Recurrence of Bleeding in Patients With Primary Intracerebral Hemorrhage
Background and Purpose Rebleeding in patients with primary intracerebral hemorrhage is considered uncommon, but there are no precise data to support this opinion. The purpose of this study was to assess the incidence and predictors of recurrent bleeding in survivors of primary intracerebral hemorrhage.
Methods As part of a prospective study, 112 survivors of a first primary intracerebral hemorrhage were followed up for a mean period of 84.1 months after their discharge. To ascertain risk factors that may influence rebleeding, several demographic, medical history, clinical, and laboratory variables were collected and analyzed.
Results Twenty-four percent (27/112) of survivors experienced one or more rebleedings during the follow-up period, in 8 cases (30%) in the first year of follow-up; in the others recurrence occurred later, up to 11.5 years. Rebleeding had a high mortality rate: 70% of patients died as a consequence of their second or third hemorrhage. Univariate and multivariate analyses showed that lobar location of the first hemorrhage was the only significant predictor of rebleeding. Patients with rebleeding were more frequently older, more often had a history of previous transient ischemic attack or ischemic stroke, and less often had hyperlipidemia than patients without rebleeding, although these correlations did not reach statistical significance. During follow-up, poor control of arterial hypertension was found in 7% of hypertensive patients without rebleeding and in 47% of hypertensive patients with rebleeding.
Conclusions Our study showed that rebleeding after a first primary intracerebral hemorrhage is not as uncommon as is usually believed. The risk of rebleeding seems to be particularly high after hemorrhage at the junction of the gray and white matter, a site regarded as typical of hemorrhages due to amyloid angiopathy, and when arterial hypertension is poorly controlled.
Recurrent stroke has been reported to be one of the major causes of morbidity and mortality among stroke survivors. Although the prognosis of patients with cerebrovascular disease has been the subject of many studies, the problem of recurrent bleeding in patients with primary intracerebral hemorrhage has rarely been evaluated.1 2 3 4 5 Evaluation of the frequency of rebleeding may help to clarify the natural course of this stroke subtype. The identification of risk factors may have therapeutic implications and may improve secondary prevention. Therefore, we evaluated the incidence, predictors, and impact on mortality of recurrent bleeding occurring after hospital discharge in a population of survivors of primary intracerebral hemorrhage.
Subjects and Methods
Patients entering the study were selected from those consecutively hospitalized in our institute during the 5-year period from January 1978 to December 1982 for intracerebral hemorrhage (138 men, 93 women; mean age, 63 years; range, 18 to 89 years). Of these patients, 148 survived the acute event. After exclusion of patients with hemorrhage known to be due to intracerebral aneurysms, arteriovenous malformations, primary and metastatic brain tumors, and hemorrhagic disorders, a total of 112 survivors were diagnosed as having suffered a primary intracerebral hemorrhage. Diagnosis was confirmed by CT brain scan in all cases. A further angiographic examination was performed in 31 patients in whom vascular malformations were suspected.
Patients were followed up at variable intervals up to 1993. At each follow-up examination, data were collected on neurological status, new cerebrovascular episodes, appearance of new risk factors, and effectiveness of treatment of preexisting risk factors. The treatment of arterial hypertension was defined as poor when the patient was found more than once to have a systolic blood pressure greater than 160 mm Hg or diastolic pressure greater than 90 mm Hg. Surviving patients were examined for a final assessment during 1993. The diagnosis of rebleeding was confirmed in all cases by CT brain scan or brain autopsy.
To ascertain risk factors that may predict a recurrent hemorrhage, certain demographic, medical history, and clinical and laboratory variables of groups of patients with and without rebleeding were compared. The variables examined were age; sex; history of hypertension (previous diagnosis of arterial hypertension: systolic blood pressure >160 mm Hg or diastolic >90 mm Hg or both and/or past or present use of antihypertensive agents); diabetes (previous diagnosis of diabetes and/or past or present use of antidiabetic agents); current smoking (nonsmokers, ≤20 cigarettes per day, >20 cigarettes per day); alcohol consumption expressed in milliliters per week of pure ethanol (none, ≤400 mL/wk, >400 mL/wk); hyperlipidemia (cholesterol >250 mg/100 mL or triglycerides >180 mg/100 mL or both); previous coronary artery disease (CAD) (angina, myocardial infarction); previous transient ischemic attack (TIA) or ischemic stroke; electrocardiographic (ECG) evidence of myocardial infarction, atrial fibrillation or flutter, and/or left ventricular hypertrophy; and site of hemorrhage (basal ganglia and thalamic regions, brain stem, and cerebellum versus lobar or primary intraventricular). All these variables were examined individually by univariate analysis. Significant variables and those deemed clinically important were included in a multiple logistic regression model. The life-table method was used to determine the cumulative proportion of recurrence-free survival.
The 112 patients (mean age, 63.7±10.2 years; range, 35 to 89 years) consisted primarily of men (73 men, 39 women). In 61 patients (54%) the hemorrhage was located in the basal ganglia and thalamic regions, in 42 patients (38%) it was lobar, and in 8 (7%) it was located in the cerebellum or brain stem (Table 1⇓). More than 67% of the patients had arterial hypertension, 10% had diabetes, 25% had hyperlipidemia, 20% had a history of TIA or ischemic stroke, 29% had a history of CAD or abnormal ECG, 41% were smokers, and 28% were heavy drinkers (>400 mL/wk of pure ethanol). The average follow-up period after discharge from the hospital was 84.1 months (range, 1 to 189 months).
Of the 112 patients, 27 (24%) had one or more instances of rebleeding. In 21 patients (78%) rebleeding occurred in the first 5 years of follow-up (8 in the first year, 4 in the second, 4 in the third, 1 in the fourth, and 4 in the fifth); in the others rebleeding occurred after a longer period, up to 11.5 years. The cumulative proportion of survival without rebleeding was 79% after 5 years of follow-up and 71% after 10 years of follow-up (Figure⇓). Rebleeding occurred in the same site as the first hemorrhage in 9 of 27 patients (33%) and in a different site in the others. In general, recurrent hemorrhages had the same type of location (deep or superficial) as the first hemorrhage. Rebleeding was highly lethal: 19 of 27 patients (70%) died as a consequence of the second or third hemorrhage (Table 2⇓). In the same period, 14 patients (3 with rebleeding and 11 without) had cerebral ischemic events (8 strokes, 6 TIAs).
Univariate analysis showed that the risk of rebleeding was not significantly associated with factors such as age; sex; hypertension; hyperlipidemia; smoking; heavy drinking; diabetes; previous CAD, TIA, or ischemic stroke; or abnormal ECG. However, patients with rebleeding were more often older, more often had a history of previous TIA or ischemic stroke, and less often had hyperlipidemia than patients without rebleeding. The only individual factor significantly associated with recurrence of bleeding was lobar location of the first hemorrhage (63% in patients with rebleeding and 31% in patients without rebleeding) (Table 3⇓).
On the basis of the results of univariate analysis, five potential predictors (age, arterial hypertension, previous TIA or ischemic stroke, hyperlipidemia, and hemorrhage site) were selected for multivariate analysis by logistic regression. Lobar location of hemorrhage was the only significant predictor (P<.001) of rebleeding.
During follow-up, 9 patients (7 without rebleeding and 2 with rebleeding) presented with newly diagnosed arterial hypertension. Poor control of arterial hypertension was detected in 7% (4/59) of hypertensive patients without rebleeding and in 47% (9/19) of hypertensive patients with rebleeding and was strongly related (P<.0001) to recurrence of bleeding.
Evaluation of topographic features of the first hemorrhage in patients with lobar localization showed that in 50% of patients with rebleeding and 27% of patients without rebleeding the hemorrhage was small and located at the junction of the gray and white matter, with a preference for the posterior regions of the cerebral hemispheres.
Rebleeding after spontaneous intracerebral hemorrhage is considered to be rare, but there are no precise data to support this opinion. Although the short-term outcome of patients with cerebral hemorrhage has been extensively studied, the problem of long-term prognosis and particularly that of rebleeding has rarely been investigated. There are many reasons for this, but in the words of Marquardsen,6 the main reason is probably the conviction that “survivors from haemorrhage are too few to justify any statements concerning the risk of recurrence in this type of stroke.” With advances in diagnostic possibilities offered by CT and perhaps also improved therapies, the situation has changed, and survivors from cerebral hemorrhage are no longer too few.
The few previous studies partly regard follow-up of patients with cerebral hemorrhage1 2 3 4 5 7 and partly patients with ischemic and hemorrhagic strokes in general.8 9 10 In most of these studies the populations were small,1 2 8 9 follow-up was short,3 4 no distinction was made between recurrence of hemorrhage and ischemia,4 9 10 or patients with secondary cerebral hemorrhage were not excluded.7 8 9 10 Fieschi et al3 and Douglas and Haerer1 failed to observe rebleeding in follow-up studies of 1 year and 29 months, respectively. Other studies reported a 2.6% and 6.8% recurrence of bleeding with follow-up periods of 54 and 32 months, respectively.2 5 The data from other studies cannot be interpreted because no attempt was made to distinguish recurrence of bleeding from recurrence of ischemia, and all types of cerebral hemorrhage were included.4 7 8 9 10
Our results suggest that in patients with primary intracerebral hemorrhage the risk of rebleeding is not negligible: 24% of patients experienced one or more episodes of rebleeding during a mean follow-up period of 84.1 months. This risk seemed to be highest in the first year after the first hemorrhage.
It is reasonable to assume that correction of factors predisposing for cerebral hemorrhage might improve the long-term prognosis of patients with primary intracerebral hemorrhage. Certain conditions favoring cerebral hemorrhage, however, cannot currently be corrected. Among these, cerebral amyloid angiopathy (CAA) is a well-recognized cause of intracerebral hemorrhage, particularly in the elderly.11 12 13 The hemorrhages are lobar in location and usually located at the junction of the gray and white matter, with a preference for the posterior regions of the cerebral hemisphere, particularly the occipital lobe, reflecting the distribution of the most severely CAA-affected vessels.11 12 14 15 In some of our patients with rebleeding, the location of the first and subsequent hemorrhages strongly suggested CAA. CAA may not be invoked in patients with basal ganglia or brain stem hemorrhage, since the penetrating vessels supplying these structures are not involved in this vasculopathy.12 13 14 In these cases, inadequate control of arterial hypertension may be the main factor for rebleeding.
In conclusion, our study shows that rebleeding after a first primary intracerebral hemorrhage is not as infrequent an event as is commonly thought. The risk of rebleeding seems to be high after hemorrhage at the junction of the gray and white matter, a site regarded as typical of hemorrhages due to amyloid angiopathy, and when arterial hypertension is poorly controlled.
This study was supported in part by research grants from the University of Siena (Contributi per la Ricerca Scientifica).
Reprint requests to Stefano Passero, MD, Istituto di Clinica delle Malattie Nervose e Mentali, Universita’ di Siena, Viale Bracci, I-53100 Siena, Italy. E-mail firstname.lastname@example.org.
- Received March 6, 1995.
- Revision received April 10, 1995.
- Accepted April 14, 1995.
- Copyright © 1995 by American Heart Association
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