Review Article

Incidence, Mortality, and Risk Factors for Oral Anticoagulant–associated Intracranial Hemorrhage in Patients with Atrial Fibrillation Rebbeca Grysiewicz, DO,* and Philip B. Gorelick, MD†

Warfarin, a vitamin K epoxide reductase inhibitor, is the oral anticoagulant most commonly used to reduce the risk of stroke in patients with atrial fibrillation (AF). Warfarin has proved to be efficacious for this purpose in multiple clinical trials. However, warfarin use is laborious and associated with an increased risk of intracranial hemorrhage (ICH). Various factors increase the risk of warfarin-related ICH, including older age, intensity of anticoagulation, hypertension, and history of cerebrovascular disease. The emergence of newer classes of oral anticoagulants will offer therapeutic alternatives to reduce the risk of stroke in patients with AF. Recently, the United States Food and Drug Administration approved 3 new agents—dabigatran etexilate, a direct thrombin inhibitor, and rivaroxaban and apixaban, factor Xa inhibitors—to reduce the risk of stroke and systemic embolism in patients with nonvalvular AF. We discuss the incidence, mortality, and risk factors predisposing to oral anticoagulant–associated ICH in patients with AF. Key Words: Anticoagulation— intracranial hemorrhage—atrial fibrillation—warfarin. Ó 2014 by National Stroke Association

Introduction Warfarin is a well-established oral anticoagulant used to reduce the risk of stroke in patients with atrial fibrillation (AF). However, warfarin use is complicated by the need for frequent monitoring, drug and dietary interactions, and a risk of major bleeding, including intracranial hemorrhage (ICH).1 These challenges and complications have led to the development of alternative orally administered anticoagulants (OACs), including direct thrombin inhibitors and factor Xa (FXa) inhibitors, for the prevention of stroke in patients with AF. Dabigatran etexilate,

From the *Beaumont Neuroscience Center, Royal Oak, MI; and †Department of Translational Science and Molecular Medicine, Michigan State University College of Medicine and Saint Mary’s Health Care, Grand Rapids, MI. Received January 17, 2013; revision received June 5, 2014; accepted June 29, 2014. The authors acknowledge the writing and editorial assistance of Medicus and of Envision Scientific Solutions, whose services were funded by Boehringer Ingelheim Pharmaceuticals, Inc. The authors meet criteria for authorship as recommended by the International

a direct thrombin inhibitor, has been approved by the United States Food and Drug Administration (FDA) to reduce the risk of stroke and systemic embolism (SSE) in patients with nonvalvular atrial fibrillation (NVAF).2 It has also been approved for the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients who have been treated with a parenteral anticoagulant for 5-10 days, and to reduce the risk of recurrence of DVT and PE in patients who have been previously treated. Apixaban and rivaroxaban have been approved to reduce the risk of SSE in patients with NVAF. Apixaban has also been approved for the Committee of Medical Journal Editors, were fully responsible for all content and editorial decisions, and were involved in all stages of article development. The authors received no compensation related to the development of the article. Address correspondence to Rebbeca Grysiewicz, DO, Beaumont Neuroscience Center, 3555 West 13 Mile Road, Suite N120, Royal Oak, MI 48073. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2014 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.06.031

Journal of Stroke and Cerebrovascular Diseases, Vol. 23, No. 10 (November-December), 2014: pp 2479-2488

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prophylaxis of DVT, which may lead to PE in patients who have undergone hip or knee replacement surgery.3 Rivaroxaban has also been approved for the treatment of DVT and PE, for the reduction in the risk of recurrence of DVT and of PE, and for the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery.4 Given the emergence of these new classes of OACs, it is timely to review the incidence, mortality, and risk factors for OAC-associated ICH in patients with AF. Risk factor data are derived from studies of patients receiving warfarin and may or may not apply to patients treated with new oral anticoagulants.

Efficacy of Vitamin K Antagonist in AF: Overview AF is a common cardiac arrhythmia, particularly in the elderly. The prevalence of NVAF increases significantly with age and is observed in more than 9% of persons 80 years and older. The prevalence of AF is predicted to increase 2.5-fold over the next 50 years.5 AF is associated with increased morbidity and mortality and is an independent risk factor for ischemic stroke. The Framingham Study showed an approximately 5-fold increased stroke risk in persons with AF and a 23.5% risk of stroke attributable to AF in persons aged 80-89 years.6 Warfarin, a vitamin K epoxide reductase inhibitor commonly termed a vitamin K antagonist (VKA), prevents the gamma carboxylation of the vitamin K-dependent coagulation prothrombin factors (factors II, VII, IX, and X).7 Warfarin was first approved for clinical use as a therapeutic anticoagulant in 1954.7 The VKAwas the only class of OACs used in clinical practice until recently and has proved to be efficacious for stroke prevention.8 The antiplatelet acetylsalicylic acid (ASA) is another oral agent commonly used for stroke risk reduction in patients with AF. It is much less effective than warfarin, and recent guidelines recommend ASA only for patients at low risk of stroke.9 A number of major clinical trials have established the efficacy of warfarin for stroke prevention in AF, compared with both placebo and ASA therapy (Table 1). In 1991, the Stroke Prevention in Atrial Fibrillation (SPAF) study of 1330 patients with AF demonstrated that ASA and warfarin were effective in reducing the risk of ischemic stroke in patients with AF compared with placebo.10 However, the investigators were unable to detect a difference in the magnitude of effect between warfarin and ASA. Further evidence from a pooled analysis of 5 randomized trials of warfarin versus placebo showed a relative risk reduction of 68% favoring warfarin for stroke prevention (1889 and 1802 patient-years for warfarin and placebo, respectively).11 The European Atrial Fibrillation Trial demonstrated the advantage of warfarin over both placebo and ASA in patients with a history of stroke or transient ischemic attack (TIA) who were deemed eligible for anticoagulation therapy, showing a 40% relative decrease

in the yearly rate of stroke and related events in patients on warfarin (n 5 225) compared with those on ASA (n 5 230).12 The Boston Area Anticoagulation Trial for Atrial Fibrillation; the Atrial Fibrillation, Aspirin, Anticoagulation study; and the SPAF III trial provided further evidence of the superiority of warfarin compared with ASA in risk reduction of ischemic stroke in patients with AF (Table 1).13-15 The Atrial Fibrillation, Aspirin, Anticoagulation, Boston Area Anticoagulation Trial for Atrial Fibrillation, and Canadian Atrial Fibrillation Anticoagulation studies were terminated early because of greater than predicted reduction of events with warfarin.16

Incidence and Mortality of AF-associated ICH Incidence Although more effective for preventing stroke than ASA, warfarin is also associated with a higher risk of hemorrhage. A meta-analysis of 6 published clinical trials comparing warfarin with ASA in more than 4000 patients with AF reported that warfarin treatment in 1000 patients for 1 year would prevent 23 ischemic strokes but was associated with 9 additional major bleeds.17 Although ICH made up only 21.9% of the major bleeding events, it accounted for more than 50% of fatal hemorrhages.17 Nearly 70% of warfarin-related ICHs are intracerebral hemorrhages, whereas subdural hematomas account for most of the remaining intracranial bleeds.18 Over the past few decades, the absolute risk of intracerebral hemorrhage in patients on OAC has been estimated at approximately 1% per year,18 but more recent studies report rates of warfarin-related intracerebral hemorrhage ranging from .3% to .6% per year.19 A 5-year Swedish cohort study of 4434 patients receiving anticoagulation observed rates of intracerebral hemorrhage 10 times higher than the rate observed in the general population.20

Mortality ICH remains one of the most feared complications of warfarin therapy because of a high mortality rate— ranging from 46% to 68%.18 A multivariate analysis of intracerebral hemorrhage patients as part of the Genetic and Environmental Risk Factors of Hemorrhagic Stroke study showed that patients with OAC-associated intracerebral hemorrhage had higher mortality at day 1 compared with those who had intracerebral hemorrhage not associated with OAC (33.2% vs. 16.3%, P , .001).21 In this study, warfarin-related intracerebral hemorrhage most commonly occurred in the cerebellum, and cerebellar intracerebral hemorrhage was associated with increased mortality compared with other intracerebral hemorrhage locations (odds ratio [OR], 2.2; 95% confidence interval [CI], 1.2-4.0).21 Hematoma volume in intracerebral hemorrhage is directly related to mortality,22 and warfarin therapy has been associated with both increased hematoma volumes and later detection in the hospital course. For example,

Intracranial hemorrhage incidence, n/N (%) Clinical trial SPAF36

EAFT12

BAATAF13 AFASAK14 SPAF III15

Methods ASA 325 mg daily or warfarin (INR, 2.0-4.5), compared with placebo; or ASA 325 mg daily compared with placebo* ASA 300 mg daily or placebo compared with oral anticoagulation, or ASA 300 mg daily compared with placebo (in patients with recent TIA or minor stroke)* Placebo (choice to take ASA) compared with low-dose warfarin (PT ratio, 1.2-1.5) ASA 75 mg daily or placebo, compared with warfarin (INR, 2.8-4.2) ASA 325 mg daily and low-intensity, fixeddose warfarin (INR, 1.2-1.5) compared with adjusted-dose warfarin (INR 2.0-3.0)

Follow-up (mean years)

Warfarin

Placebo

Aspirin

ASA or warfarin reduce the risk of stroke compared with placebo

1.3

1/210 (.5)

0/211y (0), 0/568z (0)

NA, 1/552z (.2)

Anticoagulation reduces the risk of stroke; ASA is less effective

2.3

0/225 (0)

0/214yx (0), 0/378zx (0)

1/404zx (.2)

Low-dose warfarin reduces the risk of stroke compared with placebo Warfarin reduces the risk of stroke compared with ASA and placebo Adjusted-dose warfarin reduces the risk of stroke compared with ASA plus fixed-dose warfarin

2.2

1/212 (.5)

0/208k (0)

NA

2

1/335 (.3)

0/336 (0)

0/336 (0)

1.1

3/523{ (.6)

NA

5/521# (1)

Primary outcome

ORAL ANTICOAGULATION AND ICH

Table 1. Clinical trials demonstrating efficacy of warfarin for stroke prevention in atrial fibrillation

Abbreviations: AFASAK, Atrial Fibrillation, Aspirin, Anticoagulation; ASA, acetylsalicylic acid; BAATAF, Boston Area Anticoagulation Trial for Atrial Fibrillation; EAFT, European Atrial Fibrillation Trial; INR, International Normalized Ratio; NA, not applicable; PT, prothrombin; SPAF, Stroke Prevention in Atrial Fibrillation; TIA, transient ischemic attack. *These trials had 2 subgroups: one warfarin eligible, randomized to warfarin, placebo, or ASA; the other nonwarfarin eligible, randomized to placebo or ASA. yData are calculated out of the warfarin-eligible subgroup. zData are calculated out of the combined warfarin-eligible and warfarin-ineligible subgroups. xTwo additional events were not counted in the study, as they occurred in patients with previous ICH. kPlacebo group includes patients taking either ASA or placebo. {Adjusted-dose warfarin group. # ASA plus low intensity fixed-dose warfarin group.

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in a prospective cohort study of intracerebral hemorrhage outcomes in 183 patients, hematoma expansion (defined as $33% increase in volume) was more frequent among warfarin-treated patients compared with those not on warfarin (54% vs. 16%, P 5 .007).23 The median time to hematoma detection in warfarin-treated patients was 21.4 hours, compared with 8.4 hours in those not taking warfarin, which suggested to the investigators that warfarin-treated patients might have experienced prolonged bleeding.23 Hematoma expansion associated with intracerebral hemorrhage was also examined in the placebo arm of the Cerebral Hematoma and NXY Treatment study, which compared 282 patients with spontaneous intracerebral hemorrhage and 21 patients with OAC-associated intracerebral hemorrhage.24 Multivariate analysis demonstrated that patients with warfarin-related intracerebral hemorrhage had an increased incidence of hematoma expansion (56% of patients with warfarinrelated intracerebral hemorrhage, compared with 26% of patients with spontaneous intracerebral hemorrhage, P 5 .006) and increased mortality (62% vs. 17%, respectively, P , .001).24 Additional predictors of mortality in warfarin-related intracerebral hemorrhage include lower level of consciousness (median Glasgow Coma Scale sum score of 9) and larger intracerebral hemorrhage volumes (.73.4 mL) at initial presentation.25,26

Risk Factors for Warfarin-related ICH In general, the most frequently reported risk factors for warfarin-related ICH are age (particularly in individuals older than 75 years), intensity of anticoagulation, hypertension, and history of cerebrovascular disease. Other, less established factors that have been reported include cerebral amyloid angiopathy (CAA), genetic polymorphism of the cytochrome P450 2C9 (CYP2C9) enzyme, concomitant antiplatelet use, and cerebral microbleeds on T2-weighted magnetic resonance imaging (Table 2). These are reviewed in detail below.

Age Warfarin use in the United States quadrupled from the late 1980s to the late 1990s, and the incidence of

anticoagulant-associated intracerebral hemorrhage increased 5-fold during this period, by 1 estimate.27 As the US population ages, both the prevalence of AF and the use of warfarin are likely to increase still further.5,28 A case– control analysis of 121 patients with ICH taking warfarin showed that age of 80 years and older was a significant risk factor for both intracerebral hemorrhage and subdural hematoma (OR, 2.8; 95% CI, 1.3-5.8; P 5 .006 and OR, 5.7; 95% CI, 2.0-16.4; P 5 .001, respectively).29 The SPAF II study revealed intracerebral hemorrhage rates of 1.8% per year in patients older than 75 years compared with .5% per year among patients 75 years or younger taking warfarin, respectively (P 5 .05).30 Advanced age, however, has not consistently been reported as a risk factor for warfarin-related intracerebral hemorrhage compared with ASA treatment in clinical trials. For example, the Birmingham Atrial Fibrillation Treatment of the Aged study showed a similar annual risk of ICH for elderly (.75 years) patients treated with warfarin or ASA (1.9% risk per year vs. 2.0% risk per year; relative risk [RR] 5 .96; 95% CI, .53-1.75; P 5 .90).31 Results of a study of 783 NVAF patients on warfarin suggest that careful laboratory monitoring of anticoagulant effect in elderly patients is warranted to reduce the risk of intracerebral hemorrhage.28,29,32 Cerebral microbleeds, more often associated with ICH than with other stroke subtypes, are more common in the elderly and have been associated with a number of factors including use of antiplatelet and antithrombotic medications.33-35 Although the presence of cerebral microbleeds has been reported to increase the risk of warfarin-related ICH more than 80-fold, the results of several studies have demonstrated close associations between use of antiplatelet agents and microbleeds but a nonsignificant risk with anticoagulant therapy.34,35 However, investigators suggest that the lack of a significant association between cerebral microbleeds and anticoagulant use might be explained in part by the presence of relatively few anticoagulated patients in the study population or by hypothetical differences in the effects of the drug classes, that is, sealing of a vessel wall defect with antiplatelet agents versus clot stabilization with anticoagulants.35

Table 2. Risk factors for warfarin-associated intracranial hemorrhage Risk factor

Evidence of risk

Demographic at highest risk

Age27 Intensity of anticoagulation38 Hypertension40 History of cerebrovascular disease32,38,44 Cerebral amyloid angiopathy47 Genetic polymorphisms of CYP45049 Concomitant antiplatelet use52 Cerebral microbleeds34,54

Well established Well established Well established Well established Less established Less established Less established Less established

.75 years of age INR .436 Systolic blood pressure $160 mm Hg History of stroke Presence of apoE epsilon 2 allele Presence of CYP2CP9*3 polymorphism INR above goal Multiple microbleeds

Abbreviations: apoE, apolipoprotein E; CYP, cytochrome P450; INR, international normalized ratio.

ORAL ANTICOAGULATION AND ICH

Intensity of Anticoagulation Warfarin anticoagulant therapy to prevent SSE in patients with AF may increase the risk for intracerebral hemorrhage. The SPAF III study compared low intensity, fixed-dose warfarin (international normalized ratio [INR], 1.2-1.5) plus ASA with adjusted-dose warfarin alone (INR, 2.0-3.0) in 1044 patients with NVAF.15 In these patients, most warfarin-related ICH occurred at an INR greater than 3.0.36 A case–control study of 170 patients with intracerebral hemorrhage on warfarin showed that the risk of intracerebral hemorrhage increased with an INR of 3.5-3.9 (adjusted OR, 4.6; 95% CI, 2.3-9.4), but the risk of intracerebral hemorrhage did not differ significantly between an INR of less than 2 and an INR ranging from 2 to 3 (adjusted OR, 1.3; 95% CI, .8-2.2).37 In a separate study of more than 13,000 patients with NVAF, Hylek et al38 showed that there was no substantial increase in the rate of intracerebral hemorrhage in patients receiving warfarin for AF until the INR reached 4.0-4.5 (2.7 per 100 person-years; 95% CI, 1.0-7.3).38 Furthermore, a prospective study of patients with supratentorial intracerebral hemorrhage identified the intensity of anticoagulation as an independent predictor of 3-month mortality in patients with intracerebral hemorrhage. Warfarin therapy increased the risk of mortality from 25.8% for patients not receiving warfarin to 52.0%, and the risk increased further with higher INR levels (P , .01 for trend).39

Hypertension Hypertension is an additional risk factor for warfarinrelated intracerebral hemorrhage, especially when systolic blood pressure is at least 160 mm Hg.40 A retrospective study of 173 intracerebral hemorrhage events in strokefree patients with NVAF revealed that in patients with hypertension, warfarin treatment increased intracerebral hemorrhage risk 3.3-fold (RR 5 3.25; 95% CI, 2.32-4.55).41 Similarly, a small, case–control study of 68 patients receiving warfarin therapy demonstrated that hypertension is an independent risk factor for warfarinrelated ICH (OR, 2.69; 95% CI, 1.04-6.97).42 The percentage of patients with hypertension in studies of warfarinrelated intracerebral hemorrhage is variable, and improvements in the control of hypertension in recent trials may have influenced the frequency of warfarin-related intracerebral hemorrhage. Nonetheless, hypertension has historically remained an important risk factor for intracerebral hemorrhage in general and a predisposing factor for warfarin-related intracerebral hemorrhage specifically.41,42 Furthermore, when in combination with other risk factors (eg, INR .3 and cerebrovascular disease), poorly controlled hypertension may pose an even greater risk for warfarin-related intracerebral hemorrhage, as seen in the Stroke Prevention in Reversible Ischemia Trial, in which average blood pressure was in the hypertensive range and INR levels were targeted

2483 43

from 3.0 to 4.5. Stroke Prevention in Reversible Ischemia Trial was terminated early because of a high rate of major bleeding complications; 53 major bleeding complications, including 27 ICH, occurred in the anticoagulated group, compared with only 6 major bleeding complications, including 3 ICH, in the ASA group.43

History of Cerebrovascular Disease A history of cerebrovascular disease is another risk factor for warfarin-related ICH. One prospective study of 783 patients with AF on OAC showed an increased bleeding risk in patients with a history of ischemic stroke or TIA (OR, 2.5; 95% CI, 1.3-4.8; P 5 .007).32 Similarly, in a cohort of 565 outpatients treated with warfarin, a known history of stroke was associated with an increased risk of ICH (RR 5 6.6).44 Previous stroke was also identified by Hylek and Singer29 as an independent risk factor for ICH in patients receiving warfarin (OR, 2.3; 95% CI, 1.4-3.7; P ,.001). This observation was confirmed by a case–control study showing that patients with warfarin-related ICH were more likely than their matched controls to have a history of cerebrovascular disease (37% vs. 20%, P , .001).37

Cerebral Amyloid Angiopathy CAA is recognized as a major contributor to the etiology of primary nontraumatic lobar hemorrhage in the elderly. Lobar hemorrhage associated with CAA in turn is correlated with the apolipoprotein E (apoE) genotype. Specifically, the apoE epsilon 4 and apoE epsilon 2 alleles are both enriched in patients with CAA-associated cerebral hemorrhage, although whether this effect is independent of Alzheimer disease status is unclear.45,46 Moreover, Rosand et al47 found that the apoE epsilon 2 allele was overrepresented in patients with warfarin-related lobar hemorrhages compared with warfarin-treated controls who did not have intracerebral hemorrhage (allele frequency .13 vs .04, P 5 .031). After adjustment for other risk factors associated with intracerebral hemorrhage, carriers of the apoE epsilon 2 allele were 3.8 times as likely as noncarriers to have lobar intracerebral hemorrhage (95% CI, 1.0-14.6). Together, these data suggest that genetic predisposition for CAA also plays a role in determining risk for warfarin-related intracerebral hemorrhage.

Genetic Polymorphisms of Cytochrome P450 CYP2C9 is the main rate-limiting enzyme in warfarin metabolism.48 Multiple variant polymorphisms have been identified and shown to vary by ethnicity.49 Two common polymorphisms, CYP2CP9*2 and CYP2CP9*3, occur in approximately 12% and 8%, respectively, of Caucasians; however, the prevalence is only 1%-3% in African Americans.49 Patients homozygous for CYP2CP9*3 are estimated to require a 3.3-fold lower mean dose of warfarin than homozygous carriers of CYP2C9*1.49

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Higashi et al demonstrated that when compared with patients with no variant alleles (CYP2CP9*2 or CYP2CP9*3), individuals with at least 1 variant allele had an increased risk of having an INR more than the recommended range (hazard ratio [HR] 5 1.40; 95% CI, 1.03-1.90). These patients also required more time to achieve stable dosing, with a 95-day median difference (HR 5 .65; 95% CI, .45-.94; P 5 .004). Variant genotypes may be associated with an increased risk of major bleeding events.50

Concomitant Antiplatelet Use A retrospective cohort analysis of 10,093 Medicare patients discharged on warfarin for stroke prophylaxis in AF found a concomitant antiplatelet use of 19.4%.51 The antiplatelet most often prescribed (nearly 90% of all prescriptions) was ASA alone.51 Compared with the warfarin-alone group, patients receiving combined warfarin–antiplatelet treatment had a 3-fold increase in intracerebral hemorrhage rate that persisted up to 180 days after discharge (.3% vs. .9%; OR, 2.95; 95% CI, 1.58-5.51).51 Hart et al52 conducted a meta-analysis of 6 randomized clinical trials (a total of 3874 patients) that combined ASA and oral anticoagulant therapy for various indications, including valve replacement, primary prevention of ischemic heart disease, and AF. The analyses revealed that addition of ASA to oral anticoagulants more than doubled the frequency of ICH compared with OAC alone (RR 5 2.4; 95% CI, 1.2-4.8; P 5.02).52 The clinical significance of this result, however, is likely to be dependent on other factors, such as anticoagulation intensity.

Cerebral Microbleeds The presence of cerebral microbleeds can be evaluated on the gradient recalled-echo T2-weighted magnetic resonance imaging sequence.53 A small (N 5 48) case–control study showed that warfarin-treated patients with a history of intracerebral hemorrhage had more microbleeds than warfarin-treated patients without a history of intracerebral hemorrhage (79.2% vs. 22.9%, P , .001), and the number of microbleeds was correlated with the presence of OAC-associated intracerebral hemorrhage (r 5 .29, P , .001).34 Similar results were observed in a cohort by Ueno et al,54 who also reported that the presence of cerebral microbleeds was independently associated with OAC-associated intracerebral hemorrhage (OR, 7.38; 95% CI, 1.05-51.83) regardless of anticoagulation intensity or hypertension. A separate meta-analysis of published and unpublished cohort data that included 1460 patients with intracerebral hemorrhage showed an increased rate of concurrent cerebral microbleeds in warfarin-treated patients with intracerebral hemorrhage compared with patients with intracerebral hemorrhage who were not treated with warfarin (OR, 2.7; 95% CI, 1.6-4.4; P , .001).55 In addition, pooled follow-up data

of 768 patients receiving antithrombotic therapy showed that baseline cerebral microbleeds greatly increased the risk of subsequent intracerebral hemorrhage (OR, 12.1; 95% CI, 3.4-42.5; P , .001).55 Large, randomized, prospective clinical trials are needed to validate these findings.

Management of Anticoagulant-related Intracerebral Hemorrhage According to the 2010 American Heart Association/ American Stroke Association guidelines for management of spontaneous ICH, patients receiving oral anticoagulant therapies were estimated to constitute 12%-14% of patients with ICH more than a decade ago, a proportion that was evidently increasing with the expanded use of warfarin.56 The risk for rapid neurologic deterioration and the frequency of poor long-term outcomes after ICH emphasize the necessity of prompt and aggressive management of this medical emergency. As the initial signs and symptoms are suggestive rather than specific, and diagnosis cannot be based solely on clinical characteristics, neuroimaging is mandatory to differentiate ICH from ischemic stroke.56 Computed tomography is considered the gold standard for identification of acute hemorrhage.56 Regardless of the anticoagulant in use, early treatment measures may include anticoagulant withdrawal, steps to reverse coagulopathy, management of blood pressure and glycemia, intubation, external ventricular drainage or invasive monitoring, and treatment of intracranial pressure.56 For patients on warfarin, the general recommendation is to correct the INR as rapidly as possible by withdrawal of warfarin and administration of vitamin K and therapy to replace vitamin K-dependent coagulation factors.56 Specific reversal agents are in development but are not yet available for the new oral anticoagulants. For most patients with ICH, the utility of hematoma evacuation by surgery has not been confirmed; early surgery to limit compression of the brain and the deleterious effects of blood may limit injury but at the expense of an increased risk of bleeding.56 Once cessation of bleeding has been established, resumption of anticoagulation with low-dose subcutaneous low-molecular-weight heparin or unfractionated heparin may be considered for prevention of venous thromboembolism in patients who have restricted mobility after 1-4 days from onset.56 Selection of longer-term therapy to prevent ICH recurrence will depend on the patient’s clinical profile. Following are descriptions of the 3 new FDA-approved oral anticoagulants and summaries of the results of clinical trials in patients with NVAF.

Direct Thrombin Inhibitor Dabigatran Etexilate Dabigatran etexilate is an oral prodrug that is converted rapidly by esterases to dabigatran, a competitive

ORAL ANTICOAGULATION AND ICH 57

direct thrombin inhibitor. Dabigatran etexilate (Boehringer Ingelheim, Ingelheim, Germany), 150 mg given twice daily, has been approved by the FDA to reduce the risk of SSE in patients with NVAF and creatinine clearance above 30 mL/minute. A 75-mg twice daily dose is indicated for patients with creatinine clearance from 15 to 30 mL/minute. The phase 3 Randomized Evaluation of Long-Term Anticoagulation Therapy trial compared open-label, dose-adjusted warfarin (INR, 2.0-3.0) with dabigatran etexilate (blinded 110 mg or 150 mg twice daily) for the prevention of SSE in more than 18,000 patients with NVAF.58 Eligible patients had NVAF documented on electrocardiography performed at screening or within 6 months beforehand and at least 1 additional stroke risk factor. After a mean follow-up of 2 years, the 150mg twice daily dose of dabigatran etexilate was superior to warfarin (mean of 64.4% of time in therapeutic INR range) for the prevention of SSE (1.11% per year vs. 1.71% per year; RR 5 .65; 95% CI, .52-.81; P , .001 for superiority).58,59 Patients receiving dabigatran etexilate 110 mg twice daily experienced rates of SSE similar to those in patients receiving warfarin (1.54% per year vs. 1.71% per year; RR 5 .90; 95% CI, .74-.81; P 5 .30 for superiority).59 Compared with patients receiving warfarin, patients receiving dabigatran etexilate 110 mg and 150 mg twice daily had lower and similar rates of major bleeding, respectively (3.57% per year vs. 2.87% per year; RR 5 .80; 95% CI, .70-.93; P , .003 for superiority and 3.57% per year vs. 3.32% per year; RR 5 .93; 95% CI, .81-1.07; P 5 .32 for superiority).59 During follow-up, 153 participants experienced a total of 154 ICH: 46% intracerebral (49% mortality), 45% subdural (24% mortality), and 8% subarachnoid (31% mortality). The annual rate of ICH with warfarin was .76% compared with .31% and .23% with dabigatran 150 mg and 110 mg, respectively (P , .001 for either dabigatran dose or warfarin).60 Fewer fatal ICH occurred among patients receiving dabigatran 150 mg and 110 mg (n 5 13 and n 5 11, respectively) than among those receiving warfarin (32 patients; P , .01 for both).60 Independent predictors of ICH included warfarin treatment (RR 5 2.9; P ,.001), concomitant ASA use (RR 5 1.6; P 5.01), increasing age (RR 5 1.1 per year; P , .001), and history of stroke/TIA (RR 5 1.8; P 5 .001). Although the clinical spectrum of ICH was similar for all patients regardless of treatment, absolute rates of hemorrhage at all sites and rates of fatal ICH were lower with dabigatran than with warfarin. Concomitant ASA therapy was the most important modifiable independent risk factor for ICH in this trial.60

FXa Inhibitors Multiple oral direct FXa inhibitors are currently in different phases of evaluation for the prevention of SSE in patients with AF.61 Rivaroxaban and apixaban

2485

are in clinical use; edoxaban remains under investigation.

Rivaroxaban Rivaroxaban 20 mg once daily was compared in a blinded fashion with dose-adjusted warfarin (INR, 2.0-3.0) in the phase 3 Rivaroxaban Once daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation trial.62 The study included more than 14,000 patients with NVAF who had a moderate-to-high risk of stroke because of a history of stroke, TIA or systemic embolism, or at least 2 additional stroke risk factors.62 The protocol specified that the proportion of patients with a history negative for ischemic stroke, TIA, or systemic embolism and with no more than 2 risk factors was limited to 10% of each regional cohort; the remaining patients were required to have either prior thromboembolism or at least 3 risk factors.62 Patients were followed up for a median of 2.0 years.62 For the primary composite outcome of SSE, rivaroxaban was noninferior to warfarin (mean of 55% of time in therapeutic INR range) in the intention-to-treat population (2.1 events and 2.4 events per 100 patientyears, respectively; HR 5 .88; 95% CI, .75-1.03; P , .001 for noninferiority and P 5 .117 for superiority) and superior to warfarin in the intention-to-treat population during treatment (1.7 and 2.2 events per 100 patient-years, respectively; HR 5 .79; 95% CI, .66-.96; P 5.02 for superiority).62 Rates of the primary safety end point (major and clinically relevant nonmajor bleeding) were similar between treatment groups: for rivaroxaban, 14.9 events and for warfarin, 14.5 events, per 100 patient-years (HR 5 1.03; 95% CI, .96-1.11; P 5 .44).62 Rates of intracerebral hemorrhage were lower in the rivaroxaban group than in the warfarin group (.4 and .7 events per 100 patient-years, respectively; HR 5 .67; 95% CI, .47-.93; P 5 .02).62

Apixaban Fixed-dose apixaban was compared with ASA for prevention of SSE in patients with NVAF who were determined by their physician to be unsuitable for warfarin in the phase 3 Apixaban versus Acetylsalicylic Acid to Prevent Strokes trial.63 Patients were eligible if they were 50 years of age or older and had documented NVAF and at least 1 additional risk factor for stroke. In addition, patients could not be receiving VKA therapy, either because it had already been demonstrated to be unsuitable for them or because it was expected to be unsuitable.63 Patients received ASA of 81-324 mg daily or apixaban 5 mg twice daily, with a 2.5-mg twice daily apixaban dose provided for patients with any 2 of the following criteria: serum creatinine $1.5 mg/dL, age $80 years, and body weight #60 kg. The study was terminated early as a result of preliminary findings of superiority for apixaban.63 Rates of SSE were lower in patients

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receiving apixaban than in those receiving ASA (1.6% and 3.7% per year, respectively; HR 5 .45; 95% CI, .32-.62; P , .001). Rates of intracerebral hemorrhage were low and similar between patient groups (.4% per year for both, P 5 .69).63 The phase 3 Apixaban for the Prevention of Stroke in Subjects with Atrial Fibrillation study compared apixaban and warfarin in patients with NVAF/flutter at enrollment or at least 2 electrocardiograph-documented episodes of NVAF/flutter at least 2 weeks apart in the 12 months before enrollment plus at least 1 additional risk factor for stroke.64 Fixed-dose apixaban (5 mg or 2.5 mg twice daily) was found to be superior to warfarin (target INR, 2.0-3.0; mean of 62.2% time in therapeutic INR range) for preventing SSE (1.27% vs. 1.60% per year, respectively; HR 5 .79; 95% CI, .66-.95; P ,.001 for noninferiority, P 5.01 for superiority).64 The rate of major bleeding was lower in patients receiving apixaban than in those receiving warfarin (2.13% and 3.09% per year, respectively; HR 5 .69; 95% CI, .60-.80; P , .001), as was the rate of intracerebral hemorrhage (.33% events and .80% per year, respectively; HR 5 .42; 95% CI, .30-.58; P , .001).64

Conclusion Warfarin is the most frequently used oral anticoagulant, but warfarin use is cumbersome and associated with an increased risk of ICH, ranging from .3% to .6% per year. ICH associated with warfarin therapy remains a feared complication due to high mortality and disability rates. Established risk factors for ICH include advancing age, intensity of anticoagulation, hypertension, and history of cerebrovascular disease. Other reported associated factors for warfarin-associated ICH include CAA, genetic polymorphism of the CYP2C9 enzyme in patients, concomitant antiplatelet therapy, and cerebral microbleeds. Investigators have commented that the importance of reducing the risk of ICH with the new OACs, compared with warfarin, ‘‘cannot be overemphasized’’.65 The reduction in anticoagulation-associated ICH appears to be a significant advantage conferred by the novel selective OACs when compared with warfarin.65 Orally administered direct thrombin inhibitors and FXa inhibitors appear to offer promising alternatives to warfarin anticoagulation for patients with NVAF in reducing the risk of stroke and systemic embolism, and results demonstrate an advantageous safety profile for the risk of ICH.

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