Aspirin-associated intracerebral hemorrhage

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.

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.

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).

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.