448
Intracerebral Hemorrhage, Cerebral Infarction, and Subdural Hematoma After Acute Myocardial Infarction and Thrombolytic Therapy in the Thrombolysis in Myocardial Infarction Study Thrombolysis in Myocardial Infarction, Phase II, Pilot and Clinical Trial* Joel M. Gore, MD; Michael Sloan, MD; Thomas R. Price, MD; Anna Mae Young Randall, BA; Edwin Bovill, MD; Desire Collen, MD, PhD; Sandra Forman, MA; Genell L. Knatterud, PhD; George Sopko, MD; Michael L. Terrin, MD, CM, MPH; and the TIMI Investigators In the Thrombolysis in Myocardial Infarction, Phase IT pilot and clinical trial, 908 patients [326 (35.9%) in the pilot study and 582 (64.0%) in the randomized study] were treated with 150 mg recombinant tissue-type plasminogen (rt-PA) activator in combination with heparin and aspirin, and 3,016 patients [64 (2.1%) in the pilot study and 2,952 (97.91%) in the randomized study] were treated with 100 mg rt-PA in combination with heparin and aspirin. Adverse neurological events occurred in 23 patients treated with 150 mg rt-PA (2.5%) [nine cerebral infarctions (1.0%), 12 intracerebral hemorrhages (1.3%), and two subdural hematomas (0.2%)] and in 33 patients treated with 100 mg rt-PA (1.1%) [20 cerebral infarctions (0.7%), 11 intracerebral hemorrhages (0.4%), and two subdural hematomas (0.1%)]. The difference in adverse neurological events observed comparing the two rt-PA regimens was primarily due to a higher frequency of intracerebral bleeding among patients treated with 150 mg rt-PA (1.3% versus 0.4%, p160 mm Hg or a diastolic pressure >90 mm Hg available to the Clinical Center, or is on medication for or has a history of having been on medication for hypertension." Adverse Neurological Events Adverse neurological events occurring in TIMI II were reported by study staff at each participating center, and later additional data were collected and
Downloaded from http://circ.ahajournals.org/ at Simon Fraser University--Burnaby on May 31, 2015
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classified. The earliest possible time of onset of neurological symptoms was defined as the time of onset of the first symptom or sign, compatible with central nervous system dysfunction. When a patient was asleep or unconscious and responded or awoke with obvious signs of a focal deficit, the earliest possible time was defined as the time of loss of consciousness or of going to sleep. Neurodiagnostic evaluation including computed tomography (CT) scanning, magnetic resonance imaging (MRI), lumbar puncture, noninvasive carotid studies, electroencephalography (EEG), and cerebral angiography were obtained according to clinical indications after onset of the adverse neurological event. Brain images (CT scanning or MRI) were reviewed centrally by the independent neurologists in 22 of 23 cases of intracerebral hemorrhage and 25 of 29 cases of cerebral infarction. The one patient with intracerebral hemorrhage whose CT scan could not be recovered was evaluated on the basis of clinical center CT scan reports. Two patients with cerebral infarction had CT scans that could not be recovered for central review, and two never had brain images obtained. The two patients with cerebral infarction whose CT scans could not be reviewed centrally were classified on the basis of CT scan reports and clinical information. The two patients with cerebral infarction who never had brain imaging were classified on the basis of clinical information: absence of severe headache, presence of defined focal neurological syndromes, cardiac or vascular sources of emboli identified, spinal fluid free of blood in the one who had a lumbar puncture, and clinical courses unusual for intracerebral hemorrhage in both (substantial improvement within 24 hours in one and progressive hypotension leading to shock and death within 24 hours in the other). Classification of adverse neurological events. Intracerebral hemorrhage was classified on the basis of focal neurological deficits associated with focal collections of blood in the brain parenchyma seen on a brain image (CT or MRI) with neither a normal brain image at the time of onset of neurological symptoms nor evidence on the brain image for a preceding infarction. Subdural hematoma was diagnosed if a high-density fluid collection was seen in the extradural space on brain images. A cerebral infarction was diagnosed when an episode of focal neurological dysfunction lasted more than 24 hours and there was no evidence of a subdural or parenchymal clot. Infarction with hemorrhagic conversion was diagnosed if blood appeared within an area of infarction on the first scan or there was no evidence of hemorrhage on the first brain image but hemorrhage on a subsequent image. Patients were classified as having embolic infarction if there was evidence of a specific cardiac source or there were infarctions in more than one vascular distribution on brain images and there was no other documented cause for the infarctions. Classification of intracranial hemorrhages and deaths. The Hemorrhagic Events Review Commit-
tee19 reviewed all hemorrhagic event reports and classified intracranial bleeding as a major hemorrhagic event. The Mortality and Morbidity Classification Committee reviewed all deaths and classified them as due to natural causes including cardiac disease, other vascular diseases, and nonvascular diseases or to complications including those of thrombolytic therapy, anticoagulation, PTCA, and surgery.19 Hemostasis analyses. Blood samples were collected on as many patients as possible at baseline (preinfusion) and 50, 300, and 480 minutes after the start of the rt-PA infusion. Fibrinogen, fibrin(ogen) degradation products, rt-PA antigen levels, and plasminogen levels were determined on specimens submitted to the Coagulation Core Laboratory. Details of the sample collection procedure and the analyses have been presented elsewhere.23 The fibrinogen assay was based on the coagulation rate,24 the fibrin(ogen) degradation products assay on inhibition by patient's blood serum of agglutination of fibrinogen-coated red blood cells with anti-fibrinogen antiserum,25 the rt-PA antigen level on a monoclonal antibody-based enzyme-linked immunosorbent assay,26 and the plasminogen level on a chromogenic substrate assay after addition of excess streptokinase.27 Activated partial thromboplastin times were determined at the participating centers on separate blood samples by routine, local laboratory procedures. Statistical analysis. Probability values and confidence intervals for percentages, proportions, and odds ratios were calculated using standard Z tests, Fisher's "exact" tests, and estimates of variance.28 To adjust for multiple testing, a probability value between 0.01 and 0.001 for two-sided tests has been specified as providing some evidence of differences, and probability values of less than 0.001 have been specified as providing strong evidence of differences. Step-up multiple logistic regression29 was used to adjust for baseline characteristics. Twenty-three baseline characteristics were evaluated. The step-up procedure permitted addition of these variables to the regression analysis until the probability value was more than 0.05. To include age as a continuous variable with a range of values similar to the discrete variables, it was expressed as (age -57)/10. All statistical tests were performed using the BMDP statistical software package, University of California Press, Berkeley, Calif. Results A total of 3,924 patients were enrolled in the TIMI II pilot and clinical trial.18-20 Their allocation with respect to dose of rt-PA and treatment strategy is summarized in Table 1.
Frequency, Timing, and Outcome ofAdverse Neurological Events The frequency of the different types of adverse neurological events is summarized in Table 2. Nine patients (1.0%) receiving the combination of 150 mg rt-PA, heparin, and aspirin had cerebral infarctions,
Downloaded from http://circ.ahajournals.org/ at Simon Fraser University--Burnaby on May 31, 2015
Gore et al TIMI II Pilot and Clinical Trial TABLE 1. Allocation of Patients to Thrombolysis in Myocardial Infarction, Phase II Study Groups Patients (n) Clinical trial Total Pilot 150 mg rt-PA 62 95 33 Immediate invasive 257 517 260 Delayed invasive 296 33 263 Conservative 908 326 582 Subtotal 100 mg rt-PA 133 0 133 Immediate invasive 39 1,463 1,424 Delayed invasive 25 1,420 1,395 Conservative 64 3,016 2,952 Subtotal 390 3,924 3,534 Total rt-PA, recombinant tissue-type plasminogen activator.
with eight (0.9%) identified as embolic on central review. Cerebral infarction occurred in 20 patients (0.7%) receiving 100 mg rt-PA, heparin, and aspirin with 16 (0.5%) identified as embolic on central review. Intracerebral (parenchymatous) hemorrhage occurred in 12 patients (1.3%) receiving 150 mg rt-PA and in 11 patients (0.4%) receiving 100 mg rt-PA. Subdural hematomas were found in two patients on each dose regimen (0.2% and 0.1%, respectively). When intracranial hemorrhages were first recognized as a complication in TIMI II, review of data for patients with intracranial hemorrhages identified history of stroke, intermittent cerebral ischemic attack, or other neurological disease, and high blood presTABLE 2. Type and Frequency of Cerebrovascular Complications in Thrombolysis in Myocardial Infarction, Phase II Pilot and Clinical Trial rt-PA 100 mg 150 mg Cerebrovascular event (N=3,016) (N=908) n n % S 1.0 20 0.7 9 Cerebral infarction 11 0.4 12 1.3 Intracerebral hemorrhage 2 0.1 2 0.2 Subdural hemorrhage 1.1* 2.5 33 23 Total patients
*p48 rt-PA, recombinant tissue-type plasminogen activator. n 7 3 1 1
n
n
8 1 1 1
15 4 2 2
% 65.2 17.4 8.7 8.7
n
3 0 2 4
% 33.3 0.0 22.2 44.4
Cerebral infarction 100 mg n
3 3 2 12
rt-PA
Total
(N=20)
(N=29)
% 15.0 15.0 10.0 60.0
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n
6 3 4 16
% 20.7 10.3 13.8 55.2
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TABLE 4. Outcome of Cerebrovascular Complications Intracerebral hemorrhage 150 mg 100 mg rt-PA rt-PA
(N=12)
Total (N=23)
(N=11) n
0
0
2
% 18
Full recovery Partial recoveiy, 8 4 1 36 minor residual Partial recovery, 3 25 1 9 major residual 4 67 36 8 No recovery rt-PA, recombinant tissue-type plasminogen activator. mg rt-PA patients than among the 150 mg rt-PA patients (Table 4). Only one death among intracerebral hemorrhage patients was classified as due to underlying cardiac disease. There were no consistent differences between the two rt-PA regimens in prognosis after cerebral infarction. Most deaths among cerebral infarction patients were classified as due to underlying heart disease. Clinical centers reported no lasting neurological improvements for 12 patients with no recovery after intracerebral hemorrhages; all died within 66 days from study entry. Of six patients with no recovery from cerebral infarctions, all died within 16 days. Three of four patients (75%) with subdural hematomas died within 1 week of the onset of neurological symptoms. The gravity of the adverse neurological events is reflected in their mortalities at the time of primary end point determination (6 weeks) and after 1 year: 47.8% and 60.9% for patients with intracerebral hemorrhage, 24.1% and 37.9% for patients with cerebral infarction, and 75.0% and 75.0% for patients with subdural hemorrhages, respectively.
Adverse Neurological Events and Assigned Study Treatments The occurrence of cerebrovascular complications according to randomly assigned treatment groups are summarized in Table 5. Routine coronary arteriography, 18-48 hours after rt-PA, followed by PTCA if the anatomy was suitable (delayed invasive strategy), was not associated with an increased risk of either intracerebral hemorrhage or cerebral infarction at either dose of rt-PA. Nor was an increase of intracerebral hemorrhage or cerebral infarction found among the 195 patients who underwent arteriography within 2 hours of the initiation of rt-PA infusion (immediate invasive strategy). In TIMI II-B patients with no contraindication to f3-adrenergic blocker treatment were randomized to receive either immediate intravenous fl-blocker therapy (n = 720) or deferred f-blocker therapy started on day 6 (n=714). There was a nonsignificant trend (p=0.11) for less frequent intracerebral hemorrhage in patients assigned to immediate intravenous fl-blocker therapy (0.3%) than in deferred fl-blocker patients (1.0%). There was no
150 mg rt-PA (N=9)
Cerebral infarction 100 mg rt-PA (N=20) n % 3 15
% 9
n
2
2
% 22
5
22
3
33
9
4 12
17 52
1 3
11 33
5 3
n
Total (N=29) 5
% 17
45
12
41
25 15
6 6
21 21
n
difference in cerebral infarction between the two ,B-blocker treatment groups. Taking the two treatment strategies of coronary arteriography and ,B-blocker therapies into account together, there were no significant differences in the occurrence of intracerebral hemorrhage or cerebral infarction among any of the four treatment combinations.
Intracerebral Hemorrhage/Infarction and Hemostasis Parameters The results of available hemostasis analyses for patients who developed intracerebral hemorrhage or cerebral infarction are summarized in Table 6. No important differences were observed in any of the parameters either between patients with intracerebral hemorrhage and patients with cerebral infarction or between these groups and the total cohort of patients with plasma specimens analyzed. In the entire cohort of patients, those treated with 150 mg rt-PA had lower post-treatment levels of fibrinogen and plasminogen and higher levels of fibrin(ogen) degradation products and rt-PA antigen than patients treated with 100 mg rt-PA, regardless of hemorrhage. The proportions of patients with and without intracerebral hemorrhage who had at least one activated partial thromboplastin time of 90 seconds or more on the day of study entry or the following day were not different (61% versus 61%), nor were the proportions of patients with and without cerebral infarction who had at least one activated partial thromboplastin time of 90 seconds or more on the day of study entry or the following day (59% versus 61%). rt-PA Dose and Patient Baseline Characteristics The frequency of intracerebral hemorrhage and cerebral infarction according to rt-PA dose and baseline characteristics of the patients are summarized in Tables 7 and 8, respectively. The 150 mg rt-PA dose was associated with an increased frequency of intracerebral hemorrhage compared with the 100 mg rt-PA dose (p
Intracerebral Hemorrhage, Cerebral Infarction, and Subdural Hematoma After Acute Myocardial Infarction and Thrombolytic Therapy in the Thrombolysis in Myocardial Infarction Study Thrombolysis in Myocardial Infarction, Phase II, Pilot and Clinical Trial* Joel M. Gore, MD; Michael Sloan, MD; Thomas R. Price, MD; Anna Mae Young Randall, BA; Edwin Bovill, MD; Desire Collen, MD, PhD; Sandra Forman, MA; Genell L. Knatterud, PhD; George Sopko, MD; Michael L. Terrin, MD, CM, MPH; and the TIMI Investigators In the Thrombolysis in Myocardial Infarction, Phase IT pilot and clinical trial, 908 patients [326 (35.9%) in the pilot study and 582 (64.0%) in the randomized study] were treated with 150 mg recombinant tissue-type plasminogen (rt-PA) activator in combination with heparin and aspirin, and 3,016 patients [64 (2.1%) in the pilot study and 2,952 (97.91%) in the randomized study] were treated with 100 mg rt-PA in combination with heparin and aspirin. Adverse neurological events occurred in 23 patients treated with 150 mg rt-PA (2.5%) [nine cerebral infarctions (1.0%), 12 intracerebral hemorrhages (1.3%), and two subdural hematomas (0.2%)] and in 33 patients treated with 100 mg rt-PA (1.1%) [20 cerebral infarctions (0.7%), 11 intracerebral hemorrhages (0.4%), and two subdural hematomas (0.1%)]. The difference in adverse neurological events observed comparing the two rt-PA regimens was primarily due to a higher frequency of intracerebral bleeding among patients treated with 150 mg rt-PA (1.3% versus 0.4%, p160 mm Hg or a diastolic pressure >90 mm Hg available to the Clinical Center, or is on medication for or has a history of having been on medication for hypertension." Adverse Neurological Events Adverse neurological events occurring in TIMI II were reported by study staff at each participating center, and later additional data were collected and
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classified. The earliest possible time of onset of neurological symptoms was defined as the time of onset of the first symptom or sign, compatible with central nervous system dysfunction. When a patient was asleep or unconscious and responded or awoke with obvious signs of a focal deficit, the earliest possible time was defined as the time of loss of consciousness or of going to sleep. Neurodiagnostic evaluation including computed tomography (CT) scanning, magnetic resonance imaging (MRI), lumbar puncture, noninvasive carotid studies, electroencephalography (EEG), and cerebral angiography were obtained according to clinical indications after onset of the adverse neurological event. Brain images (CT scanning or MRI) were reviewed centrally by the independent neurologists in 22 of 23 cases of intracerebral hemorrhage and 25 of 29 cases of cerebral infarction. The one patient with intracerebral hemorrhage whose CT scan could not be recovered was evaluated on the basis of clinical center CT scan reports. Two patients with cerebral infarction had CT scans that could not be recovered for central review, and two never had brain images obtained. The two patients with cerebral infarction whose CT scans could not be reviewed centrally were classified on the basis of CT scan reports and clinical information. The two patients with cerebral infarction who never had brain imaging were classified on the basis of clinical information: absence of severe headache, presence of defined focal neurological syndromes, cardiac or vascular sources of emboli identified, spinal fluid free of blood in the one who had a lumbar puncture, and clinical courses unusual for intracerebral hemorrhage in both (substantial improvement within 24 hours in one and progressive hypotension leading to shock and death within 24 hours in the other). Classification of adverse neurological events. Intracerebral hemorrhage was classified on the basis of focal neurological deficits associated with focal collections of blood in the brain parenchyma seen on a brain image (CT or MRI) with neither a normal brain image at the time of onset of neurological symptoms nor evidence on the brain image for a preceding infarction. Subdural hematoma was diagnosed if a high-density fluid collection was seen in the extradural space on brain images. A cerebral infarction was diagnosed when an episode of focal neurological dysfunction lasted more than 24 hours and there was no evidence of a subdural or parenchymal clot. Infarction with hemorrhagic conversion was diagnosed if blood appeared within an area of infarction on the first scan or there was no evidence of hemorrhage on the first brain image but hemorrhage on a subsequent image. Patients were classified as having embolic infarction if there was evidence of a specific cardiac source or there were infarctions in more than one vascular distribution on brain images and there was no other documented cause for the infarctions. Classification of intracranial hemorrhages and deaths. The Hemorrhagic Events Review Commit-
tee19 reviewed all hemorrhagic event reports and classified intracranial bleeding as a major hemorrhagic event. The Mortality and Morbidity Classification Committee reviewed all deaths and classified them as due to natural causes including cardiac disease, other vascular diseases, and nonvascular diseases or to complications including those of thrombolytic therapy, anticoagulation, PTCA, and surgery.19 Hemostasis analyses. Blood samples were collected on as many patients as possible at baseline (preinfusion) and 50, 300, and 480 minutes after the start of the rt-PA infusion. Fibrinogen, fibrin(ogen) degradation products, rt-PA antigen levels, and plasminogen levels were determined on specimens submitted to the Coagulation Core Laboratory. Details of the sample collection procedure and the analyses have been presented elsewhere.23 The fibrinogen assay was based on the coagulation rate,24 the fibrin(ogen) degradation products assay on inhibition by patient's blood serum of agglutination of fibrinogen-coated red blood cells with anti-fibrinogen antiserum,25 the rt-PA antigen level on a monoclonal antibody-based enzyme-linked immunosorbent assay,26 and the plasminogen level on a chromogenic substrate assay after addition of excess streptokinase.27 Activated partial thromboplastin times were determined at the participating centers on separate blood samples by routine, local laboratory procedures. Statistical analysis. Probability values and confidence intervals for percentages, proportions, and odds ratios were calculated using standard Z tests, Fisher's "exact" tests, and estimates of variance.28 To adjust for multiple testing, a probability value between 0.01 and 0.001 for two-sided tests has been specified as providing some evidence of differences, and probability values of less than 0.001 have been specified as providing strong evidence of differences. Step-up multiple logistic regression29 was used to adjust for baseline characteristics. Twenty-three baseline characteristics were evaluated. The step-up procedure permitted addition of these variables to the regression analysis until the probability value was more than 0.05. To include age as a continuous variable with a range of values similar to the discrete variables, it was expressed as (age -57)/10. All statistical tests were performed using the BMDP statistical software package, University of California Press, Berkeley, Calif. Results A total of 3,924 patients were enrolled in the TIMI II pilot and clinical trial.18-20 Their allocation with respect to dose of rt-PA and treatment strategy is summarized in Table 1.
Frequency, Timing, and Outcome ofAdverse Neurological Events The frequency of the different types of adverse neurological events is summarized in Table 2. Nine patients (1.0%) receiving the combination of 150 mg rt-PA, heparin, and aspirin had cerebral infarctions,
Downloaded from http://circ.ahajournals.org/ at Simon Fraser University--Burnaby on May 31, 2015
Gore et al TIMI II Pilot and Clinical Trial TABLE 1. Allocation of Patients to Thrombolysis in Myocardial Infarction, Phase II Study Groups Patients (n) Clinical trial Total Pilot 150 mg rt-PA 62 95 33 Immediate invasive 257 517 260 Delayed invasive 296 33 263 Conservative 908 326 582 Subtotal 100 mg rt-PA 133 0 133 Immediate invasive 39 1,463 1,424 Delayed invasive 25 1,420 1,395 Conservative 64 3,016 2,952 Subtotal 390 3,924 3,534 Total rt-PA, recombinant tissue-type plasminogen activator.
with eight (0.9%) identified as embolic on central review. Cerebral infarction occurred in 20 patients (0.7%) receiving 100 mg rt-PA, heparin, and aspirin with 16 (0.5%) identified as embolic on central review. Intracerebral (parenchymatous) hemorrhage occurred in 12 patients (1.3%) receiving 150 mg rt-PA and in 11 patients (0.4%) receiving 100 mg rt-PA. Subdural hematomas were found in two patients on each dose regimen (0.2% and 0.1%, respectively). When intracranial hemorrhages were first recognized as a complication in TIMI II, review of data for patients with intracranial hemorrhages identified history of stroke, intermittent cerebral ischemic attack, or other neurological disease, and high blood presTABLE 2. Type and Frequency of Cerebrovascular Complications in Thrombolysis in Myocardial Infarction, Phase II Pilot and Clinical Trial rt-PA 100 mg 150 mg Cerebrovascular event (N=3,016) (N=908) n n % S 1.0 20 0.7 9 Cerebral infarction 11 0.4 12 1.3 Intracerebral hemorrhage 2 0.1 2 0.2 Subdural hemorrhage 1.1* 2.5 33 23 Total patients
*p48 rt-PA, recombinant tissue-type plasminogen activator. n 7 3 1 1
n
n
8 1 1 1
15 4 2 2
% 65.2 17.4 8.7 8.7
n
3 0 2 4
% 33.3 0.0 22.2 44.4
Cerebral infarction 100 mg n
3 3 2 12
rt-PA
Total
(N=20)
(N=29)
% 15.0 15.0 10.0 60.0
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n
6 3 4 16
% 20.7 10.3 13.8 55.2
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Circulation Vol 83, No 2, February 1991
TABLE 4. Outcome of Cerebrovascular Complications Intracerebral hemorrhage 150 mg 100 mg rt-PA rt-PA
(N=12)
Total (N=23)
(N=11) n
0
0
2
% 18
Full recovery Partial recoveiy, 8 4 1 36 minor residual Partial recovery, 3 25 1 9 major residual 4 67 36 8 No recovery rt-PA, recombinant tissue-type plasminogen activator. mg rt-PA patients than among the 150 mg rt-PA patients (Table 4). Only one death among intracerebral hemorrhage patients was classified as due to underlying cardiac disease. There were no consistent differences between the two rt-PA regimens in prognosis after cerebral infarction. Most deaths among cerebral infarction patients were classified as due to underlying heart disease. Clinical centers reported no lasting neurological improvements for 12 patients with no recovery after intracerebral hemorrhages; all died within 66 days from study entry. Of six patients with no recovery from cerebral infarctions, all died within 16 days. Three of four patients (75%) with subdural hematomas died within 1 week of the onset of neurological symptoms. The gravity of the adverse neurological events is reflected in their mortalities at the time of primary end point determination (6 weeks) and after 1 year: 47.8% and 60.9% for patients with intracerebral hemorrhage, 24.1% and 37.9% for patients with cerebral infarction, and 75.0% and 75.0% for patients with subdural hemorrhages, respectively.
Adverse Neurological Events and Assigned Study Treatments The occurrence of cerebrovascular complications according to randomly assigned treatment groups are summarized in Table 5. Routine coronary arteriography, 18-48 hours after rt-PA, followed by PTCA if the anatomy was suitable (delayed invasive strategy), was not associated with an increased risk of either intracerebral hemorrhage or cerebral infarction at either dose of rt-PA. Nor was an increase of intracerebral hemorrhage or cerebral infarction found among the 195 patients who underwent arteriography within 2 hours of the initiation of rt-PA infusion (immediate invasive strategy). In TIMI II-B patients with no contraindication to f3-adrenergic blocker treatment were randomized to receive either immediate intravenous fl-blocker therapy (n = 720) or deferred f-blocker therapy started on day 6 (n=714). There was a nonsignificant trend (p=0.11) for less frequent intracerebral hemorrhage in patients assigned to immediate intravenous fl-blocker therapy (0.3%) than in deferred fl-blocker patients (1.0%). There was no
150 mg rt-PA (N=9)
Cerebral infarction 100 mg rt-PA (N=20) n % 3 15
% 9
n
2
2
% 22
5
22
3
33
9
4 12
17 52
1 3
11 33
5 3
n
Total (N=29) 5
% 17
45
12
41
25 15
6 6
21 21
n
difference in cerebral infarction between the two ,B-blocker treatment groups. Taking the two treatment strategies of coronary arteriography and ,B-blocker therapies into account together, there were no significant differences in the occurrence of intracerebral hemorrhage or cerebral infarction among any of the four treatment combinations.
Intracerebral Hemorrhage/Infarction and Hemostasis Parameters The results of available hemostasis analyses for patients who developed intracerebral hemorrhage or cerebral infarction are summarized in Table 6. No important differences were observed in any of the parameters either between patients with intracerebral hemorrhage and patients with cerebral infarction or between these groups and the total cohort of patients with plasma specimens analyzed. In the entire cohort of patients, those treated with 150 mg rt-PA had lower post-treatment levels of fibrinogen and plasminogen and higher levels of fibrin(ogen) degradation products and rt-PA antigen than patients treated with 100 mg rt-PA, regardless of hemorrhage. The proportions of patients with and without intracerebral hemorrhage who had at least one activated partial thromboplastin time of 90 seconds or more on the day of study entry or the following day were not different (61% versus 61%), nor were the proportions of patients with and without cerebral infarction who had at least one activated partial thromboplastin time of 90 seconds or more on the day of study entry or the following day (59% versus 61%). rt-PA Dose and Patient Baseline Characteristics The frequency of intracerebral hemorrhage and cerebral infarction according to rt-PA dose and baseline characteristics of the patients are summarized in Tables 7 and 8, respectively. The 150 mg rt-PA dose was associated with an increased frequency of intracerebral hemorrhage compared with the 100 mg rt-PA dose (p
