Direct oral anticoagulants: key considerations for use to prevent stroke in patients with nonvalvular atrial fibrillation

Figures & data

Table 1 CHADS₂ and CHA₂DS₂-VASc stroke risk scoring systems and adjusted stroke rates based on CHADS₂ and CHA₂DS₂-VASc scores

	Stroke risk scoring systems		Adjusted stroke rate based on CHADS2 score		Adjusted stroke rate based on CHA2DS2-VASc score
	CHADS2 scoring system	CHA2DS2-VASc scoring system	CHADS2 score	Adjusted stroke rate (%/year)	CHA2DS2-VASc score	Adjusted stroke rate (%/year)
Congestive heart failure	1	1	0	1.9	0	0
Hypertension	1	1	1	2.8	1	1.3
Age ≥75 years	1	2	2	4.0	2	2.2
Diabetes	1	1	3	5.9	3	3.2
Previous stroke or TIA	2	2	4	8.5	4	4.0
Vascular disease	–	1	5	12.5	5	6.7
Age, 65–74 years	–	1	6	18.2	6	9.8
Female sex	–	1	–	–	7	9.6
Maximum score	6	9	–	–	8	6.7
	–	–	–	–	9	15.2

Note: Data from Gage et al,^10,12 Lip et al,¹³ and Camm et al.¹⁵

Abbreviations: CHADS₂, Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, and Stroke or TIA previous event (2 points); CHA₂DS₂-VASc, Congestive heart failure/left ventricular dysfunction, Hypertension, Age ≥75 years (2 points), Diabetes, Stroke or TIA previous event/thromboembolism (2 points), Vascular disease, Age 65–74 years, and Sex category (female); TIA, transient ischemic attack.

Table 2 Characteristics of direct oral anticoagulants compared with those of warfarin

Characteristics	Warfarin	Apixaban	Dabigatran	Rivaroxaban	Edoxaban
Bioavailability	>95%	~50% for doses up to 10 mg	~7%	>80% for 10 mg dose (regardless of food intake) and 20 mg dose (taken with food); 66% for 20 mg dose (under fasting conditions)	~62% for 60 mg dose
Time to peak activity	24–36 hours	3–4 hours	0.5–2 hours	2.0–4 hours	1–2 hours for 10–150 mg single dose
Half-life	20–60 hours	~12 hours	11–14 hours	5–9 hours (young individuals); 11–13 hours (elderly individuals)	6–11 hours for 10–150 mg single dose
Dosing frequency in AF	Once daily	Twice daily	Twice daily	Once daily	Once daily
Drug interactions	Numerous drugs including substrates of CYP2C9, CYP3A4, and CYP1A2; various foods	Strong inhibitors/inducers of both CYP3A4 and P-gp	Strong P-gp inhibitors and inducers	Strong inhibitors of both CYP3A4 and P-gp; strong CYP3A4 inducers	Strong P-gp inhibitors
Renal elimination	<1%	~27%	85%	66% of the dose undergoes metabolic degradation, with half then being eliminated renally and the other half eliminated via the hepatobiliary route. The final 33% of the dose undergoes direct renal excretion	~50%

Note: Data from Bristol-Myers Squibb, Pfizer,²³ Boehringer Ingelheim International GmbH,²⁴ Bayer Pharma AG,²⁵ Daiichi Sankyo Inc.,²⁶ Eriksson et al,²⁸ Harder,³⁰ Verma and Brighton,³¹ Stampfuss et al,⁹⁴ Matsushima et al,⁹⁵ and Mendell et al.⁹⁶

Abbreviations: AF, atrial fibrillation; CYP, cytochrome P450; P-gp, P-glycoprotein.

Table 3 Study designs for ARISTOTLE, AVERROES, RE-LY, ENGAGE AF-TIMI 48, and ROCKET AF

	ARISTOTLE^Citation34	AVERROES^Citation35	RE-LY^Citation32	ENGAGE AF-TIMI 48^Citation36	ROCKET AF^Citation33
Study drug	Apixaban	Apixaban	Dabigatran	Edoxaban	Rivaroxaban
Comparator	Warfarin	ASA	Warfarin (open-label)	Warfarin	Warfarin
Study design
Blinding	Double-blind, double-dummy	Double-blind, double-dummy	Blinded dabigatran (two doses)	Double-blind, double -dummy	Double-blind, double-dummy
Statistical objective	Noninferiority	Superiority	Noninferiority	Noninferiority	Noninferiority
Doses studied	5 mg bida	5 mg bid	110 mg bid and 150 mg bid	30 mg od and 60 mg odb	20 mg odc
Number of risk factors	≥1	≥1	≥1	≥1	≥2
Study outcomes
Primary efficacy	Composite of stroke and systemic embolism	Composite of stroke and systemic embolism	Composite of stroke and systemic embolism	Composite of stroke and systemic embolism	Composite of stroke and systemic embolism
Principal safety	Major bleedingd	Major bleedingd	Major bleedinge	Major bleedingf	Majorg and nonmajor clinically relevant bleedingh

Notes:

a A reduced dose of apixaban (2.5 mg bid) was used in patients with ≥2 of the following criteria: age ≥80 years, body weight ≤60 kg, or a serum creatinine level ≥1.5 mg/dL;

b both doses of edoxaban were halved if the patients had CrCl of 30–50 mL/min; body weight ≤60 kg; or concomitant use of verapamil, quinidine, or dronedarone at randomization or during the study;

c a reduced dose of rivaroxaban (15 mg od) was used in patients with moderate renal impairment (CrCl 30–49 mL/min);

d defined according to the criteria of the ISTH as clinically overt bleeding accompanied by a decrease in hemoglobin level of ≥2 g/dL over a 24-hour period or transfusion of ≥2 units of whole blood or red cells, occurring at a critical site or resulting in death;

e defined as a reduction in hemoglobin level of ≥20 g/L, transfusion of ≥2 units of blood, or symptomatic bleeding in a critical area or organ;

f defined as clinically overt bleeding associated with fatal outcome, involving a critical site, or clinically overt bleeding associated with a fall in hemoglobin concentration of ≥2 g/dL adjusted for blood transfusions or a fall in hematocrit of ≥6.0% adjusted for blood transfusions;

g defined as clinically overt bleeding associated with fatal outcome, involving a critical site, or clinically overt bleeding associated with a fall in hemoglobin concentration of ≥2 g/dL, or leading to transfusion of ≥2 units of packed red blood cells or whole blood;

h defined as overt bleeding not meeting the criteria for major bleeding but associated with medical intervention, unscheduled contact with a physician (visit or telephone call), temporary cessation (ie, by delaying the next administration) of study drug, pain, or impairment of daily activities.

Abbreviations: ARISTOTLE, Apixaban for Reduction In STroke and Other ThromboemboLic Events in atrial fibrillation; ASA, acetylsalicylic acid; AVERROES, Apixaban VERsus acetylsalicylic acid to pRevent stroke in atrial fibrillation patients who have failed Or are unsuitablE for vitamin K antagoniSt treatment; bid, twice daily; CrCl, creatinine clearance; ENGAGE AF-TIMI 48, Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis In Myocardial Infarction Study 48; ISTH, International Society on Thrombosis and Haemostasis; od, once daily; RE-LY, Randomized Evaluation of Long-term anticoagulation therapy; 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.

Table 4 Summary of key findings from the four Phase III outcome trials of rivaroxaban, apixaban, edoxaban, and dabigatran versus warfarin in patients with atrial fibrillation

Trial name and direct OAC	ARISTOTLE^Citation34	RE-LY^Citation32,Citation37,Citation38,Citation41		ENGAGE AF-TIMI 48^Citation36		ROCKET AF^Citation33
	Apixaban	Dabigatran		Edoxaban		Rivaroxaban
Direct OAC dose	5 mg bida	110 mg bid	150 mg bid	30 mg odb	60 mg odb	20 mg odc
Patient characteristics
Total number of patients	18,201	18,113		21,105		14,264
Median age, years	70 vs 70	71 vs 72d	72 vs 72d	72 vs 72	72 vs 72	73 vs 73
Mean CHADS2 score	2.1 vs 2.1	2.1 vs 2.1	2.2 vs 2.1	2.8 vs 2.8	2.8 vs 2.8	3.5 vs 3.5
Prior stroke or TIA, %	19 vs 20	20 vs 20	20 vs 20	29 vs 28	28 vs 28	55 vs 55
Mean TTR (warfarin patients), %	62	64		65		55
Main outcomes (relative risk vs warfarin)
Stroke or systemic embolisme	0.79 (0.66–0. 95)f	0.89 (0.73–1.09)	0.65 (0.52–0.81)	1.13 (0.93–0.34)g	0.87 (0.73–1.04)g	0.88 (0.75–1.03)h
Major bleedingi	0.69 (0.60–0.80)f	0.80 (0.70–0.93)	0.94 (0.82–1.08)	0.47 (0.41–0.55)	0.80 (0.71–0.91)	1.04 (0.90–1.20)
Intracranial bleedingi	0.42 (0.30–0.58)f	0.30 (0.19–0.45)	0.41 (0.28–0.60)	0.30 (0.21–0.43)	0.47 (0.34–0.63)	0.67 (0.47–0.93)
Gastrointestinal bleedingi	0.89 (0.70–1.15)f	1.08 (0.85–1.38)	1.48 (1.18–1.85)	0.67 (0.53–0.83)	1.23 (1.02–1.50)	3.15% vs 2.16%; P<0.001
Fatal bleedingi	34 vs 55 patientse	0.58 (0.35–0.97)	0.7 (0.43–1.14)	0.35 (0.21–0.57)	0.55 (0.36–0.84)	0.50 (0.31–0.79)

Notes:

a 2.5 mg bid in patients with ≥2 of the following: age ≥80 years, body weight ≤60 kg, serum creatinine ≥1.5 mg/dL;

b halving of dose if CrCl 30–50 mL/min; body weight ≤60 kg; or concomitant use of verapamil, quinidine, or dronedarone;

c 15 mg od in patients with CrCl 30–49 mL/min;

d mean;

e ITT population;

f hazard ratio (95% CI);

g the primary efficacy analysis was prespecified to be performed in the on-treatment modified ITT population set that includes all randomized subjects who received ≥1 dose of randomized study drug. The treatment period was defined as the period between administration of the first dose of the study drug and either 3 days after the receipt of the last dose or the end of the double-blind therapy;

h the primary efficacy analysis was prespecified to be performed in the per-protocol population, which included all patients who received ≥1 dose of a study drug, did not have a major protocol violation, and were followed for events while receiving a study drug or within 2 days after discontinuation;

i safety population.

Abbreviations: ARISTOTLE, Apixaban for Reduction In STroke and Other ThromboemboLic Events in Atrial Fibrillation; bid, twice daily; CHADS₂, Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, and Stroke or TIA previous event (2 points); CI, confidence interval; CrCl, creatinine clearance; ENGAGE AF-TIMI 48, Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis In Myocardial Infarction Study 48; ITT, intent-to-treat; OAC, oral anticoagulant; od, once daily; RE-LY, Randomized Evaluation of Long-term anticoagulation therapy; 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; TIA, transient ischemic attack; TTR, time in therapeutic range for international normalized ratio.

Table 5 Summary of guidance in agreement with the Summary of Product Characteristics approved by the European Medicines Agency for use of direct oral anticoagulants for stroke prevention in patients with atrial fibrillation

Recommended dose	Apixaban^Citation23	Dabigatran^Citation24	Rivaroxaban^Citation25
	5 mg bid	150 mg bid	20 mg od
Dose adjustments	2.5 mg bid for patients with CrCl 15–29 mL/min or with serum creatinine ≥1.5 mg/dL associated with age ≥80 years or with body weight ≤60 kg	110 mg bid in patients 75–80 years with low thromboembolic risk and high risk of bleeding, or ≥80 years with CrCl 30–50 mL/min and high risk of bleeding, or receiving the strong P-gp inhibitor verapamil	15 mg od for CrCl 15–49 mL/min
Contraindications	Clinically significant active bleeding Hepatic disease associated with coagulopathy and clinically relevant bleeding risk Lesion or condition at significant risk of major bleeding Hypersensitivity to the active substance or excipients Concomitant treatment with any other anticoagulant agenta	Active clinically significant bleeding Hepatic impairment or liver disease expected to have any impact on survival Lesion or condition causing significant risk of major bleeding Hypersensitivity to the active substance or excipients Concomitant treatment with any other anticoagulant agenta CrCl <30 mL/min Concomitant treatment with systemic ketoconazole, cyclosporine, itraconazole, and dronedarone (strong P-gp inhibitors) Prosthetic heart valves requiring anticoagulant treatmentb	Clinically significant active bleeding Hepatic disease associated with coagulopathy and clinically relevant bleeding risk (including Child–Pugh B and C) Lesion or condition at significant risk of major bleeding Hypersensitivity to the active substance or excipients Concomitant treatment with any other anticoagulant agenta Pregnancy or breastfeeding
Not recommended in:	Pregnant women Patients with: • CrCl <15 mL/min • Prosthetic heart valves requiring anticoagulant treatment • Severe hepatic impairment Patients receiving concomitant systemic treatment with strong inhibitors of both CYP3A4 and P-gp, such as azole-antimycotics (eg, ketoconazole, itraconazole, voriconazole, and posaconazole) and HIV protease inhibitors (eg, ritonavir)	Patients with raised liver enzymes indicative of hepatic impairment (>2 ULN) Patients receiving concomitant treatment with HIV protease inhibitors (eg, ritonavir) Patients receiving concomitant treatment with the P-gp inhibitor tacrolimus Patients receiving concomitant treatment with P-gp inducers (eg, rifampicin, St John’s wort, carbamazepine, or phenytoin) – coadministration with dabigatran should be avoided	Children <18 years old Patients with: • CrCl <15 mL/min • Prosthetic heart valves requiring anticoagulant treatmentc • Increased bleeding risk (eg, genetic bleeding disorders, uncontrolled severe hypertension) Patients receiving concomitant systemic treatment with azole- antimycotics (such as ketoconazole, itraconazole, voriconazole, and posaconazole) or HIV protease inhibitors (eg, ritonavir) Patients receiving dronedarone – coadministration with rivaroxaban should be avoided
Drugs that should be used with caution with direct OACs (all patients)	Strong inducers of both CYP3A4 and P-gp (eg, rifampicin, phenytoin, carbamazepine, phenobarbital, or St John’s wort) NSAIDs, including ASA	Drugs affecting hemostasis by inhibition of platelet aggregation (eg, ASA, NSAIDs, clopidogrel)d Mild to moderate P-gp inhibitors (eg, amiodarone, posaconazole, quinidine, verapamil, and ticagrelor) Selective SSRIs or selective SNRIsd	NSAIDs (including ASA) and platelet aggregation inhibitors Strong CYP3A4 inducers (eg, phenytoin, carbamazepine, phenobarbital, or St John’s wort) should be avoided unless the patient is closely observed for signs and symptoms of thrombosis
Drugs requiring caution during concomitant treatment in patients with renal impairment		Close clinical surveillance is recommended in patients with mild to moderate renal impairment when dabigatran is combined with mild to moderate P-gp inhibitors (eg, amiodarone, quinidine, verapamil, and clarithromycin)	Moderate or potent inhibitors of CYP3A4 (eg, fluconazole, clarithromycin) Moderate inhibitors of both CYP3A4 and P-gp (eg, erythromycin)
Switching from a VKA to a direct OAC	Discontinue warfarin or other VKA therapy and start apixaban at INR <2.0	Discontinue VKA and start dabigatran at INR <2.0	Discontinue VKA and start rivaroxaban at INR ≤3.0e
Switching to a VKA from a direct OAC	When converting patients to a VKA, continue apixaban for at least 2 days after beginning VKA therapy. After 2 days of coadministration, obtain an INR before the next scheduled dose of apixaban, and continue coadministration until the INR is ≥2.0	VKA starting time should be based on CrCl If CrCl is ≥50 mL/min, start VKA 3 days before discontinuing dabigatran If CrCl is 30–49 mL/min, start VKA 2 days before discontinuing dabigatran	VKA and rivaroxaban should be given concurrently until the INR is ≥2.0; standard initial VKA dosing should be given for the first 2 days of the conversion period, followed by INR-guided VKA dosing; INR should not be tested earlier than 24 hours after the previous rivaroxaban dose

Notes:

a Except under specific situation of switching anticoagulants or when UFH is given at doses necessary to maintain an open central venous or arterial catheter;

b the use of dabigatran in patients with mechanical heart valves has been shown to increase the rates of thromboembolic and bleeding complications compared with warfarin; this observation led to the premature termination of the Phase II RE-ALIGN trial;⁹⁷

c not recommended because there is a lack of safety and efficacy studies with this agent in patients with prosthetic heart valves;

d concomitant treatment with dabigatran and NSAIDs, antiplatelet agents, SSRIs, or SNRIs increases the risk of major bleeding and, therefore, requires careful risk assessment. Dabigatran should be used in patients on these medications only if the potential benefit outweighs the bleeding risks;

e for patients being treated for a venous thromboembolism and switching from a VKA to rivaroxaban, the VKA should be discontinued and rivaroxaban treatment started when the INR is ≤2.5.

Abbreviations: ASA, acetylsalicylic acid; bid, twice daily; CrCl, creatinine clearance; CYP, cytochrome P450; HIV, human immunodeficiency virus; INR, international normalized ratio; NSAID, nonsteroidal anti-inflammatory drug; OAC, oral anticoagulant; od, once daily; P-gp, P-glycoprotein; SNRI, serotonin-norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; UFH, unfractionated heparin; ULN, upper level of normal; VKA, vitamin K antagonist.

Table 6 Consensus recommendations for antithrombotic management of patients with atrial fibrillation after percutaneous coronary intervention

Hemorrhage risk	Clinical setting	Stroke riska	Recommendations for antithrombotic therapy
			Timing of treatment after PCI	Therapy	Details
Low or moderate (HAS-BLED ≤2)	Stable CAD (elective PCI)	Moderate	≥4 weeks <6 months	Triple therapyb	Reduced-dose OAC + ASA + clopidogrel
			Up to 12th month	Dual therapyc	Reduced-dose OAC + clopidogrel or Reduced-dose OAC + ASA
			Lifelong	Single therapy	Standard-dose OACd
		High	≥4 weeks <6 months	Triple therapye	Reduced-dose OAC + ASA + clopidogrel
			Up to 12th month	Dual therapy	Reduced-dose OAC + clopidogrel or Reduced-dose OAC + ASA
			Lifelong	Single therapy	Standard-dose OACd
	ACS (urgent PCI)	Moderate	Up to 6th month	Triple therapy	Reduced-dose OAC + ASA + clopidogrel
		or high	Up to 12th month	Dual therapyf	Reduced-dose OAC + clopidogrel or Reduced-dose OAC + ASA
			Lifelong	Single therapy	Standard-dose OACd
High (HAS-BLED ≥3)	Stable CAD (elective PCI)	Moderate	Up to 12th month	Dual therapyc	Reduced-dose OAC + clopidogrel
			Lifelong	Single therapy	Standard-dose OACd
		High	4 weeks	Triple therapyb	Reduced-dose OAC + ASA + clopidogrel
			Up to 12th month	Dual therapy	Reduced-dose OAC + clopidogrel or Reduced-dose OAC + ASA
			Lifelong	Single therapy	Standard-dose OACd
	ACS	Moderate	4 weeks	Triple therapye	Reduced-dose OAC + ASA + clopidogrel
	(urgent PCI)	or high	Up to 12th month	Dual therapy	Reduced-dose OAC + clopidogrel or Reduced-dose OAC + ASA
			Lifelong	Single therapy	Standard-dose OACd

Notes: Unless specified, ASA dose is 75–100 mg/day and clopidogrel dose is 75 mg/day. Reduced-dose OAC refers to either a VKA with a target INR of 2.0–2.5 or direct OAC at the lowest tested dose in AF (apixaban 2.5 mg bid, rivaroxaban 15 mg od, or dabigatran 110 mg bid). Tailored guidance for patients with AF already on a reduced dose of direct OAC before a PCI is not given.

a Stroke risk assessed via CHA₂DS₂-VASc; moderate risk is defined as a score of 1, high risk is defined as a score of ≥2; only male patients with AF undergoing PCI can be defined as moderate risk – female patients with AF undergoing PCI will have a CHA₂DS₂-VASc score of ≥2;

b combination of reduced-dose OAC + clopidogrel 75 mg/day or dual antiplatelet therapy consisting of ASA 75 mg/day and clopidogrel 75 mg/day may be considered as an alternative;

c dual antiplatelet therapy consisting of ASA 75 mg/day and clopidogrel 75 mg/day may be considered as an alternative;

d in selected patients (eg, those with stenting of the left main proximal bifurcation, or recurrent myocardial infarctions), dual therapy with OAC and single antiplatelet therapy may be continued beyond 12 months;

e combination of OAC and clopidogrel 75 mg/day may be considered as an alternative;

f in selected patients at high stroke risk, continuation of triple therapy between 6 and 12 months may be considered. Data from Lip et al.⁶⁴

Abbreviations: ACS, acute coronary syndrome; AF, atrial fibrillation; ASA, acetylsalicylic acid; bid, twice daily; CAD, coronary artery disease; CHA₂DS₂-VASc, Congestive heart failure/left ventricular dysfunction, Hypertension, Age ≥75 years (2 points), Diabetes, Stroke or transient ischemic attack previous event/thromboembolism (2 points), Vascular disease, Age 65–74 years, and Sex category (female); INR, international normalized ratio; OAC, oral anticoagulant; od, once daily; PCI, percutaneous coronary intervention; VKA, vitamin K antagonist; HAS-BLED, Hypertension, Abnormal Liver Function, Stroke History, Bleeding Predisposition, Labile INRs, Elderly, Drugs Concomitantly.

Table 7 European Heart Rhythm Association recommendations for timing of treatment interruption of approved direct oral anticoagulants prior to elective surgery according to renal function and surgery bleeding risk

Direct oral anticoagulant	Dabigatran		Apixaban or rivaroxaban
Surgery bleeding risk	Lowa	Highb	Lowa	Highb
Normal renal function (CrCl ≥80 mL/min), hours	≥24	≥48	≥24	≥48
Mild renal impairment (CrCl 50–80 mL/min), hours	≥36	≥72	≥24	≥48
Moderate renal impairment (CrCl 30–50 mL/min), hours	≥48	≥96	≥24	≥48
Severe renal impairment (CrCl 15–30 mL/min), hours	Dabigatran contraindicated		≥36	≥48
Renal failure (CrCl <15 mL/min)	Dabigatran contraindicated		Apixaban and rivaroxaban not recommended

Notes:

a Surgeries/procedures with low risk of bleeding include: endoscopy with biopsy, prostate or bladder biopsy, electrophysiological study or radiofrequency catheter ablation for supraventricular tachycardia, angiography, and pacemaker or implantable cardioverter defibrillator implantation;

b surgeries/procedures with high risk of bleeding include: complex left-sided ablation, spinal or epidural anesthesia, lumbar diagnostic puncture, thoracic surgery, abdominal surgery, major orthopedic surgery, liver biopsy, transurethral prostate resection, and kidney biopsy. Adapted from Heidbuchel H, Verhamme P, Alings M, et al. European Heart Rhythm Association practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace. 2013, 15, 5, 625–651, by permission of Oxford University Press.⁵³

Abbreviation: CrCl, creatinine clearance.

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