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 January 3, 2018; expires January 3, 2021

Overview

Treatment of acute ischemic stroke with recombinant tissue plasminogen activator (rtPA or t-PA) and endovascular intervention leads to improved outcome, as demonstrated in several randomized clinical trials. However, a small percentage of stroke patients receiving aggressive therapy experience symptomatic hemorrhagic conversion of the ischemic stroke, resulting in increased 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 acute stroke therapy.

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.

 

• Addition of endovascular thrombectomy to IV-tPA is superior to IV-tPA alone in appropriately selected patients with acute ischemic stroke due to occlusion of a large intracranial artery, and combination therapy carries a similar rate of hemorrhagic conversion.

 

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

Historical note and terminology

Sussman and Fitch were the first to report use of a thrombolytic agent for acute ischemic stroke (Sussman and Fitch 1958). Additional early studies of thrombolytic therapy for stroke performed during the 1970s “pre-CT era” led to treatment without knowledge of hemorrhagic stroke, and 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 (Brott 1992), resulting in cessation of thrombolytic therapy use in routine practice.

In December 1995, the National Institute of Neurological Disorders and Stroke (NINDS) r-TPA Stroke Study Group reported that recombinant tissue plasminogen activator (rtPA) administered intravenously within 3 hours of symptom onset to 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 6.4% risk of symptomatic intracerebral hemorrhage (sICH) in the treatment group (National Institute of Neurological Disorders and Stroke r-TPA Stroke Study Group 1995). The United States Food and Drug Administration approved intravenous rtPA for selected ischemic stroke patients within 3 hours from symptom onset in June 1996. 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). Finally, several 2015 published controlled trials demonstrated reduced disability in patients receiving endovascular therapy combined with IV-tPA for ischemic strokes due to large vessel occlusion when compared to IV-tPA alone, without additional risk of sICH (Powers et al 2015).

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