Patient Case:
A 62-year-old female presents to the ED with left lower extremity pain and swelling and is diagnosed with a LLE deep vein thrombosis (DVT) on ultrasound. The patient’s past medical history is significant for hypertension and she takes amlodipine at home. Laboratory values, pulse oximetry, and vital signs are within normal limits. The ED physician approaches you about discharge anticoagulation options and asks for a recommendation. Which agent would you recommend for outpatient management of this patient’s DVT?

Background:
EM pharmacists are frequently involved in the drug selection, ordering, dose verification, and patient education regarding anticoagulants in the ED for admitted and discharge patients. We are in a unique situation in which we work closely with providers everyday to make our recommendation on the the best option for individual patients based on patient-specific factors, cost, potential drug interactions, and balancing safety with efficacy.

Since FDA approval of dabigatran in 2010, the NOAC class of anticoagulants has rapidly gained popularity. Zhu et al.1 recently published data concerning NOAC use among atrial fibrillation (AF) patients between 2010 and 2017. In 2017, they identified more than 7500 new patients started on an oral anticoagulant and 79% received a NOAC compared to 21% with warfarin. Of those NOACs, apixaban was the most common agent at 50.1%, followed by rivaroxaban at 25%, and dabigatran at 3.8%. With so many options available, how do you choose which agent to send your patient home on?

Efficacy and Safety Data
Based on the results of the industry sponsored trials, we know apixaban and rivaroxaban are non-inferior to warfarin,2-5 but what about compared to each other?

Lopez-Lopez et al. completed a systematic review and meta-analysis of all available Phase II and Phase III superiority and non-inferiority trials of NOACs and VKAs for stroke prevention in patients with AF.6 The best part about this study (aside from being open-access) was they actually compared each agent against each other. In terms of efficacy, rivaroxaban 20 mg daily was shown to be no different than apixaban 5 mg twice-daily in terms of stroke and systemic embolism, ischemic stroke, myocardial infarction, or all-cause mortality (see Table 1). When looking at safety outcomes, rivaroxaban was shown to increase the risk for major bleeding, GI hemorrhage, and clinically relevant bleeding compared to apixaban with no difference in intracranial hemorrhage (see Table 2).

Table 1: Indirect efficacy comparison of rivaroxaban and apixaban
Stroke or systemic embolism
Ischemic stroke
Myocardial infarction
All-cause mortality
Rivaroxaban 20 mg daily vs apixaban 5 mg BID,
OR (95% CI)
 1.11
(0.87-1.41)
1.01
(0.74-1.38)
0.92
(0.63-1.34)
0.94
(0.76-1.17)
Table 2: Indirect safety comparison of rivaroxaban and apixaban
Major Bleeding
Intracranial hemorrhage
Gastrointestinal hemorrhage
Clinically relevant bleeding
Rivaroxaban 20 mg daily vs
apixaban 5 mg BID,
OR (95% CI)
1.45 
(1.19-1.78)
1.55
(0.97-2.49)
1.66
(1.19-2.33)
1.53
(1.33-1.75)

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).


In terms of safety outcomes including death, any bleeding event, and major bleeding events, HRs were lower with apixaban compared to warfarin, but not with rivaroxaban compared to warfarin (see Table 3). These trends favoring apixaban also continued when patients were stratified based on age of <65 or >65 years. Interestingly, intracranial hemorrhages with apixaban were no different compared to warfarin, but actually lower with rivaroxaban compared to warfarin in this cohort (see Table 3).

However, the original AMPLIFY2 and ARISTOLE4 trials both showed lower intracranial hemorrhage risk with apixaban compared to warfarin. Additionally, this systematic review and meta-analysis showed a lower ICH risk with apixaban vs warfarin and no difference between rivaroxaban vs warfarin.8 Taken together, I give the slight advantage to the RCT data over the Danish registry data given multiple trials with the same results and trust that apixaban is safer than warfarin.

Table 3: Real-world comparison of NOACs to warfarin
Apixaban vs Warfarin
HR (95% CI)< /div>
Rivaroxaban vs Warfarin
HR (95% CI)
Ischemic stroke + systemic embolism
1.08 (0.91-1.27)
0.83 (0.69-0.99)
Ischemic stroke
1.11 (0.904-1.3)
0.86 (0.72-1.04)
Ischemic stroke +
systemic embolism + death
0.79 (0.7-0.88)
0.87 (0.79-0.96)
Death
0.62 (0.56-0.75)
0.9 (0.82-1.03)
Any bleeding event
 0.63 (0.53-0.76)
0.99 (0.86-1.14)
Major bleeding
0.61 (0.49-0.75)
1.06 (0.91-1.23)
Intracranial hemorrhage
0.72 (0.42-1.24)
 0.56 (0.34-0.9)

Granted these data do not represent a direct, head-to head comparison between apixaban and ri
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:
Both apixaban and rivaroxaban require renal dose adjustments. It is very important to note the dose cutoffs for each agent vary depending on the indication (AF vs VTE). Rivaroxaban can be utilized for AF patients with a CrCl > 15 ml/min but for VTE patients the cutoff is increased to a CrCl > 30 ml/min. Apixaban’s adjustments are based on serum creatinine and not necessarily a specific CrCl cutoff. Additionally, there is some data with reduced-dose apixaban showing similar AUCs in patients on hemodialysis as standard doses in patients with normal renal function.9 As only 4% of the drug was removed during a 4-hour HD session, it is unclear if the same dosing scheme of 2.5 mg BID could be applied to non-dialysis patients with significant chronic renal impairment.

Overall, check your drug references to ensure proper dosing given the varying cutoffs in CrCl, Scr, age, and indication used. If you have a patient in your ED with renal disease and for some reason they cannot (or refuse to) be treated with warfarin, choosing an alternative oral agent may be difficult. Among AF patients, rivaroxban’s lower CrCl cutoff of 15 ml/min should encompass a large number of potential patients. Alternatively, given the PK data of apixaban in HD patients, you could consider having a conversation with the provider and patient to decide if apixaban would be worth a try.

Drug interaction considerations:
Compared to warfarin, both apixaban and rivaroxaban have less concerns for drug-drug interactions. However, significant interactions do remain and the ED pharmacist should be vigilant to identify and correct such interactions. Both agents are substrates of CYP3A4 and P-glycoprotein (see Table 4 and Table 5). The most concerning interaction for either agent is with diltiazem and apixaban as is not uncommon for patients with atrial fibrillation to be maintained on diltiazem for rate control and therefore need long term anticoagulation. It’s unknown if the approximate 40% increase in apixaban AUC has any clinical significance, but for elderly patients, or those with a high bleeding risk, this combination should likely be avoided.

Table 4: Drug interactions with apixaban10,11


Table 5: Drug interactions with rivaroxaban12
Drug
Dose
Change in apixaban AUC
Diltiazem
360 mg x10 days
↑ 40%
Ketoconazole
400 mg x6 days
↑ 100%
Naproxen
500 mg, single dose
↑ 50%
Rifampin
600 mg x11 days
↓ 54%
Drug
Dose
Change in rivaroxaban AUC
Clarithromycin
500 mg BID x5 days
↑ 54%
Erythromycin
500 mg TID x5 days
↑ 34%
Ketoconazole
200 mg x3 days
↑ 53%
Ketoconazole
400 mg x5 days
↑ 2.6-fold
Rifampin
150 mg, 300 mg, 450 mg, then 600 mg x4 days
↓ 49%
Ritonavir
600 mg BID x6 days
↑ 2.5-fold