Sage Journals: Discover world-class research

Abstract

Direct oral anticoagulants (DOACs) carry many advantages over warfarin and are now considered first line or an alternative for mnay thromboembolic disorders. With the emergence of 5 DOAC agents to the market as well as the accumulating evidence gathered from head-to-head comparisons between the agents, we attempt to provide direction for clinicians when selecting the most appropriate DOAC agent. Important aspects such as efficacy, safety, cost effectiveness, approved indications, and other drug-related factors will be addressed to highlight the major similarities and diversities among the DOACs. When considering the safety profile of DOACs, evidence points toward apixaban as the safest followed by dabigatran and then rivaroxaban. On the other hand, dabigatran currently has the only approved antidote, idarucizumab. According to the approved DOAC indications, rivaroxaban may be favorable in European countries given its additional indication for secondary prevention of myocardial infarction. Following rivaroxaban, dabigatran and apixaban have the largest number of approved indications and lastly comes edoxaban and then betrixaban. For patients with renal impairment, betrixaban is the safest option, followed by apixaban and edoxaban, then rivaroxaban and lastly dabigatran. When considering DOAC dosing, rivaroxaban, edoxaban, and betrixaban are mainly dosed once daily compared to dabigatran and apixaban, which are dosed twice daily. However, rivaroxaban and betrixaban must be administered with food, which adds another level of complexity to the DOAC dosing. Lastly, taking into consideration drug interactions, dabigatran, edoxaban, and betrixaban have the least amount of interactions compared to apixaban and rivaroxaban. Each DOAC has its own set of features that makes it better suited than others based on the exact clinical situation. Therefore, no conclusion can be drawn to the most superior DOAC based on the aspects discussed in this review.

Keywords

direct oral anticoagulants drug selection efficacy safety reversal drug interactions

Introduction

Oral anticoagulation is a cornerstone treatment to prevent stroke and/or thromboembolism in patients with atrial fibrillation, prosthetic heart valves, coronary artery disease, and venous thromboembolism (VTE).^1,2 Warfarin remained the mainstay oral anticoagulant since the 1940s until direct oral anticoagulants (DOACs) were introduced into the market in 2010.^3,4 The first approved DOAC was a direct thrombin inhibitor (dabigatran) and was then followed by a group of factor Xa inhibitors (rivaroxaban, apixaban, edoxaban, and betrixaban).^5

–9 Direct oral anticoagulants have the advantage of a predictable therapeutic effect with a fixed-dose regimen, less intracranial bleeding, lack of routine monitoring requirement, and less clinically relevant drug–drug and drug–food interactions.^10,11 These benefits come on the expense of potential drawbacks such as increased gastrointestinal adverse effects (especially for dabigatran and rivaroxaban), lack of antidote (except for dabigatran), contraindication in patients with major renal dysfunction (for most DOACs), and lack of superiority when compared to patients with well-managed warfarin therapy.^10

-13 Additionally, DOACs are quite costly in comparison to warfarin especially for patients paying out of pocket.¹⁴

Current practice guidelines incorporate DOACs as first line or as an alternative for stroke prevention in atrial fibrillation and for VTE treatment and prophylaxis.^15
-17 While there is relatively clear guidance on which patients would benefit from DOACs versus warfarin, the selection of the most appropriate DOAC necessitates more consideration. This holds especially true with the emergence of newer DOACs to the market as well as the accumulating evidence gathered from head-to-head comparisons between the agents. In this review, we attempt to provide direction for clinicians when selecting the most appropriate DOAC among the currently approved agents. Important aspects such as efficacy, safety, cost effectiveness, approved indications, and other drug-related factors will be addressed to highlight the major similarities and diversities among the DOACs.

Effectiveness and Safety

Evidence from phase III trials has established the efficacy of DOACs when compared to warfarin. However, efficacy and safety data among DOACs are limited without head-to-head comparison studies. Recently, 2 retrospective observational studies were conducted to compare the efficacy and safety of individual DOAC agents among patients with nonvalvular atrial fibrillation (NVAF). The first study conducted by Graham and colleagues compared the risk of thromboembolic stroke, intracranial hemorrhage (ICH), and major extracranial bleeding among patients with NVAF who are 65 years or older using dabigatran and rivaroxaban.¹⁸ This retrospective new-user cohort study indicated that rivaroxaban was associated with higher risk of ICH bleeding (hazard ratio [HR], 1.65; 95% confidence interval [CI], 1.20-2.26; P = .002; Adjusted incidence rate differences (AIRD) = 2.3 excess cases/1000 person-years) and extracranial bleeding (HR, 1.48; 95% CI, 1.32-1.67; P < .001; AIRD = 13 excess cases/1000 person-years) including major gastrointestinal bleeding (HR, 1.40; 95% CI, 1.23-1.59; P < .001; AIRD = 9.4 excess cases/1000 person-years) when compared to dabigatran. A trend toward higher mortality (HR, 1.15; 95% CI, 1.00-1.32; P = .051; AIRD = 3.1 excess cases/1000 person-years) as well as lower risk of stroke (HR, 0.81; 95% CI, 0.65-1.01; P = .07; AIRD=1.8 fewer cases/1000 person-years) was seen in the rivaroxaban arm.

The second study by Noseworthy and colleagues compared the risk of stroke and systemic embolism and major bleeding among patients with NVAF using dabigatran, rivaroxaban, and apixaban.¹⁹ Similar to the results from the first study, an increased risk of bleeding was observed with the rivaroxaban arm than the dabigatran arm (HR, 1.30; 95% CI, 1.10-1.53; P < .01). Additionally, apixaban showed a reduction in the risk of bleeding when compared to dabigatran (HR, 0.50; 95% CI, 0.36-0.70; P < .001) and rivaroxaban (HR, 0.39; 95% CI, 0.28-0.54; P < .001). There were no statistically significant differences in stroke between the dabigatran, rivaroxaban, and apixaban.

Based on these studies, a conclusion may be drawn that there are no differences between dabigatran, rivaroxaban, and apixaban in terms of effectiveness for stroke prevention in patients with NVAF. On the other hand, these 3 DOACs may be ranked based on their relative safety as follows: apixaban > dabigatran > rivaroxaban. These head-to-head trials have provided clinicians with valuable information with a few drawbacks. First, the comparisons were only specific to NVAF population and their effectiveness in stroke prevention. Relative efficacy and safety for other indications such as VTE treatment and for other DOACs such as edoxaban remain unknown. Furthermore, both studies lacked generalizability and were performed among patients residing in the United States. Additionally, Graham et al’s study included only elderly Medicare beneficiaries.

Cost-Effectiveness

Many pharmacoeconomic studies have been conducted to compare DOACs to warfarin; however, studies comparing the individual DOACs among each other are limited.^20

-23 With the available data, DOAC comparisons were made indirectly using gold standards such as warfarin, clopidogrel, enoxaparin, or aspirin as a reference point.^20,24,25 Additionally, majority of the cost-effectiveness studies were conducted among patients with NVAF for stroke prevention. Few systematic reviews have concluded that apixaban is likely associated with the highest net benefit and quality-adjusted life years or with a favorable incremental cost-effectiveness ratio.^20,24,26,27 While one systematic review found it challenging to conclude the most cost-effective agent due to the heterogeneity of the characteristics presented in the underlying trials and the modeling methods utilized for the indirect comparisons,²⁰ this appears to be the most reasonable conclusion given the limitations of these reviews. Conducting head-to-head pharmacoeconomic comparison studies among DOACs would be of great assistance in filling this gap.

Approved Indications

All DOACs are included in current practice guidelines as first line or as an alternative for VTE treatment and prophylaxis as well as for stroke prevention in NVAF.^15
-17 Betrixaban, as the newest direct factor Xa inhibitor, is the exception, as it is only approved for VTE prophylaxis.^5

-9 Dabigatran, rivaroxaban, and apixaban have an additional indication to reduce the risk of recurrent VTE in patients who have been previously treated. Moreover, rivaroxaban (2.5 mg twice daily) is approved for patients with acute coronary syndrome (ACS) after the acute phase in patients at high risk of thrombosis recurrence. It should be noted that this indication has only been approved by the European Medicines Agency (EMA).²⁸ This approval was based on the Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 51 (ATLAS ACS 2-TIMI 51) study.²⁹ In this trial, low-dose rivaroxaban (2.5 mg twice daily or 5 mg twice daily) was compared to placebo in more than 15 000 patients with ACS receiving dual antiplatelet therapy. The primary efficacy outcome was a composite of death from cardiovascular causes, myocardial infarction, or stroke, while the primary safety end point was Thrombolysis in Myocardial Infarction (TIMI) major bleeding not related to coronary artery bypass grafting. Both rivaroxaban doses were shown to significantly improve the primary cardiovascular efficacy outcomes (9.1% vs 10.7%, HR: 0.84, 95% CI: 0.72-0.97, for the 2.5 mg; 8.8% vs 10.7%, HR: 0.85, 95% CI: 0.73-0.98 for the 5 mg). A reduction in cardiovascular and all-cause mortality was also shown in the rivaroxaban 2.5-mg arm (2.7% vs 4.1%, HR: 0.66, 95% CI: 0.51-0.86 for cardiovascular mortality; 2.9% vs 4.5%, HR: 0.83, 95% CI: 0.72-0.97 for all-cause mortality). However, major bleeding and ICH were significantly higher in the rivaroxaban group (2.1% vs 0.6%, HR: 3.96, 95% CI: 2.46-6.38 for major TIMI bleeding; 0.6% vs 0.2%, HR: 3.28, 95% CI: 1.28-8.42 for ICH) but without significant increases in fatal bleeding.

Apart from the approved indications for DOACs, off-labeled and newly tested indications add another layer of diversity when differentiating one DOAC over the other.³⁰ These indications include use in the treatment of cancer-associated thrombosis, thrombophilia-associated thromboembolic disorders, and stable coronary artery disease.^31
–33

Pharmacokinetics, Dosing, Administration, and Precautions of DOACs

Pharmacokinetic parameters, especially renal clearance, are of utmost importance since the efficacy and safety of the particular DOAC agent is dependent on the selection of the appropriate therapeutic option. Most DOACs should be avoided in patients with a creatinine clearance (CrCl) of less than 30 mL/min (Table 1). Then again, betrixaban may prevail over other DOACs with the lowest renal clearance, with only 5% to 7% cleared after oral administration allowing favorability among patients with renal impairment.³⁴ Conversely, in patients with NVAF with a CrCl of greater than 95 mL/min, edoxaban is not recommended based on increased ischemic stroke risk observed from The Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) study.³⁵

Table 1.

Pharmacokinetics and Dosing Comparison of Direct Oral Anticoagulants.

	Dabigatran	Rivaroxaban	Apixaban	Edoxaban	Betrixaban
Half-life (hours)	12-17	6-9	8-15	6-11	19-27
Renal excretion (%)	80	66	25	35	5
Bioavailability (%)	3-7	80	50	62	34
Administration	Cannot be crushed	Can be crushed, with food	Can be crushed	Can be crushed	N/A, with food
VTE prophylaxis dosing	110 mg × 1 day, 220 mg daily	10 mg daily, CrCl < 30 mL/min: avoid	2.5 mg BID	N/A	160 mg × 1 day, 80 mg daily, CrCl 15-30 mL/min: 80 mg × 1 day, 40 mg daily
VTE treatment dosing	150 mg BID	15 mg BID × 21 days, 20 mg daily	10 mg BID × 7 days, 5 mg BID	60 mg daily, CrCl 15-50 mL/min: 30 mg daily, weight ≤60 kg: 30 mg daily	N/A
Reduction in the risk of recurrent VTE	150 mg BID, CrCl <30 mL/min: avoid	10 mg daily	2.5 mg BID	N/A	N/A
NVAF dosing	150 mg BID, CrCl 15-30 mL/min: 75 mg BID	20 mg daily, CrCL 15-50 mL/min: 15 mg daily with evening meal, CrCl < 15 mL/min: avoid	5 mg BID, age ≥ 80 years: 2.5 mg BID, weight ≤60 kg: 2.5 mg BID, SCr ≥ 1.5 mg/dL: 2.5 mg BID, CrCl < 15 mL/min or dialysis: no data	60 mg daily, CrCL >95 ml/min: avoid, CrCl 15-50 mL/min: 30 mg daily	N/A

Abbreviations: BID, twice daily; CrCl, creatinine clearance; NVAF, nonvalvular atrial fibrillation; SCr, serum creatinine; VTE, venous thromboembolism.

The oral bioavailability for the DOACs varies considerably. Dabigatran has the lowest bioavailability of 3% to 7% and is administrated as a prodrug to raise its bioavailability to 75%.³⁶ Although rivaroxaban has the highest bioavailability at 80% with the 10 mg dose and about 66% with 20 mg dose, it is recommended to be taken with food to enhance absorption.³⁷

All DOACs except apixaban are dosed once daily for VTE prophylaxis, making apixaban a less appealing choice for nonadherent patients. On the other hand, for VTE treatment and NVAF, all DOACs are dosed twice daily except for edoxaban and rivaroxaban, which becomes once daily after 21 days for VTE treatment. Betrixaban may likely fall into this category once approval is obtained for this indication based on its pharmacokinetic profile. It has a long half-life (20 hours) in comparison to other DOACs allowing for a steady anticoagulant effect over 24 hours benefiting those who tend to miss doses.³⁴ In the interim, edoxaban appears to be the better option for VTE and NVAF treatment, as it does not have to be taken with food. It is important to mention that 5 to 10 days of parental anticoagulation are necessary prior to initiation of dabigatran and edoxaban for VTE treatment, which may be cumbersome for few patients.^38,39 For patients who cannot swallow a whole capsule, dabigatran is not a viable option. However, rivaroxaban and apixaban can be crushed and administered via nasogastric tube.⁴⁰

Dabigatran should be used cautiously in patients with peptic ulcer disease and those who have undergone gastric bypass surgery since it is formulated with tartaric acid, which is responsible for causing dyspepsia in 5% to 10% of the population.⁴⁰ Betrixaban is excreted by the gut (>82%), whereby possibly predisposing patients to more gastrointestinal-related side effects such as constipation, diarrhea, and nausea.³⁴ Patients undergoing neuraxial puncture or spinal/epidural puncture and treated with any of the DOACs are at risk of developing spinal hematoma except for apixaban. However, careful consideration on timing of epidural removal and reinitiation of any DOAC is still very important. Consideration for perioperative management of DOACs is another important factor. Although discontinuation is not required in most minor surgical and dental procedures,^41
-43 it may be essential in major procedures and in patients with high risk of bleeding.⁴¹ Duration of discontinuation of DOACs may differ based on the patient’s risk of thrombosis/bleeding, renal function, and each DOAC’s duration of action. Since DOACs have relatively similar onset of action, time of reinitiation after surgical procedures may not differ widely between DOACs.⁴⁴

Drug Interactions of DOACs

Drug interactions with DOACs are not very common when compared to warfarin. However, it is still important to highlight the major differences between the individual DOAC agents (Table 2). All DOACs are substrates of ATP-binding cassette (ABC) transporters, such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).^45,46 A recent in vitro study has shown that dabigatran transport is P-gp dependent, while apixaban is BCRP dependent, and both rivaroxaban and edoxaban have equivalent P-gp- and BCRP-dependent transport.⁴⁵ However, data may not be sufficient to translate this into major clinical differences. In addition to the ABC transporter system, rivaroxaban and apixaban are also affected by the CYP3A4 pathway. Thus, concomitant use of rivaroxaban with strong dual inducers or inhibitors of P-gp/BCRP and CYP3A4 is contraindicated. Strong inducers such as carbamazepine, phenytoin, and rifampin would result in lower levels of DOACs. Strong inhibitor examples that would increase DOAC concentration levels include ketoconazole, itraconazole, lopinavir/ritonavir, and voriconazole. Less potent inhibitors such as fluconazole, clarithromycin, and erythromycin have resulted in increased rivaroxaban levels, but within an acceptable therapeutic range, which make these interactions less relevant.⁴⁷ Drugs that are strong dual inducers of P-gp/BCRP and CYP3A4 should not be concomitantly administered with apixaban due to the increased risk of thromboembolic events mediated by the reduced apixaban levels. Apixaban doses should be reduced to 2.5 mg daily when strong dual inhibitors of P-pg/BCRP and CYP3A4 are administered together with apixaban.⁷ Edoxaban, dabigatran, and betrixaban are not affected by the CYP3A4 pathway but should not be used concomitantly with P-gp inducers. Based on the Hokusai-VTE study, dosage reductions are recommended when edoxaban is used with verapamil, quinidine, or a short course of azithromycin, clarithromycin, erythromycin, oral itraconazole, or oral ketoconazole.³⁹ Likewise, dabigatran dosage reductions are recommended when dronedarone or ketoconazole are used concomitantly.⁴⁷ Concomitant use of dabigatran and P-gp inhibitors in patients with renal impairment (CrCl < 50 mL/min for VTE treatment/prophylaxis or a CrCl 15-30 mL/min for NVAF treatment) should be avoided.⁵ Dosage reductions for betrixaban are recommended when used concomitantly with amiodarone, azithromycin, verapamil, ketoconazole, and clarithromycin.⁹

Table 2.

Drug Interactions of Direct Oral Anticoagulants.

	Dabigatran	Rivaroxaban	Apixaban	Edoxaban	Betrixaban
P-gp inducers	Avoid use	Avoid use	Avoid use	Avoid use	Avoid use
P-gp inhibitors	Reduce dose 75 mg BID	Avoid use	Reduce dose 2.5 mg daily	Reduce dose 30 mg daily	Reduce dose 80 mg × 1 day, 40 mg daily
CYP3A4 inducers	Not affected	Avoid use	Avoid use	Not affected	Not affected
CYP3A4 inhibitors	Not affected	Avoid use	Reduce dose 2.5 mg daily	Not affected	Not affected

Abbreviations: BID, twice daily; P-gp, P-glycoprotein.

All DOACs except rivaroxaban can be used with strong P-pg inhibitors cautiously at reduced doses while monitoring for signs and symptoms of bleeding. Additionally, dabigatran, edoxaban, and betrixaban have the least amount of interactions compared to rivaroxaban and apixaban, as they are not affected by the CYP pathway, making these a slightly better option for patients on multiple medications.

Reversal Agents

Lack of antidote was recognized as a major limitation of DOACs when they were first introduced into the market by both patients and health-care providers.⁴⁸ Idarucizumab is currently the only approved antidote for dabigatran. Idarucizumab has a strong affinity for dabigatran and works by binding unbound and thrombin-bound dabigatran to counteract its anticoagulant effect.⁴⁹ It is supplied as two 50-mL vials containing 2.5 g of idarucizumab and stored in the refrigerator. Unopened vials may be stored in its original packaging at room temperature and protected from light for up to 48 hours. In the Reversal Effects of Idarucizumab on Active Dabigatran (REVERSE AD) trial, 5 g of intravenous idarucizumab administered as two 50-mL bolus within 15 minutes of the infusion were shown to be effective in reversing the effects of dabigatran in patients with a life-threatening bleed or those requiring emergency surgery.⁵⁰ However, there were few patients with increased dabigatran plasma levels within 12 to 24 hours possibly due to the redistribution of extravascular dabigatran into the intravascular compartment. For this reason, a standard assay to assess dabigatran levels may be necessary. Dabigatran may be reinitiated in patients 24 hours after reversal.⁵¹

Andexanet alfa is currently under review by the US Food Drug Administration and the European Commission of the EMA with an anticipated decision by first half of 2018.⁵² It will be the first reversal agent to target both direct and indirect factor Xa inhibitors. It is a recombinant modified human factor Xa decoy protein that binds with high affinity to factor Xa inhibitors while reducing plasma levels and neutralizing anticoagulant effect of the inhibitors.⁵³ In the Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of FXA Inhibitors Apixaban (ANNEXA-A) and Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of FXA Inhibitors Rivaroxaban (ANNEXA-R) trials, andexanet reversed the effects of both apixaban and rivaroxaban within 2 to 5 minutes after administration without any safety concerns.⁵⁴ In the ongoing ANNEXA-4 study, preliminary results are favorable toward the reversal of factor Xa inhibitors with andexanet among patients with major bleeding.⁵⁵ Prior to its approval, andexanet doses will need to be determined, as it will depend on the factor Xa inhibitor used. Also, the duration of administration and when to reinitiate the drug after reversal for those with an active bleeding will need to be established.

Ciraparantag (PER977) is considered a universal reversal agent that binds direct factor Xa inhibitors, dabigatran, and unfractionated and low-molecular-weight heparins. It exerts its effect by binding to these agents and forming a complex through noncovalent bonds that inhibit their anticoagulant effect.^56,57 Preliminary findings have shown PER977 100 to 300 mg intravenous to be effective in reversing edoxaban within 10 to 30 minutes over a 24-hour period. Phase II and III trials are in progress to further test its antidotal effects on edoxaban.⁵⁷ Further studies are necessary to clarify its role as a broad-spectrum reversal agent.

Based on the available agents, dabigatran is so far the only DOAC with an approved reversal agent, making it the most viable option in patients who are considered at high risk for having a life-threatening bleed. Approval of andexanet and ciraparantag will add to the complexity of not just the DOAC selection but the reversal agent as well. Antidotal response, clinical presentation of the patient, and the cost will be essential factors to consider when selecting the most appropriate reversal agent.

Summary

Based on our current review, it is very challenging to reach a conclusion on the most superior DOAC, as it is highly dependent on the clinical scenario. The similarities and variations of DOACs highlight the complexity in the decision-making process for health-care practitioners. Nonetheless, it may be reasonable to rank DOACs based on the aspects discussed in this review (Table 3).

Table 3.

Relative Comparison Between Direct Oral Anticoagulants.^a

	Dabigatran	Rivaroxaban	Apixaban	Edoxaban	Betrixaban
Relative effectiveness	++++	++++	++++	NA	NA
Relative safety	++	+	++++	NA	NA
Approved indications	+++	++++^b	+++	++	+
Renal clearance	++++	+++	++	++	+
Ease of dosing	+++	++++	+++	++++	++++
Ease of administration^c	+++	++	++++	++++	+
Drug interactions	+	++++	+++	+	+
Reversal	Yes	Under review	Under review	No	No

^a +, lowest; ++++, highest.

^b Considering the European Union-approved indication to reduce the risk of thrombosis in patients at high risk of recurrence.

^c Administration: with meals +; with meals/crushed ++; regardless of meals/cannot be crushed +++; regardless of meals/crushed ++++.

When considering the safety profile of DOACs, evidence points toward apixaban as the safest followed by dabigatran and then rivaroxaban. On the other hand, dabigatran currently has the only approved antidote, idarucizumab. However, once approval is granted for andexanet alpha, both rivaroxaban and apixaban will have the same benefit as dabigatran. Until then, apixaban (for its reduced risk of bleeding) and dabigatran (for the availability of reversal agent and relative reduced risk of bleeding) may be considered as optimal choices for patients with high risk for major bleeding events.

According to the approved DOAC indications, rivaroxaban may be favorable in European countries given its additional indication for secondary prevention of myocardial infarction. Following rivaroxaban, dabigatran and apixaban have the largest number of approved indications adding to the panel of options for clinicians. Edoxaban and lastly betrixaban follow these agents.

As for patients with renal impairment, betrixaban is the safest option. However, it is only indicated in patients in need for VTE prophylaxis limiting its use to an exclusive patient population. Apixaban and edoxaban are better alternatives for patients with renal impairment followed by rivaroxaban and lastly dabigatran.

When considering DOAC dosing, rivaroxaban, edoxaban, and betrixaban are mainly dosed once daily compared to dabigatran and apixaban, which are dosed twice daily. However, rivaroxaban and betrixaban must be administered with food, which adds another level of complexity to the DOAC dosing. Edoxaban and apixaban can be taken regardless of the mealtime and can be crushed for patients having issues with swallowing medications. This makes edoxaban and apixaban top choices for nonadherent patients.

Lastly, taking into consideration drug interactions, dabigatran, edoxaban, and betrixaban have the least amount of interactions since they are only substrates to P-gp compared to apixaban and rivaroxaban, which are also metabolized by the CYP3A4 pathway. Although drug interactions are less frequent with DOACs, most cardiac medications such as atorvastatin, amiodarone, diltiazem, and digoxin are commonly used among this patient population. Therefore, DOACs should be used with caution in patients concomitantly taking any of these medications.

Conclusion

Each DOAC has its own set of features that makes it better suited than others based on the exact clinical situation. As each patient scenario is diverse and intricate, many clinical parameters need to be considered when selecting an optimal DOAC. Therefore, no conclusion can be drawn to the most superior DOAC based on the aspects discussed in this review.

Footnotes

Author Contributions

Hazem Elewa and Bridget Paravattil contributed to conception and design, contributed to acquisition, analysis, and interpretation, drafted the manuscript, critically revised the manuscript, gave final approval, and agree to be accountable for all aspects of work ensuring integrity and accuracy.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

References

Nutescu

Shapiro

Ibrahim

West

. Warfarin and its interactions with foods, herbs and other dietary supplements. Expert Opin Drug Saf. 2006;5(3):433–451. doi:10.1517/14740338.5.3.433

Pirmohamed

. Warfarin: almost 60 years old and still causing problems. Br J Clin Pharmacol. 2006;62(5):509–511. doi:BCP2806 [pii] 10.1111/j.1365-2125.2006.02806.x

Nutescu

Spinler

Dager

Bussey

. Transitioning from traditional to novel anticoagulants: the impact of oral direct thrombin inhibitors on anticoagulation management. Pharmacotherapy. 2004;24(10 pt 2):199S–202S.

Elewa

Alhaddad

Al-Rawi

Nounou

Mahmoud

Singh

. Trends in oral anticoagulant use in Qatar: a 5-year experience. J Thromb Thrombolysis. 2017;43(3):411–416. doi:10.1007/s11239-017-1474-4

FDA Approves Pradaxa, Marking a Major Milestone to Reduce the Risk of Stroke in Patients with Non-Valvular Atrial Fibrillation [Press-Release]. Silver Spring, MD: US Food and Drug Administration; 2010.

Johnson & Johnson. FDA Approves XARELTO® (Rivaroxaban) to Reduce the Risk of Stroke and Systemic Embolism in Patients With Nonvalvular Atrial Fibrillation. Raritan, NJ: Johnson & Johnson; 2011. https://www.jnj.com/media-center/press-releases/fda-approves-xarelto-rivaroxaban-to-reducethe-risk-of-stroke-and-systemic-embolism-in-patients-withnonvalvular-atrial-fibrillation (accessed July 20, 2017).

Food and Drug Administration. FDA Approves ELIQUIS® (apixaban) to Reduce the Risk of Stroke and Systemic Embolism in Patients With Nonvalvular Atrial Fibrillation. Silver Spring, MD: FDA; 2013. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202155Orig1s000TOC.cfm (accessed July 20, 2017).

Food and Drug Administration. FDA Approves Anti-Clotting Drug Savaysa. Silver Spring, MD: FDA; 2015. https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm429523.htm. (accessed July 20, 2017).

Food and Drug Administration. FDA Approved Betrixaban (BEVYXXA, Portola) for the Prophylaxis of Venous Thromboembolism (VTE) in Adult Patients. Silver Spring, MD: Food and Drug Administration; 2017. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm564422.htm (accessed July 20, 2017).

10.

Connolly

Ezekowitz

Yusuf

. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139–1151. doi:10.1056/NEJMoa0905561

11.

Spyropoulos

Goldenberg

Kessler

. Comparative effectiveness and safety of the novel oral anticoagulants: do the pivotal clinical trials point to a new paradigm? J Thromb Haemost. 2012;10(12):2621–2624. doi:10.1111/jth.12005

12.

Wallentin

Yusuf

Ezekowitz

. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet. 2010;376(9745):975–983. doi:10.1016/S0140-6736(10)61194-4

13.

Pragst

Zeitler

Doerr

. Reversal of dabigatran anticoagulation by prothrombin complex concentrate (Beriplex P/N) in a rabbit model. J Thromb Haemost. 2012;10(9):1841–1848. doi:10.1111/j.1538-7836.2012.04859.x

14.

Huang

Siu

Wong

Shin

. Factors influencing doctors’ selection of dabigatran in non-valvular atrial fibrillation. J Eval Clin Pract. 2012;19(5):938–943. doi:10.1111/j.1365-2753.2012.01886.x

15.

January

Wann

Alpert

. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am College Cardiol. 2014;64(21):e1–e76. doi:10.1016/j.jacc.2014.03.022

16.

Camm

Lip

GYH

De Caterina

. 2012 focused update of the ESC guidelines for the management of atrial fibrillation. An update of the 2010 ESC guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J. 2012;33(21):2719–2747. doi:10.1093/eurheartj/ehs253

17.

Kearon

Akl

Ornelas

. Antithrombotic therapy for VTE disease: chest guideline and expert panel report. Chest. 2016;149(2):315–352. doi:10.1016/j.chest.2015.11.026

18.

Graham

Reichman

Wernecke

. Stroke, bleeding, and mortality risks in elderly Medicare beneficiaries treated with dabigatran or rivaroxaban for nonvalvular atrial fibrillation. JAMA Intern Med. 2016;176(11):1662–1671.

19.

Noseworthy

Yao

Abraham

Sangaralingham

McBane

Shah

. Direct comparison of dabigatran, rivaroxaban, and apixaban for effectiveness and safety in non-valvular atrial fibrillation. Chest. 2016;150(6):1302–1312. doi:10.1016/j.chest.2016.07.013

20.

Limone

Baker

Kluger

Coleman

. Novel anticoagulants for stroke prevention in atrial fibrillation: a systematic review of cost-effectiveness models. PloS One. 2013;8(4):e62183.

21.

Coyle

Cameron

. Cost-effectiveness of new oral anticoagulants compared with warfarin in preventing stroke and other cardiovascular events in patients with atrial fibrillation. Value Health. 2013;16(4):498–506. doi:10.1016/j.jval.2013.01.009

22.

Canestaro

Patrick

Avorn

. Cost-effectiveness of oral anticoagulants for treatment of atrial fibrillation. Circ Cardiovasc Qual Outcomes. 2013;6(6):724–731.

23.

Harrington

Armstrong

Nolan

Malone

. Cost-effectiveness of apixaban, dabigatran, rivaroxaban, and warfarin for stroke prevention in atrial fibrillation. Stroke. 2013;44(6):1676–1681. doi:10.1161/strokeaha.111.000402

24.

López-López

Sterne

JAC

Thom

HHZ

. Oral anticoagulants for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis, and cost effectiveness analysis. Brit Med J. 2017;359:j5058. doi:10.1136/bmj.j5058

25.

Hernandez

Smith

Zhang

. Cost-effectiveness of non-vitamin K antagonist oral anticoagulants for stroke prevention in patients with atrial fibrillation at high risk of bleeding and normal kidney function. Thromb Res. 2017;150:123–130.

26.

Liberato

Marchetti

. Cost-effectiveness of non-vitamin K antagonist oral anticoagulants for stroke prevention in non-valvular atrial fibrillation: a systematic and qualitative review. Expert Rev Pharmacoecon Outcomes Res. 2016;16(2):221–235. doi:10.1586/14737167.2016.1147351

27.

Singh

Wijeysundera

. Cost-effectiveness of novel oral anticoagulants for stroke prevention in non-valvular atrial fibrillation. Curr Cardiol Rep. 2015;17(8):61.

28.

Medscape. Rivaroxaban gets ACS indication recommendation from European regulators. Medscape. 2013.

29.

Mega

Braunwald

Wiviott

. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med. 2012;366(1):9–19. doi:10.1056/Nejmoa1112277

30.

Chang

Hoyos

Owusu

Elewa

. Direct oral anticoagulant use in atypical thrombosis-related conditions. Ann Pharmacother. 2017;52(2):185–197. doi:10.1177/1060028017731850

31.

Eikelboom

Connolly

Bosch

. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med. 2017;377(14):1319–1330.

32.

Raskob

van Es

Verhamme

. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2017;378(7):615–624.

33.

Cohen

Hunt

Efthymiou

. Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS): a randomised, controlled, open-label, phase 2/3, non-inferiority trial. Lancet Haematol. 2016;3(9):e426–e436. doi:10.1016/s2352-3026(16)30079-5

34.

Chan

Bhagirath

Eikelboom

. Profile of betrixaban and its potential in the prevention and treatment of venous thromboembolism. Vasc Health Risk Manag. 2015;11:343–351.

35.

Kato

Giugliano

Ruff

. Efficacy and safety of edoxaban for the management of elderly patients with atrial fibrillation: ENGAGE AF-TIMI 48. Am Heart Assoc. 2016; 5(5): e003432.

36.

Fontana

Robert-Ebadi

Bounameaux

Boehlen

Righini

. Direct oral anticoagulants: a guide for daily practice. Swiss Med Wkly. 2016;146:w14286.

37.

Rosovsky

Merli

. Anticoagulation in pulmonary embolism: update in the age of direct oral anticoagulants. Tech Vasc Interv Radiol. 2017;20(3):141–151.

38.

Schulman

Kearon

Kakkar

. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24):2342–2352. doi:10.1056/NEJMoa0906598

39.

Buller

Decousus

Grosso

. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369(15):1406–1415. doi:10.1056/NEJMoa1306638

40.

Schaefer

McBane

Wysokinski

. How to choose appropriate direct oral anticoagulant for patient with nonvalvular atrial fibrillation. Ann Hematol. 2016;95(3):437–449.

41.

Sunkara

Ofori

Zarubin

Caughey

Gaduputi

Reddy

. Perioperative management of direct oral anticoagulants (DOACs): a systemic review. Health Serv Insights. 2016;9(suppl 1):25–36. doi:10.4137/HSI.S40701

42.

Kwak

Nam

Park

Kim

Huh

Park

. Bleeding related to dental treatment in patients taking novel oral anticoagulants (NOACs): a retrospective study. Clin Oral Investig. 2018. doi: 10.1007/s00784-018-2458-2

43.

Patel

Woolcombe

Patel

. Managing direct oral anticoagulants in patients undergoing dentoalveolar surgery. Br Dent J. 2017;222(4):245.

44.

Spyropoulos

Al-Badri

Sherwood

Douketis

. Periprocedural management of patients receiving a vitamin K antagonist or a direct oral anticoagulant requiring an elective procedure or surgery. J Thromb Haemost. 2016;14(5):875–885.

45.

Hodin

Basset

Jacqueroux

. In vitro comparison of the role of P-glycoprotein and breast cancer resistance protein on direct oral anticoagulants disposition. Eur J Drug Metab Pharmacokinet. 2018;43(2):183–191.

46.

Vranckx

Valgimigli

Heidbuchel

. The significance of drug–drug and drug–food interactions of oral anticoagulation. Arrhythm Electrophysiol Rev. 2018;7(1):55–61. doi:10.15420/aer.2017.50.1

47.

Fitzgerald

Howes

. Drug interactions of direct-acting oral anticoagulants. Drug Saf. 2016;39(9):841–845.

48.

Elewa

DeRemer

Keller

Gujral

Joshua

. Patients satisfaction with warfarin and willingness to switch to dabigatran: a patient survey. J Thromb Thrombolysis. 2014;38(1):115–120. doi:10.1007/s11239-013-0976-y

49.

Eikelboom

Quinlan

van Ryn

Weitz

. Idarucizumab: the antidote for reversal of dabigatran. Circulation. 2015;132(25):2412–2422.

50.

Pollack

Reilly

Eikelboom

. Idarucizumab for dabigatran reversal. N Engl J Med. 2015;373(6):511–520. doi:10.1056/NEJMoa1502000

51.

Glund

Stangier

van Ryn

. Restarting dabigatran etexilate 24 h after reversal with idarucizumab and redosing idarucizumab in healthy volunteers. J Am Coll Cardiol. 2016;67(13):1654–1656.

52.

Portola Pharmaceuticals Inc. Portola Pharmaceuticals Provides Update on Biologics License Application (BLA) for AndexXa® (andexanet alfa). San Francisco, California, USA: Portola Pharmaceuticals Inc; 2018.

53.

Kaatz

Bhansali

Gibbs

Lavender

Mahan

Paje

. Reversing factor Xa inhibitors—clinical utility of andexanet alfa. J Blood Med. 2017;8:141–149.

54.

Siegal

Curnutte

Connolly

. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015;373(25):2413–2424.

55.

Connolly

Milling

Jr Eikelboom

. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med. 2016;375(12):1131–1141.

56.

Vaidya

Asirvatham

. Reversing anticoagulant effects of novel oral anticoagulants: role of ciraparantag, andexanet alfa, and idarucizumab. Vasc Health Risk Manag. 2016;12:35–44.

57.

Ansell

Bakhru

Laulicht

. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med. 2014;371(22):2141–2142.

Approaches to Direct Oral Anticoagulant Selection in Practice

Abstract

Keywords

Introduction

Effectiveness and Safety

Cost-Effectiveness

Approved Indications

Pharmacokinetics, Dosing, Administration, and Precautions of DOACs

Drug Interactions of DOACs

Reversal Agents

Summary

Conclusion

Footnotes

Author Contributions

Declaration of Conflicting Interests

Funding

References