association between a variable measured before rtPA infusion and clinically important ICH (parenchymal ICH or ICH associated with clinical deterioration). We calculated associations between baseline variables and ICH with random-effect meta-analyses. Results— We identified 55 studies that measured 43 baseline variables in 65 264 acute ischemic stroke patients. Post-rtPA ICH was associated with higher age (odds ratio, 1.03 per year; 95% confidence interval, 1.01–1.04), higher stroke severity (odds ratio, 1.08 per National Institutes of Health Stroke Scale point; 95% confidence interval, 1.06–1.11), and higher glucose (odds ratio, 1.10 per mmol/L; 95% confidence interval, 1.05–1.14). There was approximately a doubling of the odds of ICH with the presence of atrial fibrillation, congestive heart failure, renal impairment, previous antiplatelet agents, leukoaraiosis, and a visible acute cerebral ischemic lesion on pretreatment brain imaging. Little of the variation in the sizes of the associations among different studies was explained by the source of the cohort, definition of ICH, or degree of adjustment for confounding variables. Conclusions— Individual baseline variables were modestly associated with post-rtPA ICH. Prediction of post-rtPA ICH therefore is likely to be difficult if based on single clinical or imaging factors alone. These observational data do not provide a reliable method for the individualization of treatment according to predicted ICH risk.

Hemorrhagic Transformation after Ischemic Stroke in Animals and Humans

“…A meta-analysis of 55 human studies reported factors associated with tPA-related HT including older age, greater stroke severity, higher glucose, atrial fibrillation, congestive heart failure, renal impairment, previous antiplatelet agents, leukoaraiosis, and a visible acute cerebral ischemic lesion on pretreatment brain imaging. 50 These findings are consistent with animal stroke models that have found increasing age, hypertension, and blood glucose predispose to HT. [140][141][142] Clinical Factors: Age, Hypertension, Hyperglycemia, and Hemorrhagic Transformation Increasing age has frequently been associated with an increased risk of HT in patients with stroke.…”

“…We propose that the mechanisms contributing to early BBB disruption and early HT differ from those involved in delayed BBB disruption and delayed HT (Figure 3). In early HT, ROS, bloodderived MMP-9, and brain-derived MMP-2 have emerged as Congestive heart failure 50,148 Atrial fibrillation 50,148 Renal impairment 50,148 Antiplatelet use 8,50,144,[167][168][169] Platelet count 143 Anticoagulant/international normalized ratio/partial thromboplastin time 162 Time to reperfusion 144 Blood marker MMP-9 important mediators. In delayed HT, brain-derived factors including MMP-9, MMP-3, other proteases, vascular remodeling, and neuroinflammation begin to have a more prominent role.…”

“…[140][141][142] Clinical Factors: Age, Hypertension, Hyperglycemia, and Hemorrhagic Transformation Increasing age has frequently been associated with an increased risk of HT in patients with stroke. 8,26,50,[143][144][145][146][147][148] The mechanisms by which age may contribute to HT are unclear. Age may enhance the production of ROS which promotes BBB disruption.…”

“…12,42 Antiplatelet agents also increase the risk of HT in patients. 8,50,144,[167][168][169] Antiplatelet use before tPA treatment or antiplatelet use within the first 24 hours of tPA treatment increases the risk of tPA-related HT. 8,156 In addition, dual antiplatelet therapy also increased the risk of HT after stroke.…”

Intravenous Thrombolysis for Acute Ischemic Stroke in Patients Receiving Antiplatelet Therapy: A Systematic Review and Meta‐analysis of 19 Studies

“…Meta‐analyses based on only a limited number of those studies were therefore subject to inaccuracies and biases, because they did not allow us to synthesize adjusted results or to perform comprehensive subgroup analyses 5, 6. Now with data from some of the largest registries having surfaced, our attention is once again brought to the subject of intravenous thrombolysis in patients receiving antiplatelet medications 25, 26, 29.…”