Intracerebral hemorrhage due to thrombolytic therapy

Epidemiology
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By Kathleen Burger DO

Introduction. The rate of intracerebral hemorrhage following thrombolytic therapy depends on the agent, dose, timing, route of administration, patient population, concomitant treatments, and the definition of hemorrhage used. Prior to the use of intravenous t-PA in stroke, it was found that intracranial hemorrhage occurred 1% or less in patients receiving thrombolytic therapy for myocardial infarction (Hunt et al 1992; Maggioni et al 1992; Simoons et al 1993; Gore et al 1995). Dose-escalation pilot studies demonstrated safety of rt-PA administration in acute ischemic stroke in the late 1980s (Brott et al 1992; del Zoppo et al 1992). The NINDS pilot study reported 3 symptomatic hemorrhages in 74 patients treated with doses of rtPA greater than 0.9 mg/kg within 90 minutes of symptom onset (Brott et al 1992). A great appreciation for hemorrhagic conversion of ischemic stroke following thrombolytic therapy can be accomplished through the following review of selected trials.|{picture:inhemjb1.bmp}{caption:Symptomatic intracerebral parenchymal hematoma after rtPA therapy (CT)}{label:(Left) A 62-year-old man with acute left hemiparesis became obtunded with vomiting and increasing weakness 1 hour after treatment with 0.95 mg/kg rtPA given over 90 minutes, and a right parietal hematoma was detected. Middle: A 65-year-old man developed a Cerebellar hematoma after infusion of 0.95 mg/kg rtPA over 1 hour in the setting of severe hypofibrinogenemia. (Right) A 63-year old woman with acute right hemiparesis and hemisensory loss became drowsy and vomited 1 hour after receiving 0.95 mg/kg of rtPA over 90 minutes, and a left thalamic hematoma was detected. (Used with permission from: Brott TG, Haley EC Jr, Levy DE, et al. Urgent therapy for stroke. Part I. Pilot study of tissue plasminogen activator administered within 90 minutes. Stroke 1992;23(5):632-40.)}| Three patients had asymptomatic hemorrhagic transformation.|{picture:inhemjb2.bmp}{caption:Hemorrhagic conversion without hematoma (CT)}{label:CT performed at 18 to 30 hours showed hemorrhagic transformation in 3 of 71 patients without hematoma. CT findings were not associated with neurologic deterioration. Right: Acute infarction involved the deep hemisphere; a well-circumscribed old left hemispheric infarction is also seen. Used with permission (Used with permission from: Brott TG, Haley EC Jr, Levy DE, et al. Urgent therapy for stroke. Part I. Pilot study of tissue plasminogen activator administered within 90 minutes. Stroke 1992;23(5):632-40.)}| In the Burroughs-Wellcome study treatment had to be started within 8 hours of stroke onset (Wolpert et al 1993). Of the 98 patients treated with varying doses of rtPA, 11 had a symptomatic hemorrhage.|{picture:inhemjb3.bmp}{caption:Parenchymatous hematomas in 11 patients (CT)}{label:In case 2, a hematoma occurred in the occipital lobe on the opposite side from the hemorrhagic infarct. In case 9, a hematoma occurred in the cerebellum, although the infarct involved the temporal lobe and adjacent opercula. Cases 2 and 10 could be classified as either hemorrhagic infarcts or parenchymatous hematomas. (Used with permission from: Wolpert SM, Bruckmann H, Greenlee R, Wechsler L, Pessin MS, del Zoppo GJ. Neuroradiologic evaluation of patients with acute stroke treated with recombinant tissue plasminogen activator. The rtPA Acute Stroke Study Group. AJNR Am J Neuroradiol 1993;14(1):3-13.)}| The only significant baseline predictor of hemorrhage in this study was treatment greater than 6 hours from symptom onset.

Intravenous thrombolytic therapy. The NINDS rtPA Stroke Study formed the basis for FDA approval of intravenous rtPA for acute ischemic stroke within 3 hours of symptom onset (National Institute of Neurological Disorders and Stroke r-TPA Stroke Study Group 1995). In this study, the total dose of rtPA was 0.9 mg/kg, with 10% of the dose given as an initial bolus, followed by the remaining 90% via intravenous infusion over one hour. All patients were treated within 3 hours of symptom onset, with half receiving treatment within 90 minutes. Symptomatic intracerebral hemorrhage attributable to study drug was defined as a CT-documented hemorrhage, which was temporally related to a change in the patient's clinical condition in the judgment of the clinical investigator within 36 hours from treatment onset. Of the 312 patients treated with rtPA, 6.4% of patients had a symptomatic intracerebral hemorrhage compared to 0.6% of placebo-treated patients. An additional 4.2% of patients treated with rtPA had an asymptomatic hemorrhage on a protocol-mandatory CT scan at 24 hours as compared to 2.8% of placebo patients. These rates of hemorrhage are very similar to the rates in the pilot NINDS studies in which patients were treated within 3 hours, but lower than in the other randomized thrombolytic studies in which the large majority of patients were treated after 3 hours (Table 1). A severe baseline neurologic deficit, as measured by the NIHSS, and the presence of edema or mass effect on the baseline CT scan were independently associated with an increased risk of symptomatic intracerebral hemorrhage in the NINDS trial (NINDS t-PA Stroke Study Group 1997). However, these patients were still likely to benefit from use of the medication.

Table 1. Incidence of Symptomatic Intracerebral Hemorrhage in Randomized Clinical Trials Using Thrombolytic Therapy in Acute Ischemic Stroke

Studies

No. of

patients

Time

window

Drug and dose

Symptom-

atic

hemorrhage

in treatment

group

 

Symptom-

atic

hemorrhage

in control

group

 

NINDS*

1995

 

624

3 hours

rtPA 0.9 mg/kg

6.4%

0.6%

MAST I*

1995

622

6 hours

SK

1.5 million units

 

9.6%‡

2.0%‡

ECASS I**

1995

 

620

6 hours

rtPA 1.1 mg/kg

 

11.1%†

2.3%

Australian Streptokinase Study**

1996

 

340

4 hours

SK

1.5 million units

 

12.6%

2.4%

MAST E***

1996

310

6 hours

SK

1.5 million units

 

21.6%

2.9%

ECASS II**

1998

800

0-3 hours

3-6 hours

 

rtPA 0.9 mg/kg

 

8.1%

0.8%

PROACT I****

1998

46

6 hours

r-proUK

6 mg +

heparin

500 IU/hr

for 4 hrs

 

15.4%

7.1%

PROACT II****

1999

 

180

6 hours

r-proUK

9 mg

 

10%

2%

ATLANTIS B*

1999

 

613

3-5 hours

rtPA

0.9 mg/kg

 

7.0%

1.1%

ATLANTIS A*

2000

 

142

6 hours

rtPA

0.9 mg/kg

 

11.0%

0%

STAT*

2000

 

500

3 hours

Ancrod

72 hour infusion

 

5.2%

2%

ESTAT*

2006

 

1222

6 hours

Ancrod

72-hour infusion

 

7.2%

2%

ECASS III*****

2008

 

821

3 to 4.5 hours

rtPA

0.9 mg/kg

 

2.4%

0.2%

DIAS-2*****

2009

 

 

 

Tenecteplase***

2012

 

 

 

 

IMS-3

2013

 

 

 

 

MR-Rescue

2013

193

 

 

 

 

50

 

 

 

 

 

656

 

 

 

 

 

118

3 to 9 hours

 

 

 

6 hours

 

 

 

 

 

3 hours

 

 

 

 

 

8 hours

Desmoteplase

90 ìg/kg

 

125 ìg/kg

0.1 mg/kg in 25 patients

0.25 mg/kg in 25 patients

 

0.9 mg/kg in IV group vs. 0.6 mg/kg EV

 

Standard treatment vs. merci

 

3.5%

 

 

4.5%

 

4%

 

 

 

 

 

6.2%

 

 

 

 

 

4%

0%

 

 

 

 

16%

 

 

 

 

 

 

 

 

 

 

 

4%

* Symptomatic hemorrhage was defined as a CT-documented hemorrhage that was temporarily related to a change in the patient’s clinical condition in the judgment of the clinical investigator.

** Parenchymal hemorrhage type 2 is considered symptomatic/major hemorrhage and is defined as greater than 30% of the infarcted area affected by hemorrhage with mass effect or extension outside the infarct.

*** Parenchymal hematoma-homogenous area of circumscribed hyperdensity, usually with a mass effect and sometimes with ventricular extension.
**** Hemorrhagic transformation associated with neurologic deterioration of 4 or more points on the NIHSS or 1 point deterioration in level of consciousness.
***** Hemorrhagic transformation associated with neurologic deterioration of 4 or more points on the NIHSS at 72 hours or causing death by 90 days.

‡ Streptokinase and aspirin in the treatment group and aspirin alone in the control group.
† The percentages reflect the parenchymal hematoma of larger extent in the intention-to-treat population.

Table 2 lists the most important potential risk factors for intracerebral hemorrhage associated with the use of thrombolytic therapy in stroke based on the various studies that are summarized in this review. Risks most frequently found to predict symptomatic intracerebral hemorrhage across multiple studies are early CT hypodensity, elevated serum glucose or history of diabetes mellitus, and severe baseline neurologic deficit, as measured by the NIHSS (Lansberg et al 2007a).

Table 2. Risk Factors for Intracerebral Hemorrhage in Patients with Acute Ischemic Stroke

Definite

  Use of a thrombolytic agent

  Dose of thrombolytic agent

 

Probable

  Type of thrombolytic agent

  CT findings of early infarction prior to treatment

  Deeply ischemic brain tissue prior to treatment

  Hyperglycemia or history of diabetes mellitus

  High severity of stroke as determined by the NIHSS score

  Longer time to treatment

  Concomitant antithrombotic drug use

 

Possible

  Older age

  Deviation from established treatment protocols

  Elevated systolic blood pressure prior to treatment

  Prior antithrombotic drug use

  Prior stroke

  History of cardiac disease

  History of hypertension

  Non-smoking status

  Magnetic resonance imaging characteristics

  CT with leukoaraiosis

  Increased matrix metalloproteinase -9 levels

  Low platelet count

  Low LDL levels

  Low plasminogen activator inhibitor levels

In the European Acute Stroke Study (ECASS), where intravenous rtPA (1.1mg/kg) was provided within 6 hours of symptom onset, the risk of intracerebral hemorrhage was increased by 8.8% in the treatment group in the intention-to-treat analysis (Hacke et al 1995). Moderate to large regions of early cerebral infarction or a severe clinical deficit led to an increased risk of hemorrhagic transformation, whereas advanced age increased the risk of parenchymal hematoma (Hacke et al 1995; Larrue et al 1997). The rate of hemorrhage in ECASS was much higher than in the NINDS rtPA study, which may well be related to the rtPA dose (1.1 mg/kg, 100 mg maximum) that was substantially higher than in the NINDS rtPA study and most trials that followed. In the ECASS II, 800 patients were randomized to placebo or the current accepted 0.9 mg/kg dose of intravenous rtPA within a 6-hour time window (Larrue et al 2001). The rate of parenchymal hemorrhage was increased significantly in the treatment group as compared to the placebo group (8.1% vs. 0.8%); however, only 158 of the 800 patients were randomized in the 0 to 3 hour time window. Risk factors for intracerebral hemorrhage in ECASS II included large areas of hypodensity on the baseline CT scan, congestive heart failure, advanced age, and aspirin use prior to thrombolysis (Larrue et al 2001). The search for a longer treatment time window following stroke symptom onset was evaluated in the Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) studies. ATLANTIS-A and ATLANTAS-B evaluated the safety and efficacy of rtPA given between 0 and 6 hours after stroke onset, and between 0 and 5 hours post stroke onset respectively (Clark et al 1999; Clark et al 2000). An unacceptable rate of symptomatic intracerebral hemorrhage, which was as high as 11% in the treatment group, was found without clear benefit from treatment at 90 days. The relatively high hemorrhage rate in this study has been attributed to the prolonged treatment window (Clark et al 1999; Clark et al 2000).

A pooled analysis including 2775 patients from the above mentioned randomized placebo-controlled trials of intravenous rtPA indicated that there may be a clinical benefit up to 4.5 hours from symptom onset (Hacke et al 2004). This was put to the test in the ECASS III trial where efficacy and safety of intravenous rtPA between 3 and 4.5 hours after stroke symptom onset were evaluated (Hacke et al 2008). Treatment with rtPA significantly increased odds of a favorable outcome at 3 months (odds ratio 1.34, 95% confidence interval 1.02 to 1.76). Symptomatic intracerebral hemorrhage, defined as hemorrhage causally associated with a clinical deterioration of 4 or more points on the NIHSS or death, was 2.4% in the rtPA treatment arm and 0.2% in the placebo arm. Using the NINDS trial definition, the rate of symptomatic intracerebral hemorrhage in ECASS was 7.9% and 3.5% in the treatment and placebo arms, respectively. Of note, ECASS III also excluded patients older than 80 years, on oral anticoagulants, with NIHSS greater than 25, or with a history of diabetes and prior stroke. An observational study of patients treated with intravenous rtPA between 3 and 4.5 hours reported a 2.2% rate of symptomatic intracerebral hemorrhage at 7 days using the ECASS III definition (Wahlgren et al 2008a). Based on these trials, the American Heart Association/American Stroke Association (AHA/ASA) updated its guidelines in 2009 recommending intravenous rtPA for eligible patients with acute ischemic stroke up to 4.5 hours after symptom onset (del Zoppo et al 2009).

rtPA in clinical practice. Despite early concerns of a potentially higher risk of intracerebral hemorrhage associated with intravenous rtPA outside the clinical trial setting, several studies support a safety profile of rtPA in clinical practice that is comparable to the NINDS rtPA trial (Albers et al 2000; Tanne et al 2002). Following FDA approval of rtPA for ischemic stroke, Standard Treatment with Alteplase to Reverse Stroke study (STARS) and the Canadian Alteplase for Stroke Effectiveness Study (CASES), both aiming to show safety and efficacy of rtPA in clinical practice, found symptomatic intracranial hemorrhage (sICH) rates of 3.3% and 3.8%, respectively (Albers et al 2000; Shobha et al 2010). The SITS-MOST registry also reported that patients treated with intravenous rtPA 0 to 3 hours following onset of acute ischemic stroke in clinical practice were similar to those enrolled in clinical trials, with a rate of symptomatic intracerebral hemorrhage (using the NINDS rtPA trial definition) of 7.3% at 7 days (Wahlgren et al 2007).

Results from ECASS III also translate well to the community setting as seen in 104 patients treated with rtPA in the 3 to 4.5 hour window at one community hospital, giving rise to a 2.4% rate of sICH (Montano et al 2013). In a study of 50 stroke patients treated in 10 acute-care hospitals in Indianapolis, the authors found that sICH following rtPA occurred more often when protocol violations occurred (Lopez-Yunez et al 2001). A meta-analysis published by the Cochrane Database of Systematic Reviews in 2009 summarized the data of 26 randomized controlled trials completed by 2009 in 7152 acute stroke patients (Wardlaw 2009). Most of these trials tested intravenous thrombolysis up to 6 hours after symptom onset. Fifty-five percent of trials tested rtPA. Four trials evaluated intra-arterial thrombolysis. Overall, the odds of symptomatic intracranial hemorrhage were increased 3-fold (odds ratio 3.49, 95% confidence interval 2.81 to 4.33) in patients who received thrombolysis. In spite of this, there was a significantly reduced chance of poor outcome (combined death and dependency) during follow-up in patients who received thrombolytic therapy.

Multiple other thrombolytic agents – streptokinase, desmoteplase, tenecteplase, and ancrod – have been studied in randomized trials (Candelise et al 1995; Hommel et al 1995; Donnan et al 1996; Sherman et al 2000; Hacke et al 2005; Haley et al 2005; Furlan et al 2006; Hennerici et al 2006; Hacke et al 2009). However, these medications have not been approved for use in stroke patients because of safety concerns or a lack of established efficacy. Tenecteplase deserves special mention following recent completion of its phase 2B trial. After thrombolysis treatment of ischemic stroke, patients were carefully selected based on CT perfusion imaging (Parsons et al 2012). Tenecteplase was associated with significantly better reperfusion, improved clinical outcomes, and reduced symptomatic hemorrhagic conversion when compared to alteplase.

Endovascular therapy. Intra-arterial delivery of thrombolytic therapy and clot extraction would theoretically increase cerebral artery recanalization and decrease the likelihood of hemorrhage due to a lower required total tPA dose and less widespread effects of the agent. Although the reported lysis rates using endovascular delivery are higher than those reported for patients treated with intravenous thrombolytic agents, the rates of hemorrhage are similar to or greater than those in studies using intravenous rtPA within 3 hours of onset, even when performed by experienced individuals (Meyers et al 2011). A retrospective multicenter analysis comparing stroke patients treated with intravenous tPA to those treated with either intra-arterial thrombolysis or bridging intravenous plus intra-arterial therapy found an increased odds of sICH in patients receiving endovascular treatment (OR 3.47; 95% CI 1.19–10.01, p<0.05) after adjusting for baseline age, stroke severity, and stroke location (Singer et al 2009). Early studies looked at intra-arterial t-PA alternative therapy, such as Pro-urokinase in the Prolyse in Acute Cerebral Thromboembolism Trial Study I and II (PROACT I and PROACT II). PROACT I provided patients intra-arterial pro-urokinase (6 mg) and high-dose heparin (100 units/kg bolus followed by 1000 units/hour for 4 hours) and compared the results to a placebo group receiving high-dose heparin alone, resulting in an unacceptable 27% symptomatic intracerebral hemorrhage rate in the combined group and 20% for high-dose heparin alone (del Zoppo et al 1998). The PROACT II study randomized 180 patients with an acute middle cerebral artery occlusion of less than 6 hours duration (Furlan et al 1999). The treatment group received 9 mg intra-arterial pro-urokinase over 2 hours plus intravenous heparin 2000 units bolus and 500 units per hour infusion for 4 hours, whereas the placebo group received heparin only. A 15% absolute increase in favorable clinical outcome was found in the treatment group; however, an increased sICH rate was observed in 10% of the treatment group compared with 2% in the control group. Neither pro-urokinase nor urokinase are commercially available, resulting in use of tPA at many centers when intra-arterial administration is chosen as treatment for acute ischemic stroke due to large artery occlusion. Until recently, other than the early IMS trials, no published randomized controlled trials were available in the management of acute ischemic stroke comparing FDA approved intravenous tPA to more aggressive treatments such as intra-arterial (IA) tPA, mechanical devices, or combination intravenous t-PA with endovascular therapy.

The Interventional Management of Stroke Study evaluated intra-arterial rtPA given after a reduced “bridging” dose (0.6 mg/kg) of intravenous rtPA (IMS Study Investigators 2004). Eighty subjects were enrolled, and comparisons were made to match controls and rtPA-treated patients from the NINDS stroke study. The 6.6% rate of symptomatic intracerebral hemorrhage in treated patients was similar to those treated with intravenous rtPA in the NINDS trial. A second study evaluated this combined intravenous and intra-arterial approach to treatment of moderate to severe strokes within 3 hours of symptom onset (IMS II Trial Investigators 2007). Eighty-one patients were treated and compared to historical controls from the NINDS trial. This trial reported a symptomatic intracerebral hemorrhage rate of 9.9%, similar to other studies. A large multicenter study retrospectively analyzed data from 645 stroke patients treated with intravenous, intra-arterial, and intravenous plus intra-arterial thrombolysis (Singer et al 2009). This study reported DWI lesion volume on pretreatment MRI, and intra-arterial or intravenous plus intra-arterial thrombolysis independently predicted symptomatic intracerebral hemorrhage. Patients treated with intra-arterial or intravenous plus intra-arterial were 3.5 times more likely to develop symptomatic intracerebral hemorrhage than those treated with intravenous alone (Singer et al 2009). The IMS-3 trial randomized acute stroke patients within 3 hours of symptom onset to intravenous tPA alone or intravenous tPA followed by endovascular therapy. Surprisingly, clinical outcomes were similar in both groups, as were sICH rates of 5.9% and 6.2% in the placebo and study groups respectively (Broderick et al 2013). The Synthesis Expansion trial attempted to randomize patients within 4.5 hours of stroke onset into either an endovascular group where any type of accepted intervention was allowed or a control group where intravenous t-PA alone was provided. Results of this trial surprisingly showed no difference in outcome nor in sICH rates (6% in both groups) (Ciccone et al 2013).

Mechanical thrombolysis and thrombectomy have historically been shown in several uncontrolled trials to promote arterial recanalization. These endovascular techniques may be used alone or in combination with intravenous or intra-arterial administration of thrombolytic drugs. Currently, there are 2 catheter systems, the Merci Retriever® (Concentric Medical, Inc., Mountain View, CA) and the Penumbra System® (Penumbra, Inc., Alameda, CA), as well as 2 retrievable stents, Solitaire™ FR Revascularization Device and Trevo Device retrievable stents, which are often used for revascularization of patients with acute ischemic stroke secondary to large vessel occlusive disease.

The MERCI trial evaluated the safety and efficacy of the Merci clot retriever system in the treatment of ischemic stroke patients with a large vessel occlusion within 8 hours of symptom onset who were not eligible for intravenous rtPA (Smith et al 2005). Embolectomy using the Merci catheter was associated with a 7.8% rate of symptomatic intracerebral hemorrhage in the MERCI trial, defined as intracranial bleeding within 24 hours of treatment leading to a clinical worsening of greater than 4 points on the NIHSS or death. A second trial (Multi MERCI) reported a 9.8% rate of symptomatic intracerebral hemorrhage after embolectomy (Smith et al 2008). The Multi MERCI trial included patients that had persistent occlusions after standard dose intravenous rtPA and allowed adjuvant intra-arterial rtPA. Neither of these trials had a control arm; however, mechanical thrombectomy using the Merci Retriever was associated with significantly higher rates of recanalization (MERCI 46%, Multi MERCI 69.5%) than reported in the placebo arm of PROACT II (18%).

The Penumbra catheter was evaluated in a single-arm study of patients with acute ischemic stroke within 8 hours of symptom onset with a treatable intracranial large vessel occlusion (Penumbra Pivotal Stroke Trial Investigators 2009). Patients that were refractory to intravenous rtPA were included. Successful recanalization was reported in 81.6% of treated vessels, whereas sICH was reported in 11.2% of patients. MR Rescue was then designed with a goal to compare patients receiving Merci clot retriever or Penumbra system to standard treatment, with each group further divided in those with good MRI penumbral patterns (small infarct core and substantial salvageable brain tissue) and those without (large infarct core with little to no salvageable tissue). Despite an advanced imaging protocol with potential to improve selection of thrombolytic candidates, outcomes and sICH rates were similar in all groups (Kidwell et al 2013). Findings in both the IMS-3 and MR Rescue investigations correlate with current acute stroke management guidelines that strongly recommend use of intravenous rt-PA in eligible patients presenting within 4.5 hours of stroke symptom onset, only allowing consideration of endovascular therapies in cases where IV tPA was contraindicated or already administered (Jauch et al 2013).

Both the Solitaire™ FR Revascularization Device and Trevo Device retrievable stents show promise given the reportedly high recanalization rates with a low 6.7% incidence of symptomatic hemorrhage when used to treat acute ischemic stroke. However, only a limited number of case series are available to demonstrate this (Novakovic et al 2012). Although not heavily studied in randomized trials, these “stentrievers” did make their way on the scene in the later years of the IMS-3 investigation (Chimowitz 2013). Stent retrievers are thought by many experts to be underrepresented in IMS-3 and are deserving of further investigation in early post-stroke symptom onset windows.

Potential risk factors for post-thrombolysis symptomatic intracerebral hemorrhage.Following publication of a number of studies attempting to identify clinical predictors of post-thrombolysis symptomatic intracerebral hemorrhage, a systematic review of the literature identified a few risk factors that have repeatedly been associated with this dreaded complication (Lansberg et al 2007a). Lansberg and colleagues identified 12 studies that met their inclusion criteria, of which CT characteristics, elevated serum glucose or history of diabetes, and elevated NIHSS repeatedly were found to be independently associated with post-thrombolysis symptomatic intracerebral hemorrhage (NINDS t-PA Stroke Study Group 1997; Demchuk et al 1999; Jaillard et al 1999; Barber et al 2000; Dubey et al 2001; Kase et al 2001; Larrue et al 2001; Tanne et al 2002; Hill and Buchan 2005; Cocho et al 2006). Advanced age, increased time to treatment, high systolic blood pressure, low platelet count, history of congestive heart failure, low plasminogen activator inhibitor levels, prior antiplatelet use, non-smoking status, low density lipoprotein levels, MRI characteristics, and deviations from treatment protocols have also been associated with post-thrombolysis sICH in various publications, (Larrue et al 2001; Gilligan et al 2002; Selim et al 2002; Tanne et al 2002; Ribo et al 2004; Hill and Buchan 2005; Bang et al 2007; Marti-Fabregas et al 2007; Uyttenboogaart et al 2008; Wahlgren et al 2008b; Mokin et al 2012). However, not all risks were consistently replicated in follow up studies. The following are potential post-thrombolysis sICH risks selected for further review:

Elevated serum glucose and history of diabetes mellitus were identified to independently predict hemorrhage in stroke patients treated with thrombolytic therapy (NINDS t-PA Stroke Study Group 1997; Bruno et al 2002; Arnold et al 2014), as well as lead to worse outcomes 3 months post stroke (Putaala et al 2011). The exact pathophysiologic connection between glucose and post-thrombolysis hemorrhage is unclear. Current American Stroke Association guidelines recommend maintaining blood glucose within the 140 to 180 mg/dL range during hospitalization for acute stroke (Jauch et al 2013); however, no guidelines are available regarding glucose management during tPA administration (Hafez et al 2014).

Several studies have independently shown that stroke severity, as rated by high NIHSS scores, is associated with an increased risk of post-thrombolysis hemorrhage (NINDS t-PA Stroke Study Group 1997; Dubey et al 2001; Cocho et al 2006; Cucchiara et al 2009). Despite a higher risk of hemorrhage, patients with severe strokes are still more likely than not to benefit from thrombolytic therapies (NINDS t-PA Stroke Study Group 1997). Ischemic stroke patients 80 years of age and older treated with thrombolysis had almost 3 times the likelihood of sICH development in the NINDS trial (Longstreth et al 2010). Despite being chosen as an exclusion criterion in treatment within the 3 to 4.5 hour poststroke window in ECASS III, age alone has not been shown to offset the benefits of thrombolysis in stroke patients within 3 hours of onset.

Prior antiplatelet use may increase the rate of thrombolytic-associated intracerebral hemorrhage. Reports of acetylsalicylic acid (ASA) use preceding intravenous tPA-treated strokes have provided conflicting results (Anonymous 1997; Larrue et al 2001; Tanne et al 2002; Uyttenboogaart et al 2008). Patients receiving dual antiplatelet therapy with acetylsalicylic acid and clopidogrel may have particularly greater risk of thrombolysis-related sICH (Cucchiara et al 2009). In the SITS-MOST database, the rates of sICH were reported to be: 1.1% for antiplatelet naïve patients, 2.5% for any antiplatelet use, 2.5% for acetylsalicylic acid monotherapy, 1.7% for clopidogrel monotherapy, 2.3% for acetylsalicylic acid plus dipyridamole, and 4.1% for acetylsalicylic acid and clopidogrel (Diedler et al 2010). Although the rate of sICH is higher in the acetylsalicylic acid and clopidogrel cohort, this is still below the sICH rate reported in previous clinical trials and should not exclude otherwise appropriate patients from acute therapy.

A majority of stroke patients that are tPA candidates present with elevated blood pressure; however, high rates of sICH have been shown in those patients with high pre and post tPA treatment blood pressure recordings (Wahlgren et al 2008; Lansberg et al 2007). High risk of sICH has occurred in studies where elevated blood pressure was found during the initial 24 hours following thrombolysis (Derex et al 2005). Guidelines have thus evolved over the years to allow aggressive therapies in order to obtain blood pressure readings lower than 185/110 prior to treatment with tPA (Jauch et al 2013). National Get With the Guidelines-Stroke Registry (GWTG-Stroke) and Joint Commission Stroke requirements have guided participating hospitals to focus on reducing time between onset of stroke symptoms to thrombolytic treatment. As stroke centers continue to strive for rapid tPA treatment times, a national trend towards reduction of post thrombolysis sICH has transpired, supporting continued maintenance of efficient stroke protocols (Saver et al 2013).

Imaging characteristics. Several studies have demonstrated an increased risk of intracerebral hemorrhage following intravenous rtPA treatment in patients with evidence of early infarct signs on CT (NINDS t-PA Stroke Study Group 1997; Demchuk et al 1999; Jaillard et al 1999; Barber et al 2000; Dubey et al 2001; Larrue et al 2001; Tanne et al 2002; Cucchiara et al 2009). These early ischemic changes include hypoattenuation of the brain parenchyma, loss of cortical grey-white junction differentiation, and swelling with sulcal effacement. The risk of symptomatic intracerebral hemorrhage was increased in rtPA-treated patients with prominent signs of edema or mass effect on the baseline CT in the NINDS rtPA Stroke Trial (Patel et al 2001). The Alberta Stroke Programme Early CT Score (ASPECTS) is a quantitated CT score that helps predict functional outcome and intracerebral hemorrhage risk following thrombolytic therapy for acute ischemic stroke (Barber et al 2000). This score quantifies early ischemic CT changes in patients with anterior circulation strokes by subtracting points for each area of hypodensity. Several studies have correlated lower ASPECTS with higher rates of post-thrombolysis hemorrhage (Tanne et al 2002; Dzialowski et al 2006). Leukoaraiosis on CT of the brain is associated with an increased risk of symptomatic hemorrhagic transformation and worse clinical outcomes in tPA-treated stroke patients when compared to patients without leukoaraiosis (Aries et al 2010); however, rtPA should not be withheld in such cases. Despite increased risk of sICH in patients with subtle but common early infarct signs on CT, such imaging findings should not prevent an otherwise eligible patient from being treated with thrombolytic therapy where favorable outcome usually outweighs risk.

Similar to CT studies, investigators have been interested in specific MRI parameters that might identify patients who are at an increased risk for hemorrhagic transformation of an ischemic infarct in the setting of thrombolytic therapy. DWI lesion volumes predicted sICH in a retrospective analysis of patients treated with both intravenous and intra-arterial thrombolytics (Singer et al 2009). Larger infarct volumes, as measured by DWI, and reperfusion status have been shown to independently predict symptomatic intracerebral hemorrhage in patients enrolled in a study of rtPA between 3 and 6 hours identified to have a perfusion-diffusion mismatch on pretreatment MRI (Lansberg et al 2007b). In fact, thrombolysis and restoration of blood flow to ischemic brain with pretreatment regions of very low cerebral blood flow on perfusion weighted imaging was strongly associated with parenchymal hemorrhage (Campbell et al 2013). When ASPECTS is applied to DWI (DWI-ASPECTS), lower scores are associated with post tPA sICH as would be expected, whereas higher DWI-ASPECTS is not without risk (Nezu et al 2010). ASPECTS + W (DWI-ASPETS with DWI white matter scoring system) may be a better predictor of sICH risk following tPA (Kawano et al 2012).

Other potential MRI post-thrombolysis sICH predictors include use of T2* weighted MRI imaging and fluid-attenuated inversion recovery (FLAIR) sequences. Microbleeds on pretreatment T2* MRI sequence are associated with new post-treatment microbleeds and subsequent increased sICH (Kimura et al 2013). FLAIR hyperintensity on MRI seen within hours of stroke onset is thought to be associated with infarction that has evolved beyond the opportunity for thrombolysis; however, other studies have not validated sICH risk when FLAIR hyperintensities are seen in thrombolysed patients 3 to 6 hours after stroke onset (Campbell et al 2011).

A recent stroke within 3 months of an acute infarction is a contraindication to treatment with intravenous thrombolysis because of a perceived risk of increased hemorrhage risk into necrotic tissue. Up to 50% of patients who’ve experienced a transient ischemic attack have diffusion-weighted positive areas of subclinical infarction on MRI (Redgrave et al 2007). There may be an increased risk of hemorrhagic transformation with thrombolysis in stroke patients who report a recent transient ischemic attack; however, one study reported the rate of sICH in this group to be 8.3% (McKinney et al 2012), and another reported no influence of recent transient ischemic attack on post-thrombolysis outcomes (de Lecinana et al 2010).         

Risk scores for predicting post-thrombolysis intracerebral hemorrhage. Several groups have proposed risk-scoring systems to better quantify the hemorrhagic risk associated with thrombolytic treatment of acute ischemic stroke. The Multicenter Stroke Survey Scale was developed using markers identified in the Multicenter rtPA Stroke Survey of post-thrombolysis risk factors (Tanne et al 2002; Cucchiara et al 2008). The risk factors used in this scale are age greater than 60 years, NIHSS greater than 10, admission serum glucose greater than 150 mg/dL, and platelet count less than 150,000. This scoring system was both developed and tested using the Multicenter rtPA Stroke Survey data set and has not been validated in an independent prospective cohort. The rate of symptomatic intracerebral hemorrhage using this tool was 0%, 5%, 4%, and 18% for 0, 1, 2, and 3 or more risk factors present, respectively (Cucchiara et al 2008). The Hemorrhage After Thrombolysis (HAT) Score was developed using a combination of previously published markers of increased post-thrombolysis hemorrhage risk that provided the highest predictive ability in their cohorts (Lou et al 2008). Using this method, the authors identified a history of diabetes or admission glucose above 200 mg/dL, pretreatment NIHSS, and early CT hypodensity as the most important risk factors. The rate of symptomatic intracerebral hemorrhage using this scale was 2%, 5%, 10%, 15%, and 44% for HAT Scores of 0, 1, 2, 3, and more than 3, respectively. This scale was largely derived and refined from the NINDS trial data set and has only independently been validated in a single small cohort of patients at the authors’ institution. The GRASPS score assigns points for hemorrhagic risks, including glucose at presentation (G), race (Asian) (R), age (A), sex (male) (S), systolic blood pressure (P), and stroke severity (S) based on the NIHSS score. GRASPS is the first prediction tool validated in a large national data set that is available to assist clinicians in determination of symptomatic intracerebral hemorrhage risk following treatment with intravenous tPA (Menon et al 2012). Additional scores include SEDAN (sugar, early infarct signs, dense artery, age, NIHSS) (Strbian et al 2012a), THRIVE (with high scores correlating with older age, higher NISS, and whether or not patients have hypertension, diabetes, and/or atrial fibrillation) (Flint et al 2013), and DRAGON (dense artery, rankin score, age, glucose, onset to treatment time, and NIHSS) (Strbian et al 2012b).

Initially, it was thought that clinical risk-scoring schemes could provide clinicians with an additional tool to better estimate the risks associated with thrombolytic treatment in an individual patient. A recently published analysis of the Third International Stroke Trial looked at scoring potential of the above mentioned scores as well as several others, as they pertain to prediction of sICH and overall outcome. Patients were found to have more benefit than risk when treated with tPA regardless of concerning sICH prediction scores, and clinical prediction scores may not play nearly as much of a role in patient selection for tpa treatment as initially thought (Whiteley et al 2014).

In This Article

Introduction
Historical note and nomenclature
Clinical manifestations
Clinical vignette
Etiology
Pathogenesis and pathophysiology
Epidemiology
Prevention
Differential diagnosis
Diagnostic workup
Prognosis and complications
Management
Pregnancy
Anesthesia
References cited
Contributors