Non–Vitamin K Antagonist Oral Anticoagulant Use in Patients With Atrial Fibrillation and Associated Intracranial Hemorrhage: A Focused Review

ABSTRACT

Atrial fibrillation (AF) is the most common cardiac arrhythmia and predisposes patients to an increased risk of embolic stroke. After nearly 60 years, warfarin is no longer the only effective therapeutic option for patients with AF. Large randomized trials have consistently shown that non–vitamin K oral anticoagulants (NOACs) including dabigatran, rivaroxaban, apixaban, and edoxaban significantly reduce from the risk of intracranial hemorrhage (ICH) compared with warfarin. We provide a focused review regarding the NOACs and ICH in AF patients by summarizing findings of these large clinical trials, mechanisms of lower ICH, reversal strategies with specific agents, and monitoring strategies.

Background

Atrial fibrillation (AF) is the most common cardiac arrhythmia,1 afflicting approximately 3 million people in the United States alone,2 and its prevalence is expected to rise to 15.9 million by 2050.3 Atrial fibrillation increases the risk of ischemic stroke by as much as 5‐fold and accounts for approximately 15% of all strokes nationally.4 Oral anticoagulation is the standard of care for the prevention of thromboembolism in at‐risk patients with AF.5

Warfarin, a vitamin K antagonist (VKA), has long remained the most widely prescribed oral anticoagulant in the United States since being approved for use in 1954.6 Warfarin decreases the risk of stroke and systemic thromboembolism in patients with AF by as much as 68%.7 However, the clinical management of patients taking warfarin can be complex due to multiple drug‐drug interactions, dietary interactions, and routine monitoring required to attain a therapeutic window of effect. In recent years, several non–vitamin K oral anticoagulants (NOACs)—dabigatran, rivaroxaban, apixaban, and edoxaban—have been approved by the US Food and Drug Administration (FDA) for prevention of embolic stroke in at‐risk patients with nonvalvular AF. The NOACs8 work by selectively inhibiting factor IIa (dabigatran) or factor Xa (rivaroxaban, apixaban, and edoxaban). These agents do not require routine laboratory monitoring for therapeutic effect and have been studied against warfarin in randomized controlled trials with regard to safety and efficacy.9, 10, 11, 12 In these trials, it has been shown that the NOACs' efficacy is at least noninferior to warfarin,9, 10, 11, 12 with pooled analyses revealing overall superiority of the NOACs compared with warfarin in regard to reduction of thromboembolism.13

The benefit of oral anticoagulation in reducing thromboembolism risk in AF patients needs to be weighed against the increased risk of bleeding with all agents.14 Intracranial hemorrhage (ICH) is the most feared bleeding event in terms of location and severity, due to its significantly increased morbidity and mortality.14, 15 Use of anticoagulant therapy with warfarin increases the risk of developing ICH by 7‐ to 10‐fold from baseline, and anticoagulation‐associated ICH accounts for up to 19% of all ICH cases.16, 17 The anticoagulant effect of the NOACs is currently not reversible and monitoring of effect remains difficult. However, in general, the NOACs appear to be consistently less likely to cause ICH compared with warfarin.13, 18 The goal of this review is to provide an examination of the current literature in regard to the NOACs vs warfarin and the risk of ICH.

Clinical Trials of Non–Vitamin K Oral Anticoagulants vs Warfarin

The first of the NOACs to be approved by the FDA was dabigatran etexilate, which is the only FDA‐approved oral direct thrombin inhibitor. The active form, dabigatran, works by directly inhibiting both free and clot‐bound thrombin. The Randomized Evaluation of Long‐term Anticoagulation Therapy (RE‐LY) trial was a noninferiority study that compared the long‐term efficacy and safety of dabigatran vs warfarin in patients with AF.9 The trial randomly assigned 18 113 patients to one of 3 cohorts: adjustable‐dose warfarin to a goal international normalized ratio (INR) of 2–3, dabigatran 150 mg twice daily, and dabigatran 110 mg twice daily. Over a median follow‐up period of 2.0 years, dabigatran 110 mg showed noninferiority to adjusted‐dose warfarin regarding the outcome of ischemic stroke (relative risk [RR]: 1.11, 95% confidence interval [CI]: 0.89‐1.40, P = 0.35), whereas dabigatran 150 mg showed superiority compared with warfarin (RR: 0.76, 95% CI: 0.60‐0.98, P = 0.03). Both doses of dabigatran were associated with significantly lower rates of ICH: With the 110‐mg dose, the rate of ICH was 0.23% per year (RR: 0.31, 95% CI: 0.20‐0.47, P < 0.001 compared with warfarin), and with the 150‐mg dose, the rate of ICH was 0.30% per year (RR: 0.40, 95% CI: 0.27‐0.60, P < 0.001 compared with warfarin).

Rivaroxaban, apixaban, and edoxaban are 3 other NOACs that have been FDA approved, with a mechanism of action of inhibiting factor Xa. Factor Xa has a key role in the clotting cascade by selectively and competitively inhibiting free and prothrombinase/clot‐associated factor Xa through reversible interactions, thereby inhibiting thrombin formation and decreasing fibrin clot formation.19, 20, 21

The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibitor Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Arial Fibrillation (ROCKET‐AF) trial was a phase 3, randomized, double‐blind, event‐driven noninferiority trial with 14 264 patients comparing rivaroxaban with warfarin in nonvalvular AF (≥2 documented episodes) and a history of stroke, transient ischemic attack, or non–central nervous system embolism or ≥2 independent risk factors for stroke.10 The median duration of treatment exposure was 1.6 years; the median follow‐up period was 1.9 years. The rate of stroke or systemic embolism in the per‐protocol population was 1.7% per year vs 2.2% per year in the warfarin group (hazard ratio [HR]: 0.79, 95% CI: 0.66‐0.96, P < 0.001). Patients assigned to rivaroxaban had a significantly lower rate of ICH compared with the warfarin group (0.5% per year vs 0.7% per year; P = 0.02).

Apixaban is an orally active selective inhibitor of factor Xa.22 The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial was a randomized controlled trial of 18 201 patients randomized to either apixaban or warfarin.11 The median follow‐up period was 1.8 years, and the primary outcome of stroke or systemic embolism occurred 1.27% per year in the apixaban group compared with 1.60% per year in the warfarin group (HR: 0.79, 95% CI: 0.66‐0.95, P < 0.001). The rate of ICH was significantly lower for the apixaban group at 0.33% per year vs 0.80% per year in the warfarin group (HR: 0.42, 95% CI: 0.30‐0.58, P < 0.001).

Edoxaban is the latest oral, direct factor Xa inhibitor to be approved for reduction of stroke risk in patients with nonvalvular AF. Its FDA approval was based on the Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48 (ENGAGE AF‐TIMI 48) trial,12 which was a 3‐group, randomized, double‐blind, double‐dummy trial comparing 2 dose regimens of edoxaban with warfarin. The trial included 21 105 patients with a median duration of treatment exposure of 2.5 years; the median follow‐up was 2.8 years. The rate of stroke in the intention‐to‐treat cohort was 1.49% per year (high‐dose edoxaban) vs 1.69% per year (warfarin group; HR: 0.88, 95% CI: 0.75‐1.03, P = 0.11). The rate of ICH was significantly lower for the edoxaban group at 0.39% per year (high‐dose edoxaban) vs 0.85% per year in the warfarin group (HR: 0.47, 95% CI: 0.34‐0.63, P < 0.001). A summary of characteristics and outcomes in each of the pivotal NOAC trials is provided in Table 1.

Table 1.

Characteristics and Outcomes of Randomized Controlled Trials Comparing NOACs vs Warfarin in Patients With AF

Characteristics and Outcomes	Dabigatran 150 mg	Dabigatran 110 mg	Rivaroxaban 20 mg	Apixaban 5 mg	Edoxaban 60 mg	Edoxaban 30 mg
	RE‐LY9		ROCKET AF10	ARISTOTLE11	ENGAGE AF12
Randomized patients, n	6076	6015	7131	9120	7035	7034
Study design	Open‐label warfarin vs double‐blind; D 150 vs D 110		Double‐blind vs warfarin	Double‐blind vs warfarin	Double‐blind vs warfarin
Primary efficacy outcome	Stroke or SE	Stroke or SE	Stroke or SE	Stroke or SE	Stroke or SE	Stroke or SE
Primary safety outcome	Major bleeding	Major bleeding	Major bleeding and clinically relevant bleeding	Major bleeding	Major bleeding	Major bleeding
No. of patients lost to follow‐up	20		32	69	1
Median duration of follow‐up, y	2		1.9	1.9	2.8
VKA, %	49.6		62.4	57.2	58.9
% TTR in the warfarin group	64		55	62	68
Outcome, HR (95% CI)
Stroke/SE	0.66 (0.53‐0.82)	0.91 (0.74‐1.11)	0.79 (0.65‐0.95)	0.79 (0.66‐0.95)	0.79 (0.63‐0.99)	1.07 (0.87‐1.31)
Hemorrhagic stroke	0.26 (0.14‐0.49)	0.31 (0.17‐0.56)	0.59 (0.37‐0.93)	0.51 (0.35‐0.75)	0.54 (0.38‐0.77)	0.33 (0.22‐0.50)
Intracranial bleeding	0.41 (0.28‐0.60)	0.30 (0.19‐0.45)	0.67 (0.47‐0.93)	0.42 (0.38‐0.58)	0.47 (0.34‐0.63)	0.30 (0.21‐0.43)
	0.30%/y	0.23%/y	0.5%/y	0.33%/y	0.39%/y	0.26%/y
Ischemic stroke	0.76 (0.59‐0.97)	1.11 (0.89‐1.40)	0.94 (0.75‐1.17)	0.92 (0.74‐1.13)	1.00 (0.83‐1.19)	1.41 (1.19‐1.67)
Total mortality	0.88 (0.77‐1.00)	0.91 (0.80‐1.03)	0.85 (0.70‐1.02)	0.89 (0.80‐0.998)	0.92 (0.83‐1.01)	0.87 (0.79‐0.96)
Vascular mortality	0.85 (0.72‐0.99)	0.90 (0.77‐1.06)	0.89 (0.73‐1.10)	0.89 (0.76‐1.04)	0.86 (0.77‐0.97)	0.85 (0.76‐0.96)
Major bleeding	0.93 (0.81‐1.07)	0.80 (0.69‐0.93)	1.04 (0.90‐1.20)	0.57 (0.46‐0.70)	0.80 (0.71‐0.91)	0.47 (0.41‐0.55)
Fatal bleeding	0.70 (0.43‐1.14)	0.58 (0.35‐0.97)	0.50 (0.31‐0.79)	0.50 (0.33‐0.74)	0.55 (0.36‐0.84)	0.35 (0.21‐0.57)
GI bleeding	1.50 (1.19‐1.89)	1.10 (0.86‐1.41)	1.39 (1.19‐1.61)	0.89 14;(0.70‐1.15)	1.23 (1.02‐1.50)	0.67 (0.53‐0.83)

Abbreviations: AF, atrial fibrillation; ARISTOTLE, Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; CI, confidence interval; ENGAGE AF, Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation; GI, gastrointestinal; HR, hazard ratio; NOAC, non–vitamin K antagonist oral anticoagulant; NR, not reported; RE‐LY, Randomized Evaluation of Long‐term Anticoagulation Therapy; ROCKET AF, Rivaroxaban Once Daily Oral Direct Factor Xa Inhibitor Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Arial Fibrillation; SE, systemic embolism; TTR, time in the therapeutic range; VKA, vitamin K antagonist.

In terms of real‐word data, the effectiveness and relative safety of dabigatran and rivaroxaban have been published in the Dresden NOAC Registry23 and the Swedish national quality registry for atrial fibrillation and anticoagulation (AuriculA).24 These smaller real‐world studies appear to corroborate the safety profile of the NOACs in clinical trials. Active registries include the Global Registry on Long‐term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation (GLORIA‐AF)25 and the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II (ORBIT‐AF II).26 GLORIA‐AF is a large, international, observational registry involving patients with newly diagnosed nonvalvular AF at risk for stroke. The goal of the registry is to enroll 56 000 patients to study the effectiveness and safety of the NOACs and VKA in routine clinical care. ORBIT‐AF II is a multicenter, national registry of patients with AF that is enrolling up to 15 000 newly diagnosed patients with AF. Data regarding safety and efficacy from these registries are forthcoming but have not yet been fully published.

Recent research has focused on defining the risks of ICH with NOAC use in various populations. Elderly patients are more likely to experience fluctuations in renal function, experience polypharmacy, undergo hospitalization, and suffer falls. In a recent meta‐analysis of participants of clinical trials age ≥75 years, NOACs did not cause excess bleeding and were associated with equal or greater efficacy than conventional therapy.27 Altered metabolism of NOACs in the setting of impaired kidney function may subject patients with chronic kidney disease (CKD) to alterations in their efficacy and a higher risk of bleeding. A recent meta‐analysis examined the efficacy and safety of the NOACs vs warfarin in patients with CKD and found no significant difference in the primary efficacy outcomes of stroke with NOACs vs VKAs. The risk of major bleeding was similar between the groups as well.28 It is difficult to provide definitive recommendations on which NOAC is to be used in a particular patient. A recent review of considerations for using NOACs provides guidance based on expert opinion.29 Despite significant limitations of combining the results of trials of different agents, the NOACs have been shown to be associated with a significant reduction in rates of stroke or major bleeding when compared with warfarin in patients with previous stroke or transient ischemic attack.30, 31

Mechanisms of Lower Intracranial Hemorrhage Risk in the Non–Vitamin K Oral Anticoagulants vs Warfarin

The exact mechanism of brain‐protective effect of NOACs compared with warfarin remains to be fully elucidated, but potential mechanisms are summarized in Table 2. A critical difference may be the fact that warfarin inhibits vitamin K–dependent synthesis of coagulation factors II, VII, IX, and X and regulatory factor proteins C and S, whereas the NOACs target a single factor. Cell‐surface tissue factor (TF), found in high concentrations in the brain,32 forms TF‐VIIa complexes that initiate coagulation.33 TF‐VIIa complexes are suppressed by warfarin but not by the NOACs with their more highly selective targets.

Table 2.

Potential Mechanisms of Reduced ICH With NOACs

Target	Mechanism
Tissue factor–factor VIIa complexes	Found in high concentrations in the brain,31 these complexes initiate coagulation. They are suppressed by warfarin but not by target‐specific NOACs.32
P‐gp efflux transporters	Dabigatran is a P‐gp substrate, and P‐gp efflux transporters at the BBB may actively pump molecules across the barrier.33
	Animal studies show increased levels of rivaroxaban and apixaban in P‐gp double knockouts.34, 35

Abbreviations: BBB, blood–brain barrier; ICH, intracranial hemorrhage; NOAC, non–vitamin K antagonist oral anticoagulant; P‐gp, permeability glycoprotein.

Dabigatran is a zwitterion and thus a highly polar molecule, which may limit its transfer across the blood‐brain barrier (BBB).34 Another way in which the actions of dabigatran may be mitigated is via permeability glycoprotein (P‐gp) efflux transporters. These transporters exist in the BBB and provide protection against entry of potential noxious endogenous and exogenous compounds. Because dabigatran is a P‐gp substrate, P‐gp efflux transporters at the BBB may actively pump molecules across the barrier.34

Rivaroxaban (in mice)35 and apixaban (in rats)36 are found in much lower concentrations in the brain compared with plasma. These concentration differences were postulated to be due in part to P‐gp. In experimental P‐gp double knockout mice, brain‐to‐blood concentration ratios of rivaroxaban 15 and 60 minutes after oral administration were 1.6× and 3.2× higher, respectively, compared with wild‐type mice.35

Reversal Strategies

Treatment strategies for patients with anticoagulation‐associated ICH remains a fruitful area of research, given the severe morbidity and mortality associated with ICH. Therapies are divided into specific agents and coagulation factors. Specific antidotes to the NOACs are not commercially available but are under study. Strategies for reversal of the anticoagulant effect of NOACs are summarized in Table 3.

Table 3.

Strategies for Anticoagulation Reversal in Bleeding Associated With NOACs

	Dabigatran	Rivaroxaban, Apixaban, and Edoxaban
General measures	Drug discontinuation, mechanical compression, transfusional support	Drug discontinuation, mechanical compression, transfusional support
Activated charcoal	Consider if last dose <2–3 h63	Consider if last dose <2 h64
Hemodialysis	Removes 50%–60%65	Not effective66
Coagulation factors
PCC	Mixed results in human trials; does not correct coagulation parameters67, 68	Improvement of laboratory parameters with rivaroxaban in human ex vivo trials68
rFVIIa	Single case report in real‐life patient; improves clotting time69	rFVIIa was more effective than aPCC70
aPCC, FEIBA	Rare case reports in humans; may be more potent than PCC; does not correct coagulation parameters71	More effective than PCC in reversing prolongations of PT, CT, and TG70
Specific inhibitors
Idarucizumab	Humanized antibody fragment; noncompetitive binding to dabigatran72
	Phase 1: immediate, complete and sustained reversal of dabigatran‐induced anticoagulation in healthy humans
	Phase 3: ongoing
Ciraparantag (PER977)	Small, synthetic, water‐soluble, cationic molecule; binds to heparins and oral FXa and IIa inhibitors through hydrogen bonding73
	Complete reversal of anti‐Xa activity of rivaroxaban, apixaban, edoxaban, and dabigatran
	Phase 3: rapid and sustained reversal of edoxaban
Andexanet alfa (PRT064445)		Recombinant human FXa; binds competitively to direct FXa inhibitors.74 Phase 3: rapid reversal of apixaban. Ongoing trial with rivaroxaban and planned trial with edoxaban.
aDabi‐Fab	Humanized antibody fragment that binds dabigatran stronger than its affinity for thrombin and rapidly reverses its anticoagulant effects in vitro and in vivo

Abbreviations: aPCC, activated prothrombin complex concentrate; CT, clotting time; FEIBA, factor eight inhibitor bypass activity; FXa, factor Xa; IIa, factor IIa; PCC, prothrombin complex concentrate; PT, prothrombin time; rFVIIa, recombinant activated factor VII; TG, thrombin generation.

Currently, there is a lack of consensus among board‐certified vascular neurologists regarding the treatment of a patient with NOAC‐related ICH. For example, in dabigatran‐associated ICH, 73% reported that they would attempt reversal of dabigatran with the following agents: prothrombin complex concentrate (61%), fresh frozen plasma (53%), factor VIIa (24%), hemodialysis (24%), and platelet transfusion (7%).37 Randomized controlled trials are required to compare the effect of different reversal agents on bleeding rate and volume, bleeding complications, and thrombotic complications.

Monitoring Anticoagulant Effect of the Non–Vitamin K Oral Anticoagulants

The standard of care for warfarin‐related ICH is to measure and correct the INR with the goal of reversing anticoagulation and limit hemorrhage expansion using vitamin K and/or blood products such as fresh frozen plasma. However, there have been no randomized controlled trials to determine if correction of INR is associated with a reduction in hematoma expansion or results in improved outcome and decreased mortality. The coagulation assays that are used to monitor heparin derivatives or VKAs may not accurately reflect the anticoagulant activity of NOACs.38 The standard laboratory coagulation tests of prothrombin time (PT), activated partial thromboplastin time (aPTT), and thrombin time (TT) cannot establish the precise anticoagulant status of a particular patient. Further, these tests are unsuitable to monitor the effects of NOACs, which affect specific targets within the coagulation cascade.

Dabigatran prolongs the aPTT in a concentration‐dependent manner in both ex vivo and in vitro experiments. However, the dose response is linear up to a concentration of 200 to 300 ng/mL and flattens out at higher drug levels.39 This test has high interindividual and reagent variability.40 In a study of patients taking dabigatran 150 mg twice daily, 18% of participants had a normal aPTT at trough.41 Prothrombin time is less sensitive to dabigatran than the aPTT. In an ex vivo study of patients treated with dabigatran, an INR ≥1.2 was only observed with dabigatran concentrations >400 ng/mL.42 Dabigatran prolongs TT, even at low concentrations.43 Thrombin time increases in a linear dose‐dependent relationship with dabigatran concentration but shows dramatic prolongation with increasing concentration.44 For this reason, a prolonged TT can be used to indicate the presence of dabigatran, but not its concentration. Excessive sensitivity of this test may be overcome by diluting the plasma sample.45 Ecarin‐based assays, ecarin clotting time, and ecarin chromogenic assay have shown a linear relationship with dabigatran concentrations, with R² values of 0.94 to 0.99 in in vitro and ex vivo samples. All 3 factor Xa inhibitors also prolong PT and aPTT but at low sensitivity. Although PT is usually prolonged with clinically relevant concentrations of rivaroxaban, its utility is limited by interindividual variability, reagent‐dependent variability, and poor correlation between the degree of PT prolongation and the plasma concentration of rivaroxaban.46, 47 Edoxaban has also showed considerable reagent‐dependent variability in the magnitude of PT prolongation.48 Across several studies, PT was inadequately sensitive to apixaban, even above the expected trough concentration.49 A recent systematic review recommended chromogenic anti‐Xa assay to assess plasma rivaroxaban levels.49 This method can accurately measure a wide range of rivaroxaban concentrations in plasma, provided that a standard calibration curve is generated with rivaroxaban calibrators and controls.50 Accurate and reliable quantification of apixaban anticoagulant activity in plasma is possible using chromogenic anti‐Xa assays.51 Further, anti‐Xa activity correlates linearly with edoxaban over a broad range of concentrations52 and may be the best coagulation test for measuring factor Xa inhibitor levels. Despite the shortcomings of traditional tests, in the emergency setting, expert opinion favors checking aPTT for dabigatran and PT for rivaroxaban and apixaban when a readily available laboratory measurement is necessary to determine drug presence.53

The ability to assess exact anticoagulation status would be useful in specific settings, including a new‐onset vascular event like an embolic stroke, particularly for management options including use of thrombolysis. Tissue‐type plasminogen activator (tPA; Alteplase) is contraindicated in patients on treatment with warfarin with a PT/INR >1.7 because of an increased risk of bleeding.54 Warfarin use is not associated with ICH after tPA treatment in patients with acute ischemic stroke with a PT/INR <1.7.55 Although this approach cannot be used for NOACs, it suggests that tPA may be safe in patients with low levels of anticoagulant activity. Case reports of patients treated with a NOAC who underwent revascularization are sparse.56 A recent study showed that pretreatment with rivaroxaban and apixaban greatly reduced ICH compared with warfarin‐pretreated rats after thrombolytic therapy with tPA.57 Use of thrombolytic agents in patients already on a NOAC who present with thrombotic events is an area requiring further investigation.

Future Directions

A recent systematic review of 6 studies involving 57 491 patients concluded that NOACs are uniformly associated with an overall reduced risk of ICH when used for stroke prevention in AF.18 Any of the currently available NOACs can be considered first‐line therapy for patients at higher risk for ICH.18 Bleeding risk scores to quantify hemorrhage risk include HAS‐BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly, drugs/alcohol concomitantly), Computerized Registry of Patients With Venous Thromboembolism (RIETE), and Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA).58, 59, 60 Although these scores have been helpful in defining patients at elevated bleeding risk, none are specifically supported in the 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society Guideline for the Management of Patients With Atrial Fibrillation.5 The European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with nonvalvular AF uses HAS‐BLED to define patients at higher risk of bleeding.61 Scores are based on the presence of hypertension (systolic blood pressure >160 mm Hg), abnormal liver or renal function, history of stroke or bleeding, labile INRs, elderly age (>65 years), use of drugs that promote bleeding, or alcohol excess.62 A score ≥3 indicates potentially high risk for bleeding and may require closer observation. Because this formula was modeled using a population taking warfarin, and, further, labile INR is one of the variables used, further research is necessary as to whether similar models predict ICH bleeding risk in patients taking NOACs.

Conclusion

After nearly 60 years, warfarin is no longer the only effective therapeutic option for patients with AF. The NOACs are associated with an overall reduced risk of ICH when used for stroke prevention in AF across all of the NOACs tested against warfarin. Although questions persist regarding reversal and monitoring of anticoagulant effect, new insight into mechanisms of action continues to expand the role of these novel agents, particularly with their improved bleeding profile compared with warfarin in the intracranial space.