Direct Oral Anticoagulants

Last Updated

April 22, 2022

Medications listed in the tables and non-FDA approved indications included in these retrospective criteria are not indicative of Texas Vendor Drug Program formulary coverage.

Revision history
- April 2022; March 2020; May 2018; Feb. 2018.
Initially developed
- March 2017

Direct oral anticoagulants (DOACs) are FDA-approved to treat and prevent deep venous thrombosis (DVT) and pulmonary embolism (PE), reduce the risk of stroke and systemic embolism from non-valvular atrial fibrillation, and to be used as prophylaxis against DVT and PE after knee and hip surgery. DOACs work by interfering with pathways in the coagulation cascade: directly inhibiting thrombin (e.g., dabigatran); or selectively, reversibly inhibiting factor Xa (e.g., apixaban, edoxaban, rivaroxaban)^1-7. In April 2020, Portola Pharmaceuticals removed Bevyxxa® (betrixaban) from the market for independent business reasons⁸ .

Maximum recommended adult dosages for DOACs are summarized in Tables 1 and 2. Medication profiles identifying patients prescribed dosages exceeding these recommendations will be reviewed.

Table 1. Maximum Daily Adult Dosages for DOACs: Direct Thrombin Inhibitors^1-4
Drug Name	Dosage Form/Strength	Treatment Indication	Maximum Recommended Dosage
dabigatran (Pradaxa®)	75 mg, 110 mg, 150 mg capsules	Reduction in risk of stroke and systemic embolism in non-valvular AF	CrCl greater than 30 mL/min: 50 mg twice daily CrCl 15-30 mL/min: 75 mg twice daily CrCl less than 15 mL/ min: dosing recommendations cannot be provided CrCl 30-50 mL/min with concomitant use of P-gp inhibitors: 75 mg twice daily CrCl less than 30 mL/min with concomitant use of P-gp inhibitors: Avoid coadministration
dabigatran		Treatment of DVT and PE/reduction in the risk of recurrence of DVT and PE	CrCl greater than 30 mL/ min: 150 mg twice daily* CrCl less than or equal to 30 mL/ min: dosing recommendations cannot be provided CrCl less than 50 mL/ min with concomitant use of P-gp inhibitors: Avoid coadministration
dabigatran		Prophylaxis of DVT and PE following hip replacement surgery	CrCl greater than 30 mL/min: 110 mg for first day, then 220 mg once daily CrCl less than or equal to 30 mL/ min: dosing recommendations cannot be provided CrCl less than 50 mL/ min with concomitant use of P-gp inhibitors: Avoid coadministration

Legend:

AF = atrial fibrillation
DVT = deep venous thrombosis
PE = pulmonary embolism
*Requires 5 to 10 days parenteral therapy before initiation of therapy

Table 2. Maximum Daily Adult Dosages for DOACs: Factor Xa Inhibitors^1,2,5-7
Drug Name	Dosage Form/Strength	Treatment Indication	Maximum Recommended Dosage
apixaban (Eliquis®)	2.5 mg, 5 mg tablets	Reduction of risk of stroke and systemic embolism in patients with non-valvular AF	5 mg twice daily#
apixaban		Prophylaxis of DVT following hip or knee replacement surgery	2.5 mg twice daily
apixaban		Treatment of DVT and PE	10 mg twice daily for 7 days, then 5 mg twice daily
apixaban		Reduction in risk of recurrence of DVT and PE	2.5 mg twice daily^
edoxaban (Savaysa®)	15 mg, 30 mg, 60 mg tablets	Non-valvular AF: CrCl greater than 50 mL/min and less than or equal to 95 mL/min	60 mg once daily+
edoxaban		Non-valvular AF: CrCl 15-50 mL/min	30 mg once daily
edoxaban		Treatment of DVT and PE: greater than or equal to 60 kg	60 mg once daily*
edoxaban		Treatment of DVT and PE: less than 60 kg, CrCl 15-50 mL/min, adjunctive therapy with certain P-gp inhibitors	30 mg once daily*
rivaroxaban (Xarelto®)	2.5 mg, 10 mg, 15 mg, 20 mg tablets, 1 mg/ 1 mL granules for suspension	Reduction in the risk of stroke in non-valvular AF, CrCl greater than 50 mL/min	20 mg once daily with evening meal
rivaroxaban		Reduction in the risk of stroke in non-valvular AF, CrCl less than or equal to 50 mL/min	15 mg once daily with evening meal
rivaroxaban		Treatment of DVT and PE, CrCl greater than or equal to 15 mL/min	15 mg twice daily for 21 days, then 20 mg once daily
rivaroxaban		Reduction in risk of recurrence of DVT and PE (following initial treatment), CrCl greater than or equal to 15 mL/min	10 mg once daily^
rivaroxaban		Prophylaxis of DVT following hip or knee replacement surgery, CrCl greater than or equal to 15 mL/min	10 mg once daily
rivaroxaban		VTE prophylaxis in hospitalized adults with acute illness and limited mobility and other risk factors for VTE, CrCl greater than or equal to 15 mL/min	10 mg once daily
rivaroxaban		Reduction of major cardiovascular event risk in patients with chronic coronary heart disease, peripheral artery disease	2.5 mg twice daily, plus aspirin 75-100 mg once daily

Legend

AF = atrial fibrillation
DVT = deep venous thrombosis
PE = pulmonary embolism
P-gp = P-glycoprotein
VTE = venous thromboembolism
+ Avoid in patients with CrCl greater than 95 ml/min due to increased risk of ischemic stroke compared to warfarin
* Requires 5 to 10 days parenteral therapy before initiation of therapy
# Dose should be decreased to 2.5 mg twice daily in patients receiving strong inhibitors of both CYP3A4 and P-glycoprotein concurrently, or those with at least two of the following: age greater than or equal to 80 years, body weight less than or equal to 60 kg, or serum creatinine greater than or equal to 1.5 mg/dL
^ Following at least 6 months of DVT or PE treatment

1.2. Pediatrics

Apixaban and edoxaban are not recommended for use in pediatric patients, as the safety and efficacy have not been established for these agents in this patient population ^.1,2,5,6.

In June 2021, the FDA approved Pradaxa® (dabigatran) oral pellets to treat venous thromboembolism after receiving at least five days of injectable or intravenous treatment for blood clots and to reduce the risk of recurrent thromboembolism in patients 3 months to less than twelve years of age who have completed treatment for a previous venous thromboembolism⁹.

Dabigatran oral capsules were approved to treat venous thromboembolism after receiving at least five days of injectable or intravenous treatment for blood clots and to reduce the risk of recurrent thromboembolism in patients 8 years of age and older who have completed treatment for a previous venous thromboembolism⁹.

In December 2021, the FDA approved Xarelto® (rivaroxaban) tablets and oral suspension to treat venous thromboembolism and to reduce the risk of recurrent venous thromboembolism in patients less than 18 years of age who received at least five days of injectable or intravenous treatment for blood clots. Rivaroxaban was also approved to reduce the risk of blood clots in patients two years of age and older with congenital heart disease after the Fontan procedure¹⁰ .

Maximum recommended pediatric dosages for DOACs are summarized in Table 3 through Table 6. Medication profiles identifying patients prescribed dosages exceeding these recommendations will be reviewed.

Table 3. Maximum Daily Pediatric Dosages for DOACs in Pediatric Patients Less than 2 Years of Age: Direct Thrombin Inhibitors^1,2,4
Drug Name	Dosage Form/Strength	Treatment Indication	Maximum Recommended Dosage
dabigatran (Pradaxa®) oral pellets!	20 mg, 30 mg, 40 mg, 50 mg, 110 mg, 150 mg oral pellets	Treatment of VTE and to reduce the risk of VTE recurrence: 3 months to less than or equal to 2 years of age	Actual Weight: 3kg to less than 4kg^ 3 to less than 6 months: 30 mg twice daily Actual Weight: 4 kg to less than 5 kg^ 3 to less than 10 months: 40 mg twice daily Actual Weight: 5 kg to less than 7 kg^ 3 to less than 5 months: 40 mg twice daily 5 to less than 24 months: 50 mg twice daily Actual Weight: 7 kg to less than 9 kg^ 3 to less than4 months: 50 mg twice daily 4 to less than 9 months: 60 mg twice daily 9 to less than24 months: 70 mg twice daily Actual Weight: 9 kg to less than 11 kg^ 5 to less than 6 months: 60 mg twice daily 6 to less than 11 months: 80 mg twice daily 11 to less than 24 months: 90 mg twice daily Actual Weight: 11 kg to less than 13 kg^ 8 to less than 18 months: 100 mg twice daily 18 to less than 24 months: 110 mg twice daily Actual Weight: 13 kg to less than 16 kg^ 10 to less than 11 months: 100 mg twice daily 11 to less than 24 months: 140 mg twice daily Actual Weight: 16 kg to less than 21 kg^ 12 to less than 24 months: 140 mg twice daily Actual Weight: 21 kg to less than 26 kg*^ 18 to less than 24 months: 180 mg twice daily

Legend

VTE = venous thromboembolism
! Avoid dabigatran in patients with a CrCl less than 50 mL/min
* Requires at least 5 days of parenteral therapy before initiation of therapy for the treatment of VTE
^ Following appropriate treatment duration of DVT or PE treatment if used to reduce the risk of VTE recurrence

Table 4. Maximum Daily Pediatric Dosages for DOACs in Pediatric Patients 2 to Less than 12 Years of Age: Direct Thrombin Inhibitors^1,2,4
Drug Name	Dosage Form/Strength	Treatment Indication	Maximum Recommended Dosage
dabigatran (Pradaxa®) oral pellets!	20 mg, 30 mg, 40 mg, 50 mg, 110 mg, 150 mg oral pellets	Treatment of VTE and to reduce the risk of VTE recurrence: 2 to less than 12 years of age	Actual Weight: 7 kg to less than 9 kg^ 70 mg twice daily Actual Weight: 9 kg to less than 11 kg^ 90 mg twice daily Actual Weight: 11 kg to less than 13 kg^ 110 mg twice daily Actual Weight: 13 kg to less than 16 kg^ 140 mg twice daily Actual Weight: 16 kg to less than 21 kg^ 170 mg twice daily Actual Weight: 21 kg to less than 41 kg^ 220 mg twice daily Actual Weight: 41 kg or greater*^ 260 mg twice daily

Legend

VTE = venous thromboembolism
! Avoid dabigatran in patients with a CrCl less than 50 mL/min
* Requires at least 5 days of parenteral therapy before initiation of therapy for the treatment of VTE
^ Following appropriate treatment duration of DVT or PE treatment if used to reduce the risk of VTE recurrence

Table 5. Maximum Daily Pediatric Dosages for DOACs in Pediatric Patients 8 to Less than 18 Years of Age: Direct Thrombin Inhibitors^1-3
Drug Name	Dosage Form/Strength	Treatment Indication	Maximum Recommended Dosage
dabigatran (Pradaxa®) capsules!	75 mg, 110 mg, 150 mg oral capsules	Treatment of VTE and to reduce the risk of VTE recurrence: 8 to less than 18 years of age	11 kg to less than 16 kg^ 75 mg twice daily 16 kg to less than 26 kg^ 110 mg twice daily 26 kg to less than 41 kg^ 150 mg twice daily 41 kg to less than 61 kg^ 185 mg twice daily 61 kg to less than 81 kg^ 220 mg twice daily 81 kg or greater^ 260 mg twice daily

Legend

VTE = venous thromboembolism
! Avoid dabigatran in patients with a CrCl less than 50 mL/min
* Requires at least 5 days of parenteral therapy before initiation of therapy for the treatment of VTE
^ Following appropriate treatment duration of DVT or PE treatment if used to reduce the risk of VTE recurrence

Table 6. Maximum Daily Pediatric Dosages for DOACs in Patients Less than 18 Years of Age: Factor Xa Inhibitors^1,2,7
Drug Name	Dosage Form/Strength	Treatment Indication	Maximum Recommended Dosage±
rivaroxaban (Xarelto®)	10 mg, 15 mg, 20 mg tablets, 1 mg/ 1 mL granules for suspension	Treatment of VTE and to reduce the risk of VTE recurrence: less than 18 years of age	2.6 kg to 2.9 kg^# 0.8 mg three times daily 3 kg to 3.9 kg^# 0.9 mg three times daily 4 kg to 4.9 kg^# 1.4 mg three times daily 5 kg to 6.9 kg^# 1.6 mg three times daily 7 kg to 7.9 kg^# 1.8 mg three times daily 8 kg to 8.9 kg^# 2.4 mg three times daily 9 kg to 9.9 kg^# 2.8 mg three times daily 10 kg to 11.9 kg^# 3 mg three times daily 12 kg to 29.9 kg^# 5 mg twice daily 30 kg to 49.9 kg^! 15 mg once daily greater than or equal to 50 kg*^! 20 mg once daily
		Thromboprophylaxis in patients 2 years of age and older with congenital heart disease who have undergone Fontan procedure	7 kg to 7.9 kg# 1.1 mg twice daily 8 kg to 9.9 kg# 1.6 mg twice daily 10 kg to 11.9 kg# 1.7 mg twice daily 12 kg to 19.9 kg# 2 mg twice daily 20 kg to 29.9 kg# 2.5 mg twice daily 30 kg to 49.9 kg# 7.5 mg once daily greater than or equal to 50 kg! 10 mg once daily

Legend

VTE = venous thromboembolism
± Patients less than 6 months of age should meet the following criteria: at birth at least 37 weeks gestation, have at least 10 days of oral feeding, and weigh greater than or equal to2.6 kg at the time of dosing
* Requires at least 5 days parenteral therapy before initiation of therapy for treatment of VTE
^ Following appropriate treatment duration of DVT or PE treatment if used to reduce the risk of VTE recurrence
# May only use granules for suspension
! May use granules for suspension or oral tablets

2. Duration of Therapy

There is no basis for limiting DOAC therapy when prescribed to prevent thromboembolic events associated with cardiovascular or cerebrovascular disease in those with a high risk of recurrence and low risk of bleeding (e.g., unprovoked proximal DVT, recurrent DVT). However, DOAC treatment duration varies, based on medication utilized, indication for use, underlying disease states, and patient factors¹¹. The 2021 “Antithrombotic Therapy for VTE Disease: Second Update of the CHEST Guidelines and Expert Review Panel Report” indicates that extended-phase anticoagulation with DOACs does not have a defined stop date, and patients have been monitored for up to four years while on extended-phase anticoagulation. DOAC treatment durations are summarized in Table 7 through Table 10.

Table 7. DOAC Recommended Treatment Duration (Adults): Direct Thrombin Inhibitors^1-3,11
Drug Name	Indication	Maximum Treatment Duration
dabigatran (Pradaxa®)	Reduction of risk of stroke and systemic embolism in non-valvular AF	indefinite
	DVT and PE treatment	3-12 months
	DVT and PE prevention	indefinite
	Prophylaxis of DVT and PE following hip replacement surgery	28-35 days

Legend

AF = atrial fibrillation
DVT = deep venous thrombosis
PE = pulmonary embolism

Table 8. DOAC Recommended Treatment Duration (Adults): Factor Xa Inhibitors^1,2,5-7,11
Drug Name	Indication	Maximum Treatment Duration
apixaban (Eliquis®)	Reduction of risk of stroke and systemic embolism in patients with non-valvular AF	indefinite
	Prophylaxis of DVT following hip or knee replacement surgery	35 days (hip); 12 days (knee)
	Treatment of DVT and PE	3-12 months
	Reduction in risk of recurrence of DVT and PE	indefinite after at least 6 months of treatment
edoxaban (Savaysa®)	Reduction of risk of stroke and systemic embolism in patients with non-valvular AF	indefinite
	Treatment of DVT and PE	maximum of 12 months after 5-10 days of initial therapy with a parenteral anticoagulant
rivaroxaban (Xarelto®)	Reduction in the risk of stroke in non-valvular AF	indefinite
	Treatment of DVT and PE	3-12 months
	Reduction in risk of recurrence of DVT and PE	up to 12 months after an initial 6 months of treatment
	Prophylaxis of DVT following hip or knee replacement surgery	35 days (hip); 12 days (knee)
	VTE prophylaxis in hospitalized adults with acute illness and limited mobility and other risk factors for VTE	31 to 39 days
	Reduction of major cardiovascular event risk in patients with chronic coronary heart disease, peripheral artery disease	indefinite

Legend

AF = atrial fibrillation
DVT = deep venous thrombosis
PE = pulmonary embolism

The DIVERSITY trial was conducted in pediatric populations to determine the safety and efficacy of dabigatran compared to the standard of care for the treatment of VTE. The median duration of dabigatran for VTE was 84.5 days¹². An additional trial evaluated the safety and effectiveness of dabigatran in patients requiring secondary VTE prophylaxis who completed the DIVERSITY trial. Pediatric patients were treated with dabigatran for up to 12 months after the initial treatment for VTE¹³.

Table 9. DOAC Recommended Treatment Duration (Pediatrics): Direct Thrombin Inhibitors^1-4,12-14
Drug Name	Indication	Maximum Treatment Duration
dabigatran (Pradaxa®)	VTE treatment	3-12 months
	Reduction in risk of recurrence of DVT and PE	up to 12 months after initial treatment for VTE

The EINSTEIN Junior trial studied the safety and efficacy of rivaroxaban compared to standard of care in pediatric patients with VTE. When appropriate, treatment for VTE and VTE risk reduction was extended to up to 12 months in duration¹⁵. The UNIVERSE trial assessed the safety and efficacy of rivaroxaban for thromboprophylaxis in pediatric patients with congenital heart disease who have undergone the Fontan procedure. Participants took rivaroxaban for up to 12 months in the study¹⁶. However, thromboembolic risk may persist for several years after the procedure, and further therapy with antiplatelet or anticoagulant drugs may be appropriate¹⁶.

Table 10. DOAC Recommended Treatment Duration (Pediatrics): Factor Xa Inhibitors^1,2,7,14-16
Drug Name	Indication	Maximum Treatment Duration
rivaroxaban (Xarelto®)	VTE treatment	3-12 months
	Reduction in risk of recurrence of VTE	up to 12 months
	Thromboprophylaxis in patients at least 2 years of age with congenital heart disease who have undergone Fontan procedure	up to 12 months!

Legend

! Specific patient factors may require a longer duration of antiplatelet or anticoagulant therapy

3. Duplicative Therapy

Combined administration of multiple DOACs should be avoided. Concomitant DOAC use results in additive factor Xa inhibition and prolonged prothrombin time (PT), which increases bleeding risk ^1-7. No evidence demonstrating increased efficacy or augmentation of therapy from use of multiple DOACs currently exists.

4. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens, which may result in clinically significant drug-drug interactions. Major drug-drug interactions considered clinically significant for DOACs are summarized in Table 11. Only those drug-drug interactions classified as clinical significance level 1/contraindicated or those considered life threatening which have not yet been classified will be reviewed.

Table 11. DOAC Drug-Drug Interactions^1-7
Target Drug	Interacting Drug	Interaction	Recommendation	Clinical Significance Level#
dabigatran	P-gp inhibitors (e.g., amiodarone, clarithromycin)	increases dabigatran exposure and bleeding risk	Non-valvular AF: avoid use with CrCl less than 30 mL/min; reduce dose to 75 mg twice daily with CrCl 30-50 mL/min (dronedarone, systemic ketoconazole only) Treatment and prevention of DVT and PE: avoid use with CrCl less than 50 mL/min Prevention of DVT and PE after hip replacement surgery: avoid use with CrCl less than 50 mL/min; separate by several hours with CrCl greater than 50 mL/min	dabigatran, major; itraconazole, contraindicated (DrugReax) 2 – major (CP)
dabigatran, edoxaban	P-gp inducers (e.g., rifampin)	reduces serum dabigatran, edoxaban serum levels and increases thrombosis risk	avoid concurrent use	major (DrugReax) 2 – major (CP)
DOACs	anticoagulants, NSAIDs, aspirin, antiplatelet agents, fibrinolytics	increases bleeding risk	avoid concurrent use; if adjunctive administration necessary, use cautiously and monitor closely for signs/ symptoms of bleeding	major (DrugReax) anticoagulants, 2 – major; fibrinolytics, 1 – severe (CP)
DOACs	defibrotide	enhances DOAC pharmacologic effects, increasing bleeding risk	avoid concurrent use	contraindicated (DrugReax) 1 – severe (CP)
DOACs	selective serotonin reuptake inhibitors (SSRIs)/ serotonin norepinephrine reuptake inhibitors (SNRIs)	may increase bleeding risk	avoid concurrent use; if adjunctive administration necessary, use cautiously and monitor closely for signs/ symptoms of bleeding	major (DrugReax) 2 – major (CP)
DOACs	orlistat	may increase INR due to decreased vitamin K absorption	if adjunctive administration necessary, use cautiously and monitor closely for changes in coagulation factors	major (DrugReax) 3 – moderate (CP)
rivaroxaban, apixaban	dual P-gp and CYP3A4 inhibitors (e. g., ritonavir, ketoconazole)	increases serum rivaroxaban, apixaban levels, which increases bleeding risk	avoid concurrent use; reduce dose of apixaban by 50%; avoid use in patients receiving apixaban 2.5 mg twice daily	major (DrugReax) 2 – major (CP)
rivaroxaban, apixaban	dual P-gp and CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine)	decreases rivaroxaban exposure by 50%; rifampin decreases apixaban exposure by 50%; increases thrombosis risk	avoid concurrent use	major (DrugReax) 2 – major (CP)

5. References

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Dabigatran etixilate mesylate capsules (Pradaxa®) package insert. Boehringer Ingelheim Pharmaceuticals, Inc., June 2021.
Dabigatran etixilate mesylate pellets (Pradaxa®) package insert. Boehringer Ingelheim Pharmaceuticals, Inc., June 2021.
Apixaban tablets (Eliquis®) package insert. Bristol-Myers Squibb Company, September 2021.
Edoxaban tablets (Savaysa®) package insert. Daiichi Sankyo, Inc., September 2021.
Rivaroxaban tablets and granules for suspension (Xarelto®) package insert. Janssen Pharmaceuticals, Inc., January 2022.
Smith, I. Response to PREA non-compliance letter. Portola Pharmaceuticals. October 2020. Accessed March 1, 2022.
U.S. Food and Drug Administration. FDA approved first oral blood thinning medication for children. June 2021. Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-first-oral-blood-thinning-medication-children#:~:text=Today%2C%20the%20U.S.%20Food%20and,by%20injection%20for%20at%20least. Accessed March 1, 2022.
U.S. Food and Drug Administration. FDA approved drug to treat, help prevent types of blood clots in certain pediatric populations. December 2021. Available at: https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-drug-treat-help-prevent-types-blood-clots-certain-pediatric-populations#:~:text=FDA%20has%20approved%20Xarelto%20(rivaroxaban,days%20of%20injectable%20or%20intravenous. Accessed March 1, 2022.
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