Review of Direct Oral Anticoagulants and Guide for Effective Drug Utilization

Tigran Khachatryan; Christopher Hauschild; Jason Hoff; Tahmeed Contractor; Arthur Khachatryan; Huyentran Tran; Bert Matsuo; Alan Jacobson; Anthony Hilliard

Disclosures

Am J Cardiovasc Drugs. 2019;19(6):525-539.

Conclusion

The DOACs provide a viable alternative to warfarin for anticoagulation. These medications are generally at least as efficacious and safe as warfarin, and apixaban and edoxaban have been found to be superior. Their predictable pharmacology, less variable anticoagulant effect, and fewer drug–food interactions compared with warfarin have enabled the convenience of fixed dosing without the need for monitoring.

An important limitation of DOACs is that, unlike warfarin, all but apixaban are not approved for patients with end-stage renal disease receiving hemodialysis, as these patients have been excluded from the major trials. Furthermore, DOACs have either not been studied in, or in the case of dabigatran, have shown worse outcomes in, patients with mechanical heart valves, in which setting warfarin remains the mainstay treatment.^[30,34] In addition, DOACs should be used with caution in patients receiving CYP- and/or P-gp-inducing or -inhibiting medications as most are metabolized via these pathways. Thus, this review serves as a guide for the selection of DOACs in clinical practice, providing an overview of the mechanism of action of each currently FDA-approved DOAC and their indications and limitations, to aid in effective drug utilization and patient management.

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Funding
No sources of funding were used to assist with the preparation of this review.

Table 1. Indication-based dosing and reversal agents of direct oral anticoagulants in the USA
Medication	Indications				FDA-approved reversal agent
Medication	Non-valvular atrial fibrillation	Treatment of DVT/PE	Prophylaxis for DVT/PE	Stable CAD/PAD	FDA-approved reversal agent
Direct thrombin inhibitor^a
Dabigatran (Pradaxa)	CrCl > 30: 150 mg PO BID CrCl 15–30: 75 mg PO BID CrCl < 15 or HD: NR	150 mg PO BID (after 5–10 days of parenteral therapy) CrCl < 30 or HD: NR	Post-hip replacement: 110 mg PO 1–4 h post-hemostasis then 220 mg QD for 28–35 days CrCl < 30 or HD: NR	–	Idarucizumab (Praxbind)
Direct Factor Xa inhibitors^a
Apixaban (Eliquis)^b	5 mg PO BID 2.5 mg PO BID^c	10 mg PO BID for 7 days then 5 mg PO BID 2.5 mg BID after 6 months of standard therapy to reduce the risk of recurrence	Post-hip replacement: 2.5 mg PO BID 12–24 h post-hemostasis for 35 days Post-knee replacement: 2.5 mg PO BID 12–24 h post-hemostasis for 12 days	–	Andexanet alfa (Andexxa)
Rivaroxaban (Xarelto)^d	CrCl > 50: 20 mg PO QD CrCl 15–50: 15 mg PO QD CrCl < 15 or HD: NR	15 mg PO BID for 21 days then 20 mg PO QD CrCl < 30 or HD: NR 10 mg QD after 6 months of standard therapy to reduce the risk of recurrence	Post-hip replacement: 10 mg PO QD 6–10 h post-hemostasis for 35 days Post-knee replacement: 10 mg PO QD 6–10 h post-hemostasis for 12 days CrCl < 30 or HD: NR	2.5 mg PO BID	Andexanet alfa (Andexxa)
Edoxaban (Savaysa)^e	CrCl 50–95: 60 mg PO QD CrCl 15–50: 30 mg PO QD CrCl < 15 or HD: NR	After 5–10 days of parenteral therapy: 60 mg PO QD OR 30 mg PO QD^f CrCl < 15 or HD: NR	–	–	None
Betrixaban (Bevyxxa)	–	–	For hospitalized at-risk patients^g: CrCl > 30: 160 mg PO on day 1 then 80 mg daily for 35–42 days CrCl 15–30: 80 mg PO on day 1 then 40 mg daily for 35–42 days CrCl < 30: not defined	–	None

BID twice daily, CAD coronary artery disease, CrCl creatinine clearance, CYP cytochrome P450, DOAC direct oral anticoagulant, DVT deep venous thrombosis, FDA US Food and Drug Administration, HD hemodialysis, NR not recommended, PAD peripheral artery disease, PE pulmonary embolism, PO by mouth, QD every day, VTE venous thromboembolism
^aMost DOACs should be used with caution in patients taking CYP- and/or P-glycoprotein-inducing or -inhibiting medications as these can lead to altered serum drug concentrations (see text and/or medication prescribing information)
^bApixaban is the only DOAC with FDA approval for patients with end-stage renal disease and those on HD. Approval based on pharmacokinetic and pharmacodynamic data
^cDose adjustment is recommended for patients with any two of the following characteristics: creatinine ≥ 1.5 mg/dL, age ≥ 80 years, and weight ≤ 60 kg
^dRivaroxaban should be taken with food to increase bioavailability
^eNot recommended for patients with CrCl > 95 mL/min because of increased risk of ischemic stroke compared with warfarin
^fDose adjustment is recommended for patients with any of the following characteristics: CrCl 15–50 mL/min, weight ≤ 60 kg, or on P-gp inhibitors
^gBetrixaban is only approved for VTE prophylaxis in at-risk hospitalized patients due to moderate or severely restricted mobility

Table 2. Pharmacologic characteristics of direct oral anticoagulants
Property	Drug
Property	Dabigatran	Apixaban	Rivaroxaban	Edoxaban	Betrixaban
Mechanism of action	Direct thrombin inhibitor	Direct Factor Xa inhibitor	Direct Factor Xa inhibitor	Direct Factor Xa inhibitor	Direct Factor Xa inhibitor
Oral bioavailability, %	3–7	~ 50	66–100 (absolute bioavailability decreases as oral dose increases)	62	34
Plasma protein binding, %	35	87	92–95	55	60
Renal excretion, %	80	27	66 (36% as unchanged drug)	50	11
Time to C _max, h	1–2	1–3	2–4	1–2	3–4
Half-life, h	12–17	8–15	5–9 (11–13 in the elderly)	10–14	19–27
Effect of food on absorption	Delays by 2 h	None	Increased bioavailability with > 10-mg dose	None	Meal ≤ 6 h prior will decrease plasma concentration
CYP3A4 substrate	No	Yes	Yes	Yes	Not clinically significant
P-gp substrate	Yes (prodrug only)	Yes	Yes	Yes	Yes
Drug interactions^a	Potent P-gp inducers/inhibitors (e.g., rifampin, quinidine, ketoconazole, dronedarone)	Dual CYP3A4 and P-gp inducers/inhibitors (e.g., ritonavir, ketoconazole, rifampin, phenytoin, St. John's wort)	Potent CYP3A4 and P-gp inducers/inhibitors (e.g., ritonavir, ketoconazole, rifampin, phenytoin, St. John's wort)	P-gp inducers (e.g., rifampin)	P-gp inhibitors (e.g., ketoconazole, verapamil, amiodarone, azithromycin)

C _max peak plasma concentration, CYP cytochrome P450
^aListed medications for each direct oral anticoagulant are examples and not a comprehensive list. Please see Table 4 for more details

Table 3. Special considerations when choosing a direct oral anticoagulant in nonvalvular atrial fibrillation
Patient characteristics	Special considerations^a	Recommendations^a
Age ≥ 75 years	Consider agents with lower rates of major bleeding than warfarin	Apixaban
Post PCI	Any DOAC preferred over VKA. Consider agents specifically studied as part of SAPT strategy	Dabigatran, rivaroxaban
Renal impairment (CrCl < 50 mL/min)	Consider agents less dependent on renal function and agents with rates of bleeding complications that are lower than or similar to those with warfarin	Apixaban
Patients on hemodialysis	Only one agent is FDA indicated based on pharmacokinetic and pharmacodynamic data	Apixaban
Hepatic impairment	Direct Factor Xa inhibitors can be used for mild hepatic impairment but not recommended for Child–Pugh class B or C	Dabigatran, rivaroxaban, apixaban, or edoxaban
Prior GI bleed or at high risk	Consider agents with incidence of GI bleed lower than or similar to that with warfarin	Apixaban
GI upset	Consider agents with lowest reported GI effects	Apixaban, edoxaban, or rivaroxaban (avoid dabigatran)
High bleeding risk (HAS-BLED ≥ 3)	Consider agents with lower rates of extracranial hemorrhage than warfarin	Apixaban, edoxaban
Previous stroke or TIA	Consider agents with greatest reduction of secondary stroke	Apixaban, dabigatran
Patient with bioprosthetic heart valve or valve repair	Limited clinical data include subanalysis of ARISTOTLE and ENGAGE AF-TIMI 48 trials	Apixaban, edoxaban
Patients undergoing cardioversion	All agents approved for NVAF can be used	Apixaban, edoxaban, rivaroxaban, or dabigatran
Patient on CYP3A4 inducers/inhibitors	Most DOACs are affected; dose adjustment may be needed	Dabigatran or edoxaban
Patient on P-gp inducer	All DOACs are affected	All DOACs should be avoided
Patient on P-gp inhibitor	Most DOACs are affected; dose adjustments may be needed	Edoxaban, apixaban, dabigatran
Patient preference for low pill burden	Consider daily dosing formulations	Edoxaban or rivaroxaban

CrCl creatinine clearance, CYP cytochrome P450, DOAC direct oral anticoagulant, FDA US Food and Drug Administration, GI gastrointestinal, NVAF nonvalvular atrial fibrillation, PCI percutaneous coronary intervention, P-gp P-glycoprotein, SAPT single antiplatelet therapy, TIA transient ischemic attack, VKA vitamin K antagonist
^aSpecial considerations and recommendations are based on available clinical data and clinical practice at Loma Linda University Medical Center

Table 4. Direct oral anticoagulant drug–drug interactions and management strategies
DOAC [11, 13–15, 45]	Interactions [16]^a	Expected effect/outcome	Management strategies^b
Dabigatran (Pradaxa)	P-gp inducers: carbamazepine, dexamethasone, doxorubicin, nefazodone, phenobarbital, phenytoin, prazosin, rifampin, St. John's wort, tenofovir, tipranavir, vinblastine	Reduction in serum dabigatran AUC and C _max, which may lead to decreased efficacy	Avoid use
	P-gp inhibitors: alfentanil, amiodarone, atorvastatin, azole antimycotics, carvedilol, cyclosporine, diltiazem, dipyridamole, dronedarone, duloxetine, HIV protease inhibitors, fenofibrate, lovastatin, macrolide antibiotics, mefloquine, nicardipine, nifedipine, progesterone, propafenone, propranolol, quinidine, quinine, tacrolimus, tamoxifen, ticagrelor, tolvaptan, verapamil	Increase in serum dabigatran AUC and C _max, which may lead to increased bleeding	Avoid use with azoles, dronedarone, tacrolimus All other P-gp inhibitors may be used with caution (given 2 h after dabigatran) Decrease dabigatran dose or avoid use when multiple P-gp inhibitors are co-administered Avoid use with any P-gp inhibitor if CrCl < 50 mL/min
Apixaban (Eliquis)	Dual strong CYP3A4 and P-gp inducers: carbamazepine, phenobarbital, phenytoin, rifampin, St. John's wort	Significant reduction in serum apixaban AUC and C _max, which may lead to decreased efficacy	Avoid use
	Dual strong CYP3A4 and P-gp inhibitors: azole-antimycotics and HIV protease inhibitors	Significant increase in serum apixaban AUC and C _max, which may lead to increased bleeding	Generally avoid, but can still be used with a 50% dose reduction for doses of 5 mg and 10 mg
	Non-strong CYP3A4 and P-gp inducers: aprepitant, armodafinil, bosentan, clobazam, delafloxacin, echinacea, efavirenz, etravirine, lesinurad, modafinil, nafcillin, pioglitazone, prednisone, rufinamide, topiramate	Decrease in serum apixaban concentration to a lesser extent vs. strong dual inducers and may decrease efficacy	No dose adjustment needed; use with caution
	Non-strong CYP3A4 and P-gp inhibitors: amiodarone, atorvastatin, cilostazol, ciprofloxacin, clindamycin, chloramphenicol, cyclosporine, diltiazem, dronedarone, fluoxetine, imatinib, imipramine, isoniazid, lovastatin, macrolide antibiotics, simvastatin, ranolazine, verapamil	Increase in serum apixaban concentration to a lesser extent vs. strong dual inhibitors and may increase bleeding risk	No dose adjustment needed; use with caution
Rivaroxaban (Xarelto)	Dual strong CYP3A4 and P-gp inducers: carbamazepine, phenobarbital, phenytoin, rifampin, St. John's wort	Significant reduction in serum rivaroxaban AUC and C _max, which may lead to decreased efficacy	Avoid
	Dual strong CYP3A4 and P-gp inhibitors: azole-antimycotics and HIV protease inhibitors	Significant increase in serum rivaroxaban AUC and C _max, which may lead to increased bleeding	Avoid
	Non-strong CYP3A4 and P-gp inducers: aprepitant, armodafinil, bosentan, clobazam, delafloxacin, echinacea, efavirenz, etravirine, lesinurad, modafinil, nafcillin, pioglitazone, prednisone, rufinamide, topiramate	Decrease in serum rivaroxaban concentration to a lesser extent vs. strong dual inducers and may decrease efficacy	No dose adjustment needed; use with caution
	Non-strong CYP3A4 and P-gp inhibitors: amiodarone, atorvastatin, cilostazol, ciprofloxacin, clindamycin, chloramphenicol, cyclosporine, diltiazem, dronedarone, fluoxetine, imatinib, imipramine, isoniazid, lovastatin, macrolide antibiotics, simvastatin, ranolazine, verapamil	Increase in serum rivaroxaban concentration to a lesser extent vs. strong dual inhibitors and may increase bleeding risk	Avoid in patients with CrCl < 80 mL/min; use with caution in patients with normal renal function
Edoxaban (Savaysa)	P-gp inducers: carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, St. John's wort	Significant reduction in serum edoxaban AUC and C _max, which may lead to decreased efficacy	Avoid
	P-gp inhibitors: see dabigatran	Significant increase in serum edoxaban AUC and C _max, which may lead to increased bleeding	AF: no dose adjustment; DVT/PE: 50% dose reduction (i.e., 30 mg daily) if co-administered with verapamil, quinidine, macrolide antibiotics, or azole antimycotics
Betrixaban (Bevyxxa)	P-gp inducers: carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, St. John's wort	Reduction in serum betrixaban AUC and C _max, which may lead to decreased efficacy	Avoid use
	P-gp inhibitors: see dabigatran	Significant increase in serum betrixaban AUC and C _max, which may lead to increased bleeding	50% dose reduction (i.e., 80 mg initially then 40 mg daily); avoid in patients with CrCl < 30 mL/min

AF atrial fibrillation, AUC area under the plasma concentration–time curve, C _max peak plasma concentration, CrCl creatinine clearance, CYP cytochrome P450, DOAC direct oral anticoagulant, DVT deep venous thrombosis, PE pulmonary embolism, P-gp P-glycoprotein
^aList of medications includes the most commonly cited agents and may not be all inclusive. The extent of their effect will vary according to the magnitude of induction/inhibition
^bManagement strategies are based on available clinical data and clinical practice at Loma Linda University Medical Center and not entirely based on manufacturer recommendations

Table 5. Indication-based dosing of direct oral anticoagulants in Europe compared with USA ^a
Medication	Indications
Medication	NVAF	Treatment of DVT/PE	Prophylaxis for DVT/PE	Stable CAD/PAD
Direct thrombin inhibitor
Dabigatran (Pradaxa)	110 mg PO BID for patients at high bleeding risk [21]^b	110 mg PO BID for patients at high bleeding risk [22]^b,c	Post-hip replacement 75 mg PO 1–4 h post-hemostasis then 150 mg QD for 28–35 days for patients at high bleeding risk [23]^d Post-knee replacement 110 mg PO 1–4 h post-hemostasis then 220 mg QD for 10 days [23]; 75 mg PO 1–4 h posthemostasis then 150 mg QD for 10 days for patients at high bleeding risk [23]^d	-
Direct Factor Xa inhibitors
Apixaban (Eliquis)	No difference	No difference	No difference	–
Rivaroxaban (Xarelto)	No difference	No difference	No difference	No difference
Edoxaban (Lixiana)^e	USA does not recommend use for CrCl > 95 ml/min	No difference	–	–
Betrixaban (Bevyxxa)	–	–	No difference	–

BID twice daily, CAD coronary artery disease, CrCl creatinine clearance, DVT deep venous thrombosis, NVAF nonvalvular atrial fibrillation, PAD peripheral artery disease, PE pulmonary embolism, PO by mouth, QD every day
^aOnly differences in recommendation are presented in this table. Please see Table 1 for indications and dosing recommendations for the USA
^bHigh risk = age ≥ 80 years; concomitant verapamil use
^cUse of dabigatran 110 mg BID is based on pharmacokinetic and pharmacodynamic analyses and has not been studied in this clinical setting
^dHigh risk = CrCl 30–50 mL/min; concomitant verapamil, amiodarone, and quinidine use; age > 75 years
^eIn Europe, edoxaban is marketed under the brand name Lixiana

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