S E M I N A R S I N NEUROLOGY-VOLUME
I I , N O . 4 IIECBMBER 1991
Intracranial Hemorrhage Following Thrombolytic Therapy for Acute Myocardial Infarction
Stroke has long been known to be an infrequent but serious complication of acute myocardial infarction (MI). In the prethronibolytic era, stroke occurred in 1.7 to 2.4% of patients, typically within the first week after M I and, in about one third of these, within the first 24 hours.l-:' Patients with anterior o r apical MI, large infarct size, atrial arrhythmias, cardiac pump failure, left ventricular thrombus, and history of previous stroke were at greatest risk.4 Intracranial hemorrhage was exceedingly rare; only 0.05 to 0.14$Z of MI patients treated with prophylactic anticoagulant therapy developed central nervous system bleeding."." In the last decade, effective use of thrombolytic therapy fix acute MI has been accompanied by changes in the nature of cerebrovascular complications. First, the reported rate of stroke cornplicating MI in several large placebo-controlled (Table 1)"' and comparative trials (Table 2),18-'as well
as many smaller trials, has decreased, as shown in the anisoytrials involving streptokinase (SK),'-'y~"~22~2'+3i lated plasrninogen streptokinase activator complex (APSAC),l:'.14recombinant tissue-type plasminogen activator ( r t - p ~ )I ~ ,Y ~ . : ! X - + ! I .and recombinant single-chain urokinase plasrninogen activator (rscup~).?.x:{? T h e incidence of stroke in treated groups ranges from 0.5 to 2.5%, (mean, 1.06%)and in the control groups from 0.0 to 1.0% (mean, 0.81%), respectively (Tables 1,2).'-" In the ISIS-I1 study," there was an excess of early strokes in the treatment group (less than 24 hours after treatment) compared with the control group, but there were fewer strokes after the early post-MI period. 'I'his apparent reduction may have resulted from improved general treatment of high-risk patients, but is more likely d u e to exclusion of patients at high risk of s.roke.i-9.1~.21-? I T h e wide variation in stroke rates in these trials could be due to chance or, more
Table 1. Incidence of Stroke in Placebo-Controlled Trials of Coronary Thrombolysis Treatment Study (Agent)*
No.
Control %
No.
%
Subtotal 1. ASSET (rt-PA)15 2. ECSG (rt-PA)'"
Subtotal 1. AIMS (APSAC)13l 4 Total
'SK: streptokinase; APSAC: anisoylated plasminogen-streptokinase activator complex; rt-PA: recombinant tissue plasminogen activator.
I)epart~rlentof Neurology University of' Maryland School of Medicine 22 S. (;reen? Slrect H '1. 1tlmore, MI) 21201 '
Rcprint requcsls: Dl-. Sloan, Department of Neurology, University of hlarylatitl Hospital, 2 2 S. Greene Street, Baltimore, MI) 2 1201 Copyright O 1991 by Thieme Medical Publishers, Inc., 381 Pal-k Avenue South, New York, NY 10016. All rights reserved.
Downloaded by: Universite Laval. Copyrighted material.
Michael A. Sloan, M.D. and Thomas R. Price, M.D.
SEMINAKS I N N E U K O L O G Y
Cerebrovascular Complications in Recent Large Coronary Thrombolysis Trials Stroke
Study A. Streptokinase (SK) GlSSl ISIS-2 GISSI-2 ISG
Subtotal % all patients
I)E(;E,\IHER I 9 0 1
Stroke Subtypes*
NO.
7'0
4915860 6118592 5416199 4414197 208124848
(0.8) (0.7) (0.9) (1.o) (0.84)
6. Recombinant tissue plasrninogen activator (rt-PA) ASSET 5112516 (2.0) TAM l 1311696 (0.8) BURROUGHS 911900 (0.5) WELLCOME TIMI-II 150 rng 231908 (2.5) (1.1) 3313016 100 rng GISSI-2 7016182 (1.1) ISG 68141 90 (1.6) Subtotal 267120408 (1.3) OO / all patients
ICH (%)
Cl (Dh)
NS (%)
SDH ( X )
8 (16) 7 (11) 15 (28) 15 (34) 45 (22) (0.18)
9 (19)
32 (65) 54 (89) 15 (28) 7 (16) 108 (52) (0.43)
-
24 (44) 22 (50) 55 (26) (0.22)
-
-
(0.0) -
7 (14) 12 (92) 9 (100)
20 (39)
24 (47)
12 (52) 11 (33) 19 (28) 25 (37) 95 (36) (0.47)
9 (39) 20 (61) 28 (40) 26 (38) 103 (38) (0.50)
0 (0) 0 (0) 23 (32) 17 (25) 64 (24) (0.31)
7 (47) 165 (34) (0.36)
-
-
172 (35) (0.37)
5 (1) (0.01)
-
-
C. Recombinant single-chain urokinase plasrninogen activator (rscu-PA) 1511032 (1.45) 8 (53) Total 490146288 (1.06) 148 (30) % all patients (0.32)
1 (8)
-
2 (9) 2 (6)
-
5 (2) (0.02)
*ICH: intracerebral hemorrhage; SDH: subdural hernatorna; CI: cerebral infarction; NS: not specified.
likely, differing intensity of evaluation and reporting Of stroke co111p~ications.:4.88~l.lY.l:4.1.~.3)However, in the GISSI-I1 and International Study Group t r i a l s , ~ l . ' ; ' 2 the incidence of stroke was signil'icantly higher in the rt-PA gr-oup (1.3%) than in the SK group (0.993),for unclear reasons. Second, among the reported cerebrovasculat- events, the distribution of stroke subtypes has shif'ted to include parenchyniatous intracer-ebr-al hemorrhage (ICH),i-4" cerebral infarction with henlor-rhagic transfin-mation or herllorrhagic infarction ( H I ) ,1 1.!!:~.?&2!1!'.4 1.4i." sub-
nosis of' intracranial bleeding in this setting are described.
CLINICAL FEATURES OF INTRACEREBRAL HEMORRHAGE ICH has frequently been reported t o occur ciuriIlg~.-~,~:~,:~!~. I:!. I I,!')'- and usually 24 hours o r less atter iIlf'usiollu.o.~ I . I Y . I i , ~ ' : i , i ~ , .of i ~ ' the fibrinolytic agent
o r agents. In one study,':'."';' (55% of'cases occurred within 12 ant1 8 3 % 01' cases within 24 hours. P,+dural heniorrhage,l".lX.':' and subarachnoid hemor- tients typically develop a change in level of' conrhage :::3.:55.:4ei In large studies, the mean incidence sciousness, unilbcal o r multifi)cal neurologic synqlrates of' parenchymatous heniorrhage after treat- toms and signs, nausea, vonliting, heactache, and ment with SK, rt-PA, APSAC, and rscu-PA are seizures. 111 some cases, the mode of' onset is ( ~ . ~ ~ ' r ( , , ~ - ' l . l 2 . ~ . ' ; ' ~ ( ) . ~ ~ ~ , l 50.327; . l X - ~ ' !, I 1 arid (J,78%,,21 catastrophic and rapidly fatal. I i . l ~ . l . 5 . Y : i . i i-15 'I ~ I U S ,
386
respectively. These rates are not readily compara- changes in neurologic hnction during this time ble, since they are based on the frequency with period should I x regarded as highly suspicious of which cerebral symptoms are investigated using ICH. Emergent CT scanning is necessary to distillbrain images, such as computed tornography guish ICH from ischemic cerebral inf'al-ction, ef(CT)o r magnetic resonance imaging ( M K I ) (Table fects of' severe cardiac d y s f ~ ~ n c t i oonr concomitant ~,~3)~:',7-!l,l2,l5,~l,22 M1 therapy, o r both." As many as 7074 of' these In this article, current knowledge pertaining hemorrhages are lobar, occuring in the cortex and to clinical aspects, risk factors, and potential mech- subcortical white rnatter;"'."." they are f'requeritly anisms of intracranial bleeding after thrombolytic (33%') multiple.'" 'l'his pattern of' ICH location is therapy for acute M I will be presented. BI-iel'case typical of coagulopathy-inclucecl as well as other summaries will be provitietl to illustrate key con- nonhypertensive causes of intracerebr;d hemorcepts. Finally, nlanagement strategies arid prog- rtlage,"o."i
Downloaded by: Universite Laval. Copyrighted material.
Table 2.
VOI.UIL1k: 1 1 , N U M B E K 4
Table 3. lntracranial Hemorrhage Associated with Thrombolytic Therapy in Small Myocardial Infarction Trials (No. Total)
(No. of ICH)
%
Author or Group
(No. Total)
A. Streptokinase Amery et a1,261969
B. Tissue plasminogen activator TO DO^ et al.38 19'87
European Working Party,27 1971
Topol et a1,39 1987
(No. of ICH)
de B 0 n 0 , ~ ~ 1987
Bett et a1,28 1973
NHFACTG,41 I988
Ness et al,29 1974
GAUS,42 I988
European Cooperative Study
Califf et a1,43 I988
1979
Carlson et a1,441989
Rutsch 1981 et
Althouse et a1,451989
Wein~tein,~~ 1982
Tebbe et aL4V989
Ganz et a1,33 1984
Kase et a1,47 1990
Urban et a1,341984
Hsia et al,48 1990
Aldrich et a1,351985
Smalling et a1,491990
Lew et al,36 1987
Subtotal
Wei~berg,~~ 1987
C. Single-chain urokinase plasminogen activator 198 2 PRIM1 trial study
PRIM1 trial study
1989
1989
Total all agents
4548
40
Subtotal
POTENTIAL RISK FACTORS FOR INTRACEREBRAL HEMORRHAGE
T h e serious nature of intracranial hemorrhage after thrombolytic therapy for MI has led investigators to search for conditions that would permit more careful patient selection. Potential risk factors for ICH are surnniarizeti in Table 4. AGE
'l'he mortality rate in elderly patients with acute M I , even if' they are treated with SK" or rtPA," rises dramatically from less than 65 years to more than 75 years of age. A recent meta-analysis5' of' five large trials~.c~.~ I-I:~.I" suggests that thrombolytic therapy may I-educe mortality in the elderly when compared with controls (17.9% versus
22.1%, p ,Cowley M, (;oldberg S, et al. Intracoronary throrribolysis in acute myocardial infarction: clinical course following successful myocardial rcpcrlusiori. Arn Heart J IW4;108:873-8 Altlrich MS, Sherman SA, Greenberg HS. Cerebrovascular complications of' streptokinase infusion. J A M A 1985;253: 1777-9 Lcw AS, Hod H , Cercek U, et al. Mortality and morbici-
Downloaded by: Universite Laval. Copyrighted material.
SEMINAKS I N NEUKOLOGY
38.
30.
40.
41.
42.
43.
44.
,45.
46.
47.
48.
49.
50. 5 1.
52.
59.
54. 55.
56. 57. 58.
59.
60.
(51. 62. 63.
64.
65. Mi.
67.
68. 6!4. 70. 7 1. 72.
73.
74.
matoma d u e to anticoagulant metlicatiou. J Neurol Ncut-osur-g Psychiatry 1987;50: 1076.
I I , N O . 4 IIECBMBER 1991
Intracranial Hemorrhage Following Thrombolytic Therapy for Acute Myocardial Infarction
Stroke has long been known to be an infrequent but serious complication of acute myocardial infarction (MI). In the prethronibolytic era, stroke occurred in 1.7 to 2.4% of patients, typically within the first week after M I and, in about one third of these, within the first 24 hours.l-:' Patients with anterior o r apical MI, large infarct size, atrial arrhythmias, cardiac pump failure, left ventricular thrombus, and history of previous stroke were at greatest risk.4 Intracranial hemorrhage was exceedingly rare; only 0.05 to 0.14$Z of MI patients treated with prophylactic anticoagulant therapy developed central nervous system bleeding."." In the last decade, effective use of thrombolytic therapy fix acute MI has been accompanied by changes in the nature of cerebrovascular complications. First, the reported rate of stroke cornplicating MI in several large placebo-controlled (Table 1)"' and comparative trials (Table 2),18-'as well
as many smaller trials, has decreased, as shown in the anisoytrials involving streptokinase (SK),'-'y~"~22~2'+3i lated plasrninogen streptokinase activator complex (APSAC),l:'.14recombinant tissue-type plasminogen activator ( r t - p ~ )I ~ ,Y ~ . : ! X - + ! I .and recombinant single-chain urokinase plasrninogen activator (rscup~).?.x:{? T h e incidence of stroke in treated groups ranges from 0.5 to 2.5%, (mean, 1.06%)and in the control groups from 0.0 to 1.0% (mean, 0.81%), respectively (Tables 1,2).'-" In the ISIS-I1 study," there was an excess of early strokes in the treatment group (less than 24 hours after treatment) compared with the control group, but there were fewer strokes after the early post-MI period. 'I'his apparent reduction may have resulted from improved general treatment of high-risk patients, but is more likely d u e to exclusion of patients at high risk of s.roke.i-9.1~.21-? I T h e wide variation in stroke rates in these trials could be due to chance or, more
Table 1. Incidence of Stroke in Placebo-Controlled Trials of Coronary Thrombolysis Treatment Study (Agent)*
No.
Control %
No.
%
Subtotal 1. ASSET (rt-PA)15 2. ECSG (rt-PA)'"
Subtotal 1. AIMS (APSAC)13l 4 Total
'SK: streptokinase; APSAC: anisoylated plasminogen-streptokinase activator complex; rt-PA: recombinant tissue plasminogen activator.
I)epart~rlentof Neurology University of' Maryland School of Medicine 22 S. (;reen? Slrect H '1. 1tlmore, MI) 21201 '
Rcprint requcsls: Dl-. Sloan, Department of Neurology, University of hlarylatitl Hospital, 2 2 S. Greene Street, Baltimore, MI) 2 1201 Copyright O 1991 by Thieme Medical Publishers, Inc., 381 Pal-k Avenue South, New York, NY 10016. All rights reserved.
Downloaded by: Universite Laval. Copyrighted material.
Michael A. Sloan, M.D. and Thomas R. Price, M.D.
SEMINAKS I N N E U K O L O G Y
Cerebrovascular Complications in Recent Large Coronary Thrombolysis Trials Stroke
Study A. Streptokinase (SK) GlSSl ISIS-2 GISSI-2 ISG
Subtotal % all patients
I)E(;E,\IHER I 9 0 1
Stroke Subtypes*
NO.
7'0
4915860 6118592 5416199 4414197 208124848
(0.8) (0.7) (0.9) (1.o) (0.84)
6. Recombinant tissue plasrninogen activator (rt-PA) ASSET 5112516 (2.0) TAM l 1311696 (0.8) BURROUGHS 911900 (0.5) WELLCOME TIMI-II 150 rng 231908 (2.5) (1.1) 3313016 100 rng GISSI-2 7016182 (1.1) ISG 68141 90 (1.6) Subtotal 267120408 (1.3) OO / all patients
ICH (%)
Cl (Dh)
NS (%)
SDH ( X )
8 (16) 7 (11) 15 (28) 15 (34) 45 (22) (0.18)
9 (19)
32 (65) 54 (89) 15 (28) 7 (16) 108 (52) (0.43)
-
24 (44) 22 (50) 55 (26) (0.22)
-
-
(0.0) -
7 (14) 12 (92) 9 (100)
20 (39)
24 (47)
12 (52) 11 (33) 19 (28) 25 (37) 95 (36) (0.47)
9 (39) 20 (61) 28 (40) 26 (38) 103 (38) (0.50)
0 (0) 0 (0) 23 (32) 17 (25) 64 (24) (0.31)
7 (47) 165 (34) (0.36)
-
-
172 (35) (0.37)
5 (1) (0.01)
-
-
C. Recombinant single-chain urokinase plasrninogen activator (rscu-PA) 1511032 (1.45) 8 (53) Total 490146288 (1.06) 148 (30) % all patients (0.32)
1 (8)
-
2 (9) 2 (6)
-
5 (2) (0.02)
*ICH: intracerebral hemorrhage; SDH: subdural hernatorna; CI: cerebral infarction; NS: not specified.
likely, differing intensity of evaluation and reporting Of stroke co111p~ications.:4.88~l.lY.l:4.1.~.3)However, in the GISSI-I1 and International Study Group t r i a l s , ~ l . ' ; ' 2 the incidence of stroke was signil'icantly higher in the rt-PA gr-oup (1.3%) than in the SK group (0.993),for unclear reasons. Second, among the reported cerebrovasculat- events, the distribution of stroke subtypes has shif'ted to include parenchyniatous intracer-ebr-al hemorrhage (ICH),i-4" cerebral infarction with henlor-rhagic transfin-mation or herllorrhagic infarction ( H I ) ,1 1.!!:~.?&2!1!'.4 1.4i." sub-
nosis of' intracranial bleeding in this setting are described.
CLINICAL FEATURES OF INTRACEREBRAL HEMORRHAGE ICH has frequently been reported t o occur ciuriIlg~.-~,~:~,:~!~. I:!. I I,!')'- and usually 24 hours o r less atter iIlf'usiollu.o.~ I . I Y . I i , ~ ' : i , i ~ , .of i ~ ' the fibrinolytic agent
o r agents. In one study,':'."';' (55% of'cases occurred within 12 ant1 8 3 % 01' cases within 24 hours. P,+dural heniorrhage,l".lX.':' and subarachnoid hemor- tients typically develop a change in level of' conrhage :::3.:55.:4ei In large studies, the mean incidence sciousness, unilbcal o r multifi)cal neurologic synqlrates of' parenchymatous heniorrhage after treat- toms and signs, nausea, vonliting, heactache, and ment with SK, rt-PA, APSAC, and rscu-PA are seizures. 111 some cases, the mode of' onset is ( ~ . ~ ~ ' r ( , , ~ - ' l . l 2 . ~ . ' ; ' ~ ( ) . ~ ~ ~ , l 50.327; . l X - ~ ' !, I 1 arid (J,78%,,21 catastrophic and rapidly fatal. I i . l ~ . l . 5 . Y : i . i i-15 'I ~ I U S ,
386
respectively. These rates are not readily compara- changes in neurologic hnction during this time ble, since they are based on the frequency with period should I x regarded as highly suspicious of which cerebral symptoms are investigated using ICH. Emergent CT scanning is necessary to distillbrain images, such as computed tornography guish ICH from ischemic cerebral inf'al-ction, ef(CT)o r magnetic resonance imaging ( M K I ) (Table fects of' severe cardiac d y s f ~ ~ n c t i oonr concomitant ~,~3)~:',7-!l,l2,l5,~l,22 M1 therapy, o r both." As many as 7074 of' these In this article, current knowledge pertaining hemorrhages are lobar, occuring in the cortex and to clinical aspects, risk factors, and potential mech- subcortical white rnatter;"'."." they are f'requeritly anisms of intracranial bleeding after thrombolytic (33%') multiple.'" 'l'his pattern of' ICH location is therapy for acute M I will be presented. BI-iel'case typical of coagulopathy-inclucecl as well as other summaries will be provitietl to illustrate key con- nonhypertensive causes of intracerebr;d hemorcepts. Finally, nlanagement strategies arid prog- rtlage,"o."i
Downloaded by: Universite Laval. Copyrighted material.
Table 2.
VOI.UIL1k: 1 1 , N U M B E K 4
Table 3. lntracranial Hemorrhage Associated with Thrombolytic Therapy in Small Myocardial Infarction Trials (No. Total)
(No. of ICH)
%
Author or Group
(No. Total)
A. Streptokinase Amery et a1,261969
B. Tissue plasminogen activator TO DO^ et al.38 19'87
European Working Party,27 1971
Topol et a1,39 1987
(No. of ICH)
de B 0 n 0 , ~ ~ 1987
Bett et a1,28 1973
NHFACTG,41 I988
Ness et al,29 1974
GAUS,42 I988
European Cooperative Study
Califf et a1,43 I988
1979
Carlson et a1,441989
Rutsch 1981 et
Althouse et a1,451989
Wein~tein,~~ 1982
Tebbe et aL4V989
Ganz et a1,33 1984
Kase et a1,47 1990
Urban et a1,341984
Hsia et al,48 1990
Aldrich et a1,351985
Smalling et a1,491990
Lew et al,36 1987
Subtotal
Wei~berg,~~ 1987
C. Single-chain urokinase plasminogen activator 198 2 PRIM1 trial study
PRIM1 trial study
1989
1989
Total all agents
4548
40
Subtotal
POTENTIAL RISK FACTORS FOR INTRACEREBRAL HEMORRHAGE
T h e serious nature of intracranial hemorrhage after thrombolytic therapy for MI has led investigators to search for conditions that would permit more careful patient selection. Potential risk factors for ICH are surnniarizeti in Table 4. AGE
'l'he mortality rate in elderly patients with acute M I , even if' they are treated with SK" or rtPA," rises dramatically from less than 65 years to more than 75 years of age. A recent meta-analysis5' of' five large trials~.c~.~ I-I:~.I" suggests that thrombolytic therapy may I-educe mortality in the elderly when compared with controls (17.9% versus
22.1%, p ,Cowley M, (;oldberg S, et al. Intracoronary throrribolysis in acute myocardial infarction: clinical course following successful myocardial rcpcrlusiori. Arn Heart J IW4;108:873-8 Altlrich MS, Sherman SA, Greenberg HS. Cerebrovascular complications of' streptokinase infusion. J A M A 1985;253: 1777-9 Lcw AS, Hod H , Cercek U, et al. Mortality and morbici-
Downloaded by: Universite Laval. Copyrighted material.
SEMINAKS I N NEUKOLOGY
38.
30.
40.
41.
42.
43.
44.
,45.
46.
47.
48.
49.
50. 5 1.
52.
59.
54. 55.
56. 57. 58.
59.
60.
(51. 62. 63.
64.
65. Mi.
67.
68. 6!4. 70. 7 1. 72.
73.
74.
matoma d u e to anticoagulant metlicatiou. J Neurol Ncut-osur-g Psychiatry 1987;50: 1076.
