Choosing DOACs in the emergency department is a critical piece of any emergency medicine pharmacist’s knowledge. In this post, we dive deep into which DOAC wins the day (for now).
Efficacy and Safety Data for DOACs in the Emergency Department
Table 1: Indirect efficacy comparison of rivaroxaban and apixaban
Stroke or systemic embolism
Rivaroxaban 20 mg daily vs apixaban 5 mg BID,
OR (95% CI)
Table 2: Indirect safety comparison of rivaroxaban and apixaban
Clinically relevant bleeding
Rivaroxaban 20 mg daily vs
apixaban 5 mg BID,
OR (95% CI)
What about real-world data? We know that Phase II and Phase III clinical trial results don’t always translate equally to the general public, so how might these numbers change? Larsen et al. completed a large, retrospective, Danish study which extracted prescription data from three nationwide databases.7 Patients with AF were identified by first time purchases of NOACs or warfarin between 2011 and 2015. More than 122,000 patients were identified, and after exclusions approximately 62,000 patients were analyzed. Patients were mostly males aged 68 to 72 years with a CHADS2-VASC Score of 2.2-2.8. When compared to warfarin, there was no difference in hazard ratios (HR) for ischemic stroke or ischemic stroke + systemic embolism for apixaban compared to warfarin. Rivaroxaban showed a reduced HR compared to warfarin with the composite endpoint of ischemic stroke + systemic embolism (with the 95% CI upper limit at 0.99); but no difference in ischemic stroke alone. The composite endpoint of ischemic stroke + systemic embolism + death favored apixaban and rivaroxaban compared to warfarin (see Table 3).
Table 3: Real-world comparison of DOACs to warfarin
Apixaban vs Warfarin
HR (95% CI)< /div>
Rivaroxaban vs Warfarin
HR (95% CI)
Ischemic stroke + systemic embolism
Ischemic stroke +
systemic embolism + death
Any bleeding event
varoxaban (and neither did the previous study as that data was generated via an indirect method). However, when the real world data closely mirrors clinical trial data with such large study populations, I feel fairly confident generalizing these overall trends when comparing apixaban and rivaroxaban against each other in terms of efficacy and safety.
Renal dosing concerns for DOACs:
Drug interaction considerations for DOACs:
Table 4: Drug interactions12
Change in apixaban AUC
360 mg x10 days
400 mg x6 days
500 mg, single dose
600 mg x11 days
Change in rivaroxaban AUC
500 mg BID x5 days
500 mg TID x5 days
200 mg x3 days
400 mg x5 days
150 mg, 300 mg, 450 mg, then 600 mg x4 days
600 mg BID x6 days
DOACs and Cost Considerations:
Given the relative “newness” of the DOACs, generic equivalents are not yet available. Therefore, as can be expected, these medications can be expensive. However, as they are no longer brand new, a larger percentage of private insurance and some state’s Medicaid Formularies will cover at least one DOAC. Additionally, cost-effectiveness analyses have shown favorable results with DOACs compared to warfarin, with apixaban conferring the greatest cost savings.13,14
In my home state of Colorado, the Medicaid Preferred Drug List still has warfarin as its first line option. However, rivaroxaban is a “preferred” agent, albeit second-line. Patients must meet some eligibility criteria to receive coverage, but we have not encountered any problems so far when properly selecting patients for discharge on rivaroxaban.
Most private insurance companies will cover at least one DOAC, likely more. According to Eliquis’s website, almost 95% of patients nationwide “have access to Eliquis.” They even have a tool for people to enter their state or ZIP code to find common prescription insurance plans in those areas to see if coverage is an option.
Luckily, our outpatient pharmacies associated with the hospitals have the ability to offer the first 30-days of therapy for either apixaban or rivaroxaban at no cost to the patient through manufacturer-sponsored programs. Although this is classic “drug dealing behavior,” we take advantage as frequently as possible. This one month of free therapy likely increases compliance which in turn would hopefully decrease the risk for return visits related to thromboembolic events. Additionally, the free month allows the patient to work with their insurance company to verify long term prescription coverage. If a different agent is required, it allows the patient time to meet with their PCP and set up the plan for change. Overall, these free “starter packs” are a great resource. Patients love being able to leave the ED with a 30-day supply of free medication and I’ll take any opportunity for the drug companies to give out free medication. It is unclear if this is available everywhere, but it may not hurt to contact a drug rep in your area to inquire about it if it is not something already available.
Which Agent to Choose? Several points must be considered when choosing between rivaroxaban and apixaban. Both agents appear to be equally efficacious, but from a safety standpoint, apixaban is the winner in my book. Renal disease may preclude DOAC use, but for some patients rivaroxaban has a lower CrCl cutoff when used for AF than apixaban, so potentially slight advantage there. Cost considerations are very patient- and location-specific. Not mentioned thus far, but worth considering is the BID dosing of apixaban vs daily dosing with rivaroxaban. If patient compliance is a major concern, rivaroxaban will likely be preferred.
Consideration: Winning Medication for DOACs
Taken all together, there is a preferred agent in my book. Given similar efficacy, interaction potential, and medication costs, the major deciding factor is safety. Given the fact we don’t have a reliable reversal agent for Xa inhibitors at this point, and knowing the morbidity and mortality associated with major bleeding events, minimizing bleeding risk is of the utmost importance. Apixaban is a clear winner in this regard and is the reason I routinely recommend apixaban over rivaroxaban when both agents are options. In my experience so far, after having a discussion with the patient regarding the improved safety profile weighed against taking the medication twice daily, the vast majority of patients want the safer medication (and I would too). Even if the patient is only on once daily medications at home, you shouldn’t rule out apixaban as they may want the safer option and just because a patient isn’t on a BID therapy doesn’t mean they can’t start now. Have a conversation, discuss the pros and cons, and give your patient all of the information to allow them to make the best decision.
Apixaban is likely the safest oral anticoagulant available, it is equally effective as other DOACs, and with more and more patients eligible for prescription coverage, it is my preferred oral anticoagulant.
Scott Dietrich, PharmD, BCCCP@PCC_PharmDEmergency Medicine PharmacistUniversity of Colorado Health – North Region
*** Dabigatran Disclaimer ***
This post only mentions two oral anticoagulants. There are several more Xa inhibitors now available, but they are cost-prohibitive at this point. The other alternative DOAC is dabigatran. As mentioned above, in 2017, < 4% of new DOAC prescriptions were for dabigatran.1 Why? According to a series of 2014 BMJ articles,15,16 the manufacturer of dabigatran, Boehringer Ingelheim, withheld information regarding the potential utility of serum drug monitoring. The confidential internal documents were only made available during the litigation process in the US. Though not published within the initial RE-LY trial, there was a large sub-study within RE-LY that measured serum drug levels.17 While only analyzing patients receiving the 150 mg BID dose of dabigatran, researchers found a extraordinarily wide variability in measured plasma concentrations. After 30 days of therapy, plasma levels ranged from 2.3 ng/ml to a max of 1000 ng/ml. After some adjustments, the researchers determined there was a 5.5-fold variability amongst the population. While there was a negligible decrease in event rates with higher plasma levels, there was a clear linear relationship with increasing bleeding event rates (see figure below).14 Despite this, the drug company did not recommend routine drug level monitoring to ensure safety even though the company determined that measuring and appropriately dosing dabigatran could reduce major bleeding by 30-40%.16 Overall, this medication is not as safe as apixaban6 and given the unethical behavior of the manufacturer and likely requirement for drug level monitoring to ensure safety, I am not recommending dabigatran in anyone at this time.
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- Zhu J, Alexander GC, Nazarian S, Segal JB, Wu AW. Trends and variations in oral anticoagulant choice in patients with atrial fibrillation, 2010-2017. Pharmacotherapy. 2018, June [epub ahead of print]
- Agnelli G, Buller HR, Cohen et al. Oral apixaban for the treatment of acute venous thromboembolism (AMPLIFY). NEJM. 2013;29;369(9):789-808
- Prins MH, Lensing AW, Brighton TA, et al. Oral rivaroxaban versus enoxaparin with vitamin K antagonist for the treatment of symptomatic venous thromboembolism in patients with cancer (EINSTEIN-DVT and EINSTEIN-PE): a pooled subgroup analysis of two randomised controlled trials. Lancet Haematology. 2014;1(1):e37-46
- Avezum A, Lopes RD, Schulte PJ, et al. Apixaban in Comparison With Warfarin in Patients With Atrial Fibrillation and Valvular Heart Disease: Findings From the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial. Circulation. 2015;132(8):624-632
- Bansilal S, Bloomgarden Z, Halperin JL, et al. Efficacy and safety of rivaroxaban in patients with diabetes and nonvalvular atrial fibrillation: the Rivaroxaban Once-daily, Oral, Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF Trial). American Heart Journal. 2015;170(4):675-682
- Lopez-Lopez JA, Sterne JA, Thom HHZ, et al. Oral anticoagulants for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis, and cost effectiveness analysis. BMJ. 2017;359:j5058
- Larsen TB, Skoth F, Nielsen PB, Kjaeldgaard JN, Lip GYH. Comparative effectiveness and safety of no
n-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation:propensity weighted nationwide cohort study. BMJ. 2016;353:i3189
- Almutairi AR, Zhou L, Gellad WF, Lee JK, Slack MK, Martin JR, Lo-Ciganic WH. Effectiveness and Safety of Non-vitamin K Antagonist Oral Anticoagulants for Atrial Fibrillationand Venous Thromboembolism: A Systematic Review and Meta-analyses. Clinical Therapeutics. 2017;39(7):1456-1478
- Mavrakanas TA, Samer CF, Nessim SJ, Frisch G, Lipman ML. Apixaban pharmacokinetics at steady state in hemodialysis patients. J Am Soc Nephrology. 2017;28(7):2241-2248
- Horn JR, Hansten PD. Apixaban: an oral anticoagulant. Pharmacy Times. 2013, October. https://www.pharmacytimes.com/publications/issue/2013/october2013/apixaban-an-oral-anticoagulant
- Frost CE, Byon W, Song Y, et al. Effect of ketoconazole and diltiazem on the pharmacokinetics of apixaban, an oral direct factor Xa inhibitor. Br J Clin Pharmacol. 2015;79(5):838-846
- Horn JR, Hansten PD. Rivaroxaban: a new oral anticoagulant. Pharmacy Times. 2012, February. https://www.pharmacytimes.com/publications/issue/2012/february2012/rivaroxaban-a-new-oral-anticoagulant
- Amin A, Stokes M, Makenbaeva D, Wiederkehr D, Wu N, Lawrence JH. Estimated medical cost reductions associated with use of novel oral anticoagulants vs warfarin in a real-world non-valvular atrial fibrillation patient population. J Med Econ. 2014;17(11):771-781
- Amin A, Bruno A, Trocio J, LIn J, Lingohr-Smith M. Comparison of differences in medical costs when new oral anticoagulants are used for the treatment of patients with non-valvular atrial fibrillation and venous thromboembolism vs warfarin or placebo in the US. J Med Econ. 2015;18(6):399-409
- Moore TJ, Cohen MR, Mattison DR. Dabigatran, bleeding, and the regulators. BMJ. 2014;349:g4517
- Cohen D. Dabigatran: how the company withheld important analyses. BMJ. 2014;349:g4670
- Reilly PA, Lehr T, Haertter S, et al. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol. 2014;63(4):321-328