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(Stroke. 2001;32:2567.)
© 2001 American Heart Association, Inc.

Original Contributions

Management and Prognostic Features of Intracerebral Hemorrhage During Anticoagulant Therapy

A Swedish Multicenter Study

Lars Sjöblom, MD; Hans-Göran Hårdemark, MD, PhD; Arne Lindgren, MD, PhD; Bo Norrving, MD, PhD; Martin Fahlén, MD, PhD; Margareta Samuelsson, MD, PhD; Lennart Stigendal, MD, PhD; Dick Stockelberg, MD, PhD; Ali Taghavi, MD; Lena Wallrup, MD Jonas Wallvik, MD, PhD

From the Departments of Internal Medicine (L.S.) and Neurology (H.-G.H.) at Uppsala University Hospital, Uppsala; the Department of Neurology at Lund University Hospital (A.L., B.N.), Lund, and Örebro University Hospital (M.S.), Örebro; and the Departments of Internal Medicine at Kungälv Hospital (M.F.), Kungälv, Sahlgrenska University Hospital (L.S., D.S.), Göteborg, Mölndal Hospital (A.T.), Mölndal, Falu Hospital (L.W.), Falu, and Sundsvall Hospital (J.W.), Sundsvall, Sweden.

Correspondence to Hans-Göran Hårdemark, MD, PhD, Department of Neurology, Center of Clinical Neurosciences, University Hospital, S 751 85 Uppsala, Sweden. E-mail H-G.Hardemark{at}neurologi.uu.se

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose—— Patients treated with oral anticoagulants (ACs) have an increased risk of intracerebral hemorrhage (ICH), which is more often fatal than spontaneous ICH. Options to reverse the AC effect include intravenous administration of vitamin K, plasma, and coagulation factor concentrate. However, the optimal management of AC-related ICH has not been determined in any randomized trial. In this study, the present management of AC-related ICH was surveyed, and determinants of survival were assessed.

Methods—— We retrospectively reviewed the medical records of all AC-related ICHs at 10 Swedish hospitals during a 4-year period, 1993 to 1996. Survival status after the ICH was determined from the Swedish National population register.

Results—— We identified 151 patients with AC-related ICH. Death rates were 53.6% at 30 days, 63.6% at 6 months, and 77.5% at follow-up (mean 3.5 years). The case fatality ratio at 30 days was 96% among patients unconscious on admission (n=27), 80% among patients who became unconscious before active treatment was started (n=15), 55% among patients in whom no special action was taken except withdrawal of AC treatment (n=42), and 28% among patients given active anti-coumarin treatment while they were still conscious (n=64). The case fatality ratio at 30 days was 11% in the group treated with plasma (n=18), 30% in the group treated with vitamin K (n=23), and 39% in the group treated with coagulation factor concentrate (n=23). Within the first 24 to 48 hours after admission, 47% of the patients deteriorated. Choice of therapy to reverse the AC effect differed substantially between the hospitals (P<0.0001), as did the time interval from symptom onset to start of treatment. Multiple logistic regression analysis showed only 2 factors (intraventricular extension of bleeding and ICH volume) that were independently related to case fatality at both 30 days and 6 months. The results were similar when the analysis was restricted to patients who were conscious on admission.

Conclusions—— In AC-related ICH, a progressive neurological deterioration during the first 24 to 48 hours after admission is frequent, and the mortality is high. Choice of therapy to reverse the AC effect differed considerably between the hospitals. There was no evidence that any treatment strategy was superior to the others. A randomized controlled trial is needed to determine the best choice of treatment.

Key Words: anticoagulants • cerebral hemorrhage • prognosis • tomography, x-ray computed

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The use of oral anticoagulant (AC) treatment has increased significantly in Sweden during recent years. Currently, 0.8% of the Swedish population has been estimated to receive such therapy.¹ AC treatment increases the risk of intracerebral hemorrhage (ICH) 8- to 10-fold.^2,3 Among patients given AC treatment during longer periods, the annual risk of ICH is 1% to 2%. Compared with spontaneously occurring ICHs, AC-related ICHs are often larger and carry a higher mortality (44% to 68% at 1 to 6 months).^3–8 Low prothrombin complex values, ie, high international normalized ratios (INRs), increase the risk of ICH,^8,9 but the relationship between the INR value on admission and the prognosis has not been extensively studied.^3,10

Major textbooks published in the early 1990s and a recently published authorized guideline provide either no specific recommendations of pharmacological treatment of AC-related ICH in the acute phase,^11,12 or they recommend the use of vitamin K or plasma.^13,14 Administration of coagulation factor concentrate has been shown to normalize INR levels significantly faster than fresh frozen plasma^15–17 Whether this affects the clinical course has been the subject of only limited research,^16,17 and the extent of the use of coagulation factor concentrate in clinical practice is not known. The aim of the present study was to survey current management and prognosis of AC-related ICH at 10 Swedish hospitals.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We conducted the survey at 4 University hospitals (Göteborg, Lund, Uppsala, and Örebro) and 6 county hospitals (Falun, Kungälv, Mölndal, Trollhättan, Uddevalla, and Sundsvall) in Sweden. Hospital-based patient administrative systems and other local registers of patients with a code of 431X according to the International Statistical Classification of Disease and Related Health Problems, 9th revision, were screened for the 4-year period from 1993 through 1996. Medical records were reviewed, and 171 patients with ICH and concomitant oral AC treatment were identified. We excluded 20 patients from further analysis because of lack of CT- or autopsy-based diagnosis (n=7), initial treatment at another hospital (n=6), concomitant large subdural hematoma (n=2), history of severe head trauma (n=2), bleeding in previously diagnosed brain tumor (n=2), or epidural hematoma (n=1). Survival status at 30 days, 6 months, and follow-up at a mean of 3.5 years was determined from the Swedish National Population Register. The study was approved by the local ethics committee of each participating hospital.

Thus, in total, 151 patients were included in the present study. All records were reviewed by the first author, and demographic and clinical data were registered in a prespecified form. Arterial hypertension was diagnosed if patients were on hypertensive treatment or were known to be hypertensive but not currently treated. Diabetes mellitus was diagnosed if the patients were on antidiabetic treatment. The time of ictus was registered if it was exactly known or could be estimated with a precision of less than ±2 hours and was not registered in patients with symptoms present at awakening. When the onset of symptoms occurred while the patient was hospitalized for some other reason, the time of onset of symptoms to arrival was set to zero. The level of consciousness according to the Reaction Level Scale–85 (RLS-85) scale¹⁸ was registered on admission, start of medical therapy, and after 24 to 48 hours. In brief, RLS-85 is an 8-grade scale in which grade 1 patients are fully alert and patients in grade 8 are unresponsive. Patients in grades 1 to 3 are graded as conscious, and patients in grades 4 to 8 are graded as unconscious. In the present study, we defined clinical deterioration as a change from RLS-85 grade 1 to grade 3, from grade 1 to 3 to unconsciousness or death, or from unconsciousness to death within the first 24 to 48 hours after admission. It was possible to obtain sufficient data from the records to perform an RLS-85 classification of the neurological condition on the second calendar day after admission. Because the exact time for admission, second neurological examination, or death was sometimes missing from the records, we used a 24- to 48-hour time interval to capture all patients deteriorating during the first or second calendar day after admission.

Time and type of any medical or surgical intervention were registered. Prothromplex-T (Immuno) is a coagulation factor concentrate containing the following clotting factors: factors II, VII, IX, and X. In Sweden, Prothromplex-T is not a registered drug but is licensed for hospital use. The recommended dose of Prothromplex-T is 30 U/kg. Vitamin K (fytomenadion, [Konakion], Roche) is registered as a solution for injection (10 mg/mL). The recommended dose in severe bleeding associated with AC therapy is 10 to 20 mg IV. Plasma was given in doses of 300 to 600 mL, which were sometimes repeated.

Prothromplex-T, plasma, and vitamin K were used alone or in different combinations. Patients receiving Prothromplex-T alone or combined with plasma or vitamin K were classified as being treated with Prothromplex-T, whereas patients treated with plasma only or in combination with vitamin K were classified as being treated with plasma. During the study period, the intensity of anticoagulation therapy was monitored with prothrombin complex measurements. The range of the normal values was 70% to 130%. The usual therapeutic target range was 15% to 25% (INR 2.1 to 3.0); in some patients (eg, in those with mechanical heart valves), it was 10% to 15% (INR 3.0 to 4.2). Data are presented as INR values by use of a conversion formula.¹⁹

The diagnosis of ICH was established by CT in 146 patients and by autopsy in 5 patients. In 108 patients, the initial CT images were available for review, conducted by the second author without knowledge of clinical features and therapy used. Location, presence of intraventricular extension, and size of the hemorrhage were registered. ICH location was classified as lobar, basal ganglia, thalamic, cerebellar, brain stem, intraventricular, or unspecified. Any hematoma extending over >1 area was categorized according to the location from which it appeared to arise or the location that contained the largest amount of blood. To determine the hematoma size, the algorithm of an ellipsoid, ie, 4xyz/3 (where x, y, and z are the maximum diameters in perpendicular planes), was used. Midline shift at the lower part of the third ventricle was measured by a ruler and calculated as the absolute difference of the distance between the internal table of the skull and the midline structures, on the left and right side, respectively, divided by 2. In 38 patients, in whom the initial CT was no longer available for review, data from the original written report were used.

Data were analyzed with commercial statistical software (JMP 4.0, SAS Institute Inc). The statistical methods used were unpaired t test, likelihood ratio test, odds ratio, and stepwise multiple logistic regression analysis where applicable. Differences were considered significant at a value of P<0.05.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The clinical baseline characteristics of the patients and their management are presented in Tables 1 and 2. The mean and the median ages of the patients were 74.4 and 75.3 years, respectively (range 37.6 to 96.0 years). Admission median systolic blood pressure (BP) was 170 mm Hg (range 100 to 270 mm Hg), median diastolic BP was 95 mm Hg (range 60 to 150 mm Hg), and median mean BP was 120 mm Hg (range 77 to 185 mm Hg). Admission median blood glucose was 7.6 mmol/L (range 3.5 to 21.4 mmol/L), and median INR was 2.6 (range 1.1 to 6.6). Forty-five patients had an INR <3.0. Median ICH volume on first CT was 18.6 mL (range 0 to 256 mL), and median midline shift was 0.14 cm (range 0.00 to 1.67 cm).

View this table: [in this window] [in a new window]   Table 1. Baseline Clinical and CT Characteristics of 151 Patients

View this table: [in this window] [in a new window]   Table 2. Univariate Analysis of Clinical and CT Factors on Admission in Relation to Outcome

Univariate analyses of clinical and CT factors on admission in relation to mortality at 30 days are shown in Table 2. Median values as specified above were used for dichotomization of the data. Especially the degree of consciousness on admission, volume of hematoma, and presence of intraventricular blood were highly correlated with 30-day mortality (P<0.0001). No patient with an ICH volume >61 mL or a midline shift >0.81 cm was alive at 30 days, and only 1 of the 27 patients who were unconscious on admission was alive at 30 days.

RLS-85 on admission and the neurological condition 24 to 48 hours after admission are shown in the Figure. When first examined, 40% of the patients were fully alert, and >80% of the patients were conscious (RLS-85 grades 1 to 3). At 24 to 48 hours after admission, 36% in the latter group were unconscious or dead, and 47% had deteriorated (see Subjects and Methods for definitions used). Factors associated with deterioration among the 124 patients who were conscious on admission are shown in Table 3. CT features such as ICH volume, intraventricular extension of bleeding, and midline shift were associated with early deterioration. However, it should be recognized that in many patients, CT was first performed after deterioration had already occurred. Of clinical features, only age was related (inversely) to deterioration.

View larger version (23K): [in this window] [in a new window]   RLS-85 on admission, grades 1 to 8, in relation to neurological condition 24 to 48 hours after admission. Black bars indicate conscious; gray bars, unconscious; white bars, dead.

View this table: [in this window] [in a new window]   Table 3. Univariate Analysis of Clinical and CT Factors on Admission in Relation to Clinical Deterioration Within 24 to 48 h in 124 Patients Who Were Conscious on Admission

Median time from onset of symptoms to arrival at hospital was 2.2 (range 0.0 to 39.8) hours. In 8 patients, the onset of the ICH symptoms occurred when the patient was hospitalized for other reasons. Median time from arrival to CT was 3.3 (range 0.4 to 68.4) hours and from CT to start of medical treatment was 2.0 (range -20.1 to 71.3) hours. In 7 patients, pharmacological treatment was started before CT was performed. Time of onset of symptoms could not be assessed in 23 patients. Data were missing regarding time of arrival in 18 patients, time of CT in 24 patients, and time of start of treatment in 7 patients. Total time from symptom onset to start of treatment could be assessed in 74 patients and differed considerably (although not statistically significantly) between hospitals (P=0.11). Median time from onset to start of treatment was 4.7 hours among 10 of 11 treated patients in one hospital compared with 16.3 hours among 9 of 10 treated patients in another hospital. Time from onset of symptoms to arrival was similar among conscious and unconscious patients on admission. However, time from arrival to CT tended to be shorter for unconscious patients (median 1.8 hours, mean 2.1 hours) than for conscious patients on admission (median 3.6 hours, mean 7.0 hours) (P=0.05).

Death rates were 53.6% at 30 days, 63.6% at 6 months, and 77.5% at follow-up (mean 3.5 years). The case fatality ratio at 30 days was 96% among patients unconscious on admission (n=27), 80% among patients who became unconscious before active treatment was started (n=15), 55% among patients in whom no special action was taken except withdrawal of AC treatment (n=42), 28% among patients given active anti-coumarin treatment while they still were conscious (n=64), and 2/3 in 3 patients with prosthetic heart valves given heparin only at 2 hospitals according to local guidelines.

There was a statistically significant variation in choice of treatment between hospitals (P<0.0001).

Prothromplex-T was used in 19 of 26 patients in 1 hospital and in a total of 1 of 37 patients in 4 hospitals. Plasma was used in 4 of 7 patients in 1 hospital and in a total of 2 of 34 patients in 4 hospitals. Vitamin K was used in 22 of 54 patients in 4 hospitals and in a total of 3 of 61 patients in 4 hospitals. No action was taken in 2 of 26 patients in 1 hospital and in a total of 23 of 40 patients in 4 hospitals.

Five patients with cerebellar hematomas had surgery. In 4 cases, the hematomas were evacuated, and the patients were alive at 3 months. One patient with a cerebellar hematoma was treated with a ventricular drainage only and died after a few days. Lobar hemorrhages in 2 patients were evacuated, but none of the patients survived. Another 3 patients with massive ventricular bleeding were treated with ventricular drainage, and 2 survived.

Between hospitals, variations in mortality rates were noted at 30 days (P=0.05), at 6 months (P=0.11), and at follow-up (P=0.28), but differences in baseline factors such as age (P<0.002) and ICH volume (P=0.07) were also observed.

On admission, 27 patients were unconscious, and 15 other patients deteriorated during the initial hospital course before any therapy was administered to reverse the AC effect. The various factors associated with choice of initial medical management and outcome in the remaining 106 patients, excluding the 3 patients who were given heparin, are shown in Table 4. Among these patients, there was a significant difference in mortality among different treatment groups (P<0.05) at 30 days, 6 months, and follow-up. For instance, the 30-day mortality was lower in the plasma-treated (11%) and vitamin K–treated (30%) groups compared with the groups treated with Prothromplex-T (39%) or given no treatment (55%). It should be pointed out that the groups were not balanced regarding several prognostic parameters. For instance, regarding the presence of intraventricular blood, which is one of the most important prognostic parameters, only 3 of 18 patients in the plasma group as opposed to 10 of 23 patients in the Prothromplex-T group had such a hemorrhage. Patients having no active treatment had significantly higher mortality than did patients having any active treatment, but they also had significantly larger ICHs with more midline shift, probably accounting for the worse prognosis.

View this table: [in this window] [in a new window]   Table 4. Factors Associated With Choice of Initial Management and Outcome in 106 Patients Not Unconscious on Admission and Without Deterioration Before Onset of Treatment

The results of multiple logistic regression analyses of clinical factors, CT findings, and management in relation to mortality at 30 days and 6 months are shown in Table 5. Only 2 factors, intraventricular extension of bleeding and ICH volume, although significantly interrelated, were independently related to mortality at both 30 days and 6 months. The results were similar when the analysis was restricted to patients who were conscious on admission. No effect of the initial INR levels or choice of treatment was noted in these models.

View this table: [in this window] [in a new window]   Table 5. Multiple Logistic Regression Analysis of Clinical Factors, CT Findings, and Management in Relation to Outcome

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
To our knowledge, this is the largest study of patients with AC-related ICH. The distribution of supratentorial, infratentorial, and purely intraventricular hemorrhage (81%, 18%, and 1%, respectively) was similar to the proportions observed among 185 patients with AC-related ICH aggregated from 6 other studies.^{3,7,16,20–22} The mean age of our patients was higher than in the previous studies, whereas other demographic variables and risk factors were similar. Also, the distribution of indications for AC treatment was within the range of previous studies. The time of assessment of mortality has varied in previous studies, but mean mortality has been 59%, a figure between the mortality rates at 30 days and 6 months reported in the present study.

A statistical analysis of aggregated data from previous studies shows that mortality in AC-related ICH is, on average, 14% units higher (range 10% to 32% units) than in spontaneous ICH^3–5,8 (P<0.01). Although it was not the main aim of the present study, we could verify this observation in a subset of our patients because a comparison could be made with a previously published patient material of spontaneous ICH from 1 hospital.²³ Case fatality at 30 days, 6 months, and 3.5 years in 20 of our patients with AC-related ICH during the 3-year study period was 55%, 70%, and 85%, respectively, and in 140 patients with spontaneous first-ever ICH, it was 27%, 36%, and 53%, respectively (B. Johansson, personal communication). The differences were statistically significant (P<0.05).

We found a high rate of early clinical deterioration, 47%, within the first 24 to 48 hours, which was similar to the deterioration rate reported by Franke et al.³ Early clinical deterioration has generally been associated with hematoma enlargement but has previously been considered a rare phenomenon.²⁴ However, during recent years, several studies of ICH, in which AC-related ICH generally has been excluded^25,26 or has only been present in a minority of the patients,²⁷ have shown that an early increase of hematoma size occurs in 13% to 38% of the patients. Studies among ICH patients not treated with ACs^3,28,29 and among patients with only a minority treated with ACs^30,31 have shown that early clinical deterioration occurs in 23% to 46%. Thus, it seems that early clinical deterioration occurs in a higher proportion in patients with AC-related ICH than spontaneous ICH. This is supported by an analysis of the aggregated data on early deterioration in AC-related ICH, ie, our data and the results published by Franke et al³ and data of the studies on deterioration in ICH patients with no patients or only a small proportion of the patients (on average, 6%) having AC treatment.^3,28–31 This analysis shows that there is a statistically significant difference in the 47% average deterioration rate in AC-treated patients compared with the 33% average deterioration rate in the above-cited studies (odds ratio 1.77, 95% CI 1.26 to 2.49). Although the exact cause of deterioration among our patients could not be assessed because repeated CT scans were rarely performed, hematoma enlargement is the most likely cause, given that deterioration occurred within the first 2 days.²⁷ In contrast, thrombin-associated edema formation usually appears at a later stage, after several days.^32–34

We found that more than half of the patients with AC-related ICH arrived at the hospital within 2.2. hours. However, in the majority of patients, there was a significant delay of >3 hours after admission until a CT was performed and another 2 hours before treatment was started. ICH generally causes dramatic symptoms, and ICH patients seek medical attention earlier than stroke patients in general.^35,36 The time from arrival to CT was <2 hours among unconscious patients, illustrating that the personnel at the hospitals recognized the condition as a medical emergency. Unfortunately, these patients generally had a very bad prognosis. However, patients being conscious on admission generally had to wait for CT during a much longer time, and at least theoretically, this group of patients might have had the largest benefit of early intervention. In many of these patients, the records indicated that clinical deterioration had already occurred when the CT was performed or that deterioration had occurred before treatment was started.

We found a considerable, although not statistically significant, difference in mortality between hospitals presumably related to differences in case mix (age and volume of ICH). Furthermore, it should be recognized that 7 patients with a possible diagnosis of AC-related ICH were not included in our material because of lack of diagnostic verification by CT or autopsy. If it is assumed that these patients all had ICH, the differences in mortality between hospitals become less prominent.

The present study is the largest, so far, to report on the effect of various medical treatments on outcome in AC-related ICH. Four previously published studies have contained some information about medical treatment.^3,16,20,21 Two of these studies reported on the use of coagulation factor concentrate,^3,16 and only 1 small study of 17 patients has attempted to analyze the possible effect of different treatment strategies on outcome.¹⁶ In that study, mean prothrombin time INR decreased faster in the coagulation factor concentrate–treated group, and there was a slower clinical deterioration compared with the plasma-treated group. There was no difference in mortality. A small study of 13 patients with various intracranial hemorrhages (5 intracerebral) compared treatment with plasma and coagulation factor concentrate in a randomized fashion.¹⁷ The rate of correction of INR was greater, and the time to correction was shorter in the coagulation factor concentrate–treated group. No difference in neurological outcome between the groups was detected. We found a significantly lower 30-day mortality in coagulation factor concentrate–treated patients who were already unconscious on admission or who had deteriorated significantly before treatment. However, this positive effect might have been attributed to the fact that 4 patients in this group had surgery (for cerebellar hematomas in 2 patients), which might have been lifesaving. In the group treated before deterioration, we found a lower overall mortality in the plasma-treated and vitamin K–treated groups compared with the coagulation factor concentrate and nontreated groups. The reason for this might be explained by chance caused by the relatively small number of patients in each group, 41 and 65, respectively. It also may partly be explained by an imbalance between the groups regarding important prognostic parameters, eg, the presence of intraventricular blood. However, although the multivariate analysis did not support this view, differences might also reflect a true difference in treatment effect and should be studied further.

From a theoretical point of view, coagulation factor concentrate should be the preferred treatment in early management of AC-related ICH because it has been shown to normalize coagulation faster than plasma.^15,16 Based on these studies, the use of coagulation factor concentrate in life-threatening ICH has been recommended.³⁷ However, because there is no clear evidence from the previous studies that coagulation factor concentrate treatments affect outcome, this view can be challenged. Also, there is no indication in the present study that the mortality is lower in coagulation factor concentrate–treated patients than in patients treated with plasma or vitamin K.

We could not identify any factors (except CT factors, such as ICH volume and ventricular extension) that were associated with early deterioration. Because early deterioration most probably is caused by hematoma enlargement and because hematoma size is a major determinant of prognosis,^38–41 interventions that might prevent this growth should be of major importance. Especially among AC-related ICH patients, immediate normalization of coagulation ought to be a major target for therapy. However, because there is no association between INR level on admission and outcome and because therapeutic intervention has only a minor influence on outcome, this can be questioned. It is probable that factors involved in ICH progression in general are also involved in AC-related ICH and that a successful therapy must focus on such factors as well as on coagulation factors. Unfortunately, previous studies have not been able to clearly identify the most important and potentially treatable factors involved in early ICH progression. Low fibrinogen levels,²⁶ coagulopathy,⁴² high systolic BP (>200 mm Hg), and badly controlled diabetes have been suggested, but other authors have found no specific factors related to hematoma enlargement.²⁵ Thus, the target for intervention to prevent the common hematoma enlargement even in non–AC-related ICH has not been established.

Randomized controlled trials of presently used therapies are recommended. Such trials are necessary to characterize efficacy, and stratification of patients should be based on prognostic variables such as ICH location, volume, and degree of ventricular extension.

	Acknowledgments

 
The authors want to express their gratitude to Baxter Medical Co, who provided an unconditional grant for the study.

Received May 25, 2001; revision received July 30, 2001; accepted August 17, 2001.

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