Novel Anticoagulants in Atrial Fibrillation: A Primer for the Primary Physician

Article Figures & Data

Table 1. Comparison of the CHADS₂ and CHA₂ DS₂-VASc^* Risk Stratification Scores for Subjects With Nonvalvular Atrial Fibrillation⁵

Definition	Possible Score	Stroke Risk Stratification
Definition	Possible Score	CHADS₂ and CHA₂DS₂-VASc Scores	Adjusted Stroke Rate (% per year)
CHADS₂ acronym		CHADS₂ acronym^{^†}
Congestive HF	1	0	1.9
Hypertension	1	1	2.8
Age ≥75 years	1	2	4.0
Diabetes mellitus	1	3	5.9
Stroke/TIA/TE	2	4	8.5
Maximum score	6	5	12.5
		6	18.2
CHA₂DS₂-VASc acronym		CHA₂DS₂-VASc acronym^{^‡}
Congestive HF	1	0	0
Hypertension	1	1	1.3
Age ≥75 years	2	2	2.2
Diabetes mellitus	1	3	3.2
Stroke/TIA/TE	2	4	4.0
Vascular disease (prior MI, PAD, or aortic plaque)	1	5	6.7
Age 65 to 74 years	1	6	9.8
Sex category (eg, female sex)	1	7	9.6
Maximum score	9	8	6.7
		9	15.20

↵† These adjusted stroke rates are based on data for hospitalized patients and atrial fibrillation and were published in 2001.⁸ Because stroke rates are decreasing, actual stroke rates in contemporary nonhospitalized cohorts might vary from these estimates.
↵‡ Adjusted stroke rate scores are based on data from Lip and colleagues.⁹ Actual rates of stroke in contemporary cohorts might vary from these estimates.
AF = atrial fibrillation
↵* CHADS₂ = congestive heart failure; hypertension; age ≥75 years; diabetes mellitus, prior stroke or transient ischemic attack (TIA), or thromboembolism (doubled). CHA₂DS₂-VASc = congestive heart failure; hypertension; age ≥75 years (doubled); diabetes mellitus; prior stroke or TIA or thromboembolism (doubled); vascular disease; age 65 to 74 years; sex category.
HF, heart failure; MI, myocardial infarction; PAD, peripheral artery disease; TE, thromboembolic.^9,10

Table 2. Assessment of Bleeding Risk (HAS-BLED) in Patients With Atrial Fibrillation

Letter	Risk	Points	HAS-BLED Score	Bleeds per 100 Patient-Years
H	Hypertension (uncontrolled, systolic blood pressure >160 mmHg)	1	0	1.13
A	Abnormal ± renal function^* Abnormal liver function^{^†}	1 or 2	1	1.02
S	Stroke history	1	2	1.88
B	Bleeding (major bleed: anemia or predisposition to bleed)	1	3	3.74
L	Labile INRs (time in therapeutic range <60%)	1	4	8.7
E	Elderly (age >65 years)	1	5–9	Insufficient data^{^‡}
D	Drugs or alcohol (antiplatelets or NSAIDs, or excess alcohol^{^§})	1 or 2	—	—

↵* Abnormal renal function is classified as the presence of chronic dialysis, renal transplantation, or serum creatinine ≥200 μmol/L (2.26 mg/dL).
↵† Abnormal liver function is defined as chronic hepatic disease (eg, cirrhosis) or biochemical evidence of significant hepatic derangement (bilirubin 2 to 3 times the upper limit of normal, in association with aspartate aminotransferase/alanine aminotransferase raise/alkaline phosphatase 3 times the upper limit of normal).
↵‡ Insufficient events at HAS-BLED scores of >5 in initial validation cohort.
↵§ Excess alcohol is defined as the consumption of ≥8 alcoholic units/wk.
Reproduced with permission from Lip.¹¹
INR, international normalized ratio; NSAID, nonsteroidal anti-inflammatory agent.

Table 3. Review of Novel Oral Anticoagulant Pharmacokinetics²³

Characteristics	Warfarin	Dabigatran	Rivaroxaban	Apixaban	Edoxaban
Target	Synthesis of II, VII, IX, X	IIa (thrombin)	Xa	Xa	Xa
Dose (mg)	Variable	150 110^* 75^{^†}	20 (15)	5 (2.5)	30 60
Frequency	Once a day	Twice a day	Once a day	Twice a day	Once a day
Hour to C_max	72–96	22–4.5	1–3	1–2	—
Half-life (hours)	40	12–14	5–9	8–15	10–14
		>24 if creatinine <30	9–13 (Elderly)
Interactions	CYP2C9/3A4/1A2	P-gP	CYP3A4/2J2 P-gP	CYP3A4 P-gP	P-gP
Renal elimination (%)	<1	80	33	25	35

↵* The 110-mg dose not available in the United States.
↵† Use 75-mg dose in patients with creatinine clearance 15–30 mL/min.
P-gP, P-glycoprotein; CYP, cytochrome P; IIa, factor IIa (thrombin); Xa, factor Xa.

Table 4. Review of the Landmark Trials in Atrial Fibrillation and the Use of Novel Anticoagulants^28–34

Drug	Trial	Design	Treatment	Duration	TTR (%)	Patients	Mean CHAD₂ Score	Efficacy/Outcome	Safety/Outcome
Dabigatran	RE-LY	Blinded	VKA/dabigatran (150 mg bid)	24 months	64	18,113 patients with nonvalvular Afib	2.1	Stroke or systemic emboli, 1.11% Dabigatran 1.69% VKA group	Major bleeding in 2.71% Dabigatran in 3.36% of VKA group
Rivaroxaban	Rocket AF	DB	VKA/rivaroxaban (20 mg daily)	30 months	55	14,264 patients with nonvalvular Afib	3.5	Stroke or systemic emboli 1.7% rivaroxaban 2.2% VKA group	Major bleeding: 3.6% in rivaroxaban group, 3.4% in VKA group
Rivaroxaban	X-Vert	DB	VKA/rivaroxaban (20 mg daily)	Months	55	1504 patients needed cardioversion for Afib	3.2	Stroke or systemic emboli: 0.5% in rivaroxaban group and 1.02 in the VKA group	Major bleeding: 0.61% in rivaroxaban group vs 0.8% in VKA group
Apixaban	AVVEROUS	DB	ASA/apixaban 5 mg bid or 2.5 mg bid	13 months	62	5,599 patients with nonvalvular Afib could not take warfarin	2.1	Stroke or systemic emboli: 1.6% in apixaban group vs 3.7% in the ASA group	Major bleeding: 1.4% in apixaban group vs 1.2% in ASA group
	ARISTOTLE	DB	VKA/apixaban 5 mg bid or 2.5 mg bid	22 months	62	18,201 patients with nonvalvular Afib	2.1	Stroke or systemic emboli 1.27% apixaban 1.6% VKA group	Major bleeding 2.1 apixaban 3.09% VKA group
Edoxaban	ENGAGE-TIMI 48	DB	VKA/edoxaban 60 mg daily and 30 mg daily	34 months	64	21,105 patients with nonvalvular Afib	2.8	Stroke or systemic emboli: 1.18% in edoxaban group vs 1.5% in VKA group	Major bleeding: 2.75% in edoxaban group vs 3.43% in VKA group

Afib, atrial fibrillation; ASA, aspirin; DB, double blind; TTR, time in therapeutic range; VKA, Vitamin K antagonist.

Table 5. Common Drug–Drug Interactions With Novel Oral Anticoagulants

	Novel Oral Anticoagulants
	Dabigatran	Rivaroxaban	Apixaban	Edoxaban
Ketoconazoles	Avoid	Avoid	Avoid	Avoid
Clarithromycin	No adjustment	Precaution^*	Avoid	Avoid
Erythromycin	Precaution^*	Precaution^*	^Precaution^	Avoid
Fluconazole	Avoid	Precaution^*	Avoid	Avoid
Rifampin	Avoid	Avoid	Avoid	Safe
NSAIDs/ASA	Caution	Caution	Caution	Caution
Clopidogrel/antiplatelet agents	Caution	Caution	Caution	Caution
Diltiazem	NK	Caution	Caution	NK
Verapamil	Avoid^{^†}	Caution	Caution	Avoid
Heparin/anticoagulants/ticagrelor	Avoid	Avoid	Avoid	Avoid

↵* Especially in renal impairment.
↵† Administer novel oral anticoagulant 2 hours before if choosing to use both agents; caution implies increased bleeding risk
ASA, aspirin; NK, not known; NSAID, nonsteroidal anti-inflammatory drug.

Table 6. Suggestions for Novel Oral Anticoagulation Discontinuation Prior to Planned Surgical Intervention^46,47^*

Creatinine Clearance (mL/min)	Dabigatran		Rivaroxaban		Apixaban
Creatinine Clearance (mL/min)	Low Risk	High Risk	Low Risk	High Risk	Low Risk	High Risk
>50	≥2 Days	≥3 Days	≥2 Days	≥3 Days	≥2 Days	≥3 Days
30–50	≥3 Days	≥4 to 5 Days	≥2 Days	≥3 Days	≥3 Days	≥4-5 Days
15–30	Not indicated	Not indicated	≥3 Days	≥4 Days	Not indicated	Not indicated
<15	No official indication for use