Original Article
The Risk of Stroke in Patients with Acute Myocardial Infarction after Thrombolytic and Antithrombotic Treatment
N Engl J Med 1992; 327:1-6July 2, 1992
- Abstract
- Abstract
Background.
Many trials in patients with acute myocardial infarction have demonstrated that thrombolytic therapy is not associated with an excessive risk of stroke, as compared with conventional treatment. However, the incidence of various forms of stroke in patients treated with different thrombolytic and antithrombotic regimens and the associated effect of risk factors for stroke are largely unknown.
Methods.
Strokes occurring in patients hospitalized with acute myocardial Infarction who were enrolled in either of two large trials were analyzed. The patients were randomly assigned to receive streptokinase (1.5 million units) or recombinant tissue plasminogen activator (t-PA) (100 mg) and also randomly assigned to receive subcutaneous heparin or no heparin. Ninety-one percent of the patients also received aspirin.
Results.
Complete data were available on 20,768 patients. A total of 236 (1.14 percent) had strokes in the hospital; 0.36 percent had hemorrhagic strokes, 0.48 percent ischemic strokes, and 0.30 percent strokes of undefined cause. Patients treated with t-PA had a small but significant excess of stroke as compared with those who received streptokinase (1.33 vs. 0.94 percent; adjusted odds ratio, 1.42; 95 percent confidence Interval, 1.09 to 1.84). The administration of subcutaneous heparin in addition to a thrombolytic agent did not increase the risk of stroke (risk with heparin, 1.13 percent; without heparin, 1.14 percent). Older age, a higher Killip class, and the occurrence of anterior infarction significantly increased the risk of stroke, whereas a higher body-mass index or a history of hypertension, diabetes, or smoking did not.
Conclusions.
Patients with acute myocardial infarction who receive thrombolytic therapy have a small risk of stroke. Treatment with t-PA as compared with streptokinase resulted in a small but significant excess of stroke. Subcutaneous heparin, given together with t-PA or streptokinase and aspirin, did not result in an increased risk of stroke. (N Engl J Med 1992;327:1–6.)
Media in This Article
Table 1
Unadjusted and Adjusted Analyses of the Relation between Stroke and Treatment.*Table 2
Unadjusted and Adjusted Analyses of the Relations between Stroke and Age, Sex, Site of Infarction, and Killip Class at Entry.*Article Activity
- Article
THE clinical trials that have demonstrated the efficacy of thrombolytic therapy in reducing mortality from acute myocardial infarction1 2 3 4 have also consistently shown that thrombolytic treatment does not impose an excess risk of stroke. The favorable risk—benefit relation of thrombolysis also applies to groups of patients considered to be at higher risk of stroke, such as the elderly or those with risk factors for stroke.5 , 6 In more than 20,000 patients with acute myocardial infarction, the second Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-2)7 and the International Study Group8 have demonstrated a small but significant excess of stroke in patients treated with alteplase (recombinant tissue plasminogen activator, or t-PA), as compared with those given streptokinase, in the absence of a significant difference in hospital mortality. In these trials, it was also shown that adding subcutaneous heparin to t-PA or streptokinase and aspirin did not affect the rate of stroke or mortality. In the present study, we explored further the effects of thrombolytic therapy and risk factors for stroke on the occurrence of both ischemic and hemorrhagic stroke.
Methods
Trial Design, Selection of Patients, and Treatment
The details of the design and main results of GISSI-2 and the International Study are provided in the original reports.7 , 8 In brief, patients were enrolled in the study if they had chest pain with ST-segment elevation of 1 mm or more in any limb lead of the electrocardiogram, 2 mm or more in any precordial lead, or both; if they were admitted to the hospital within six hours of the onset of symptoms; and if they had no clear contraindications to thrombolytic and antithrombotic treatment. There was no age limit, and each randomized patient remained in the originally assigned treatment group in the intention-to-treat analysis. The following were considered contraindications to thrombolytic and heparin treatment: a surgical procedure or trauma within the previous two weeks; recent or current bleeding; the occurrence of a cerebrovascular accident within the previous six months; uncontrolled hypertension (systolic blood pressure, ≥200 mm Hg; diastolic pressure, ≥110 mm Hg); and treatment with streptokinase within the past six months. Randomization was carried out with use of a 24-hour telephone service.
With the authorization of the ethics committee, no informed consent was obtained at the time of admission, because of the critical condition of the patients and because only standard treatments were given.
A total of 20,891 patients were randomized within six hours of the onset of symptoms. Complete clinical data were available for 20,768 patients: 10,396 received streptokinase (1.5 million units over a period of 30 to 60 minutes), and 10,372 received t-PA (100 mg over a 3-hour period). According to the factorial design, 10,361 patients were also randomly assigned to receive subcutaneous heparin (12,500 units twice daily), whereas 10,407 patients did not receive heparin. The first dose of heparin was given 12 hours after the start of the infusion of the thrombolytic agent. It was recommended that in the absence of contraindications, all the patients should receive aspirin (325 mg daily) and intravenous atenolol as soon as possible.
At randomization, the base-line characteristics of the study groups were balanced with respect to all clinical variables and the use of recommended treatments (aspirin and intravenous atenolol). Aspirin was given to 91 percent of the total study population, and intravenous atenolol to 36 percent.
The Killip scale was used to stratify the severity of myocardial infarction at the time of admission. Body-mass index was calculated as the patient's weight in kilograms divided by the square of the height in meters. A scale was used on which 1 represented a body-mass index ranging from 1 to 20; 2, an index from more than 20 to 25; 3, an index from more than 25 to 30; and 4, an index greater than 30.
Definition of Stroke
Stroke was defined as a sudden focal neurologic deficit lasting more than 24 hours. Only strokes occurring in the hospital were considered, and their cause was defined when the results of CT scanning (performed within 15 days of the event) or autopsy were available. When there was neither CT scanning nor an autopsy, the strokes were defined as being of unknown cause. For each patient who had a stroke, a copy of the complete clinical record was required, including the results of CT scanning, autopsy reports, or both, when available.
The data on 124 strokes occurring among 12,381 patients in the GISSI-2 study were reviewed by a central committee (comprising two senior cardiologists and two neurologists) blinded to the treatment assignment. For practical reasons, there was no such committee to study the 112 additional strokes that occurred in the 8387 patients enrolled in a total of 13 countries outside Italy.
Statistical Analysis
In the presentation of the results, the chief areas of interest were as follows: the comparison of the randomized treatments (streptokinase vs. t-PA and heparin vs. no heparin); the relation between stroke and the patient's previous clinical history; the relation between stroke and the clinical variables at the time of admission; and the effect of the recommended treatments. The data are presented first in the form of an unadjusted analysis in which statistical significance was analyzed by the chi-square test. Results are presented as MantelHaenszel odds ratios with 95 percent confidence intervals.9
An adjusted analysis was also performed. In this analysis, multiple logistic-regression models10 were used to assess the simultaneous effects of risk factors for stroke and treatment. The following factors were considered in the models: age (<60, 60 to 70, or >70 years), sex, body-mass index (on a scale from 1 to 4 ), systolic blood pressure at the time of randomization (<100, 100 to 150, or > 150 mm Hg), diastolic blood pressure at randomization (<100, 100 to 110, or >110 mm Hg), infarct site (e.g., anterolateral or posteroinferior), rating on the Killip scale at the time of admission (class 1 to class 4), and any history of diabetes, hypertension, or smoking. The results of the adjusted analysis are presented as odds ratios with 95 percent confidence intervals. All P values are two-tailed.
Results
Two hundred thirty-six of the 20,768 patients randomized (1.14 percent) had a stroke in the hospital. The cause of stroke could be defined in 174 of 236 cases (74 percent) by either CT scanning (144 patients) or autopsy (30 patients). Intracerebral hemorrhage accounted for 31 percent of the cases (74 of 236), and ischemic stroke for 42 percent (100 of 236). The cause remained unknown in 26 percent (62 of 236). The incidence rates of intracerebral hemorrhage, cerebral infarction, and stroke of unknown cause were 0.36, 0.48, and 0.30 percent, respectively. Of the 236 strokes, 127 (54 percent) occurred on days 0 (the day of randomization) and 1 of hospitalization, 30 (13 percent) on days 2 and 3, and 79 (33 percent) after day 3. The majority of the hemorrhagic strokes were diagnosed on days 0 and 1 (58 of 74, or 78 percent), whereas for days 2 and 3 and the days after day 3 the incidence rates were 12 percent (9 of 74) and 10 percent (7 of 74), respectively. Ischemic stroke occurred later during hospitalization: the reported incidences were 38 percent (38 of 100), 14 percent (14 of 100), and 48 percent (48 of 100), respectively, on days 0 and 1, on days 2 and 3, and after day 3. The majority of the strokes of unknown cause occurred on days 0 and 1 (31 of 62, or 50 percent), whereas on days 2 and 3 and after day 3 the incidence rates were 11 percent (7 of 62) and 39 percent (24 of 62), respectively.
Comparison of the Randomized Treatments
Table 1Table 1
Unadjusted and Adjusted Analyses of the Relation between Stroke and Treatment.* shows the incidence of stroke in the different treatment groups. More hemorrhagic or ischemic strokes occurred in the patients treated with t-PA than in those treated with streptokinase. These differences were not statistically significant when they were analyzed separately, but the difference was significant when the overall incidence was considered: 1.33 percent for t-PA as compared with 0.94 percent for streptokinase (P = 0.008). The excess number of strokes of any type with t-PA was most prominent in the elderly (2.6 percent vs. 1.6 percent for streptokinase in patients over 70 years of age, as compared with 0.9 percent and 0.7 percent, respectively, in those 70 or under) and in women (2.3 percent vs. 1.1 percent) as compared with men (1.1 percent vs. 0.9 percent). This was also true for hemorrhagic stroke: the reported incidences were 0.7 percent for t-PA and 0.3 percent for streptokinase in patients over 70, as compared with 0.4 percent and 0.3 percent in patients 70 or under; in women, the incidences were 0.8 percent and 0.4 percent, respectively, as compared with 0.3 percent for both agents in men. The overall increase in the risk of stroke associated with t-PA treatment remained statistically significant in the adjusted analysis.No differences in the overall incidence of stroke or the incidence of either hemorrhagic or ischemic stroke were found with respect to the use of heparin treatment.
Epidemiologic Variables and the Incidence of Stroke
Table 2Table 2
Unadjusted and Adjusted Analyses of the Relations between Stroke and Age, Sex, Site of Infarction, and Killip Class at Entry.* shows the relation among stroke, age, and sex. Older age was associated with a significantly higher risk of stroke. Female sex also appeared significantly related to a higher incidence of stroke, especially hemorrhagic stroke, whereas no such relation was found in the case of ischemic stroke. In the adjusted analysis, the increased risk of stroke due to any cause associated with older age remained statistically significant, but the risk associated with female sex did not. For hemorrhagic stroke, logistic-regression models confirmed the association between female sex and the risk of intracerebral hemorrhage, whereas older age was no longer significant. The association between ischemic stroke and age remained statistically significant when logistic regression was applied.No relation was found between body-mass index and stroke: for the four categories of body-mass index from 1 through 4, stroke of any cause occurred in 1.0, 1.1, 1.2, and 0.7 percent of patients, respectively. Hemorrhagic stroke occurred in 0.2, 0.3, 0.3, and 0.3 percent of patients in the respective categories, and ischemic stroke in 0.5, 0.5, 0.4, and 0.3 percent. Body-mass index was unrelated to hemorrhagic stroke in both the patients treated with streptokinase and those treated with t-PA. However, data on body-mass index were missing for 1501 patients who were equally distributed between the treatment groups. In these patients, the incidences of stroke of any cause and hemorrhagic stroke were 2.7 percent and 1.1 percent, respectively — significantly higher than in all the other patients: adjusted odds ratio for any type of stroke, 3.17 (95 percent confidence interval, 1.33 to 7.55); and for hemorrhagic stroke, 8.76 (95 percent confidence interval, 1.16 to 66.33). It is likely that the occurrence of stroke or another major complication early in the hospitalization made the collection of data on weight and height impossible.
There was no relation between a history of diabetes and the occurrence of stroke. Among the patients for whom data on a history of diabetes were available, the incidence of any type of stroke in the diabetic patients was 1.2 percent (33 of 2767), as compared with 1.1 percent (192 of 17,118) in the nondiabetic patients (adjusted odds ratio, 0.94; 95 percent confidence interval, 0.65 to 1.38).
The unadjusted analysis suggested that a history of smoking had a protective role against stroke, but this disappeared after standard adjustments (adjusted odds ratio for any type of stroke, 0.79; 95 percent confidence interval, 0.58 to 1.06; for hemorrhagic stroke, 0.66; 95 percent confidence interval, 0.39 to 1.13; and for ischemic stroke, 0.90; 95 percent confidence interval, 0.58 to 1.40).
Stroke and Clinical Variables
Table 2 shows the relation betweeen stroke and the site of myocardial infarction or the patient's Killip class on admission. Patients with anterior infarction were more likely to have a stroke than those with infarcts in other locations. Ischemic stroke was significantly associated with anterior infarction. There was no relation between the location of the infarct and the incidence of hemorrhagic stroke. Strokes of any type and ischemic stroke occurred more often in patients with more extensive cardiac impairment — i.e., those who were in Killip class 2 or higher at entry (Table 2).
In the adjusted analysis, anterior infarction and higher Killip class at the time of randomization remained significantly associated with a higher risk of stroke. Anterior infarction and Killip class 2 were no longer significantly associated with a higher risk of ischemic stroke, but a statistically significant association persisted for Killip classes 3 and 4 in the adjusted analysis. Killip class 2 was also associated with a higher risk of hemorrhagic stroke, as the adjusted analysis confirmed.
Table 3Table 3
Unadjusted and Adjusted Analyses of the Relation between Stroke and a History of Hypertension, Systolic and Diastolic Blood Pressure at Admission, and Use of Aspirin.* shows the relation among stroke, a history of hypertension, and blood pressure at entry. A history of hypertension was associated with a higher risk of any type of stroke and specifically with a higher risk of hemorrhagic stroke, but this finding was statistically significant only in the unadjusted analysis. Systolic blood pressure over 150 mm Hg and diastolic blood pressure between 100 and 110 mm Hg were not significantly related to stroke. However, diastolic blood pressure over 110 mm Hg was strongly associated with an increased risk of both any type of stroke and hemorrhagic stroke. The latter association was confirmed by the adjusted analysis.Effect of Recommended Treatments
The use of intravenous atenolol did not affect the occurrence of stroke. The reported incidences of 1.2, 0.3, and 0.5 percent for all strokes, hemorrhagic strokes, and ischemic strokes, respectively, in 13,209 patients who did not receive atenolol were very similar to those of 1.0, 0.4, and 0.4 percent found in the 7546 patients who received atenolol. As shown in Table 3, aspirin use was associated with a lower incidence of all types of stroke in both the unadjusted and the adjusted analyses.
Clinical Outcomes in Patients with Stroke
As would be expected, outcomes in patients with stroke were worse than those in patients without stroke (Table 4Table 4
Mortality Rates from Various Types of Stroke and Combined Incidence of Mortality and Nonfatal Stroke, According to Treatment.). There were no differences in the rates of mortality from stroke among the patients randomly assigned to different treatments. Also, the combined incidence of death and nonfatal stroke was very similar in the different treatment groups (unadjusted odds ratio for t-PA vs. streptokinase, 1.08; 95 percent confidence interval, 0.98 to 1.18; and for no heparin vs. heparin, 1.05; 95 percent confidence interval, 0.95 to 1.15).Discussion
This analysis of strokes occurring in the GISSI-2 and International Study trials confirms the low incidence (1.14 percent) of this complication after thrombolytic and antithrombotic therapy. The data in this large cohort of patients (20,768) were analyzed to help clarify the debated issue of the reported excess of stroke with t-PA and to provide a better understanding of the risk factors for stroke in patients with acute myocardial infarction who are receiving thrombolytic and antithrombotic therapy. This issue has also recently been examined in the Third International Study of Infarct Survival (ISIS-3) trial, with results generally similar to ours.11
The only significant finding related to the randomized treatments was that as compared with streptokinase, t-PA was associated with a somewhat higher risk of stroke (four excess events for every 1000 treated patients) after adjustment for the presence of risk factors for stroke. This increased risk has to be evaluated in the context of the overall efficacy of the different treatment assignments. With the dosages of t-PA, streptokinase, and heparin used in these trials, no differences in hospital mortality (with t-PA, 8.9 percent; with streptokinase, 8.5 percent; with heparin, 8.5 percent; and with no heparin, 8.9 percent) or major cardiac complications were found between the different treatment groups. There were also no differences between the treatments with regard to the combined incidence of death and nonfatal stroke. The incidence of stroke in the patients treated with t-PA was comparable with that recently found in the second Thrombolysis in Myocardial Infarction (TIMI-II) trial,12 when the dosage of the drug used was 100 mg.
The addition of subcutaneous heparin to a combined thrombolytic and antiplatelet regimen did not affect mortality in the hospital or the occurrence of stroke.7 , 8 , 13 It should, however, be noted that in all major trials, as in this one, the majority of strokes were nonhemorrhagic. Therefore, it is conceivable that in particular subgroups of patients — for example, those with large anterior infarctions — higher levels of heparinization (including perhaps the use of intravenous heparin) may be useful to reduce the incidence of ischemic stroke. The concomitant administration of high-dose intravenous heparin14 with t-PA to prevent early coronary reocclusion must be viewed with caution, however, because of a possible increase in the risk of hemorrhagic stroke.
The large number of strokes we studied allowed us to analyze the effect of the principal risk factors for stroke reported in the literature.5 , 6 , 15 , 17 Age was confirmed as a strong predictor of stroke and, more specifically, ischemic stroke. Despite this increased risk, the overall risk—benefit profile in elderly patients remains favorable for thrombolytic therapy, and older age cannot be considered a contraindication for such treatment.
A significant excess of hemorrhagic stroke was found in women, even after adjustment for the predefined risk factors. The reasons for this higher incidence are not clear. It is possible that an inherent biologic difference makes women more likely to have a hemorrhagic stroke. A similar biologic vulnerability has been cited as a possible explanation for the higher rate of hospital mortality among women.18
In our study, the incidence of stroke was analyzed in relation to body-mass index, which takes height and weight into account. In a finding at variance with the findings of TIMI-II,19 there was no relation between the body-mass index and the incidence of stroke, either in the population as a whole or in the t-PA group.
The already well established5 , 15 , 20 association between ischemic stroke and both anterior infarction and poor hemodynamic status (as manifested by a higher Killip class) was confirmed. Echocardiographic studies21 , 22 have shown that the majority of patients with visible mural thrombi have had an anterior infarction, whereas patients with good left ventricular function and inferior infarction rarely had detectable thrombi. The presence of mural thrombi was associated with an increased risk of peripheral embolization and stroke. Our data confirm the association between anterior infarction and stroke, but no echocardiographic data on the presence of thrombi were available.
According to the study protocol, patients with high blood pressure at entry were excluded from randomization, but patients with a history of hypertension were eligible.7 , 8 There was no independent association between stroke and a history of hypertension or specific levels of systolic and diastolic blood pressure at entry, except in the case of diastolic blood pressures higher than 110 mm Hg on admission. Although diastolic blood pressure in excess of 110 mm Hg was a criterion for exclusion, 155 patients with pressures at or above this level were randomized at the discretion of the local physicians. The risk of hemorrhagic stroke in these patients was more than four times higher than that in patients with diastolic blood pressures of less than 100 mm Hg. In patients with diastolic blood pressures above 110 mm Hg, the possible benefit of thrombolysis must be carefully weighed against the increased risk of stroke.
The administration of aspirin and intravenous atenolol was not randomized. Therefore, the observed effects of these treatments on the occurrence of stroke must be interpreted with caution. The incidence of hemorrhagic or ischemic stroke and of strokes of all types was similar whether or not intravenous atenolol was given. Therefore, our data do not support the suggestion of a protective effect of beta-blockers against cerebral hemorrhages that has been put forward by the TIMI-II investigators.23
The patients who received aspirin had a lower incidence of stroke of either hemorrhagic or ischemic cause. Multivariate analysis confirmed this effect. The favorable effect of aspirin on ischemic stroke was expected, because previous trials2 and overviews24 have documented its efficacy for the prevention of thromboembolic events. The protective effect against hemorrhagic stroke was surprising, however. In ISIS-2,2 aspirin significantly reduced the incidence of overall stroke and did not lead to an excess of hemorrhagic strokes when administered with streptokinase, but no protective effect was suggested. It should be stressed that our findings are derived from the study of nonrandomized patients. Furthermore, a chance association cannot be excluded.
Finally, our study confirms the very poor prognosis in patients with stroke during the course of a myocardial infarction.3 4 5 No information on the residual disability of patients with stroke who are sent home from the hospital has been collected in our trials.
Address reprint requests to Dr. Maggioni at the GISSI-2 Coordinating Center, Via Eritrea 62, 20157 Milan, Italy, or to Dr. Van de Werf at the International Study Group, c/o Division of Cardiology, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium.
*A complete list of collaborators and participating centers has appeared in Lancet 1990;336:65–71 and Lancet 1990;336:71–5.
GISSI-2 Steering Committee: G.A. Feruglio, A. Lotto, F. Rovelli, P. Solinas, L. Tavazzi, and G. Tognoni. International Study Group Steering Committee: F. Van de Werf, R.G. Wilcox, G.I. Barbash, J.R. Hampton, J. Heikkila, A. Kristinsson, S. Moulopoulos, E. Paolasso, E. Sandoe, J. Simes, L. Tavazzi, G. Tognoni, T. Van der Werf, M. Verstraete, G. von der Lippe, and H. White.
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