Aspirin-associated intracerebral hemorrhage
Clinical and radiologic features
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Abstract
Objective: To identify the clinical and radiologic features of intracerebral hemorrhage (ICH) in aspirin users.
Background: Although the benefits of aspirin outweigh its hemorrhagic risks for patients at high risk of vascular diseases, prolonged use of aspirin is associated with an increased risk of ICH.
Methods: The authors enrolled consecutive patients with acute stroke who were admitted to a regional hospital from 1993 to 1998 into a stroke registry. From this registry, they identified all stroke patients who had ICH confirmed by CT scan and then selected those taking regular aspirin before ICH as the study group. For each study patient, they selected the immediate next two patients with ICH but not taking aspirin as controls.
Results: The authors identified 58 aspirin users and 1193 nonusers among all patients hospitalized for ICH. From the group of nonusers, they selected 116 patients as controls. The locations of the hematoma were different (p = 0.002), with more lobar hematoma in the aspirin group (32.8%) than in the control group (10.3%). Prior cerebrovascular disease was the reason for taking aspirin in 37 (64%) patients but five patients had prior ICH.
Conclusions: The propensity for lobar hematoma in aspirin-associated ICH suggests its pathology may be somewhat different from spontaneous ICH among nonaspirin users. Further research to examine the risks and benefits of aspirin use in certain subgroups at risk of both thrombotic and hemorrhagic events is needed.
Antithrombotic agents are used extensively for the treatment and prevention of stroke. However, agents that inhibit the thrombotic process also increase the risk of intracerebral hemorrhage (ICH). For example, the most feared complication of thrombolytic therapy for acute ischemic stroke and of the chronic use of warfarin for atrial fibrillation is hemorrhage into the brain. For patients at high risk of vascular disease, the benefits of aspirin far outweigh the risk of hemorrhage.1,2 However, use of aspirin is associated with about 1 excess ICH in 1000 patients treated.3-8 As a result, there are suggestions that patients with high risk of ICH, such as Asians and hypertensive patients with low cholesterol level, should not be treated with aspirin.4 Understanding the characteristics of aspirin-associated ICH may provide insights into its mechanism and may help to design clinical studies to improve the risk–benefit ratio of aspirin. Unlike warfarin-associated ICH,9 there has not been a detailed description of the clinical and radiologic features of aspirin-associated ICH in the English literature. We examine the features of aspirin-associated ICH in comparison with ICH in nonaspirin users.
Methods.
This study was performed in a community-based teaching hospital located at the New Territories in Hong Kong. We did not have stroke patients referred from other hospitals for acute management. We reviewed a prospectively conducted stroke registry for consecutive patients admitted with acute stroke from January 1, 1993 to December 31, 1998. This registry enrolled consecutive acute stroke patients who were admitted to a large regional hospital. Each morning, a stroke nurse examined all hospital admissions and identified patients admitted for acute stroke within 7 days of onset. Each patient’s sex, age, medical history, and current medications were recorded. We defined acute stroke as “rapidly developing clinical signs of focal (or global) disturbance of cerebral function, with symptoms lasting 24 hours or longer or leading to death, with no apparent cause other than of vascular origin” according to the World Health Organization criteria. History of hypertension, diabetes mellitus, stroke or TIA, and cardiac diseases (including atrial fibrillation and ischemic heart diseases) was sought and noted. We defined hypertension as previous record of at least two blood pressure readings of more than 160/90 or the requirement of regular antihypertensive drugs. We defined diabetes as having a fasting plasma glucose level of more than 7.8 mmol/L, a random glucose level of more than 11.1 mmol/L, or the requirement of regular hypoglycemic drugs.
From this registry, we identified all patients with ICH. The diagnosis of ICH required the presence of intracerebral hematoma on a CT scan of the head. We excluded patients with hemorrhagic transformation of cerebral infarcts, patients who had ICH within a week of ischemic stroke, or if CT scan was not done. In our hospital, nearly all stroke patients had CT scan examination within 24 hours; therefore, misdiagnosis of hemorrhagic transformation of an infarct as ICH should be minimal. Hemorrhages associated with trauma or brain tumor were also excluded. We also excluded patients on warfarin treatment. We determined the status of aspirin users or nonaspirin users at the time when patients’ details were entered into the stroke registry. We regarded aspirin users as those who require long-term use of aspirin for prevention of cardiovascular diseases. Patients who did not require long-term use of aspirin were regarded as nonaspirin users, even though they might take occasional aspirin-containing compounds. We took the following steps to ascertain the intake or nonintake of aspirin before the index ICH: 1) history from patient or a relative on admission; 2) positive identification of aspirin tablets among the current medications brought in by patient or a relative; and 3) written evidence of regular prescription of aspirin on the medical records of ambulatory care or hospital notes. We did not test urine for aspirin or its metabolites.
Ideally, a cohort study design should be used. However, a cohort study would require much more resources than were available to us. Therefore, we opted for a less labor-intensive case-control design. For each patient with aspirin-associated ICH, we selected the next two patients with ICH who were not taking aspirin as controls. The CT scans of the aspirin users and the controls were reviewed systematically by a qualified radiologist who was blinded to the clinical details. The locations of the hematoma were classified into basal ganglion, thalamus, lobar, posterior cranial fossa, and caudate. If there was more than one hematoma, we took the location of the hematoma that corresponded to the presenting symptoms. The volume of the hematoma was estimated by means of the ABC/2 method.10 The locations of previous cerebral infarcts or hemorrhage according to the medical records and previous CT scans (if present), were also noted. Case fatality included any death within the first 30 days after ICH.
Statistical analysis.
Statistical analysis was performed with SPSS 8.0 and GraphPad InStat 3.00. Bivariate analysis comparing the demographic characteristics, medical history, admission status, and CT results was done between ICH patients with and without aspirin. These crude associations for the qualitative factors were assessed by the preliminary cross-tabulations with the χ2 test. For the quantitative variables, t-test was used for comparing the normally distributed variables, and for the skewed distributed variables, Mann-Whitney U test was applied. The differences were considered significant at a value of p < 0.05. Multivariate logistic regression was used to perform the odds ratio for aspirin-associated ICH after adjusting for age, sex, medical history of hypertension, diabetes, previous cerebrovascular disease, cardiac disease, smoking, and premorbid disability. All variables were entered in a regression analysis simultaneously without stepwise exclusion of any variables.
Results.
There were 1251 patients admitted with ICH from 1993 to 1998. Among these patients, 58 were aspirin users and 1193 were nonusers. We selected 116 nonaspirin users as controls. In 54 aspirin users (93%), there was additional physical evidence of aspirin intake apart from history from the patient or a relative. We found written evidence of repeated aspirin prescriptions in 46 patients: 45 from patients’ medical records and 1 from nursing home records. The average number of aspirin prescriptions was 7 (range 1 to 20). In eight patients, we could not retrieve medical records but were able to positively identify aspirin among the current medications brought in by them. In four patients the history of aspirin intake could not be corroborated by additional physical evidence. The clinical characteristics and the radiologic features of the studied patients are summarized in table 1. There was no difference in sex or age between the aspirin group and the controls. History of hypertension, cerebrovascular disease, or cardiac disease was significantly more frequent in the aspirin group. The difference remains significant after adjustment for sex, age, and other risk factors in a multivariate analysis.
Intracerebral hemorrhage patient characteristics in relation to aspirin used
The location of the hematoma was significantly different between the two groups, mainly because lobar hematoma was much more common in the aspirin group than the controls (χ2 test p = 0.002). In addition, there was a nonsignificant trend for patients in the aspirin group to have a larger hematoma (median 17.5 mL versus 13.3 mL) and higher case fatality (27.6% versus 20.7%). There were four patients who had more than one hematoma. All four patients were in the nonaspirin group. The locations of the principal hematoma (secondary hematoma) were: occipital (cerebellum), parietal (temporal), thalamus (basal ganglia), and frontal (parietal).
Characteristics of patients with aspirin-associated ICH.
The mean dosage of aspirin was 118 mg (range 75 to 300 mg) daily and the median duration of aspirin treatment was 15 months (range 1 to 120 months). Thirty-seven patients (63.8%) were given aspirin for the management of prior cerebrovascular disease (table 2). The specific diagnoses of prior cerebrovascular diseases included 26 ischemic strokes, 5 ICH, 2 unknown types, and 4 TIA. For the patients who had prior ICH, aspirin was not given on discharge from the hospital but was later started by primary care physicians, who were probably unaware of the stroke type. Among 26 patients who had previous ischemic stroke, the sites of ICH were different from the previous infarcts in 20 patients (77%), the same in 1 patient, and unknown in 3 patients. Among five patients with prior ICH, the sites of the new ICH were different in three patients (from parietal lobe to putamen; from left putamen to right putamen; from occipital lobe to frontal lobe) and the same in two patients (both in the left occipital lobe). Twenty patients took aspirin for cardiac disease and four patients for primary prevention.
Indications for taking aspirin (n = 58)
Discussion.
Our data do not establish the causality of aspirin in the development of ICH among the aspirin users. The best evidence to prove that aspirin is an independent factor of the development of ICH is randomized control trial and meta-analysis of such trials. A number of randomized trials and meta-analyses indicate aspirin is associated with increased risk of ICH.4-8,11 However, randomized control trials and meta-analyses do not provide detailed clinical and radiologic features of individual patients. The aim of our study is to supplement the currently available data by describing the clinical and radiologic features of ICH in aspirin users.
The locations of the hematoma in the aspirin users differ significantly from those of nonusers. This difference is primarily produced by the higher number of patients with lobar hematoma among the aspirin users. The proportion of lobar hemorrhages varies from 19% to 47% among different reported series.12 Therefore, it is important to compare the distribution of hemorrhages in aspirin users with a control group in the same population. In the aspirin users, 32% of ICH are lobar hematoma, compared with only 10% in the nonaspirin users. The differences in the distribution of hemorrhages are highly significant. Our observation is concordant with the excessive lobar hematoma in patients with myocardial infarction who are treated with IV thrombolytic agents. In the GUSTO-1 trial, 77% of the 244 ICH patients had lobar hematoma.13 In an overview of warfarin-associated ICH, 30% of ICH were located in the lobar region.9 Unfortunately, none of these reported series include a control group for comparison. To our knowledge, this is the first report of disproportionate location of aspirin-associated ICH in the lobar region.
The propensity for lobar hematoma may provide insights into the potential mechanism of aspirin-associated ICH. Spontaneous ICH is mostly caused by chronic hypertension and usually located at the basal ganglia. For cerebral hemorrhage located mainly in the lobar areas, vascular abnormality such as amyloid angiopathy and occult angioma should be considered.14 Amyloid angiopathy tends to affect older patients,15 similar to our patients, and some investigators suggest it may be associated with thrombolysis-associated ICH.13,16,17 Recent studies have shown that hemosiderin deposit as shown on gradient echo MRI may be a marker of amyloid angiopathy.15,18 At the conclusion of this study, we asked all survivors in the aspirin group to be examined by gradient echo MRI for evidence of hemosiderin deposit. Seven patients agreed and all of them had evidence of microhemorrhages at sites other than previous ICH. Further prospective studies are needed to test the hypothesis that cerebral amyloid angiopathy is a risk factor of aspirin-associated ICH.
Although the benefit of aspirin outweighs the hemorrhagic risk in randomized clinical trials, the hemorrhagic risk may be higher in routine clinical practice.19,20 Patients with prior ICH also have a substantial risk of recurrent hemorrhage.21 Therefore, we need further research to examine the risk–benefit ratio of aspirin use in certain subgroups at risk of both thrombotic and hemorrhagic events, such as those with cerebral amyloid angiopathy.
- Received September 21, 1999.
- Accepted in final form March 17, 2000.
References
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- ↵Gebel JM, Sila CA, Sloan MA, et al. Thrombolysis-related intracranial hemorrhage: a radiographic analysis of 244 cases from the GUSTO-1 trial with clinical correlation. Stroke 1998;29:563–569.
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