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(Stroke. 2003;34:1710.)
© 2003 American Heart Association, Inc.

Original Contributions

Can Patients Be Anticoagulated After Intracerebral Hemorrhage?

A Decision Analysis

Mark H. Eckman, MD; Jonathan Rosand, MD; Katherine A. Knudsen, BA; Daniel E. Singer, MD Steven M. Greenberg, MD, PhD

From the Division of General Internal Medicine and the Center for Clinical Effectiveness, University of Cincinnati, Cincinnati, Ohio (M.H.E.), and Departments of Neurology (J.R., K.A.K., S.M.G.) and Medicine (D.E.S.), Massachusetts General Hospital, Boston.

Correspondence to Mark H. Eckman, MD, University of Cincinnati Medical Center, PO Box 670535, Cincinnati, OH 45267-0535. E-mail mark.eckman{at}uc.edu

	Abstract

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Background and Purpose— Warfarin increases both the likelihood and the mortality of intracerebral hemorrhage (ICH), particularly in patients with a history of prior ICH. In light of this consideration, should a patient with both a history of ICH and a clear indication for anticoagulation such as nonvalvular atrial fibrillation be anticoagulated? In the absence of data from a clinical trial, we used a decision-analysis model to compare the expected values of 2 treatment strategies—warfarin and no anticoagulation—for such patients.

Methods— We used a Markov state transition decision model stratified by location of hemorrhage (lobar or deep hemispheric). Effectiveness was measured in quality-adjusted life years (QALYs). Data sources included English language literature identified through MEDLINE searches and bibliographies from selected articles, along with empirical data from our own institution. The base case focused on a 69-year-old man with a history of ICH and newly diagnosed nonvalvular atrial fibrillation.

Results— For patients with prior lobar ICH, withholding anticoagulation therapy was strongly preferred, improving quality-adjusted life expectancy by 1.9 QALYs. For patients with prior deep hemispheric ICH, withholding anticoagulation resulted in a smaller gain of 0.3 QALYs. In sensitivity analyses for patients with deep ICH, anticoagulation could be preferred if the risk of thromboembolic stroke is particularly high.

Conclusions— Survivors of lobar ICH with atrial fibrillation should not be offered long-term anticoagulation. Similarly, most patients with deep hemispheric ICH and atrial fibrillation should not receive anticoagulant therapy. However, patients with deep hemispheric ICH at particularly high risk for thromboembolic stroke or low risk of ICH recurrence might benefit from long-term anticoagulation.

Key Words: atrial fibrillation • decision support techniques • intracerebral hemorrhage • Markov chains • warfarin

	Introduction

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Warfarin greatly increases both the likelihood and the mortality of intracerebral hemorrhage (ICH).^1–5 The high mortality associated with warfarin ICH influences the decision of whether an individual patient can be safely anticoagulated.

An approach for assessing treatment options in situations in which there are no specific data from randomized trials is to use decision analysis.⁶ Decision-analysis models for anticoagulation in atrial fibrillation have accounted for variations in an individual’s risk for thromboembolic stroke,^7–9 falls,¹⁰ and upper gastrointestinal tract bleeding¹¹ but have generally ignored variations in risk for developing ICH. History of ICH is a strong risk factor for subsequent ICH, particularly for ICH occurring in lobar brain regions.^12,13 A vexing dilemma occurs when a patient with a history of ICH develops a clear indication for anticoagulation such as atrial fibrillation. Although clinical series have suggested that anticoagulation can be withheld safely for short periods after ICH, even in patients with mechanical heart valves,¹⁴ studies have not addressed whether long-term anticoagulation can be safely reinstituted after hemorrhage. Because it is unlikely that a randomized trial examining this question could ethically be performed, we have explored the question using a decision-analysis model incorporating data from studies of the risk of recurrent ICH and the outcome of warfarin and nonwarfarin ICH.^4,5,14

	Methods

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We used a Markov state transition model⁶ incorporating a standard computer program (Decision Maker)¹⁵ to analyze decision trees and to perform sensitivity analyses. We evaluated strategies that explored initiating or withholding anticoagulant therapy with warfarin for a hypothetical 69-year-old man with newly diagnosed nonvalvular atrial fibrillation and prior ICH. Because >80% of hemorrhagic strokes are located in the lobar (frontal, parietal, temporal, or occipital) or deep hemispheric (thalamus or basal ganglia) brain regions (Rosand et al, manuscript in preparation), we focused on these 2 locations as the site of initial ICH.

Decision Model Structure and Assumptions
Model Structure
The Markov model contains 28 states of health (see Figures I and II , which can be found online at http://stroke.ahajournals.org, for the decision tree). During each monthly cycle, patients face the chance of thromboembolic and hemorrhagic events (ICH, subdural hematoma, and non–central nervous system bleeds). All of these events may lead to death, severe or mild permanent morbidity, or resolution. Baseline values for parameters used in the decision-analysis model are summarized in Table 1.

View larger version (31K): [in this window] [in a new window]   Figure i.

View larger version (20K): [in this window] [in a new window]   Figure ii.

View this table: [in this window] [in a new window]   TABLE 1. Data Required in the Analysis: Probabilities, Rates, and Quality of Life

Assumptions
We made several simplifying assumptions. First, a non–central nervous system hemorrhagic event without permanent morbidity will lead to temporary (1 month) discontinuation of anticoagulant therapy. However, ICH or subdural hematoma will lead to permanent discontinuation of anticoagulation. In patients not receiving anticoagulant therapy, any embolic event will lead to the initiation of long-term anticoagulant therapy (except in patients with recurrent ICH or a subdural hematoma).⁷

Second, we assumed that events with permanent morbidity reduced quality of life (Q) to a fixed lower level, which stays constant until the patient dies. Rather than modeling improving neurological functioning each month after recurrent ICH, we assumed a fixed Q based on neurological functioning at 3 months. Although this may overestimate Q in the early months and slightly underestimate Q in the later months, it should provide a reasonable estimate across the patient’s lifetime.

Quality-adjustment factors for states of health after stroke were obtained from a study of utility assessments in patients with atrial fibrillation (Table 1).¹⁶ To correlate these stroke outcomes with the Glasgow Outcome Scores (GOS)¹⁷ used to measure ICH outcome at our institution, we assumed that GOS=3 (functional dependence) corresponded to severe stroke with Q=0.11 and GOS=4 (functional independence) corresponded to a mild stroke with Q=0.76. A GOS of 5 was interpreted as very good recovery without significant long-term disability (ie, Q=1). A recent study has noted the high variability of Q values used in studies of stroke, particularly with regard to severe stroke.¹⁸ We therefore performed sensitivity analyses over the range of 0.11 to 0.39 for the utility of GOS=3 to account for the possibility that this outcome might encompass a range of disabilities spanning the Q values for moderate and severe stroke.

Review of the Data
Outcomes and Incidence of Recurrent ICH
We used our data from a prospective cohort of 435 consecutive ICH patients admitted between July 1, 1994, and June 30, 2001, to a single tertiary care center with a neurological intensive care unit (Massachusetts General Hospital) (Rosand et al). Using standard logistic regression methods, we normalized data on 3-month outcome for age and sex to reflect expected outcomes for a 69-year-old man with lobar or deep hemispheric ICH receiving or not receiving warfarin (Table 1).

In a prospective study of 71 consecutive elderly patients who survived lobar ICH, recurrent ICH occurred in 13.6% at 1 year, 20.7% at 2 years, and 36.3% at 3 years (mean follow-up, 23.9±14.8 months).¹² Fitting these data points to a declining exponential with a constant rate, we calculated an annual recurrence rate of 15% for patients with lobar ICH (Table 1). The rate of recurrent ICH in 823 survivors of deep hemispheric ICH described in a review of 4 studies was 2.1% per patient-year.¹³ We assumed that risk for recurrent ICH is constant over a patient’s lifetime.

In the absence of data describing the effect of warfarin on recurrent ICH, we selected as our base-case estimate a relative risk of 2 (Table 1) and explored the effects of this assumption through sensitivity analyses. Data from studies of warfarin and risk of initial ICH suggest that this assumption is conservative. Relative risks for ICH in the range of a 7 to 10 are associated with the use of warfarin (target international normalized ratio [INR], 3.0),² with even higher risks when the INR is less strictly regulated.^4,19,20 In controlled trials of patients with nonvalvular atrial fibrillation, a pooled analysis found a 3-fold increase in risk of ICH on warfarin.^1,21

Annual Excess Mortality and Functional Impairment After Stroke
Stroke survivors have an increased long-term mortality risk. In a study examining prognosis after ischemic, lacunar, or hemorrhagic stroke among patients who survived at least 30 days, 72.0% remained alive at 4 years.²² Using mortality rate data from life tables,²³ along with the age distribution of patients discharged alive in this study, we calculated age-adjusted annual excess mortality rates for survivors of both hemorrhagic and nonhemorrhagic stroke (Table 1).

Risk of Stroke in Patients With Nonvalvular Atrial Fibrillation
In summary analyses of 5 randomized trials, the baseline risk of thromboembolism is 4.5% per year, whereas the efficacy of warfarin for stroke prevention is 68%.¹

Risk of Extracranial Hemorrhage
In a review of 16 trials examining the use of anticoagulant and antiplatelet agents for the prevention of stroke, the rate of major extracranial hemorrhage averaged 0.6% per year in patients not receiving anticoagulant therapy. The relative risk for major extracranial hemorrhage in patients receiving anticoagulant therapy was 2.4, resulting in an average rate of 1.4% per year.²⁴

Aspirin
In structural sensitivity analyses, we examined aspirin as a third strategy. The effect of aspirin on ICH outcome was determined from the prospective cohort of ICH patients seen at the Massachusetts General Hospital (Rosand et al). The efficacy and risk of subdural and extracranial bleeding in patients receiving aspirin are described in Table 1.

	Results

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Base-case analyses were performed separately for patients with a prior history of either deep or lobar ICH. For a hypothetical 69-year-old man with a previous lobar ICH, "do not anticoagulate" resulted in an expected 5.4 quality-adjusted life years (QALYs), whereas "anticoagulate" resulted in 3.5 QALYs (Table 2). Anticoagulation was predicted to increase both the frequency and the severity of future strokes. For 1000 patients with lobar hemorrhage, anticoagulation would result in 31 fewer thromboembolic strokes at a cost of 150 additional ICHs during the first year of treatment. We also assessed the sensitivity of this result to variations in the assumed values for risk of ischemic stroke, risk of recurrent ICH, effect of warfarin on risk of ischemic and hemorrhagic stroke, stroke outcome, and the Q value assigned to poststroke quality of life (Table 3). The superiority of "do not anticoagulate" for lobar ICH survivors was not affected over wide ranges in these values (Figure 1). The recommendation not to anticoagulate survivors of lobar hemorrhage thus appeared robust to any realistic assumption about likelihood of ischemic or hemorrhagic stroke.

View this table: [in this window] [in a new window]   TABLE 2. Results of Decision Analysis

View this table: [in this window] [in a new window]   TABLE 3. Results of Sensitivity Analyses: Lobar and Deep Hemispheric ICH

View larger version (24K): [in this window] [in a new window]   Figure 1. Lobar ICH. Top, Relative risk of recurrent ICH. "Do not anticoagulate" is preferred at all values for the relative risk of ICH. Middle, Rate of recurrent ICH in patients not receiving anticoagulant therapy. "Do not anticoagulate" is preferred unless the rate of recurrent ICH is <1.4% per year. Bottom, Rate of ischemic stroke resulting from atrial fibrillation. "Do not anticoagulate" is preferred at all values.

Results for patients with prior deep ICH were less clear cut, largely because of the lower rate of ICH recurrence.¹³ "Do not anticoagulate" was preferred under the baseline assumptions (7.8 versus 7.5 QALYs). A breakdown of the expected frequency and severity of strokes indicated that the "anticoagulate" strategy would yield fewer strokes, but with more severe outcome, than "do not anticoagulate." For 1000 patients with deep hemorrhage, anticoagulation would result in 31 fewer thromboembolic strokes at a cost of 19 additional ICHs during the first year of treatment. "Anticoagulate" was preferred when the relative risk of ICH associated with warfarin was <1.6, the baseline rate of recurrent ICH was <1.4% per year, or the baseline risk of ischemic stroke was >6.5% per year (Figure 2). In a 2-way sensitivity analysis of the relative risk of ICH with warfarin and the risk of ischemic stroke for patients with prior deep ICH, the base case was within the region in which withholding anticoagulant therapy is best (Figure 3A).

View larger version (25K): [in this window] [in a new window]   Figure 2. Deep hemispheric ICH. Top, Relative risk of recurrent ICH. "Do not anticoagulate" is preferred unless the relative risk of ICH on warfarin is <1.6. Middle, Rate of recurrent ICH in patients not receiving anticoagulant therapy. "Do not anticoagulate" is preferred unless the rate of recurrent ICH is <1.4% per year. Bottom, Rate of ischemic stroke resulting from atrial fibrillation. "Do not anticoagulate" is preferred unless the rate of ischemic stroke is >7% per year.

View larger version (13K): [in this window] [in a new window]   Figure 3. Two-way sensitivity analyses: rate of ischemic stroke resulting from atrial fibrillation (horizontal axis) and the relative risk of recurrent ICH (vertical axis). A, Deep ICH. Diagonal threshold line divides the graph into 2 regions. In the bottom right region where the relative risk of ICH is low and the rate of ischemic stroke is high, "anticoagulate" is preferred. In the top left where the relative risk of ICH is high and the rate of ischemic stroke is low, "do not anticoagulate" is preferred. When a higher relative risk of 3 is used for recurrent ICH, "do not anticoagulate" is preferred unless the rate of ischemic stroke is >11% per year (dotted lines). B, Deep ICH with aspirin as a third strategy. Vertical axis describes the relative risk of ICH on aspirin. At low risks for recurrent ICH on aspirin (relative risk <1.4), there is a region at intermediate rates of ischemic stroke in which aspirin might be preferred. C, Lobar ICH with aspirin. Region in which aspirin is preferred is shifted toward higher rates of ischemic stroke and lower relative risks of ICH.

We also considered the impact of adding aspirin as a third treatment strategy. Among patients with deep ICH, a 2-way sensitivity analysis of the relative risk of ICH with aspirin use and the risk of ischemic stroke showed that aspirin was preferred within a region of intermediate risk for ischemic stroke and very low risk for ICH (Figure 3B). The base case was within the region in which aspirin was preferred if the relative risk for ICH on aspirin was <1.3. A similar pattern was seen among patients with lobar ICH (Figure 3C). However, the region in which aspirin was preferred was shifted toward both a higher rate of ischemic stroke and a lower relative risk of recurrent ICH. For patients with lobar ICH at average risk for ischemic stroke (4.5% per year), aspirin was preferred only if the relative risk was <1.04.

	Discussion

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We used epidemiologic data from the medical literature and empiric data from our own study on ICH outcome to analyze a relatively common clinical decision: whether to anticoagulate a patient with both nonvalvular atrial fibrillation and history of prior ICH. The results of this analysis indicated that in settings in which the risk of ICH recurrence is high, the increased mortality associated with warfarin ICH is itself sufficient to argue against anticoagulation. In the case of lobar ICH in particular, the strategy of "do not anticoagulate" appeared robust to any realistic assumptions regarding the risk of stroke and the relative risks associated with warfarin. The risks and benefits of anticoagulation were more closely balanced when applied to patients with deep hemispheric ICH, in which the risk of recurrence is substantially lower.¹³ Analysis of this scenario suggested that anticoagulation could be the preferred strategy, eg, when the risk of thromboembolic stroke is felt to be particularly high (Figures 2 and 3). However, this conclusion is still highly dependent on the relative risk of recurrent ICH on warfarin, for which there are no data reported in the medical literature. Thus, for the vast majority of patients with deep hemorrhage, anticoagulation therapy cannot currently be recommended, with a possible exception for patients at very high risk of ischemic stroke, appreciating that the recurrence rate of ICH is based on a fairly small sample and the relative risk of recurrent ICH caused by warfarin is unknown. Our assumption of a doubling of risk of ICH on warfarin may be a sizable underestimate, given the 5- to 10-fold increase in ICH associated with warfarin in the general population.^19,20 Even less information is available to describe the relative risk of recurrent ICH in patients receiving aspirin. However, aspirin almost certainly has a lower relative risk than warfarin²⁵ and may therefore be a reasonable strategy for patients with deep hemispheric ICH with an intermediate risk of ischemic stroke. If future studies find the relative risk to be very low, aspirin may even be a reasonable strategy in selected patients with prior lobar ICH.

The different results obtained from analysis of lobar and deep hemorrhages are due largely to the distinct rates of recurrent ICH associated with these 2 conditions,^12,13 reflecting their differing underlying pathophysiologies.^26,27 Hypertensive vasculopathy appears to be the most important mechanism for ICH in the deep hemispheric regions, whereas cerebral amyloid angiopathy may be the most common underlying pathophysiology in this age group for lobar ICH.^27,28 Risk of recurrent hypertensive ICH can be limited by control of hypertension.^29,30 Cerebral amyloid angiopathy, on the other hand, lacks any known treatment. It is associated with both recurrent hemorrhagic strokes¹² and small, clinically asymptomatic hemorrhagic lesions³¹ that might serve as the substrate for larger hemorrhagic strokes on warfarin.² The presence of cerebral amyloid angiopathy is thus probably accompanied by continued risk for lobar ICH over the lifetime of the patient.

Further clarification of risk factors for developing ICH on warfarin (eg, identification of microbleeds through MRI techniques such as gradient-echo imaging)³¹ and risk factors for poor outcome from warfarin ICH may help to clarify the risk-benefit analysis of warfarin administration in individual patients and lead to increased appropriate usage of the medication. Genetic risk factors may also have a role in properly selecting patients for warfarin. The apolipoprotein E genotype (apoE) appears to have specific effects on risk of lobar ICH, with possession of the apoE 2 or 4 allele associated with increased risk of lobar ICH and recurrent ICH resulting from cerebral amyloid angiopathy.^12,32 In addition, genetic polymorphisms have been identified that predispose to decreased dose requirements for warfarin and may predispose to increased risk for high INR.^33–35 Until randomized trials can be performed to assess the role of specific risk factors, however, decision-analysis models will serve a crucial role in guiding clinicians confronted with difficult decisions regarding the risks and benefits of anticoagulation.^36–39

	Acknowledgments

 
Dr Rosand is supported by fellowship training awards from the National Stroke Association and the American Academy of Neurology Education and Research Foundation. We thank Yuchiao Chang, PhD, for assistance with statistical methods.

Received October 17, 2002; revision received February 6, 2003; accepted February 25, 2003.

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