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(Stroke. 1997;28:1107-1114.)
© 1997 American Heart Association, Inc.

Articles

Ischemic Cerebral Infarction After rt-PA and Heparin Therapy for Acute Myocardial Infarction

The TIMI-II Pilot and Randomized Clinical Trial Combined Experience

Michael A. Sloan, MD; Thomas R. Price, MD; Michael L. Terrin, MD, CM, MPH; Sandra Forman, MA; Joel M. Gore, MD; Bernard R. Chaitman, MD; Morrison Hodges, MD; Hiltrud Mueller, MD; William J. Rogers, MD; Genell L. Knatterud, PhD; Eugene Braunwald, MD; for the TIMI Investigators

From the Maryland Medical Research Institute (M.A.S., T.R.P., M.L.T., S.F., G.L.K.) and the Department of Neurology, University of Maryland School of Medicine (M.A.S., T.R.P.), Baltimore; the Department of Medicine, University of Massachusetts School of Medicine, Worcester (J.M.G.); the Division of Cardiology, St Louis (Mo) University Medical Center (B.R.C.); the Cardiology Division, University of Minnesota, Minneapolis (M.H.); the Division of Cardiology, Albert Einstein College of Medicine, New York, NY (H.M.); the Department of Medicine, University of Alabama Medical Center, Birmingham (W.J.R.); and the Department of Medicine, Brigham and Women's and Beth Israel Hospitals, Harvard Medical School, Boston, Mass (E.B.).

Correspondence to Michael A. Sloan, MD, Maryland Medical Research Institute, 600 Wyndhurst Ave, Baltimore, MD 21210.


*    Abstract
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Background and Purpose Ischemic cerebral infarction (CI) is a serious complication of acute myocardial infarction (MI). Little information exists on CI after thrombolytic therapy for MI.

Methods Of 3924 MI patients treated with recombinant tissue plasminogen activator (rt-PA) and heparin, 29 (0.7%) developed CI after treatment. All CI patients had detailed neurological evaluations, and 27 (93%) had CT scans centrally reviewed.

Results Age range was 40 to 74 years (mean, 60 years); 25 patients (86%) were men, and 22 (76%) were white. The electrocardiographic location of MI was anterior in 22 (76%) and nonanterior in 7 (24%). Five CIs occurred within 6 hours, 4 between 6 to 24 hours, 8 during the remainder of the first week, 10 during the second week, and 2 others distributed over the 4 weeks after study entry. Six of 29 CIs did not involve the cerebral cortex; 9 patients (31%) had multiple CIs. Of 28 CIs thought to be embolic in origin, 17 showed strong evidence for at least one cardiac abnormality (mural clot, wall-motion abnormality, aneurysm, or atrial fibrillation) known to be associated more specifically with embolism than MI. Eight of 27 CIs (30%) with CT scans had hemorrhagic transformation of varying degrees; 5 were symptomatic.

Conclusions The time of occurrence and sites of CI after rt-PA and heparin therapy for acute MI are similar to those reported during the prethrombolytic era.


Key Words: cerebral infarction • heparin • myocardial infarction • thrombolytic therapy


*    Introduction
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 *Introduction
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In the prethrombolytic era, ischemic CI was reported to complicate the course of acute MI in 1.7% to 3.2% of patients, with a case fatality rate of 54% to 61%.1 2 3 4 5 A "typical" stroke occurred during the first week after MI; as many as 33% occurred within 24 hours of MI onset.2 Stroke was associated with anterior or apical MI, large infarct size, atrial arrhythmias, cardiac pump failure or cardiogenic shock, and history of prior stroke.1 2 6 Most, if not all, strokes were attributed to cerebral embolism.2

Some investigators have expressed concern that thrombolytic therapy for MI may lyse mural thrombus and lead to cerebral and other systemic embolism.7 8 The ranges of the reported frequencies of definite CI in large or comparative coronary thrombolysis trials are 0.15% to 0.75% for streptokinase,9 10 11 12 13 14 15 16 17 18 0.43% to 1.24% for rt-PA,13 14 15 17 18 19 20 21 22 23 0.33% for anisoylated plasminogen streptokinase activator complex (APSAC),17 0.65% for accelerated rt-PA plus streptokinase,18 0.41% for recom-binant single-chain urokinase plasminogen activator (r-scuPA),24 25 and 0.35% for urokinase.26

The TIMI-II study previously reported that 29 of 56 cerebrovascular complications were ischemic CIs.22 Ischemic CI was associated with increasing age and anterior site of MI. The overall case-fatality rate was 12/29 (41%), with no differences between the 150-mg and 100-mg rt-PA groups. In this report, we delineate the clinical and radiological features, manner of presentation and temporal course, and mechanisms of CI after thrombolytic therapy for acute MI.


*    Subjects and Methods
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 *Subjects and Methods
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TIMI-II Protocol
Detailed descriptions of the TIMI-II methods, cardiovascular and hemostatic findings, overall results, and protocol have been reported previously.22 27 28 29 The TIMI-II study assessed effects on mortality, reinfarction, other morbidity, and left ventricular function of an invasive treatment strategy (cardiac catheterization and PTCA, if angiographic findings demonstrated appropriate anatomy, or CABG if coronary anatomy was too complex or hazardous for PTCA) versus a conservative strategy after intravenous rt-PA and heparin therapy for acute MI. Patients presenting within the first 4 hours of acute MI with ST-segment elevation received rt-PA, heparin, and aspirin. An initial 5000-IU bolus of intravenous heparin was given at the start of rt-PA infusion; continuous heparin infusion began within 1 hour at a rate of 1000 IU/h, and the dose was then adjusted to maintain the aPTT at between 1.5 to 2.0 times that of control. For the present analysis, an aPTT >=60 seconds was considered to be above therapeutic range.

Clinical Evaluation
Detailed information regarding circumstances surrounding the onset of CI in the Pilot and Clinical Trial phases of the study was recorded, including the date and time of onset of neurological symptoms and signs. The earliest possible time was defined as the time of onset of first symptoms or signs, compatible with central nervous system dysfunction. This could be a headache with or without a focal neurological deficit.30 31 32 When a patient was asleep or unconscious and responded or woke with obvious signs of a focal deficit, the earliest possible time was defined as the time of loss of consciousness or going to sleep. The latest possible time was defined as the time when unequivocal evidence of central nervous system dysfunction was present.

Neurological data and other relevant information were recorded or provided by a neurologist or other responsible physician and abstracted by study staff on special data-collection forms. Particular attention was paid to the mode of onset (rapid, gradual, or stepwise), time interval to maximal deficit, level of consciousness, and nature and distribution of presenting neurological symptoms and signs. Diagnostic evaluation consisted of CT or MRI scans, transthoracic echocardiography, and carotid noninvasive studies, if available. CT scans for 27 of 29 patients (93%) were reviewed centrally by two investigators (M.A.S., T.R.P.). CT scans for two patients (7%) could not be obtained for review. These patients were evaluated on the basis of local CT scan reports and other information provided by clinical center staff.

Classification of CIs
Ischemic CI was defined as a focal neurological deficit that lasted longer than 24 hours, with or without a corresponding lesion on neuroimaging studies. The primary site was defined as the lesion most likely to be responsible for each patient's presenting symptoms and signs. An HI was defined by the appearance of blood within the presumed CI location if (1) blood densities were not present on the initial CT scan image or (2) blood densities on the first CT scan were surrounded by a region of radiolucency consistent with ischemic CI.22 33 34 35 The extent of HI may range from petechial change (variable hypodensity/hyperdensity) to confluent hematoma, thus mimicking a primary intracerebral hemorrhage.34 35

A cardiogenic embolic stroke was diagnosed36 37 38 39 40 41 42 when one or more of the following factors were present in addition to MI: (1) strong evidence for coexisting cardiac source(s) (atrial fibrillation; akinetic wall-motion abnormality, mural thrombus, or left ventricular aneurysm on transthoracic echocardiography); (2) preceding invasive cardiovascular treatment strategy (coronary angiography or PTCA or cardiac surgery [CABG, other]); (3) specific clinical syndrome, such as aphasia or homonymous hemianopsia30 36 37 41 42 ; (4) presence of multiple CIs43 ; or (5) presence of HI.33 34 35 In patients who underwent more than one invasive procedure before CI onset, the procedure immediately preceding the presence of neurological symptoms or signs was taken to be associated with MI. Lacunar stroke was diagnosed when the patient had (1) typical restricted clinical syndrome, such as pure motor hemiparesis; (2) CT or MRI that showed normal results or a lesion <1.5 cm in expected locations39 42 44 ; and (3) no evidence for embolism (as noted above). Atherosclerotic stroke was diagnosed if the patient had evidence of hemodynamically significant (>=60% diameter reduction) stenosis of an appropriate large cerebral artery.38 44 With these criteria and use of the available diagnostic workup,45 the reported agreements ({kappa} statistics) for classification of the various stroke subtypes are 0.59 (95% confidence interval, 0.45 to 0.72) for cardiogenic embolic stroke, 0.60 (0.42 to 0.74) for atherosclerotic stroke, and 0.28 (0.13 to 0.44) for lacunar stroke.44


*    Results
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General Clinical Data
Table 1Down summarizes the baseline characteristics of the 29 CI patients. Twelve (41%) were in their seventh decade, and 7 (24%) were in their eighth decade. Fifteen (52%) developed or maintained a systolic blood pressure >=160 mm Hg or a diastolic blood pressure >=90 mm Hg during the study infusion. Twenty-two patients (76%) developed hypotension within 24 hours of the study drug infusion. Five patients (17%) developed hypotension during the study drug infusion; 4 of these 5 patients also had elevated blood pressures during the study drug infusion. One patient (3%) had atrial fibrillation at baseline, while 2 patients (7%) developed atrial fibrillation before neurological symptom onset. Only 1 patient (3%) had prior nonvascular neurological disease.


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  		Table 1. Baseline Characteristics of 29 Patients With Ischemic CI After Coronary Thrombolysis

Timing, Clinical Features, and Temporal Course
Fig 1Down shows the timing of the 29 CIs in this study. Nine of the 29 CIs (31%) occurred within the first 24 hours after initiation of treatment (8, or 89%, with anterior MI). Sixteen (55%) occurred more than 48 hours after initiation of study treatment. Three patients had two separate neurological events. Table 2Down summarizes the clinical features of the 29 CI patients. One lethargic patient was receiving intravenous lidocaine at the time of symptom onset. Two of the 4 patients with headache had cerebellar infarctions. Nine patients (31%) had more than one neurological abnormality documented at the time of symptom onset. Twenty-three patients (79%) had more than one type of deficit. Clinical improvement within 24 hours of neurological symptom onset occurred in 13 patients (45%).



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  		Figure 1. Time of onset of ischemic cerebral infarction after coronary thrombolysis.


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  		Table 2. Symptoms, Signs, and Temporal Profile of 29 Patients With Ischemic CI After Coronary Thrombolysis

Hemostatic Measurements
Of the 14 patients with available fibrinogen and fibrinogen degradation product levels, 9 (64%) had elevated fibrinogen degradation products, while none had a fibrinogen level <100 mg/dL. Four patients had mild to moderate thrombocytopenia (77 000, 117 000, 103 000, and 102 000 platelets/mm3, respectively) at or near the time of neurological symptom onset. Of 7 patients receiving heparin therapy at the time of CI onset, 5 had aPTT values below the target value of 1.5 to 2.0 times control. Thus, only 2 of 29 patients (7%) were receiving therapeutic anticoagulation at the time of CI.

Site and Vascular Territory of CI
The sites of the primary CI for the 29 patients were lobar in 17 (59%), unspecified cerebral hemisphere in 5 (17%), cerebellum in 2 (7%), and at other distinct sites in 5 others. Specific primary lobar sites included frontoparietal in 4 (14%), fronto-temporal-parietal in 4 (14%), frontal in 3 (10%), occipital in 3 (10%), parieto-occipital in 1, temporo-occipital in 1, and insular-opercular in 1. Multiple distinct CI sites were present in 9 patients (31%). Only 1 of these 9 patients was known to have CT evidence of remote CI. Of 19 patients (66%) with anterior circulation CI, areas of infarction were in the distribution of the proximal middle cerebral artery in 8 patients, in the superior division of the middle cerebral artery in 6, and in separate vascular territories in 5 others. Of 8 patients (28%) with CI in the posterior circulation, 4 (14%) were in the distribution of the proximal posterior cerebral artery, 2 (7%) in the posterior inferior cerebellar artery, and 2 (7%) occurred in other vascular territories. In 2 patients (7%), the vascular territory could not be determined from the available information.

Hemorrhagic Infarctions
Table 3Down shows the clinical and laboratory features of the 8 patients (28%) who had HI. The mean time interval to CI was 72 hours. The mean time interval between CI onset and demonstration of HI on a CT scan was 36 hours. The CT characteristics of HI ranged from subtle petechial change to confluent hematoma (Fig 2Down). The observed HI was not very dense in 1 patient (Fig 2ADown and 2BDown), was seen on the second CT scan in 2 (Fig 2CDown and 2DDown), was seen on the first CT scan after a second clinical event in 2 (Fig 2EDown), or was surrounded by an ischemic zone in 1 (Fig 2FDown). The mean hematocrit value at the time of HI was 37.7%. Five HIs were symptomatic. Four of 5 HI patients (80%) with aPTTs >=60 seconds had increasing neurological deficits, but only 1 died of neurological complications. Two patients made full recoveries, 4 patients had minor residual deficits, and 1 died of ventricular fibrillation.


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  		Table 3. Hemorrhagic CIs After Thrombolytic Therapy for Acute MI



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  		Figure 2. Spectrum of hemorrhagic transformation of cerebral infarction after thrombolysis for acute MI. A and B, Patient with a left frontal lobe hemorrhagic infarction that was not very dense. C and D, Patient who developed left hemiparesis 6 hours after treatment initiation. Intravenous heparin was discontinued. Initial CT scan (C) was normal, weakness improved, and heparin was restarted. Seventeen hours later, there was worsening hemiparesis. Interval CT scan (D) showed dense confluent hemorrhagic infarction in the right basal ganglia with rupture into the ventricular system. E, Patient who developed dysarthria, aphasia, and right hemiparesis 12.5 hours after treatment initiation. Three hours later, he became lethargic, more aphasic, and more hemiparetic. CT scan (E) shows confluent hemorrhagic infarction in the left frontal lobe. F, Patient who developed a right homonymous hemianopsia 21 hours after treatment initiation. CT scan 24 hours later (F) showed a left temporo-occipital confluent hemorrhagic infarction.

Stroke Mechanisms
The neurodiagnostic evaluation of CI patients varied in the amount of information collected. Seven patients (24%) had carotid noninvasive studies. Eight patients were not studied with echocardiography or cardiac catheterization.

Twenty-eight patients (96%) were demonstrated to have cardioembolic CI (Table 4Down). Of 25 patients (86%) with strong evidence for a cardiac source of embolization, 17 had at least one cardiac abnormality (mural clot, wall-motion abnormality, atrial fibrillation) known to be associated more specifically with embolism than is MI. One patient had mural thrombus appearing on the second echocardiogram after onset of neurological symptoms. Twelve patients (41%) had CI temporally associated with invasive cardiovascular procedures: CABG surgery in 5 (with preceding PTCA complicated by coronary artery dissection in 1), aortic dissection repair in 1, ventricular septal defect repair in 1, cardiac catheterization in 3, and PTCA in 2. One patient had an inferior MI associated with an aortic dissection and cardiogenic shock leading to aortic repair and subsequent right parieto-occipital (middle/posterior cerebral artery) and right frontoparietal (anterior/middle cerebral artery) border-zone infarctions. One patient with a left temporo-occipital infarction in the distribution of the left posterior cerebral artery had hemodynamically significant internal carotid stenoses by direct Doppler examinations (right, 12.9 kHz; left, 8.9 kHz). In 6 patients (20%), hypotension may have been a contributing factor.


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  		Table 4. Stroke Mechanisms in Patients With Ischemic CI After Thrombolytic Therapy for Acute MI


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowSubjects and Methods
 up arrowResults
 *Discussion
down arrowReferences
 
In TIMI-II, clinically evident ischemic CI occurred in 0.7% of patients treated with rt-PA and intravenous heparin, which is comparable with the frequency found in other studies using rt-PA12 13 14 15 16 18 21 22 23 or other thrombolytic regimens.9 10 11 12 13 14 15 16 17 18 The characteristics of CI in this study are in many ways similar to those of CI in the prethrombolytic era. The distribution of times of CI occurrence is essentially unchanged, including the 31% of cases within 24 hours of study entry.1 2 3 4 5 Twenty-two patients (76%) had anterior-wall MI consistent with other studies but different from those seen by Bodenheimer et al.46

Despite concerns expressed in several case reports,7 8 47 therapy with rt-PA and intravenous heparin does not unconditionally increase the risk of clot fragmentation followed by embolization to the brain. Our results demonstrate a case-fatality rate from CI of 41% (99% confidence interval, 15% to 67%), similar to the overall stroke-related mortality in other large coronary thrombolysis trials in both treated (range, 22% to 64%; mean, 42%) and control (range, 18% to 75%; mean, 37%) patients.9 10 11 13 19 20 21 22 23

In TIMI-II, the clinical features of CI after rt-PA and heparin therapy for acute MI appear to be somewhat different than for parenchymatous ICH.48 Patients with CI were more likely to present with a focal neurological deficit (20/29 or 68% versus 8/23 or 35%; {chi}2=6.03, P=.014) and seem less likely to have a decreased level of consciousness at onset (11/29 or 38% versus 15/23 or 65%; {chi}2=3.82, P=.051) than patients with ICH. These findings should be viewed with some caution because the number of patients is small and CT scans are necessary to definitively distinguish between CI and ICH. However, the differences in clinical presentation in TIMI-II may help clinicians to classify stroke occurring within 24 hours of thrombolysis as probable CI or probable ICH in centers where CT scans are not readily available. Further studies are necessary to clarify these observations.

Cardiogenic embolism is the predominant mechanism of CI after rt-PA and heparin therapy for acute MI. Clinical and radiographic features suggestive of embolism were rapid onset in 12 patients (41%),40 altered mental state or coma in 13 (45%),40 42 posterior circulation sites in 8 (28%),30 49 50 multiple acute infarctions in 8 (28%),43 and hemorrhagic conversion of infarction in 8 (30% of patients with CT scans).33 34 35 Twenty-five of 28 patients (89%) classified as having cardioembolic stroke had strong evidence for a cardiac source other than anterior-wall MI.

Transthoracic echocardiographic studies of patients not receiving thrombolytic therapy demonstrate that left ventricular mural thrombi occur in 28% to 34% of anterior MIs and 1.5% of inferior MIs.51 52 Left ventricular thrombi typically occur during the first week after MI,53 although they have been reported to appear both within 4 hours of MI onset53 54 and after hospital discharge.55 A number of studies have demonstrated an association between left ventricular mural thrombus and systemic and cerebral embolization.51 52 56 57 58 59

In TIMI-II, 8 of 9 CI patients (89%) with mural thrombus had a variety of associated structural or functional abnormalities, such as an akinetic region, left ventricular aneurysm, ventricular septal defect, or atrial fibrillation, usually associated with extensive anterior MI. Structural abnormalities predisposing to mural thrombus formation, such as akinetic region or aneurysm,55 were found in 5 others. Recent reports from other studies suggest that "aggressive" short- and long-term anticoagulation may reduce but not totally prevent mural thrombus formation57 58 59 and occurrence of stroke.1 3 4 5 60 61 62 63 The occurrence of aPTT values below the target range in 5 of 7 heparinized patients (71%) who developed CI is consistent with these observations.

Ischemic CI is a well-known complication of invasive cardiovascular procedures such as CABG, occurring in 0.3% to 5.2% of patients.22 64 65 66 67 68 69 70 71 In TIMI-II, 12 of 29 CI patients (41%) had CI associated with invasive cardiovascular procedures: 5 with CABG (1 with preceding PTCA), coronary angiography in 3, PTCA in 2, aortic dissection repair in 1, and ventricular septal defect repair in 1. Border-zone CI has rarely been documented after cardiovascular surgery66 72 ; 1 TIMI-II patient had multiple border-zone CIs after repair of an aortic dissection.

Ischemic CI occurs in 0.3% of patients undergoing coronary angiography73 74 and 0.06% to 0.3% of patients undergoing PTCA.75 76 The frequency of ischemic CI after coronary angiography and in this series appears similar to previously reported rates.74 75 76 Both ischemic and hemorrhagic strokes have occurred following PTCA and thrombolysis.75 In the series of Brown and Topol,76 2 CI patients received a continuous overnight infusion of urokinase into coronary artery bypass grafts; 1 was associated with hypotension induced by bleeding from the femoral access site, while the other was classified as embolic. In the series of Bredlau et al,75 1 patient developed a right occipital lobe infarction after PTCA. The TIMI-II regimen differed from those of Brown and Topol76 and Bredlau et al.75 In TIMI-II, PTCA followed intravenous rt-PA and heparin therapy. Also, documented cardiac structural abnormalities included an akinetic region and aneurysm in 2 patients and a mild wall-motion abnormality in 1 patient. One patient who underwent PTCA complicated by a coronary artery dissection developed a right occipital lobe infarction after emergency CABG surgery. However, the invasive treatment strategy was not associated with an increased risk of CI.22

The occurrence of HI has infrequently been described or considered to follow thrombolytic therapy for acute MI.22 48 HI is believed to occur either when there is early reperfusion in a damaged vascular bed with impaired autoregulation or through collateral circulation with or without acute hypertension or anticoagulant use.33 77 78 HI most frequently occurs within 2 to 4 days after onset of cardioembolic stroke,33 79 but it may occur as early as the first day34 or as late as 10 to 14 days after stroke onset.80 81 When large areas of petechiae merge to form confluent purpura or parenchymatous hematoma, a CT scan abnormality may be indistinguishable from primary ICH.33 34

We previously reported a patient diagnosed to have ICH 74 hours after rt-PA and heparin therapy with anterior MI, atrial fibrillation, and prior stroke; this patient was documented to have had massive confluent HI at autopsy 3 months after the neurological event.48 The patient's clinical setting was most consistent with CI, but the CT scan was most consistent with primary ICH. When clinical signs and imaging information are discrepant, the true diagnosis may only become apparent with serial imaging or pathological examinations.

The roles of anticoagulants and thrombolytic agents in causing symptomatic brain hemorrhage and death after cardioembolic stroke are controversial. Clinical CT studies of nonanticoagulated patients indicate that HI occurs in 5% to 43% of cases.78 82 83 Some investigators have reported poor outcomes81 84 85 ; others report benign courses in anticoagulated patients, even if HI is present.86 One recent study34 reported that early spontaneous confluent HI formation may be associated with clinical worsening (67%) and death within 30 days (27%). In the present series, 8 of 29 CI patients (28%) were proven to have HI, similar to the findings of previous studies.78 82 83 The time interval between CI onset and demonstration of HI was similar to the intervals previously reported.33 34 79 80 81 In TIMI-II, 3 patients had HI within 24 hours after initiation of rt-PA and heparin therapy. It is possible that active fibrinolysis may have contributed to these occurrences,46 87 88 with a fatal outcome in 1. Our limited data are similar to those of one recent study.86 Cerebral HI after thrombolytic therapy for acute MI may have a more favorable prognosis than HI following cardiogenic embolism in the non-MI setting.34 81 84 85 There is no clear relationship between aPTT at the time of HI diagnosis and outcome, although the small number of patients with CI in TIMI-II does not permit statistical inference. However, in the Global Utilization of Strategies to Open Occluded Coronary Arteries (GUSTO-I) trial,18 HI occurred in 34 of 281 CI patients (12.1%). In that study,18 among HI patients mortality was 32%, and 38% were disabled, with a trend toward worse outcome with a more intensive thrombolytic/antithrombotic regimen.


*    Selected Abbreviations and Acronyms
 
aPTT = activated partial thromboplastin time
CABG = coronary artery bypass grafting
CI = cerebral infarction
HI = hemorrhagic infarction
ICH = intracerebral hemorrhage
MI = myocardial infarction
PTCA = percutaneous transluminal coronary angioplasty
rt-PA = recombinant tissue plasminogen activator
TIMI-II = Thrombolysis in Myocardial Infarction Phase II Pilot Study and Clinical Trial


*    Acknowledgments
 
This work was supported by National Heart, Lung, and Blood Institute research contracts and grants. The authors wish to thank the clinicians and pathologists who made data available for this study and Lisa Shipp for typing the manuscript.


*    Footnotes
 
The TIMI-II Investigators and Institutions have been previously reported in the New England Journal of Medicine (1989;320:618-627).

Received October 14, 1996; revision received February 18, 1997; accepted March 17, 1997.


*    References
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 up arrowAbstract
 up arrowIntroduction
 up arrowSubjects and Methods
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 *References
 

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