Use of oral anticoagulants in African-American and Caucasian patients with atrial fibrillation: is there a treatment disparity?

Figures & data

Table 1 Guideline recommendations on the use of warfarin and novel oral anticoagulants for the prevention of stroke in patients with nonvalvular atrial fibrillation

Guideline	Guidance by risk	Guidance by agent	Guidance by renal function
AHA/ACC/HRS^Citation33	• CHA2DS2-VASc score  ○ ≥2 or prior stroke or TIA: use warfarin, dabigatran, rivaroxaban, or apixaban  ○ 1: no antithrombotic therapy, OAC, or aspirin  ○ 0: no antithrombotic therapy	• Warfarin-treated: determine INR weekly, then monthly when stable • If unable to maintain INR, use dabigatran, rivaroxaban, or apixaban	• Evaluate prior to NOAC initiation and annually thereafter (or when clinically indicated) • Use warfarin in patients with NVAF with CHA2DS2-VASc ≥2 and end-stage CKD (CrCl <15 mL/min) or undergoing hemodialysis • Consider reduced NOAC dose in patients with NVAF with moderate-to-severe CKD and CHA2DS2-VASc ≥2 (safety and efficacy not established) • Dabigatran and rivaroxaban not recommended in AF patients with end-stage CKD undergoing hemodialysis
AHA/ASA^Citation2,a	• Warfarin (INR 2.0–3.0) in all patients at high risk and many at moderate risk of stroke • Aspirin in patients at low risk and some moderate risk, based on patient preference, bleeding risk, and access to monitoring	• Warfarin, dabigatran, apixaban and rivaroxaban indicated for first and recurrent stroke prevention in NVAF patients • Dabigatran useful alternative to warfarin in patients with AF and risk factors for stroke or SE who do not have prosthetic heart valve or hemodynamically significant valve disease, severe renal failure (CrCl <15 mL/min), or advanced liver disease • Safety of combining NOACs with antiplatelet agents not established • Apixaban 5 mg BID is an alternative to warfarin (or aspirin in patients unable to take a VKA), in patients with NVAF who have ≥1 additional risk factor and ≥1 of the following characteristics: age ≥80 years, weight #60 kg, serum creatinine ≥1.5 mg/dL • Apixaban 2.5 mg BID is an alternative to warfarin (or aspirin in patients unable to take a VKA) in patients with NVAF who have ≥1 additional risk factor and ≥2 of the following criteria: age ≥80 years, weight #60 kg, or serum creatinine ≥1.5 mg/dL • Rivaroxaban (20 mg/day) is reasonable in NVAF patients at moderate-to-high risk of stroke (prior history of TIA, stroke, or SE, or ≥2 additional risk factors)	• For patients with renal impairment and NVAF at moderate-to-high risk of stroke (prior history of TIA, stroke, or SE, or ≥2 additional risk factors), with a CrCl of 15–50 mL/min, consider rivaroxaban 15 mg/day (efficacy and safety not established) • Can use dabigatran 150 mg BID instead of warfarin for the prevention of first and recurrent stroke in NVAF patients with ≥1 additional risk factor who have CrCl .30 mL/min • On the basis of PK data, the use of dabigatran 75 mg BID in patients with NVAF and ≥1 additional risk factor who have a low CrCl (15–30 mL/min) (based on PK data only; safety and efficacy not established)
ESC^Citation6,a	• CHA2DS2-VASc score  ○ ≥2: use VKA (INR 2.0–3.0), dabigatran, rivaroxaban, or apixaban, unless contraindicated  ○ 1: consider VKA (INR 2.0–3.0), dabigatran, rivaroxaban, or apixaban, based on bleeding risk and patient preference	• If VKA cannot be used in patients with AF when recommended, use dabigatran, rivaroxaban, or apixaban • Where OAC recommended, use an NOAC rather than VKA for most NVAF patients, based on net clinical benefit • Use dabigatran 150 mg BID, or lower 110 mg BID dose (in Europe) in patients aged ≥80 years, using concomitant interacting drugs (eg, verapamil), with a high bleeding risk (HAS-BLED ≥3) or moderate renal impairment (CrCl 30–49 mL/min) • Use rivaroxaban 20 mg QD, or lower dose (15 mg QD) in patients with a high bleeding risk (HAS-BLED ≥3) or moderate renal impairment (CrCl 30–49 mL/min)	• NOACs not recommended in patients with severe renal impairment (CrCl <30 mL/min)
ACCP^Citation3,a	• CHADS2 score  ○ 0: no therapy rather than antithrombotic therapy; for those who choose therapy, use aspirin (75–325 mg QD)  ○ 1: OAC rather than no therapy, or aspirin; in patients unable to take OACs, use combination therapy with aspirin and clopidogrel  ○ ≥2: OAC rather than no therapy, or combination therapy; for patients unsuitable for OACs, use combination therapy rather than aspirin	• When OACs recommended, dabigatran 150 mg BID suggested rather than VKA (INR 2.0–3.0)	• No recommendation provided by renal function
ASA/AHA^Citation34	• Patients with valvular AF with CHA2DS2-VASc ≥2 and acceptably low risk of hemorrhage: use long-term VKA (INR 2.0–3.0) • NVAF: CHA2DS2-VASc score  ○ ≥2 OACs recommended, including warfarin, dabigatran, apixaban, and rivaroxaban  ○ 1: no antithrombotic therapy, anticoagulant therapy, or aspirin may be considered  ○ 0: no antithrombotic therapy	•Selection of OAC should be based on individual risk factors, cost, tolerability, patient preference, potential drug interactions, and other clinical characteristics	• No recommendation provided by renal function

Note:

a Guidelines reflect the fact that apixaban had not been approved at the time of publication.

Abbreviations: AF, atrial fibrillation; ACC, American College of Cardiology; ACCP, American College of Chest Physicians; AHA, American Heart Association; ASA, American Stroke Association; BID, bis in die (twice daily); CKD, chronic kidney disease; CrCl, creatinine clearance; ESC, European Society of Cardiology; HRS, Heart Rhythm Society; INR, international normalized ratio; NVAF, nonvalvular atrial fibrillation; OAC, oral anticoagulant; PK, pharmacokinetic; QD, quaque die (once daily); SE, systemic embolism; TIA, transient ischemic attack; NOAC, novel oral anticoagulant; VKA, vitamin K antagonist.

Figure 1 Sites of NOAC action in the coagulation cascade.

Abbreviations: F, factor; T*, thrombin.

Table 2 Comparison of pharmacokinetic/pharmacodynamic interactions and dosing of warfarin and novel oral anticoagulants

	Warfarin^Citation45	Dabigatran^Citation58	Rivaroxaban^Citation60	Apixaban^Citation59	Edoxaban^Citation57
Mode of action	Inhibitor of factors II, VII, IX, and X, and the anticoagulant proteins C and S	Direct thrombin inhibitor	Factor Xa inhibitor	Factor Xa inhibitor	Factor Xa inhibitor
Route of administration	Oral or IV	Oral (tablet)	Oral (tablet or nasal gastric tube) taken with food	Oral (tablet or nasal gastric tube)^Citation61	Oral (solution or tablet)
Approved dose (US)	Target INR 2.0–3.0	150 mg BID (75 mg BID for patients with CrCl 15–30 mg/mL)	20 mg QD	5 mg BID	60 mg QD (30 mg QD for patients with CrCl 15 to 50 mL/min) Not approved in patients with CrCl .95 mL/min
Half-life	40 hours	12–17 hours	5–9 hours	∼12 hours	10–14 hours
Monitoring	Daily INR determination upon initiation until stable INR 2.0–3.0 achieved; INR every 1–4 weeks thereafter	Prolongs aPTT, ECT, and TT; insensitive to INR measurements	Cannot be monitored using standard laboratory tests; PT, aPTT, and Heptest^® (Heptest Laboratories, St Louis, MO, USA) are prolonged dose-dependently; anti-FXa activity is also influenced by rivaroxaban	Prolongs PT, INR, and aPTT, but changes at therapeutic dose are small, subject to a high degree of variability; Rotachrom^® heparin (Diagnostica Stago, Parsippany, NJ, USA) chromogenic assay produced a concentration-dependent increase in anti-FXa activity, but is not recommended to assess the anticoagulant effect of apixaban	Prolongs PT and aPTT but changes in PT, INR and aPTT at the expected therapeutic dose are small and subject to a high degree of variability
Reversal	• Vitamin K	• A specific reversal agent for dabigatran is not available • Hemodialysis can remove dabigatran; however, clinical experience is limited • aPPCs, rFVIIa, or concentrates of coagulation factors II, IX, or X may be considered, but have not been evaluated in clinical trials • Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of dabigatran • Consider administration of platelet concentrates in cases where thrombocytopenia is present or long-acting antiplatelet drugs have been used	• A specific antidote for rivaroxaban is not available • Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable • Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban • Partial reversal of PT prolongation has been seen after administration of PCCs in healthy volunteers • The use of other procoagulant reversal agents like aPPC or rFVIIa has not been evaluated	• A specific antidote for apixaban is not available • Hemodialysis does not appear to have a substantial impact on apixaban exposure • Protamine sulfate and vitamin K would not be expected to affect the anticoagulant effect of apixaban • There is no experience with antifibrinolytic agents in patients receiving apixaban • There is neither scientific rationale for reversal nor experience with systemic hemostatics in patients receiving apixaban • PCCs, aPCC, or rFVIIa may be considered, but havenot been evaluated in clinical trials • Activated charcoal reduces absorption of apixaban, thereby lowering apixaban plasma concentration	• A specific antidote for edoxaban is not available • Hemodialysis does not significantly contribute to edoxaban clearance • Protamine sulfate, vitamin K, and tranexamic acid are not expected to reverse the anticoagulant activity of edoxaban
Reasons for dose reductions	Dose and administration individualized to each patient	Patients with CrCl 15–30 mL/min should take reduced dose (75 mg BID)	Patients with CrCl 15–50 mL/min should take reduced dose (15 mg QD)	≥2 of the following: age ≥80 years, weight <60 kg, or serum creatinine ≥1.5 mg/dL	Patients with CrCl 15 to 50 mL/min
Food interactions	Foods high in vitamin K (eg, kale, spinach, turnip greens, scallions, brussels sprouts, raw broccoli, grapefruit juice, prunes, asparagus, avocado, beef liver)	None	Should be taken with the evening meal; bioavailability decreases if not taken with food	None	None
Drug interactions	Monitor INR closely if used concurrently with inhibitors or inducers of: CYP3A4, CYP2C9, or CYP1A2 Closely monitor concurrent use with drugs that can increase bleeding risk	Avoid concomitant use with P-gp inducers Decrease dose when used concomitantly with P-gp inhibitors, dronedarone, or systemic ketoconazole in patients with moderate renal impairment (CrCl 30–50 mL/min) Bleeding risk increases if used concomitantly with drugs that affect bleeding risk	Avoid concomitant use with combined P-gp and strong CYP3A4 inhibitors Avoid concomitant use with combined P-gp and strong CYP3A4 inducers Increase monitoring if used concomitantly with NSAIDs or aspirin Avoid concurrent use with other platelet-aggregation inhibitors or antithrombotic agents	Decrease dose when used concomitantly with strong dual inhibitors of P-gp and CYP3A4 Avoid concomitant use with strong dual inducers of P-gp and CYP3A4 Bleeding risk increases if used concomitantly with drugs that affect hemostasis	Avoid concomitant use of edoxaban with P-gp inducers (rifampin) Bleeding risk increases if used concomitantly with drugs that affect hemostasis
Effect of race on treatment	Asian patients may require lower initiation and maintenance doses of warfarin SNPs in the CYP2C9 and VKORC1 genes have been associated with variable warfarin-dose requirements	No information available	Healthy Japanese subjects were found to have on average 20%–40% higher exposure compared with other ethnicities, including Chinese	No dose adjustment is required based on race/ethnicity	In a population PK analysis, edoxaban exposures in Asian and non-Asian patients were similar

Abbreviations: aPCC, activated prothrombin complex concentrate; anti-FXa, anti-factor Xa; aPTT, activated partial thromboplastin time; BID, bis in die (twice daily); CrCl, creatinine clearance; ECT, ecarin clotting time; INR, international normalized ratio; IV, intravenous; NSAID, nonsteroidal anti-inflammatory drug; rFVIIa, recombinant factor VIIa; PCC, prothrombin complex concentrate; P-gp, p-glycoprotein; PK, pharmacokinetic; PT, prothrombin time; QD, quaque die (once daily); SNP, single-nucleotide polymorphism; TT, thrombin time.

Table 3 Phase III clinical trial results for the novel oral anticoagulants

	RE-LY (dabigatran 110 mg)^Citation69,Citation70	RE-LY (dabigatran 150 mg)^Citation69,Citation70	ROCKET AF (rivaroxaban 20 mg)^Citation73	ARISTOTLE (apixaban, 5 mg)^Citation72	ENGAGE AF-TIMI 48 (edoxaban 60 mg)^Citation71	ENGAGE AF-TIMI 48 (edoxaban, 30 mg)^Citation71
Stroke or systemic embolism	RR 0.90 (95% CI 0.74–1.10)	RR 0.65 (95% CI 0.52–0.81)	HR 0.88 (95% CI 0.75–1.03)	HR 0.79 (95% CI 0.66–0.95)	HR 0.79 (97.5% CI 0.63–0.99)b	HR 1.07 (97.5% CI 0.87–1.31)b
	P<0.001 (noninferiority)	P<0.001 (noninferiority)	P<0.001 (noninferiority)	P<0.001 (noninferiority)	P<0.001 (noninferiority)	P=0.005 (noninferiority)
	P=0.30	P<0.001	P=0.12a	P=0.01	P=0.08	P=0.10
Hemorrhagic stroke	RR 0.31 (95% CI 0.17–0.56)	RR 0.26 (95% CI 0.14–0.49)	HR 0.59 (95% CI 0.37–0.93)c	HR 0.51 (95% CI 0.35–0.75)	HR 0.54 (95% CI 0.38–0.77)	HR 0.33 (95% CI 0.22–0.50)
	P<0.001	P<0.001	P=0.024	P<0.001	P<0.001	P<0.001
Intracranial hemorrhage	RR 0.30 (95% CI 0.19–0.45)	RR 0.41 (95% CI 0.28–0.60)	HR 0.67 (95% CI 0.47–0.93)c	HR 0.42 (95% CI 0.30–0.58)c	HR 0.47 (95% CI 0.34–0.63)c	HR 0.30 (95% CI 0.21–0.43)c
	P<0.001	P<0.001	P=0.02	P<0.001	P<0.001	P<0.001
Myocardial infarction	RR 1.29 (95% CI 0.96–1.75)	RR 1.27 (95% CI 0.94–1.71)	HR 0.81 (95% CI 0.63–1.06)c	HR 0.88 (95% CI 0.66–1.17)	HR 0.94 (95% CI 0.74–1.19)	HR 1.19 (95% CI 0.95–1.49)
	P=0.09	P=0.12	P=0.121	P=0.37	P=0.60	P=0.13
All-causemortality	RR 0.91 (95% CI 0.80–1.03)	RR 0.88 (95% CI 0.77–1.00)	HR 0.92 (95% CI 0.82–1.03)	HR 0.89 (95% CI 0.80–0.998)	HR 0.92 (95% CI 0.83–1.01)	HR 0.87 (95% CI 0.79–0.96)
	P=0.13	P=0.051	P=0.15	P=0.047	P=0.08	P=0.006
Major bleeding	RR 0.80 (95% CI 0.70–0.93)	RR 0.93 (95% CI 0.81–1.07)	HR 1.04 (95% CI 0.90–1.20)c	HR 0.69 (95% CI 0.60–0.80)c	HR 0.80 (95% CI 0.71–0.91)c	HR 0.47 (95% CI 0.41–0.55)c
	P=0.003	P=0.32	P=0.58	P<0.001	P<0.001	P<0.001

Notes:

a The primary end point for ROCKET-AF used the per-protocol population. In the per-protocol analysis, the HR for stroke or SE with rivaroxaban versus warfarin was 0.79 (95% CI 0.66–0.96, P<0.001 for noninferiority);

b modified intention-to-treat population in the treatment period;

c safety on-treatment population. All values are for the intention-to-treat populations unless otherwise stated. All P-values are for superiority unless otherwise stated.

Abbreviations: CI, confidence interval; HR, hazard ratio; RR, relative risk; RE-LY, Randomized Evaluation of Long-term anticoagulant therapY; ARISTOTLE, Apixaban for Reduction In STroke and Other ThromboemboLic Events in atrial fibrillation; ROCKET AF, Rivaroxaban Once daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation; ENGAGE AF-TIMI 48, Effective aNticoaGulation with factor XA next GEneration in Atrial Fibrillation – Thrombolysis In Myocardial Infarction 48 study.

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