Intracerebral hemorrhage due to thrombolytic therapy

Kathleen Burger DO (Dr. Burger of the George Washington University Hospital has no relevant financial relationships to disclose.)
Steven R Levine MD, editor. (Dr. Levine of the SUNY Health Science Center at Brooklyn has received honorariums from Genentech for service on a scientific advisory committee and a research grant from Genentech as a principal investigator.)
Originally released July 16, 1996; last updated December 1, 2014; expires December 1, 2017

Overview

Treatment of acute ischemic stroke with recombinant tissue plasminogen activator (rtPA or t-PA) leads to improved outcome, as seen in several randomized clinical trials. However, a small percentage of stroke patients treated with thrombolysis experience symptomatic hemorrhagic conversion of their ischemic stroke, with some cases resulting in further disability or death. In this article, the author reviews the clinical presentation, risk factors, and management of thrombolysis-induced hemorrhagic transformation of cerebral ischemic stroke, the most dreaded complication of rtPA.

Key points

 

• Thrombolytic therapies provide an effective treatment for select patients with acute ischemic stroke; however, these therapies have a risk of intracerebral hemorrhage.

 

• The myriad definitions of symptomatic intracerebral hemorrhage have caused variability in the reported risk of hemorrhage and associated risk factors.

 

• The 1995 NINDS rtPA Stroke Study reported a 6.4% rate of symptomatic intracerebral hemorrhage after intravenous rtPA for stroke within 3 hours of symptom onset, and a rate of 5% to 6% has been reported in subsequent series of patients treated in clinical practice.

 

• As of 2008, the American Stroke Association recommends intravenous rtPA for patients presenting within 4.5 hours of stroke symptom onset with a few additional accepted exclusion criteria resulting in improved clinical outcomes and a 2.4% risk of symptomatic hemorrhagic complications.

 

• Endovascular thrombolytic therapy in ischemic stroke (ie, intra-arterial t-PA, clot retrieval devices, stentreivers) carries similar or higher rates of hemorrhagic conversion of ischemic infarcts, with no obvious benefit over intravenous rtPA.

 

• Severe stroke, early CT changes, hyperglycemia, or a history of diabetes have consistently been reported to be independent risk factors for post-thrombolysis intracerebral hemorrhage.

Historical note and terminology

In 1958, Sussman and Fitch first reported the use of a thrombolytic agent for acute ischemic stroke (Sussman and Fitch 1958). In the early studies of thrombolytic therapy for stroke performed in the 1960s and 1970s, computer tomography was not yet available, which lead to treatment without knowledge of hemorrhagic stroke. Also, patients often received thrombolytic therapy several hours or days after stroke onset. It is not surprising that the rate of intracranial hemorrhage and death associated with thrombolytic agents in these studies was high, without any clear benefit (Meyer et al 1965; Fletcher et al 1976; Brott 1992). For this reason, thrombolytic therapy for ischemic stroke was temporarily abandoned from routine practice.

In December 1995, the results of the National Institute of Neurological Disorders and Stroke (NINDS) tissue plasminogen stroke study were published (National Institute of Neurological Disorders and Stroke r-TPA Stroke Study Group 1995). This study reported that recombinant tissue plasminogen activator (rtPA) administered intravenously within 3 hours of symptom onset to selected patients with ischemic stroke resulted in a 30% or more likelihood of near-normal function at 3 months compared to patients who received placebo, in spite of a risk of symptomatic intracerebral hemorrhage of 6.4% with rtPA. On June 18, 1996, the FDA approved intravenous rtPA for selected ischemic stroke patients within 3 hours from symptom onset. Favorable outcomes with an acceptable hemorrhagic conversion rate of 2.4% led to the ASA/AHA guideline recommendations for rtPA administration in the 3.0 to 4.5 post-stroke symptom onset window (Hacke et al 2008); however, this is not yet approved by the FDA (Chapman et al 2014). This article discusses the incidence, risk factors, clinical presentation, and management of intracranial hemorrhage resulting from thrombolytic therapy.

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