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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
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.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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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
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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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.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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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
(
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
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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General Clinical Data
Table 1
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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Timing, Clinical Features, and Temporal Course
Fig 1 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 2
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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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 3 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 2).
The observed HI was not very dense in 1 patient (Fig 2A and 2B), was
seen on the second CT scan in 2 (Fig 2C and 2D), was seen on the first
CT scan after a second clinical event in 2 (Fig 2E), or was surrounded
by an ischemic zone in 1 (Fig 2F). 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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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 4). 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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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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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%;
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%; 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.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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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.
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Footnotes |
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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.
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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