Hematology

Risk of intracerebral hemorrhage in patients treated with warfarin

Risk of intracerebral hemorrhage in patients treated with warfarin
Authors
W David Freeman, MD
Maria I Aguilar, MD
Jeffrey Weitz, MD
Section Editors
Lawrence LK Leung, MD
Jose Biller, MD, FACP, FAAN, FAHA
Deputy Editor
Stephen A Landaw, MD, PhD
Last literature review version 19.3: Fri Sep 30 00:00:00 GMT 2011 | This topic last updated: Tue Oct 18 00:00:00 GMT 2011 (More)

INTRODUCTION — Antithrombotic therapies (eg, antiplatelet agents, the heparins, vitamin K antagonists, direct thrombin inhibitors, factor Xa inhibitors) are widely used in clinical medicine based upon well-designed randomized clinical trials that have rigorously defined their benefits relative to associated bleeding risks. In most of these trials, patients presumed to be at especially high risk for intracerebral hemorrhage (ICH) were excluded from participation, in large part because the antithrombotic benefits were yet to be fully defined while the bleeding risks appeared unduly high.

Because of under-representation in clinical trials, determining the relative efficacy and safety of antithrombotic agents in patients at varying increased risks for ICH is problematic. Nevertheless, clinicians are regularly faced with risk/benefit decisions regarding antithrombotic therapy for such patients. (See “Antithrombotic therapy to prevent embolization in nonvalvular atrial fibrillation” and “Anticoagulation in older adults”, section on ‘Considerations about treatment choices’.)

The risk of intracerebral hemorrhage in patients treated with warfarin will be reviewed here. The management of warfarin-associated intracerebral hemorrhage is discussed separately. (See “Management of warfarin-associated intracerebral hemorrhage”.)

There are a number of other settings in which anticoagulant or antiplatelet therapy might be considered for the prevention of thromboembolism, although in the presence of certain co-morbid conditions (eg, intracranial aneurysm, brain tumor, prior ICH), such treatment may place patients at considerable risk of central nervous system (CNS) bleeding. These important, highly complex issues are discussed separately and include patients with the following:

 

  • An unruptured intracranial aneurysm (see “Anticoagulant and antiplatelet therapy in patients with an unruptured intracranial aneurysm”)
  • An acute or prior ICH (see “Anticoagulant and antiplatelet therapy in patients with an acute or prior intracerebral hemorrhage”)
  • An increased risk for ocular hemorrhage (see “Anticoagulant, antiplatelet, and fibrinolytic (thrombolytic) therapy in patients at high risk for ocular hemorrhage”)
  • A primary or metastatic brain tumor (see “Anticoagulant and antiplatelet therapy in patients with brain tumors”)

 

ICH RISK WITH ANTITHROMBOTIC THERAPY — Intracranial hemorrhage, primarily intracerebral and less frequently subdural or subarachnoid, is the most serious and lethal complication of antithrombotic therapy. Intracerebral hemorrhage causes approximately 90 percent of the deaths and most of the permanent disability in patients with warfarin-associated bleeding [1]. The frequency with which antithrombotic therapy-associated ICH occurs is illustrated by the following observations:

 

  • Anticoagulation with warfarin increases the risk of ICH two- to fivefold, depending upon the intensity of anticoagulation [2,3].
  • Warfarin anticoagulation is estimated to account for approximately 3500 excess ICHs annually, or approximately 5 percent of all non-traumatic episodes of ICH in the United States [2-4].
  • A population-based study has reported a fourfold increase in the incidence of warfarin-associated ICH during the 1990s due to the increasing use of warfarin in elderly patients [5].
  • Antiplatelet therapy with aspirin increases ICH risk by approximately 40 percent, although estimates from meta-analyses of randomized trials range from 22 to 84 percent; this increase is probably independent of the aspirin dosage [6,7].
  • Dual antiplatelet therapy with aspirin plus clopidogrel increases the risk of ICH twofold compared with aspirin alone (0.4 percent versus 0.2 percent, respectively; relative risk 1.87) [8].
  • Combining adjusted-dose warfarin with aspirin appears to double the ICH risk compared with similar intensity of warfarin anticoagulation without aspirin [9,10].

 

In terms of absolute risk, the rate of spontaneous ICH among 70-year-old subjects averages 0.15 percent per year. In those anticoagulated with warfarin to an INR of 2.0 to 3.0, the risk of ICH is increased to 0.3 to 0.8 percent per year. This small absolute increase in ICH is generally offset by larger reductions in ischemic events. However, in certain patient populations, the absolute increase in ICH is substantially higher, and the benefit/risk margin for warfarin anticoagulation narrows or disappears (see ‘High risk patients’ below).

Over half of the patients with warfarin-associated ICH die within the first 30 to 90 days—a substantially higher mortality rate than that of spontaneous ICH in those not receiving anticoagulants [2,11-16], or that of warfarin-associated extracranial hemorrhage [1].

 

  • In one study, for example, the 90-day mortality rate for supratentorial ICH was 52 versus 26 percent for those taking or not taking warfarin at the time of ICH, respectively [2].
  • In a second study, the 90-day mortality rates for ICH patients were 62 and 17 percent for those taking or not taking warfarin, respectively [14].

 

Warfarin-associated ICHs are larger, on average, than spontaneous ICHs and the extent of the bleed is directly proportional to the INR at the time of bleeding [17]. Available data are conflicting about whether the concomitant use of antiplatelet agents increases the severity and early mortality associated with ICH [2,12,13,18,19].

Effect of ethnicity — The incidence of spontaneous ICH varies by ethnicity, being highest in Asians, intermediate in blacks, and lowest in whites. Mexican Americans also have a higher incidence of ICH than non-Hispanic whites. (See “Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis”, section on ‘Epidemiology’.)

The effect of ethnicity on the incidence of warfarin-associated ICH was studied in a multiethnic stroke-free cohort of 18,867 hospitalized patients with non-valvular atrial fibrillation [20]. Study results, which were adjusted for age, gender, hypertension, diabetes mellitus, and heart failure, included the following:

 

  • The crude rates of ICH for the entire cohort were 0.47 and 0.15 per 100 patient-years for those taking or not taking warfarin, respectively. As expected, the magnitude of the increased risk due to warfarin was greater among older subjects and in those with hypertension.
  • After adjustment for other factors predictive of ICH, the hazard ratio for warfarin-associated ICH relative to the group of white patients, was 4.1 (95% CI 2.5-6.7) for Asians and 2.1 (95% CI 1.3-3.2/3.4) for Hispanics and Blacks.
  • The absolute rate of ICH in those receiving warfarin was 0.3 per 100 patient-years in whites, while in Blacks, Hispanics, and Asians the absolute rates were 0.8, 0.7, and 1.8 per 100 patient-years, respectively. The higher observed ICH rate in Asians receiving warfarin raises the possibility that the risks might outweigh any benefits. However, these data were based on only 17 events among 971 patients from a single retrospective study. The study findings also emphasize the special importance of blood pressure management and careful INR monitoring in this ethnic group, especially because Asian-Americans may be more sensitive to treatment with warfarin. (See “Therapeutic use of warfarin”, section on ‘Vitamin K epoxide reductase complex 1’.)

 

PATHOGENESIS

Cerebral microbleeds — As people age, small arterioles within the brain weaken and rupture with worrisome regularity. Most ruptures result in subclinical foci of self-limited bleeding, termed “microbleeds”, which can be found at autopsy or detected using special gradient sequence MRI techniques. Advancing age, especially age >75 years, and hypertension are the strongest predictors of this phenomenon [21,22]. These microbleeds are believed to be the result of an underlying angiopathy that predisposes patients to intracerebral bleeding. Occasionally, leakage of blood from an arteriolar rupture is not stopped by normal hemostatic mechanisms and/or compression by surrounding tissue and a larger ICH ensues. This phenomenon underlies the pathogenesis of spontaneous ICH, an especially devastating type of stroke. (See “Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis”, section on ‘Cerebral microbleeds’.)

Effect of anticoagulants — Anticoagulants increase the likelihood that spontaneously-occurring arteriolar ruptures will enlarge to cause clinically evident ICH, but anticoagulants do not appear to increase the incidence of asymptomatic cerebral microbleeds [23]. Thus, anticoagulant therapy appears to “unmask” the inherent rate of spontaneous cerebral microbleeds as their most serious complication. As a result, patients at the highest risk for spontaneous ICH are those who are also at highest risk for anticoagulant-associated intracerebral bleeding.

SEE MORE:  Pathogenesis of the antiphospholipid syndrome

This construct explains why intensities of warfarin anticoagulation that are rarely complicated by ICH in middle-aged people undergoing anticoagulation for venous thromboembolism (ie, patients with a very low inherent rate of spontaneous microbleeds) result in substantially increased absolute rates of ICH among anticoagulated octogenarians with atrial fibrillation, particularly if their blood pressure is not well-controlled [24].

There is no lower threshold of anticoagulation intensity that does not accentuate the risk of warfarin-associated ICH. Although INRs above 4.0 are associated with high rates of ICH in the elderly [25], most warfarin-associated ICHs occur at anticoagulation intensities that are within the conventional therapeutic range (ie, INRs in the range of 2.0 to 3.0) [2,11].

The potential role of imaging to detect cerebral microbleeds in patients taking anticoagulants is discussed below. (See ‘Imaging cerebral microbleeds’ below.)

Dabigatran — Dabigatran, an oral direct thrombin inhibitor, has been approved for the prevention of stroke in patients with non-valvular atrial fibrillation [26]. In a randomized trial (RE-LY) [27,28], two twice daily dose regimens of dabigatran were compared with warfarin. The lower dose regimen (110 mg) was non-inferior to adjusted dose warfarin for stroke prevention, and was associated with fewer major bleeding complications (2.71 percent and 3.36 percent, respectively) [29]. The higher dose dabigatran regimen (150 mg) significantly reduced the rate of stroke compared with warfarin and was associated with a similar rate of major bleeding (3.11 percent).

Of importance when considering the risk of intracerebral bleeding in anticoagulated patients with non-valvular atrial fibrillation, the annual rates of ICH were significantly lower in the dabigatran 110 and 150 mg groups compared with warfarin (0.12, 0.10, and 0.39 percent per year; RR 0.31, 95% CI 0.17-0.56 and 0.26, 95% CI 0.14-0.49, respectively).

Although dabigatran is a promising agent for stroke prevention in atrial fibrillation, there is no specific antidote to reverse its anticoagulant effect. The dabigatran dose should be adjusted based on renal function, and amiodarone, an antiarrhythmic drug that is frequently used in AF patients, potentiates the anticoagulant effect. The clinical significance of this interaction is uncertain because amiodarone use was not restricted in the RELY trial. (See “Anticoagulants other than heparin and warfarin”, section on ‘Dabigatran’.)

Effect of antiplatelet agents — Hypothetically, the same principles apply to antiplatelet therapy. Consistent with this hypothesis is the observation that in a review of patients with ICH, 64 percent were taking aspirin for a prior cerebrovascular event [18]. More specifically, a second study indicated that asymptomatic microbleeds were a risk factor for ICH in aspirin-treated patients [30]. Also, patients taking antiplatelet agents, such as aspirin, who have reduced platelet reactivity may also be at risk for ICH expansion and a worse outcome [31,32].

HIGH RISK PATIENTS — Emphasis has properly focused on identifying patients at high risk for warfarin-associated ICH in order to maximize the benefit-to-risk profile of warfarin therapy [33]. Predictors of ICH with warfarin or other oral vitamin K antagonists have been identified and, as predicted, these risk factors overlap with those for spontaneous ICH (table 1) [3].

Cerebral amyloid angiopathy (CAA) is also a risk factor, although the diagnosis of CAA prior to hemorrhage is not yet possible. CAA is associated with a high ICH rate that is further increased by antithrombotic therapy, even if the INR is well-controlled [34]. As a result, the general rule is to avoid these agents in patients with clinically suspected CAA. (See “Cerebral amyloid angiopathy”, section on ‘Avoidance of anticoagulants and antiplatelet agents’.)

Additional probable risk factors include:

 

  • Combination therapy with warfarin plus aspirin [9]
  • Diabetes mellitus [16]
  • Falls with attendant head trauma (subdural hematoma) (see ‘Falls’ below)
  • Excessive alcohol consumption

 

Intensity of anticoagulation — The intensity of anticoagulation is the strongest predictor of ICH. With warfarin, an INR >3.5 is associated with substantial ICH rates in the elderly, while an INR >3.0 is associated with high ICH rates in patients with a history of prior stroke or transient ischemic attacks. The magnitude of the anticoagulation intensity effect was evaluated in a number of studies, two of which are illustrated in the accompanying table (table 2) [2,25,35,36]:

 

  • In a review of two studies of patients receiving vitamin K antagonists, the incidence of ICH increased by a factor of 1.37 for each 0.5 unit increase in the INR in those with a prior history of cerebral ischemia [36].
  • In a case-control study of 170 patients with non-valvular atrial fibrillation who developed ICH while taking warfarin, the adjusted odds ratios for ICH (relative to an INR of 2.0 to 3.0) were 4.6 and 8.8 for INRs in the range of 3.5 to 3.9 and ≥4.0, respectively [35]. Of interest, the risk of ICH with INRs <2.0 was not significantly lower than that with INRs between 2.0 and 3.0 (OR 1.3, 95% CI 0.8-2.2). This is consistent with the observation that there is no lower threshold of anticoagulation intensity that does not accentuate the risk of warfarin-associated ICH.
  • In a study of 102 patients taking warfarin at the time of ICH, the risk of death at 90 days was significantly associated with higher INRs, with odds ratios of 1.5, 2.0, and 3.7 for INRs in the range of <2.0, 2.0 to 3.0, and >3.0, respectively [2].

 

Accordingly, good INR control together with aggressive blood pressure management are important in order to minimize the risk of ICH in warfarin-treated patients. This approach is less likely to be effective in patients with cerebral amyloid angiopathy where most ICHs associated with warfarin therapy occur at an INR ≤3.0 [34].

Blood pressure control — The risk of spontaneous ICH is highly correlated with blood pressure. As an example, among patients with prior cerebral ischemia, a modest reduction of blood pressure of 9/4 mmHg decreased the rate of ICH by one-half (1.2 versus 2.4 percent) in the randomized PROGRESS trial of over 6000 patients with a mean baseline blood pressure of 147/86 mmHg [37]. Thus, control of hypertension is essential for reducing the risk of ICH associated with anticoagulant and antiplatelet therapies. The importance of blood pressure control is magnified in patients who have other high risk features. (See ‘High risk patients’ above and “Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis”, section on ‘Hemorrhage enlargement’ and “Treatment of hypertension in patients who have had a stroke”.)

Uncontrolled hypertension (ie, blood pressure consistently >160/90 mmHg) is a contraindication to anticoagulation with warfarin. Lowering the blood pressure profoundly reduces the ICH risk in patients with mild hypertension [37]; the goal should be a blood pressure <140/90 mmHg in anticoagulated patients.

Advanced Age — The risk of ICH in anticoagulated patients increases with advancing age [35]. However, the absolute ICH rate in very elderly patients varies in different reports.

 

  • In the Birmingham Atrial Fibrillation Treatment in the Aged (BAFTA) randomized trial, the ICH rate was 0.6 percent per year among 488 patients >75 years old (mean age 81.5 years) who were given warfarin, achieved a median INR of 2.3, and were followed for 2.7 years [38]. This was similar to the ICH rate of 0.5 percent per year in subjects randomly assigned to receive aspirin.
  • In contrast, when a cohort of 472 warfarin-naïve patients with atrial fibrillation with a mean age of 77 years were given warfarin, the ICH rate was 2.5 percent per year even though 58 percent of the INR values were within the target therapeutic range of 2 to 3 [39].

 

The most likely explanation for the difference in ICH rates in BAFTA versus the cohort followed at the Massachusetts General Hospital was that first-year exposure to warfarin, the period when the risk for serious bleeding is greatest, made up only 22 percent of the BAFTA exposure versus 100 percent of the latter. In addition, blood pressure control during follow-up in BAFTA was remarkably good, with an average systolic blood pressure averaging 137 mmHg.

SEE MORE:  Spontaneous upper extremity venous thrombosis

Falls — Patients with a history of multiple falls tend to be older and have more comorbidities and an increased risk of stroke. However, such patients respond favorably to treatment with warfarin. This was shown in a retrospective analysis of 1245 Medicare beneficiaries with atrial fibrillation who were documented to be at high risk for falls [40]. In those subjects with a CHADS2 score of 2 or more (table 3), treatment with warfarin was significantly protective against the composite endpoint of out-of-hospital death or hospitalization for stroke, myocardial infarction, or hemorrhage (hazard ratio 0.75; 95% CI 0.61-0.91). (See “Antithrombotic therapy to prevent embolization in nonvalvular atrial fibrillation” and “Falls in older persons: Risk factors and patient evaluation”.)

A risk of falling, with the potential for the development of a subdural hematoma, is often considered a contraindication to the use of anticoagulation in the elderly. However, one study that reviewed 49 published anticoagulation studies of patients with atrial fibrillation found that ICH (subdural hematoma or intracerebral hemorrhage) was uncommon [41]. A Markov decision analytic model demonstrated that, regardless of the patient’s age or baseline risk of stroke, the risk of falling was not an important factor for determining the optimal antithrombotic therapy (ie, aspirin, warfarin, or no therapy) [42].

The risk of a subdural hematoma from falling is so small that patients with atrial fibrillation with an average risk of stroke (5 percent per year in the absence of anticoagulation) (table 4) would have to fall approximately 300 times in a year for the risk of anticoagulation to outweigh its benefits [41-43]. The decision as to whether or not to perform intracranial imaging in a patient taking warfarin who has suffered head trauma is discussed separately. (See “Correcting excess anticoagulation after warfarin”, section on ‘Intracranial injury after head trauma’.)

Concomitant aspirin use — About 20 percent of elderly patients receiving warfarin also take aspirin [10,35]. However, the risk of adding aspirin to warfarin is unclear, as shown in the following studies:

 

  • In a retrospective study of a large hospital discharge cohort of 10,093 elderly patients (mean age 77 years) receiving warfarin for atrial fibrillation, use of antiplatelet therapy was associated with a threefold increase in ICH (0.9 versus 0.3 percent per year; relative risk 3.0, 95% CI 1.6-5.5) [10].
  • A case-control study did not find concomitant aspirin use to be a predictor of ICH during anticoagulation [35].

 

Although the data are inconsistent, it is likely that concomitant use of aspirin and warfarin increases the risk of ICH [9,44]. In younger patients with prosthetic cardiac valves or coronary artery disease who have an inherently low ICH risk, the absolute rates of ICH with combined warfarin-aspirin therapy are low. However, in older patients or in patients with target INRs >3.0, the use of aspirin in conjunction with warfarin should be reserved for patients in whom the benefits clearly outweigh the increased risk of ICH.

Imaging and genetic markers — Other factors that may predict an increased rate of ICH include the following [33]:

 

  • White matter thinning (leukoaraiosis), as detected by brain CT or MRI [36,45]
  • Presence of “microbleeds” as detected by gradient-echo MRI (see ‘Cerebral microbleeds’ above)
  • The presence of the apolipoprotein E (APOE) epsilon 2 and 4 genotypes [34] (see “Cerebral amyloid angiopathy”, section on ‘Pathogenesis’)

 

Leukoaraiosis is detected by attenuation of the cerebral white matter on CT or, with much greater sensitivity, on MRI. Its causes are multifactorial, but in the elderly it is often a manifestation of subcortical ischemic vascular disease and correlates with the presence of microbleeds. The presence of leukoaraiosis has been linked to the risk of warfarin-associated ICH [36,45], although the clinical utility of this finding awaits standardized methods of detection and ascertainment of positive and negative predictive values for this finding. These limitations also apply to the use of MRI-detected microbleeds as a method for stratifying risk of warfarin-associated ICH.

Based on currently available information, a decision analysis has concluded that genetic and MRI predictors of warfarin-associated ICH are not useful for patient management [33].

Because of the smaller increase in ICH risk with antiplatelet therapy, specific predictors have been harder to identify, but they likely overlap with those identified for anticoagulation therapy.

Imaging cerebral microbleeds — Standardized MRI data acquisition protocols and criteria for the detection of microbleeds are lacking. Consequently, clinical application awaits the ability to standardize microbleed detection and to determine whether MRI-detected microbleeds predict spontaneous or anticoagulant-associated ICH [46,47]. The following studies suggest the potential importance of such imaging:

The presence of cerebral microbleeds as a risk factor for warfarin-associated ICH (WAICH) was studied in a retrospective analysis of 25 warfarin-treated patients with, and 48 patients without, WAICH (controls). All patients had an MRI study, which could be evaluated for the presence or absence of microbleeds. The following findings were noted [48]:

 

  • Both the incidence of microbleeds (79 versus 23 percent) and the number of microbleeds per patient (9 versus 0.5) were significantly greater in the patients with WAICH compared with controls.
  • With regard to location of the microbleeds, those in the lobar area, basal ganglia, and cerebellum were significantly associated with WAICH, whereas those in the brainstem and thalamus were not.
  • The INR was significantly higher in those with WAICH than in the controls (3.2 ± 1.9 versus 2.21 ± 0.6, respectively).
  • On multivariate analysis, only the presence of microbleeds (OR 83; 95% CI 6-1200) and the INR (OR 4.1; 95% CI 1.4-13) were significantly associated with the risk of WAICH.

 

In a second report, asymptomatic microbleeds were found to be a risk factor for ICH in patients treated with aspirin [30]. Since nasal bleeding (epistaxis) in aspirin users was a powerful independent risk factor for ICH in a case-control study, this suggests that the antiplatelet effect of aspirin is responsible for initiating clinically detected bleeding at both sites [49].

AVOIDING ICH DURING WARFARIN THERAPY — The frequency of warfarin-associated ICH is increasing due to the more widespread use of warfarin in elderly patients with atrial fibrillation and the concomitant use of aspirin and other antiplatelet agents in older patients. Relatively small differences in the ICH rate of 1 to 2 percent per year can shift the balance of therapeutic benefit versus harm. The following principles should be followed in order to minimize the risk of ICH (table 5) [3]:

 

  • Good control of warfarin intensity and limiting the use of aspirin will reduce the risk of ICH.
  • Blood pressure control is especially important for avoiding ICH. The use of warfarin in elderly patients should be contingent upon a commitment to aggressive blood pressure management.
  • If patients on long-term warfarin have a history of falls, a multidisciplinary risk factor screening/intervention program for reducing the risk of falls may be of value. (See ‘Falls’ above and “Prevention of falls and complications of falls in community-dwelling older persons”, section on ‘Preventing falls’.)

 

SUMMARY AND RECOMMENDATIONS — Intracranial hemorrhage, primarily intracerebral hemorrhage (ICH) and less frequently subdural or subarachnoid hemorrhage, is the most serious and lethal complication of antithrombotic therapy. ICH causes about 90 percent of deaths and most of the permanent disability from warfarin-associated bleeding. Risk factors for such bleeding are shown in the table (table 1). (See ‘Pathogenesis’ above and ‘High risk patients’ above.)

 

  • Prevention of ICH includes the following components (table 5). (See ‘Avoiding ICH during warfarin therapy’ above.)

 

 

  • Assuring good control of warfarin intensity (ie, avoiding INRs >3.0)
  • Limiting the use of aspirin and other antiplatelet agents
  • A commitment to aggressive blood pressure management if hypertension is present
  • Institution of a screening/intervention program for those at risk for falling
SEE MORE:  CDC: HPV vaccination coverage among teens remains 'unacceptably low'

 

 

  • The treatment of warfarin-associated ICH is discussed separately. (See “Management of warfarin-associated intracerebral hemorrhage”.)
  • While this review has focused on the risk of ICH in patients treated with warfarin, the rates of hemorrhagic stroke in the RE-LY trial were significantly lower in patients with non-valvular atrial fibrillation who were treated with dabigatran than in those treated with warfarin. (See ‘Dabigatran’ above and “Antithrombotic therapy to prevent embolization in nonvalvular atrial fibrillation”, section on ‘Dabigatran’.)

REFERENCES

  1. Fang MC, Go AS, Chang Y, et al. Death and disability from warfarin-associated intracranial and extracranial hemorrhages. Am J Med 2007; 120:700.
  2. Rosand J, Eckman MH, Knudsen KA, et al. The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. Arch Intern Med 2004; 164:880.
  3. Hart RG, Tonarelli SB, Pearce LA. Avoiding central nervous system bleeding during antithrombotic therapy: recent data and ideas. Stroke 2005; 36:1588.
  4. Woo D, Sauerbeck LR, Kissela BM, et al. Genetic and environmental risk factors for intracerebral hemorrhage: preliminary results of a population-based study. Stroke 2002; 33:1190.
  5. Flaherty ML, Kissela B, Woo D, et al. The increasing incidence of anticoagulant-associated intracerebral hemorrhage. Neurology 2007; 68:116.
  6. He J, Whelton PK, Vu B, Klag MJ. Aspirin and risk of hemorrhagic stroke: a meta-analysis of randomized controlled trials. JAMA 1998; 280:1930.
  7. Hart RG, Halperin JL, McBride R, et al. Aspirin for the primary prevention of stroke and other major vascular events: meta-analysis and hypotheses. Arch Neurol 2000; 57:326.
  8. ACTIVE Investigators, Connolly SJ, Pogue J, et al. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med 2009; 360:2066.
  9. Hart RG, Benavente O, Pearce LA. Increased risk of intracranial hemorrhage when aspirin is combined with warfarin: A meta-analysis and hypothesis. Cerebrovasc Dis 1999; 9:215.
  10. Shireman TI, Howard PA, Kresowik TF, Ellerbeck EF. Combined anticoagulant-antiplatelet use and major bleeding events in elderly atrial fibrillation patients. Stroke 2004; 35:2362.
  11. Sjöblom L, Hårdemark HG, Lindgren A, et al. Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a Swedish multicenter study. Stroke 2001; 32:2567.
  12. Saloheimo P, Ahonen M, Juvela S, et al. Regular aspirin-use preceding the onset of primary intracerebral hemorrhage is an independent predictor for death. Stroke 2006; 37:129.
  13. Foerch C, Sitzer M, Steinmetz H, Neumann-Haefelin T. Pretreatment with antiplatelet agents is not independently associated with unfavorable outcome in intracerebral hemorrhage. Stroke 2006; 37:2165.
  14. Cucchiara B, Messe S, Sansing L, et al. Hematoma growth in oral anticoagulant related intracerebral hemorrhage. Stroke 2008; 39:2993.
  15. Zubkov AY, Mandrekar JN, Claassen DO, et al. Predictors of outcome in warfarin-related intracerebral hemorrhage. Arch Neurol 2008; 65:1320.
  16. Huhtakangas J, Tetri S, Juvela S, et al. Effect of increased warfarin use on warfarin-related cerebral hemorrhage: a longitudinal population-based study. Stroke 2011; 42:2431.
  17. Flaherty ML, Tao H, Haverbusch M, et al. Warfarin use leads to larger intracerebral hematomas. Neurology 2008; 71:1084.
  18. Wong KS, Mok V, Lam WW, et al. Aspirin-associated intracerebral hemorrhage: clinical and radiologic features. Neurology 2000; 54:2298.
  19. Toyoda K, Okada Y, Minematsu K, et al. Antiplatelet therapy contributes to acute deterioration of intracerebral hemorrhage. Neurology 2005; 65:1000.
  20. Shen AY, Yao JF, Brar SS, et al. Racial/ethnic differences in the risk of intracranial hemorrhage among patients with atrial fibrillation. J Am Coll Cardiol 2007; 50:309.
  21. Koennecke HC. Cerebral microbleeds on MRI: prevalence, associations, and potential clinical implications. Neurology 2006; 66:165.
  22. Viswanathan A, Chabriat H. Cerebral microhemorrhage. Stroke 2006; 37:550.
  23. Orken DN, Kenangil G, Uysal E, Forta H. Cerebral microbleeds in ischemic stroke patients on warfarin treatment. Stroke 2009; 40:3638.
  24. Fang MC, Go AS, Hylek EM, et al. Age and the risk of warfarin-associated hemorrhage: the anticoagulation and risk factors in atrial fibrillation study. J Am Geriatr Soc 2006; 54:1231.
  25. Hylek EM, Go AS, Chang Y, et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 2003; 349:1019.
  26. Walsh, S. FDA approves Pradaxa to prevent stroke in people with atrial fibrillation. file://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm230241.htm (Accessed on December 03, 2010).
  27. Ezekowitz MD, Connolly S, Parekh A, et al. Rationale and design of RE-LY: randomized evaluation of long-term anticoagulant therapy, warfarin, compared with dabigatran. Am Heart J 2009; 157:805.
  28. Wallentin L, Yusuf S, Ezekowitz MD, et al. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet 2010; 376:975.
  29. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361:1139.
  30. Wong KS, Chan YL, Liu JY, et al. Asymptomatic microbleeds as a risk factor for aspirin-associated intracerebral hemorrhages. Neurology 2003; 60:511.
  31. Naidech AM, Jovanovic B, Liebling S, et al. Reduced platelet activity is associated with early clot growth and worse 3-month outcome after intracerebral hemorrhage. Stroke 2009; 40:2398.
  32. Naidech AM, Bassin SL, Bernstein RA, et al. Reduced platelet activity is more common than reported anti-platelet medication use in patients with intracerebral hemorrhage. Neurocrit Care 2009; 11:307.
  33. Eckman MH, Wong LK, Soo YO, et al. Patient-specific decision-making for warfarin therapy in nonvalvular atrial fibrillation: how will screening with genetics and imaging help? Stroke 2008; 39:3308.
  34. Rosand J, Hylek EM, O’Donnell HC, Greenberg SM. Warfarin-associated hemorrhage and cerebral amyloid angiopathy: a genetic and pathologic study. Neurology 2000; 55:947.
  35. Fang MC, Chang Y, Hylek EM, et al. Advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation. Ann Intern Med 2004; 141:745.
  36. Gorter JW. Major bleeding during anticoagulation after cerebral ischemia: patterns and risk factors. Stroke Prevention In Reversible Ischemia Trial (SPIRIT). European Atrial Fibrillation Trial (EAFT) study groups. Neurology 1999; 53:1319.
  37. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet 2001; 358:1033.
  38. Mant J, Hobbs FD, Fletcher K, et al. Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. Lancet 2007; 370:493.
  39. Hylek EM, Evans-Molina C, Shea C, et al. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation 2007; 115:2689.
  40. Gage BF, Birman-Deych E, Kerzner R, et al. Incidence of intracranial hemorrhage in patients with atrial fibrillation who are prone to fall. Am J Med 2005; 118:612.
  41. Man-Son-Hing M, Laupacis A. Anticoagulant-related bleeding in older persons with atrial fibrillation: physicians’ fears often unfounded. Arch Intern Med 2003; 163:1580.
  42. Man-Son-Hing M, Nichol G, Lau A, Laupacis A. Choosing antithrombotic therapy for elderly patients with atrial fibrillation who are at risk for falls. Arch Intern Med 1999; 159:677.
  43. Sellers MB, Newby LK. Atrial fibrillation, anticoagulation, fall risk, and outcomes in elderly patients. Am Heart J 2011; 161:241.
  44. Buresly K, Eisenberg MJ, Zhang X, Pilote L. Bleeding complications associated with combinations of aspirin, thienopyridine derivatives, and warfarin in elderly patients following acute myocardial infarction. Arch Intern Med 2005; 165:784.
  45. Smith EE, Rosand J, Knudsen KA, et al. Leukoaraiosis is associated with warfarin-related hemorrhage following ischemic stroke. Neurology 2002; 59:193.
  46. Greenberg SM, Vernooij MW, Cordonnier C, et al. Cerebral microbleeds: a guide to detection and interpretation. Lancet Neurol 2009; 8:165.
  47. Cordonnier C, Potter GM, Jackson CA, et al. improving interrater agreement about brain microbleeds: development of the Brain Observer MicroBleed Scale (BOMBS). Stroke 2009; 40:94.
  48. Lee SH, Ryu WS, Roh JK. Cerebral microbleeds are a risk factor for warfarin-related intracerebral hemorrhage. Neurology 2009; 72:171.
  49. Saloheimo P, Juvela S, Hillbom M. Use of aspirin, epistaxis, and untreated hypertension as risk factors for primary intracerebral hemorrhage in middle-aged and elderly people. Stroke 2001; 32:399.