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Heparin Therapy for Recent Transient Focal Cerebral Ischemia
Heparin Therapy for Recent Transient Focal Cerebral Ischemia
DOUGLAS S. KEITH, M.D., Department of Internal Medicine; STEPHEN J. PHILLIPS, M.B.,B.S., Department of Neurology; JACK P. WHISNANT, M.D., Departments of Neurology and Health Sciences Research; KATSUYA NISHIMARU, M.D.,* Visiting Scientist, Department of Neurology; W. MICHAEL O'FALLON, Ph.D., Section of Biostatistics The Mayo Clinic medical records and records linkage system were used to identify stroke-free residents of Rochester, Minnesota, who were examined within 30 days after the first transient cerebral ischemic attack (TIA) during the period 1955 through 1979. The patients were divided into two groups: those given heparin within 30 days after the first attack and those not given heparin. Death, stroke, and either stroke or TIA were separate endpoints in Kaplan-Meier analyses of data from the day of initial examination through the 30th day thereafter. The probabilities of survival, survival free from stroke, and survival free from TIA for the heparin-treated group were not significantly different from those probabilities for the comparison group. The rate of hemorrhagic complications was 3.2 per 100 person-days of heparin therapy. Retroperitoneal hemorrhage, the most serious complication, was the cause of one death and one case of femoral neuropathy.
Anticoagulant therapy is intended to prevent cerebral infarction in patients who have had transient focal cerebral ischemia due to thrombotic or embolic mechanisms. Intravenous ad ministration of heparin is considered rational immediate treatment for such patients who are examined early because there is evidence that the risk of stroke is highest during the month after the first transient ischemic attack (TIA).1 This use of heparin, however, has never been tested in a prospective, randomized clinical trial. In a nonrandomized study of the use of heparin in the
*Present address: Fukuoka University School of Medicine, Fukuoka, Japan. This study was supported in part by Grant NS 06663 from the National Institutes of Health, Public Health Service. Dr. Phillips' work is supported in part by the Weston Foundation of Canada. Address reprint requests to Dr. J. P. Whisnant, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905. Mayo Clin Proc 62:1101-1106, 1987
initial management of 74 patients with recent TIAs, Putman and Adams 2 found that 6.8% sub sequently had cerebral infarction and 12.2% had hemorrhagic complications. A recent doubleblind, placebo-controlled trial in patients with acute partial stable stroke of presumed thrombotic mechanism demonstrated no benefit from the intravenous administration of heparin to pre vent progression of stroke. 3 In this article, we report the results of a population-based study of patients with TIAs of recent onset who sought medical assistance at our institution during a 25-year period. Moreover, we compared the short-term outcome in heparintreated patients and those who did not receive heparin. PATIENTS A N D METHODS The Mayo Clinic medical records and records linkage system were used to identify, for the period 1955 through 1979, residents of Rochester, Minnesota, who had a TIA (defined as a tempo-
1101
1102
HEPARIN THERAPY FOR CEREBRAL ISCHEMIA
rary, focal episode of neurologic dysfunction of presumed vascular origin lasting less than 24 hours). 4 The symptoms used to determine the vascular site of the ischemia (carotid or vertebrobasilar territory) are presented in Table 1. Attacks in which dysphasia occurred were classified on the basis of the accompanying symptoms. When symptoms could not be localized to either vascu lar territory, the TIA was labeled "either." Ver tigo alone, diplopia alone, unexplained uncon sciousness, syncope, amnesia, confusion, or focal symptoms associated with epilepsy or migraine were excluded. Only those patients who received medical at tention within 30 days after the first TIA were included in the study. Patients who had had a stroke before the initial examination were excluded. Patients who received intravenous heparin therapy within 30 days after the initial TIA were compared with the rest of the cohort by using death, stroke, and either stroke or TIA as separate endpoints. Kaplan-Meier life-table analyses of data from the day of the initial examination through the 30th day thereafter were used to estimate the probabilities of sur viving 30 days without reaching the endpoints. Probability estimates for various groups were compared by the Peto-Peto Wilcoxon and logrank tests (two-tailed). Patients who had carotid endarterectomy within the period of the analysis were withdrawn from the study on the day of the operation. The use of stroke and of stroke or TIA as endpoints in these analyses necessitated the withdrawal, on the day of death, of patients who died of causes other than stroke. Hemorrhagic events that occurred during administration of heparin were used to calculate the number of complications per 100 person-days of heparin therapy. Hemorrhagic complications were attrib uted to the use of heparin regardless of whether warfarin therapy was administered concurrently.
RESULTS Of the 392 stroke-free residents of Rochester, Minnesota, who had their first TIA during the period 1955 through 1979, 289 were initially ex amined within 30 days after the first attack. Of these 289 patients, 102 (35%) were given heparin intravenously within 30 days after the first TIA. The 187 patients who did not receive heparin
Mayo Clin Proc, December 1987, Vol 62
Table 1.—Symptoms Used to Determine the Vascular Site of Ischemia in Patients With Transient Focal Cerebral Attacks Vascular territory Symptom Carotid 1. Unilateral motor or sensory abnormalities (or both) 2. Aphasia 3. Amaurosis fugax 4. Any combination of 1-3 5. Homonymous hemianopia plus any combination of 1-3 6. Dysarthria plus unilateral motor or sensory abnormalities (or both) Vertebrobasilar
1. Bilateral motor or sensory abnormalities (or both) 2. Bilateral appendicular or gait ataxia 3. Bilateral homonymous hemianopia 4. Any combination of 1-3 5. Dysarthria plus any combination of 1, 2, 3, 9, and 10 6. Homonymous hemianopia alone 7. Homonymous hemianopia plus any combination of 1, 2, 9, and 10 8. Unilateral motor or sensory abnormalities (or both) plus any combination of 2, 3, 9, and 10 9. Vertigo plus any combination of 1-8 10. Diplopia plus any combination of 1-9
formed the comparison group. None of the pa tients had had a stroke before the initial exam ination for TIA. The groups were similar in terms of age and sex distributions and blood pressure measure ments at the time of initial examination (Table 2). The mean time between the first TIA and examination was 4 days for each group; 82% of the patients were examined within 7 days after the onset of initial symptoms. The duration of heparin treatment ranged from 1 to 15 days (mean, 4 days). In 87 patients (85%), the heparin was administered intravenously by bolus injec tions every 4 hours; the rest of the patients re ceived continuous intravenous infusions. Ther apy was adjusted to maintain the activated partial thromboplastin time at 1.5 to 2.0 times the normal rate. Before the use of this measure ment, anticoagulation was considered therapeu tic when the Lee-White clotting time was twice the normal value. The cumulative probability of survival to the 30th day after initial examination was estimated to be 96% for the heparin-treated group and 97% for the comparison group (P - 0.9). Four patients (4%) in the heparin-treated group and eight pa-
HEPARIN THERAPY FOR CEREBRAL ISCHEMIA
>1 TIA before initial examination Vascular territory of first TIA Carotid Vertebrobasilar "Either" Symptoms of large-vessel disease* Carotid endarterectomy Warfarin therapy Antiplatelet therapy
No. 50 87 12 3 29 6 81 5
% 49
No. 44
% 24
85 12 3 28 6 79 5
135 42 10 49 3 54 21
72 23 5 26 2 29 11
30 Heparin-treated group • ^
a·*
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lity,
_
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Stroke
Table 2.—Selected Characteristics of 289 Patients Examined Early After First Transient Ischemic Attack (TIA) Heparin Comparison group group Characteristic (N = 102) (N = 187) Sex (M:F) 82:105 46:56 Mean age (yr) 70 69 Mean blood pressure at initial examination (mm Hg) 163/90 158/89 Time from first TIA to initial 4 examination (days) 4
1103
-
n = 102 Z'
_-
'
n = 187
3
Mayo Clin Proc, December 1987, Vol 62
0
10
20
Days after first medical attention
30
$&>
Fig. 1. Cumulative probability of stroke (given survival) for two groups of patients examined within 30 days after first transient ischemic attack.
*Amaurosis fugax or aphasia during first TIA.
tients (4%) in the comparison group died (Table 3). Heparin-induced retroperitoneal hemorrhage resulted in the death of one patient. The cumulative probability of stroke (given survival) within 30 days after initial examination was estimated to be 9% for the heparin-treated group and 7% for the comparison group (P = 0.5) (Fig. 1). We identified only one hemorrhagic stroke, which occurred in a patient in the com parison group who died of an intracerebral hemorrhage (Table 4). Analyses with use of stroke or TIA as the endpoint provided estimates of the cumulative probability of a cerebral ischemic event (given survival) within 30 days after initial examination—18%o for the heparintreated group and 13% for the comparison group (P = 0.3). Table 3.—Deaths Within 30 Days After Initial Examination in 289 Patients With First Transient Ischemic Attack Comparison Heparin group group Cause of death (N = 187) (N = 102) Cerebral infarction Intracerebral hemorrhage Stroke of unknown type Myocardial infarction Retroperitoneal hemorrhage Other Total
The outcome of patients who received medical attention within 1 day after the first TIA was analyzed separately because these patients had the greatest potential for benefit from treatment aimed at preventing early stroke. In such pa tients, the estimated cumulative probability of stroke (given survival) within 30 days after initial examination was 7% for patients treated with heparin (N = 61) and 5% for those who did not receive heparin (N = 108) (P = 0.6). Fifty patients (49%) in the heparin-treated group and 44 (24%) in the comparison group had more than one TIA before the initial examination (Tables 2 and 5). This difference was thought to be a consequence of the belief that patients who are initially examined after multiple TIAs of recent onset are at higher risk of stroke and thus require more aggressive management than those who are examined after only one attack. There fore, stroke probability was analyzed as a func-
Table 4.—Strokes Within 30 Days After Initial Examination in 289 Patients With First Transient Ischemic Attack Heparin Comparison group group (N = 102) (N = 187) Type of stroke 10 Cerebral infarction 1 Intracerebral hemorrhage 2 Unknown Total 13
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HEPARIN THERAPY FOR CEREBRAL ISCHEMIA
Mayo Clin Proc, December 1987, Vol 62
Table 5.—Number of Transient Ischemic Attacks (TIAs) Occurring Before Initial Examination in 289 Study Patients TIAs before initial examination (no.) 1 2-4 >5 Total
lotai Heparin group No. % 52 51 37 36 13 13 102 100
tion of the number of TIAs occurring before initial examination, regardless of subsequent treatment. The estimated cumulative probability of stroke (given survival) within 30 days after medical attention for patients examined after one, two to four, or five or more TIAs was 6%, 7%, and 20%, respectively (P = 0.03). Of the 25 patients who had five or more TIAs before ex amination, 5 had a stroke within 30 days. Four of these patients were receiving heparin at the time the stroke occurred, and one patient was in the comparison group. In the heparin-treated group, 87 patients (85%) had carotid artery TIAs, 12 (12%) had vertebrobasilar TIAs, and 3 (3%) had TIAs categorized as "either." The corresponding figures for the comparison group were 135 (72%), 42 (23%), and 10 (5%) (Table 2). To explore how these differences may have biased the results, we analyzed the probability of stroke as a function of the vascular territory of the first TIA, regardless of subsequent treatment. The estimated cumulative probability of stroke (given survival) within 30 days after initial examination was 8% for the carotid group (N = 222) and 6% for the vertebrobasilar group (N = 54) (P = 0.8) (Fig. 2). The same estimate for the "either" group (N = 13) was 8%. When the analysis was repeated with these 13 patients added, first to the carotid group and then to the vertebrobasilar group, the difference in outcome between the carotid and vertebrobasilar groups was still not significant. Of the 102 heparin-treated patients, 13 had hemorrhagic complications (Table 6). Bleeding necessitated the termination of heparin therapy in four of these patients, two of whom required blood transfusion. One death (1%) and one case of femoral neuropathy were due to heparininduced retroperitoneal hemorrhage. The overall hemorrhagic complication rate was 3.2 events per 100 person-days of heparin therapy.
Comparison No. 143 32 12 187
group % 77 17 6 100
%
No. 195 69 25 289
heparinized 27 54 52
DISCUSSION In this population-based study of the initial man agement of TIAs of recent onset, patients treated with heparin fared the same—in terms of prob ability of death, stroke, and either stroke or TIA during the 30 days after initial examination—as those who did not receive heparin. These results should be interpreted cautiously, however, be cause of the retrospective, nonrandomized design of the study. The patients in the comparison group were not untreated controls, and those in the heparfn-treated group were not uniformly managed after the period of administration of heparin. Patients who had TIAs due to various mechanisms were analyzed collectively, but in clinical practice, heparin is used to provide im mediate prophylaxis for stroke while the under lying cause of the TIA is investigated. In this situation it is quicker to exclude patients on the basis of contraindications to heparin therapy than it is to identify an indication for its use.
30 — Carotid TIA
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— Vertebrobasilar TIA
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20
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I
I
I
10
20
30
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Fig. 2. Cumulative probability of stroke (given survival) by vascular territory of first transient ischemic attack (TIA), for 276 patients examined within 30 days after first attack, regardless of subsequent treatment.
Mayo Clin Proc, December 1987, Vol 62
Table 6.—Complications of Heparin Therapy Among 102 Patients Examined Early After First Transient Ischemic Attack Complication No. Retroperitoneal hemorrhage 2*t Hemarthrosis If Upper gastrointestinal hemorrhage It Rectal bleeding 1 Hematuria 1 Epistaxis, bleeding gums, or both 4 Ecchymosis, hematoma, or both 3 Total 13 *Blood transfusion required. tHeparin therapy stopped.
Our observations provide some support for the contention that patients who are initially exam ined after multiple TIAs are at higher risk of stroke than those who have had few attacks. The subgroup of patients who had five or more TIAs before initial examination was too small to allow firm inferences, but the observation that four of the five strokes in this subgroup occurred in heparin-treated patients is in accordance with the principal conclusion of the study. The heparin and comparison groups were also dissimilar with respect to the vascular territory of the first TIA (Table 2). This difference prob ably did not bias the analysis of the risk of stroke for the two treatment groups, however, because the cumulative 30-day probabilities of stroke for all patients with carotid TIAs and for all pa tients with vertebrobasilar TIAs were not sig nificantly different (Fig. 2). This observation is consistent with the results of most studies that have examined the long-term risk of stroke after TIA.5"9 Studies in which the probability of stroke seemed lower after vertebrobasilar TIAs than after carotid TIAs have included patients with isolated symptoms such as vertigo that may have "diluted" the vertebrobasilar groups with condi tions that do not predispose to stroke.10,11 Exposing patients to the potential complica tions of heparin therapy can be justified only if the risks are clearly outweighed by the benefits of the treatment. Although no evidence of such a benefit exists, the possibility that heparin ther apy is of value in certain patients with TIA cannot be excluded. This possibility is an issue worthy of a definitive answer, which can be provided only by a randomized, prospective trial.
HEPARIN THERAPY FOR CEREBRAL ISCHEMIA
1105
We have calculated that, if heparin therapy de creases the probability of stroke during the first month after TIA from 8% to 4%, a trial with a significance level of 5% (P - 0.05, one-tailed) would have to include approximately 1,200 pa tients to have only a 10% risk of failing to reject the null hypothesis—that is, that heparin ther apy is no better than no therapy. 12 Experimental studies of deep arterial injury have suggested that optimal antithrombotic therapy consists of both a platelet inhibitor and an anticoagulant. 13 A trial designed to test this hypothesis, in which patients are randomized to receive heparin and aspirin in one arm of the trial or either drug alone in another arm, would necessitate an even larger sample. If a subset of patients at higher risk of stroke could be identified, a trial could be con ducted in fewer patients; the time required for re cruitment, however, would probably be prohibitive. Currently, no scientific evidence supports the routine use of heparin as emergency therapy for all patients with a history suggestive of recent TIA.
REFERENCES
1. Whisnant JP, Matsumoto N, Elveback LR: The effect of anticoagulant therapy on the prognosis of patients with transient cerebral ischemic attacks in a community: Rochester, Minnesota, 1955 through 1969. Mayo Clin Proc 48:844-848, 1973 2. Putman SF, Adams HP Jr: Usefulness of heparin in initial management of patients with recent transient ischemic attacks. Arch Neurol 42:960-962, 1985 3. Duke RJ, Bloch RF, Turpie AGG, Trebilcock R, Bayer N: Intravenous heparin for the prevention of stroke progression in acute partial stable stroke: a randomized controlled trial. Ann Intern Med 105:825-828, 1986 4. Committee on Cerebrovascular Diseases: A classifica tion and outline of cerebrovascular diseases II. Stroke 6:564-616, 1975 5. Baker RN, Schwartz WS, Rose AS: Transient ischemic strokes: a report of a study of anticoagulant therapy. Neurology 16:841-847, 1966 6. Friedman GD, Wilson S, Mosier JM, Colandrea MA, Nichaman MZ: Transient ischemic attacks in a com munity. JAMA 210:1428-1434, 1969 7. Ostfeld AM, Shekelle RB, Klawans HL: Transient ischemic attacks and risk of stroke in an elderly poor population. Stroke 4:980-986, 1973 8. Cartlidge NEF, Whisnant JP, Elveback LR: Carotid and vertebral-basilar transient cerebral ischemic attacks: a community study, Rochester, Minnesota. Mayo Clin Proc 52:117-120, 1977 9. Muuronen A, Kaste M: Outcome of 314 patients with transient ischemic attacks. Stroke 13:24-31, 1982 10. Marshall J: The natural history of transient ischaemic cerebro-vascular attacks. Q J Med 33:309-324, 1964
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HEPARIN THERAPY FOR CEREBRAL ISCHEMIA
11. Ziegler DK, Hassanein RS: Prognosis in patients with transient ischemic attacks. Stroke 4:666-673, 1973 12. Lachin JM: Introduction to sample size determination and power analysis for clinical trials. Controlled Clin Trials 2:93-113, 1981
Mayo Clin Proc, December 1987, Vol 62
13. Chesebro JH, Fuster V: Antithrombotic therapy for acute myocardial infarction: mechanisms and prevention of deep venous, left ventricular, and coronary artery thromboembolism. Circulation 74 (Suppl 3):1-10, 1986
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DOUGLAS S. KEITH, M.D., Department of Internal Medicine; STEPHEN J. PHILLIPS, M.B.,B.S., Department of Neurology; JACK P. WHISNANT, M.D., Departments of Neurology and Health Sciences Research; KATSUYA NISHIMARU, M.D.,* Visiting Scientist, Department of Neurology; W. MICHAEL O'FALLON, Ph.D., Section of Biostatistics The Mayo Clinic medical records and records linkage system were used to identify stroke-free residents of Rochester, Minnesota, who were examined within 30 days after the first transient cerebral ischemic attack (TIA) during the period 1955 through 1979. The patients were divided into two groups: those given heparin within 30 days after the first attack and those not given heparin. Death, stroke, and either stroke or TIA were separate endpoints in Kaplan-Meier analyses of data from the day of initial examination through the 30th day thereafter. The probabilities of survival, survival free from stroke, and survival free from TIA for the heparin-treated group were not significantly different from those probabilities for the comparison group. The rate of hemorrhagic complications was 3.2 per 100 person-days of heparin therapy. Retroperitoneal hemorrhage, the most serious complication, was the cause of one death and one case of femoral neuropathy.
Anticoagulant therapy is intended to prevent cerebral infarction in patients who have had transient focal cerebral ischemia due to thrombotic or embolic mechanisms. Intravenous ad ministration of heparin is considered rational immediate treatment for such patients who are examined early because there is evidence that the risk of stroke is highest during the month after the first transient ischemic attack (TIA).1 This use of heparin, however, has never been tested in a prospective, randomized clinical trial. In a nonrandomized study of the use of heparin in the
*Present address: Fukuoka University School of Medicine, Fukuoka, Japan. This study was supported in part by Grant NS 06663 from the National Institutes of Health, Public Health Service. Dr. Phillips' work is supported in part by the Weston Foundation of Canada. Address reprint requests to Dr. J. P. Whisnant, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905. Mayo Clin Proc 62:1101-1106, 1987
initial management of 74 patients with recent TIAs, Putman and Adams 2 found that 6.8% sub sequently had cerebral infarction and 12.2% had hemorrhagic complications. A recent doubleblind, placebo-controlled trial in patients with acute partial stable stroke of presumed thrombotic mechanism demonstrated no benefit from the intravenous administration of heparin to pre vent progression of stroke. 3 In this article, we report the results of a population-based study of patients with TIAs of recent onset who sought medical assistance at our institution during a 25-year period. Moreover, we compared the short-term outcome in heparintreated patients and those who did not receive heparin. PATIENTS A N D METHODS The Mayo Clinic medical records and records linkage system were used to identify, for the period 1955 through 1979, residents of Rochester, Minnesota, who had a TIA (defined as a tempo-
1101
1102
HEPARIN THERAPY FOR CEREBRAL ISCHEMIA
rary, focal episode of neurologic dysfunction of presumed vascular origin lasting less than 24 hours). 4 The symptoms used to determine the vascular site of the ischemia (carotid or vertebrobasilar territory) are presented in Table 1. Attacks in which dysphasia occurred were classified on the basis of the accompanying symptoms. When symptoms could not be localized to either vascu lar territory, the TIA was labeled "either." Ver tigo alone, diplopia alone, unexplained uncon sciousness, syncope, amnesia, confusion, or focal symptoms associated with epilepsy or migraine were excluded. Only those patients who received medical at tention within 30 days after the first TIA were included in the study. Patients who had had a stroke before the initial examination were excluded. Patients who received intravenous heparin therapy within 30 days after the initial TIA were compared with the rest of the cohort by using death, stroke, and either stroke or TIA as separate endpoints. Kaplan-Meier life-table analyses of data from the day of the initial examination through the 30th day thereafter were used to estimate the probabilities of sur viving 30 days without reaching the endpoints. Probability estimates for various groups were compared by the Peto-Peto Wilcoxon and logrank tests (two-tailed). Patients who had carotid endarterectomy within the period of the analysis were withdrawn from the study on the day of the operation. The use of stroke and of stroke or TIA as endpoints in these analyses necessitated the withdrawal, on the day of death, of patients who died of causes other than stroke. Hemorrhagic events that occurred during administration of heparin were used to calculate the number of complications per 100 person-days of heparin therapy. Hemorrhagic complications were attrib uted to the use of heparin regardless of whether warfarin therapy was administered concurrently.
RESULTS Of the 392 stroke-free residents of Rochester, Minnesota, who had their first TIA during the period 1955 through 1979, 289 were initially ex amined within 30 days after the first attack. Of these 289 patients, 102 (35%) were given heparin intravenously within 30 days after the first TIA. The 187 patients who did not receive heparin
Mayo Clin Proc, December 1987, Vol 62
Table 1.—Symptoms Used to Determine the Vascular Site of Ischemia in Patients With Transient Focal Cerebral Attacks Vascular territory Symptom Carotid 1. Unilateral motor or sensory abnormalities (or both) 2. Aphasia 3. Amaurosis fugax 4. Any combination of 1-3 5. Homonymous hemianopia plus any combination of 1-3 6. Dysarthria plus unilateral motor or sensory abnormalities (or both) Vertebrobasilar
1. Bilateral motor or sensory abnormalities (or both) 2. Bilateral appendicular or gait ataxia 3. Bilateral homonymous hemianopia 4. Any combination of 1-3 5. Dysarthria plus any combination of 1, 2, 3, 9, and 10 6. Homonymous hemianopia alone 7. Homonymous hemianopia plus any combination of 1, 2, 9, and 10 8. Unilateral motor or sensory abnormalities (or both) plus any combination of 2, 3, 9, and 10 9. Vertigo plus any combination of 1-8 10. Diplopia plus any combination of 1-9
formed the comparison group. None of the pa tients had had a stroke before the initial exam ination for TIA. The groups were similar in terms of age and sex distributions and blood pressure measure ments at the time of initial examination (Table 2). The mean time between the first TIA and examination was 4 days for each group; 82% of the patients were examined within 7 days after the onset of initial symptoms. The duration of heparin treatment ranged from 1 to 15 days (mean, 4 days). In 87 patients (85%), the heparin was administered intravenously by bolus injec tions every 4 hours; the rest of the patients re ceived continuous intravenous infusions. Ther apy was adjusted to maintain the activated partial thromboplastin time at 1.5 to 2.0 times the normal rate. Before the use of this measure ment, anticoagulation was considered therapeu tic when the Lee-White clotting time was twice the normal value. The cumulative probability of survival to the 30th day after initial examination was estimated to be 96% for the heparin-treated group and 97% for the comparison group (P - 0.9). Four patients (4%) in the heparin-treated group and eight pa-
HEPARIN THERAPY FOR CEREBRAL ISCHEMIA
>1 TIA before initial examination Vascular territory of first TIA Carotid Vertebrobasilar "Either" Symptoms of large-vessel disease* Carotid endarterectomy Warfarin therapy Antiplatelet therapy
No. 50 87 12 3 29 6 81 5
% 49
No. 44
% 24
85 12 3 28 6 79 5
135 42 10 49 3 54 21
72 23 5 26 2 29 11
30 Heparin-treated group • ^
a·*
Comparison group
lity,
_
r> (0
Q.
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n o
Stroke
Table 2.—Selected Characteristics of 289 Patients Examined Early After First Transient Ischemic Attack (TIA) Heparin Comparison group group Characteristic (N = 102) (N = 187) Sex (M:F) 82:105 46:56 Mean age (yr) 70 69 Mean blood pressure at initial examination (mm Hg) 163/90 158/89 Time from first TIA to initial 4 examination (days) 4
1103
-
n = 102 Z'
_-
'
n = 187
3
Mayo Clin Proc, December 1987, Vol 62
0
10
20
Days after first medical attention
30
$&>
Fig. 1. Cumulative probability of stroke (given survival) for two groups of patients examined within 30 days after first transient ischemic attack.
*Amaurosis fugax or aphasia during first TIA.
tients (4%) in the comparison group died (Table 3). Heparin-induced retroperitoneal hemorrhage resulted in the death of one patient. The cumulative probability of stroke (given survival) within 30 days after initial examination was estimated to be 9% for the heparin-treated group and 7% for the comparison group (P = 0.5) (Fig. 1). We identified only one hemorrhagic stroke, which occurred in a patient in the com parison group who died of an intracerebral hemorrhage (Table 4). Analyses with use of stroke or TIA as the endpoint provided estimates of the cumulative probability of a cerebral ischemic event (given survival) within 30 days after initial examination—18%o for the heparintreated group and 13% for the comparison group (P = 0.3). Table 3.—Deaths Within 30 Days After Initial Examination in 289 Patients With First Transient Ischemic Attack Comparison Heparin group group Cause of death (N = 187) (N = 102) Cerebral infarction Intracerebral hemorrhage Stroke of unknown type Myocardial infarction Retroperitoneal hemorrhage Other Total
The outcome of patients who received medical attention within 1 day after the first TIA was analyzed separately because these patients had the greatest potential for benefit from treatment aimed at preventing early stroke. In such pa tients, the estimated cumulative probability of stroke (given survival) within 30 days after initial examination was 7% for patients treated with heparin (N = 61) and 5% for those who did not receive heparin (N = 108) (P = 0.6). Fifty patients (49%) in the heparin-treated group and 44 (24%) in the comparison group had more than one TIA before the initial examination (Tables 2 and 5). This difference was thought to be a consequence of the belief that patients who are initially examined after multiple TIAs of recent onset are at higher risk of stroke and thus require more aggressive management than those who are examined after only one attack. There fore, stroke probability was analyzed as a func-
Table 4.—Strokes Within 30 Days After Initial Examination in 289 Patients With First Transient Ischemic Attack Heparin Comparison group group (N = 102) (N = 187) Type of stroke 10 Cerebral infarction 1 Intracerebral hemorrhage 2 Unknown Total 13
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HEPARIN THERAPY FOR CEREBRAL ISCHEMIA
Mayo Clin Proc, December 1987, Vol 62
Table 5.—Number of Transient Ischemic Attacks (TIAs) Occurring Before Initial Examination in 289 Study Patients TIAs before initial examination (no.) 1 2-4 >5 Total
lotai Heparin group No. % 52 51 37 36 13 13 102 100
tion of the number of TIAs occurring before initial examination, regardless of subsequent treatment. The estimated cumulative probability of stroke (given survival) within 30 days after medical attention for patients examined after one, two to four, or five or more TIAs was 6%, 7%, and 20%, respectively (P = 0.03). Of the 25 patients who had five or more TIAs before ex amination, 5 had a stroke within 30 days. Four of these patients were receiving heparin at the time the stroke occurred, and one patient was in the comparison group. In the heparin-treated group, 87 patients (85%) had carotid artery TIAs, 12 (12%) had vertebrobasilar TIAs, and 3 (3%) had TIAs categorized as "either." The corresponding figures for the comparison group were 135 (72%), 42 (23%), and 10 (5%) (Table 2). To explore how these differences may have biased the results, we analyzed the probability of stroke as a function of the vascular territory of the first TIA, regardless of subsequent treatment. The estimated cumulative probability of stroke (given survival) within 30 days after initial examination was 8% for the carotid group (N = 222) and 6% for the vertebrobasilar group (N = 54) (P = 0.8) (Fig. 2). The same estimate for the "either" group (N = 13) was 8%. When the analysis was repeated with these 13 patients added, first to the carotid group and then to the vertebrobasilar group, the difference in outcome between the carotid and vertebrobasilar groups was still not significant. Of the 102 heparin-treated patients, 13 had hemorrhagic complications (Table 6). Bleeding necessitated the termination of heparin therapy in four of these patients, two of whom required blood transfusion. One death (1%) and one case of femoral neuropathy were due to heparininduced retroperitoneal hemorrhage. The overall hemorrhagic complication rate was 3.2 events per 100 person-days of heparin therapy.
Comparison No. 143 32 12 187
group % 77 17 6 100
%
No. 195 69 25 289
heparinized 27 54 52
DISCUSSION In this population-based study of the initial man agement of TIAs of recent onset, patients treated with heparin fared the same—in terms of prob ability of death, stroke, and either stroke or TIA during the 30 days after initial examination—as those who did not receive heparin. These results should be interpreted cautiously, however, be cause of the retrospective, nonrandomized design of the study. The patients in the comparison group were not untreated controls, and those in the heparfn-treated group were not uniformly managed after the period of administration of heparin. Patients who had TIAs due to various mechanisms were analyzed collectively, but in clinical practice, heparin is used to provide im mediate prophylaxis for stroke while the under lying cause of the TIA is investigated. In this situation it is quicker to exclude patients on the basis of contraindications to heparin therapy than it is to identify an indication for its use.
30 — Carotid TIA
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30
Days after first medical attention
Fig. 2. Cumulative probability of stroke (given survival) by vascular territory of first transient ischemic attack (TIA), for 276 patients examined within 30 days after first attack, regardless of subsequent treatment.
Mayo Clin Proc, December 1987, Vol 62
Table 6.—Complications of Heparin Therapy Among 102 Patients Examined Early After First Transient Ischemic Attack Complication No. Retroperitoneal hemorrhage 2*t Hemarthrosis If Upper gastrointestinal hemorrhage It Rectal bleeding 1 Hematuria 1 Epistaxis, bleeding gums, or both 4 Ecchymosis, hematoma, or both 3 Total 13 *Blood transfusion required. tHeparin therapy stopped.
Our observations provide some support for the contention that patients who are initially exam ined after multiple TIAs are at higher risk of stroke than those who have had few attacks. The subgroup of patients who had five or more TIAs before initial examination was too small to allow firm inferences, but the observation that four of the five strokes in this subgroup occurred in heparin-treated patients is in accordance with the principal conclusion of the study. The heparin and comparison groups were also dissimilar with respect to the vascular territory of the first TIA (Table 2). This difference prob ably did not bias the analysis of the risk of stroke for the two treatment groups, however, because the cumulative 30-day probabilities of stroke for all patients with carotid TIAs and for all pa tients with vertebrobasilar TIAs were not sig nificantly different (Fig. 2). This observation is consistent with the results of most studies that have examined the long-term risk of stroke after TIA.5"9 Studies in which the probability of stroke seemed lower after vertebrobasilar TIAs than after carotid TIAs have included patients with isolated symptoms such as vertigo that may have "diluted" the vertebrobasilar groups with condi tions that do not predispose to stroke.10,11 Exposing patients to the potential complica tions of heparin therapy can be justified only if the risks are clearly outweighed by the benefits of the treatment. Although no evidence of such a benefit exists, the possibility that heparin ther apy is of value in certain patients with TIA cannot be excluded. This possibility is an issue worthy of a definitive answer, which can be provided only by a randomized, prospective trial.
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We have calculated that, if heparin therapy de creases the probability of stroke during the first month after TIA from 8% to 4%, a trial with a significance level of 5% (P - 0.05, one-tailed) would have to include approximately 1,200 pa tients to have only a 10% risk of failing to reject the null hypothesis—that is, that heparin ther apy is no better than no therapy. 12 Experimental studies of deep arterial injury have suggested that optimal antithrombotic therapy consists of both a platelet inhibitor and an anticoagulant. 13 A trial designed to test this hypothesis, in which patients are randomized to receive heparin and aspirin in one arm of the trial or either drug alone in another arm, would necessitate an even larger sample. If a subset of patients at higher risk of stroke could be identified, a trial could be con ducted in fewer patients; the time required for re cruitment, however, would probably be prohibitive. Currently, no scientific evidence supports the routine use of heparin as emergency therapy for all patients with a history suggestive of recent TIA.
REFERENCES
1. Whisnant JP, Matsumoto N, Elveback LR: The effect of anticoagulant therapy on the prognosis of patients with transient cerebral ischemic attacks in a community: Rochester, Minnesota, 1955 through 1969. Mayo Clin Proc 48:844-848, 1973 2. Putman SF, Adams HP Jr: Usefulness of heparin in initial management of patients with recent transient ischemic attacks. Arch Neurol 42:960-962, 1985 3. Duke RJ, Bloch RF, Turpie AGG, Trebilcock R, Bayer N: Intravenous heparin for the prevention of stroke progression in acute partial stable stroke: a randomized controlled trial. Ann Intern Med 105:825-828, 1986 4. Committee on Cerebrovascular Diseases: A classifica tion and outline of cerebrovascular diseases II. Stroke 6:564-616, 1975 5. Baker RN, Schwartz WS, Rose AS: Transient ischemic strokes: a report of a study of anticoagulant therapy. Neurology 16:841-847, 1966 6. Friedman GD, Wilson S, Mosier JM, Colandrea MA, Nichaman MZ: Transient ischemic attacks in a com munity. JAMA 210:1428-1434, 1969 7. Ostfeld AM, Shekelle RB, Klawans HL: Transient ischemic attacks and risk of stroke in an elderly poor population. Stroke 4:980-986, 1973 8. Cartlidge NEF, Whisnant JP, Elveback LR: Carotid and vertebral-basilar transient cerebral ischemic attacks: a community study, Rochester, Minnesota. Mayo Clin Proc 52:117-120, 1977 9. Muuronen A, Kaste M: Outcome of 314 patients with transient ischemic attacks. Stroke 13:24-31, 1982 10. Marshall J: The natural history of transient ischaemic cerebro-vascular attacks. Q J Med 33:309-324, 1964
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11. Ziegler DK, Hassanein RS: Prognosis in patients with transient ischemic attacks. Stroke 4:666-673, 1973 12. Lachin JM: Introduction to sample size determination and power analysis for clinical trials. Controlled Clin Trials 2:93-113, 1981
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13. Chesebro JH, Fuster V: Antithrombotic therapy for acute myocardial infarction: mechanisms and prevention of deep venous, left ventricular, and coronary artery thromboembolism. Circulation 74 (Suppl 3):1-10, 1986
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