Hemorrhagic Transformation in Acute Ischemic Stroke
Potential Contributing Factors in the European Cooperative Acute Stroke Study
Background and Purpose Recent studies suggest that thrombolytic therapy may be of benefit to patients with acute ischemic stroke. However, the treatment also carries a significant risk of hemorrhagic transformation (HT). The purpose of this study was to select potential contributors to HT.
Methods We provide an explanatory analysis of the European Cooperative Acute Stroke Study (ECASS) data. ECASS was a multicenter, placebo-controlled, randomized trial of recombinant tissue plasminogen activator in ischemic stroke, within 6 hours of symptom onset, which enrolled 620 patients. HTs were classified into either hemorrhagic infarction or parenchymal hemorrhage according to their CT scan appearance. We used logistic regression analysis to select potential contributing factors to each type of HT.
Results The severity of initial clinical deficit (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.6 to 4.0) and the presence of early ischemic changes on CT scan (OR, 3.5; 95% CI, 2.3 to 5.3) were associated with increased risk of hemorrhagic infarction. Increasing age (in decades; OR, 1.3; 95% CI, 1.0 to 1.7) and treatment with recombinant tissue plasminogen activator (OR, 3.6; 95% CI, 2.1 to 6.1) were related to the risk of parenchymal hemorrhage.
Conclusions Since all potential contributing factors are readily discernible upon hospital admission, they should be used to improve selection of patients into future studies.
Recent studies suggest that thrombolytic therapy may be of benefit to patients with acute ischemic stroke.1 2 However, the treatment also carries a significant risk of HT.1 2 3 4 5 A better selection of patients is needed to improve the safety of this treatment.6
The search for potential risk factors for HT in patients with acute ischemic stroke who were treated with a plasminogen activator is complicated by the fact that spontaneous HT of cerebral infarct is a common event.7 HT is usually classified into either HI or PH. HI is characterized by scattered distribution of areas of high attenuation with indistinct margins. PH is defined as a homogeneous region of circumscribed high attenuation.7 8 Most spontaneous HTs are HIs that do not affect clinical outcome. Spontaneous PHs, which are usually responsible for clinical deterioration, are far less common.7 Previous studies have suggested that age, a severe neurological deficit, decreased consciousness, and ischemic edema as depicted by early CT scan are associated with increased risk of HT.7 8 9 10 11 In patients treated with a plasminogen activator, time from symptom onset to treatment has also been considered an important variable.12 However, these studies included small numbers of patients, and the risk assessment remains uncertain, especially for PH, the less common form of HT.
In this report we analyzed data from the ECASS, a placebo-controlled trial of intravenous thrombolytic treatment with rTPA in acute ischemic stroke, which enrolled 620 patients. The aim was to recognize potential contributors to the different types of HT.
Subjects and Methods
The design and primary results of ECASS have been recently reported.1 13 Briefly, ECASS was a double-blind, placebo-controlled, randomized trial with eligibility based on clinical symptoms and CT scan, performed between late 1992 and early 1994 at 75 centers in 14 European countries. Six hundred twenty patients received either rTPA (1.1 mg/kg IV) or placebo, within 6 hours from stroke onset. Patients with severe hypertension (systolic >200 mm Hg or diastolic >110 mm Hg) were excluded. Full-dose heparin and antiplatelet agents were prohibited during the 24 hours after treatment.
A first CT scan was performed before randomization to exclude brain hemorrhages and to assess possible early ischemic changes. A second CT scan was done at 24±12 hours and a third one between days 6 and 8. All CT scans were read by an independent committee. The members of that committee were blinded to the assigned treatment. According to definitions published elsewhere,1 14 15 HI was defined as small petechiae along the margins of the infarct or more confluent petechiae within the infarcted area but without space-occupying effect. PH was defined as blood clot with space-occupying effect. PHs were further classified into either PHs that developed within the boundaries of cerebral infarct or remote PHs that occurred at distance of the ischemic area, within presumably normal brain. In 11 patients, CT scans had been omitted or were too poor to be readable. Thus, only 609 patients remained for analysis with a complete set of CT scans.
For each patient we recorded age, sex, body weight, history of hypertension, hypertension on admission (systolic >160 mm Hg or diastolic >90 mm Hg), history of coronary heart disease, history of diabetes mellitus, atrial fibrillation on admission, stroke severity on admission (as assessed by the Scandinavian Stroke Scale16 ), level of consciousness on admission, time from onset of symptoms to initiation of treatment, activated partial thromboplastin time, fibrinogen and platelet count on admission, prior treatment with aspirin, and early ischemic changes on CT scan (attenuation of density, sulcal effacement, or ventricular compression). Some variables were clustered according to the coherence of their biological significance (ie, cardiovascular variables, neurological variables, and hemostatic variables ). Logistic regression analysis was first performed on each of the following subsets of variables: age and sex; body weight in women; body weight in men; cardiovascular variables; neurological variables; hemostatic variables; and early ischemic changes on CT scan. Significant risk factors at P<.05 were then entered into a final logistic model together with treatment with rTPA as independent variables. Risk factors for PH were selected on the whole sample (n=609), whereas risk factors for HI were selected on the subset of patients that did not include those with PH (ie, patients with HI or no HT; n=527). This was done because most PHs (17/20 in the placebo group and 40/62 in the rTPA group) developed within the boundaries of the ischemic area, and we assumed that these PHs resulted from increased severity of HI. Results were expressed as adjusted odds ratios and corresponding 95% confidence intervals.
The overall incidence of HT was not significantly different between the treatment groups: 247 patients had HT, 113 patients in the placebo group (37%) and 134 patients in the rTPA group (44%) (P=.14, Fisher’s exact test). Patients receiving rTPA had more PHs and fewer HIs than the patients who received placebo (P<.001; Table 1⇓). Twenty-two PHs (35%) in the rTPA group and three (15%) in the placebo group developed at a distance from the cerebral infarct. Most PHs (87%) occurred within 24 hours of initiation of treatment, whereas only 24% of HIs were apparent on CT scan at this time. Mortality at 90 days in patients with HI was not different from that of patients without HT (14.6% versus 14.1%; P=.894). In contrast, mortality increased to 45.1% in patients with PH (P<.001).
The distribution or the mean±SD value of possible risk factors for both types of HT is shown in Table 2⇓. The initial clinical severity of stroke and the presence of early ischemic changes on CT scan were associated with increased risk of HI. These variables remained significant risk factors for HI in the final logistic model, whereas treatment with rTPA did not increase the risk of HI (Table 3⇓).
Advanced age and atrial fibrillation on admission were associated with increased risk of PH. Only age remained related to the risk of PH in the final model. Treatment with rTPA increased the risk of PH (Table 4⇓). The time from onset of symptoms to initiation of treatment was not related to the risk of PH. Further analysis of our data limited to the rTPA-treated patients and with the use of a logistic model in which age and delay of treatment were entered as independent variables failed to demonstrate an association between delay of treatment and PH (odds ratio, 0.8; 95% confidence interval, 0.4 to 1.7). The distribution of PHs according to classes of age did not show a clear cutoff value (Figure⇓).
Patients treated with rTPA had more PHs and fewer HIs than those who received placebo. This suggests that some PHs in the rTPA-treated patients resulted from increased severity of HI. However, more than one third of PHs in the rTPA-treated patients developed at a distance from the ischemic area, within presumably normal brain. Such remote PHs were also seen in patients who received placebo, although less commonly. These observations suggest that some PHs may also be due to mechanisms other than HT of cerebral infarct. Therefore, we decided to analyze potential risk factors for HI and potential risk factors for PH separately.
The association between clinical severity of stroke and risk of HI was apparent even though the ECASS excluded patients with the most severe clinical deficits, such as hemiplegia plus fixed eye deviation.13
The presence of early ischemic changes on CT scan was a stronger risk factor for HI. Early ischemic changes have been recently reviewed.17 They include decrease in x-ray attenuation and mass effect (sulcal effacement or ventricular compression). Hypodensity results from increase of cerebral water content.11 It has been demonstrated that the development of brain edema is related to the depth of ischemia.18 Therefore, our finding is consistent with the observation that the risk of HT is higher when the residual cerebral blood flow is markedly reduced.19 The relationship of HI to brain edema, as depicted by CT, suggests that HI might occur through retrograde reperfusion via the pial collaterals initially pressed by brain edema and then reopened as the edema reduces7 The fact that in ECASS HI was detected more frequently on CT performed on days 6 to 8 is consistent with this hypothesis.
Advanced age was associated with increased risk of PH. Studies of factors related to intracranial hemorrhage in patients receiving rTPA for acute myocardial infarction support this finding.20 Cerebral amyloid angiopathy may predispose older patients to PH. Indeed, the neuropathologic examination of five patients with fatal intracerebral hemorrhage after rTPA therapy for acute myocardial infarction demonstrated cerebral amyloid angiopathy in three.21 Cerebral amyloid angiopathy, which is an important cause of spontaneous cerebral hemorrhage in the elderly,22 might also explain the rare occurrence of remote PH in patients who received placebo in the ECASS.
Atrial fibrillation was associated with PH before adjustment for other potential risk factors but did not have independent predictive value in the final logistic model. This discrepancy might be explained by the higher prevalence of atrial fibrillation in older patients.23
Data from the NINDS study suggest that the risk of PH is related to hypertension.24 We could not find such a relation in this data set. However, it should be pointed out that patients with very high blood pressure at presentation were excluded from the ECASS. Therefore, the possibility remains that severe hypertension could be associated with increased risk of PH.
Similarly, the ECASS protocol prohibited full-dose heparin during the 24 hours after treatment. Because most PHs occurred within 24 hours of randomization, our data do not permit us to address the question of whether heparin increases the risk of PH. However, certainly heparin did not contribute to HT in this time frame.
In some previous studies, the dose of rTPA and the delay of treatment were related to the risk of PH.12 24 Because all the patients enrolled in the ECASS received the same body weight–adjusted dose of rTPA (1.1 mg/kg), our data do not permit us to explore the relationship between dose of rTPA and risk of PH. Levy et al24 reported PH in 4 (18%) of 22 patients given an rTPA dose of at least 0.9 mg/kg versus only 1 PH in the remaining 72 patients who were treated with lower doses. The larger experience of thrombolytic treatment after acute myocardial infarction also supports the notion of increased risk of PH with higher doses of rTPA.17 On the other hand, no relationship between the dose and rate of rTPA and HT was observed in the study by del Zoppo et al.12 However, only 10 PHs were analyzed in that study.
We did not find a greater risk of PH in patients treated between 3 and 6 hours than in those treated within 3 hours of stroke onset. This result gives support to the recently expressed view that a rigid and universal time window for stroke therapy might not be appropriate for the heterogeneity of the individual pathophysiological states.25 However, this result should be viewed with caution because only 87 patients were enrolled in the ECASS within 3 hours of stroke onset.
In the NINDS trial, patients were given 0.9 mg/kg of rTPA within 3 hours from onset of symptoms. Only 6.4% of patients given rTPA had symptomatic intracerebral hemorrhage.2 However, the incidence of symptomatic intracerebral hemorrhage in patients receiving placebo in the NINDS trial was also much lower than the incidence of PH among those receiving placebo in the ECASS. This suggests that the two study populations were not comparable.6 Of significance, the lower frequency of symptomatic intracerebral hemorrhage in the rTPA-treated group significantly contributed to mortality.2 For this reason, defining contributors to hemorrhagic risk is essential to improved outcome after the use of plasminogen activators in ischemic stroke.
In conclusion, using logistic regression analysis, we selected potential independent contributors to the different types of HT in patients with acute ischemic stroke enrolled in the ECASS. Treatment with rTPA increased the risk of PH but not that of HI. A severe clinical deficit and the presence of early ischemic changes on CT scan were related to the risk of HI. Advanced age was associated with increased risk of PH. These variables were readily discernible at hospital admission. They may be used in future studies to decide whether a given patient may be treated with rTPA or a comparable plasminogen activator. All efforts should be made to prospectively test these potential contributors to HT to reduce the apparent risk.
Selected Abbreviations and Acronyms
|ECASS||=||European Cooperative Acute Stroke Study|
|NINDS||=||National Institute of Neurological Disorders and Stroke|
|rTPA||=||recombinant tissue plasminogen activator|
The ECASS was sponsored exclusively by Karl Thomae GmbH, a member of Boehringer Ingelheim, Biberach, Germany.
- Received November 14, 1996.
- Revision received January 9, 1997.
- Accepted February 14, 1997.
- Copyright © 1997 by American Heart Association
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