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UW Medicine Anticoagulation Services

Apixaban (Eliquis)

Dosing

An oral direct factor Xa inhibitor approved for:

  1. Stroke prevention in non-valvular atrial fibrillation, using the following dosing
    • 5 mg twice daily
    • 2.5 mg twice daily if at least two of the following characteristics:
      • Age ≥ 80 years old
      • Weight ≤ 60kg
      • Scr ≥ 1.5mg/dL
    • 2.5 mg twice daily when used concurrently with agents that are strong dual inhibitors of CYP3A4 and p-glycoprotein
    • In patients already taking 2.5 mg twice daily, avoid coadministration with strong dual inhibitors of CYP3A4 and p-glycoprotein
  2. Treatment of DVT/PE (10 mg twice daily for 7 days, then 5mg twice daily)
  3. Long-term prevention of DVT/PE after initial 6 months of treatment (2.5 mg twice daily)
  4. Prevention of DVT/PE following hip or knee replacement (2.5 mg twice daily)

NOTE:  Not recommended for patients with severe hepatic impairment.

 

Renal Dosing Adjustment

The presence of chronic kidney disease is an independent risk factor for increased bleeding events, including hemorrhagic stroke. Please carefully consider the risks and benefits of any oral anticoagulant prior to initiating therapy.

CrCl     FDA Recommended Dose for Stroke Prevention in Atrial Fibrillation                                    Treatment of VTE AUC                  t 1/2             
> 80 ml/min 5mg BID 2.5mg BID if any two of the following:
Scr > 1.5
Age > 80 years
Body weight < 60 kg		 10mg BID x 7 days, then 5mg BID (reference) 15.1 hrs
50-79 ml/min 16% increase 14.6 hrs
30-49 ml/min 29% increase 17.6 hrs
15-29 ml/min Use with caution:
Clinical trials excluded patients with serum creatinine > 2.5 or CrCl < 25 ml/min		 Use with caution, consider alternatives. Clinical trials excluded patients with serum creatinine > 2.5 or CrCl < 25 ml/mi 44% increase 17.3 hrs
< 15 ml/min Not recommended not reported
Hemodialysis 3 times per week Use with caution Avoid use, no data for use in this population not reported

NOTE:  Use for long-term DVT/PE prevention and DVT/PE prevention in hip/knee replacement (2.5 mg twice daily) the manufacturer does not recommend dose adjustment. However, patients with CrCl < 15 ml/min or receiving dialysis were excluded from clinical trials.

Chang M, et al. Effect of renal impaitment on the pharmcokinetics, pharmacodynamics, and safety of apixaban. J Clin Pharmacol 2016; 56(5):637-645.

 

Conversions

CONVERSION UW MEDICINE RECOMMENDATION
from warfarin to apixaban Stop warfarin and start apixaban when INR < lower limit of therapeutic range
from apixaban to warfarin

(NOTE: apixaban is not intended to be used as a short-term "bridge" to warfarin.  These recommendations refer to transitioning patients who are taking apixaban on a long-term basis and are switching to warfarin instead)

 Start warfarin and stop apixaban 3 days later
OR IF continuous, uninterrupted anticoagulation is necessary:
a. Stop apixaban
b. Begin both a parenteral anticoagulant (LMWH/fondaparinux or UFH) and warfarin at the same time that the next dose of apixaban would have been given
c. Stop the parenteral anticoagulant when INR is > lower limit of therapeutic range
from LMWH/fondaparinux to apixaban Stop LMWH/fondaparinux and start apixaban at the same time that the next dose of LMWH/fondaparinux would have been given
from IV heparin to apixaban Stop IV heparin and start apixaban simultaneously
from apixaban to parenteral anticoagulant Stop apixaban and administer the first dose of parenteral anticoagulant at the time that the next dose of apixaban would have been given
from apixaban to dabigatran, edoxaban, or rivaroxaban Stop apixaban and begin the other agent at the time that the next scheduled dose of apixaban would have been given

 

Drug Interactions

Pharmacodynamic Interactions

The concurrent use of apixaban with other anticoagulants, antiplatelet agents, and nonsteroidal anti-inflammatory agents is expected to increase the risk of bleeding in comparison to the use of apixaban alone.

Pharmacokinetic Interactions

  1. The absorption of apixaban is mediated by P-glycoprotein (P-gp). P-gp inhibitors can increase the absorption of apixaban, increasing both AUC and Cmax. Conversely, P-gp inducers can reduce the absorption of apixaban, decreasing AUC and Cmax.
  2. The metabolism of apixaban is mediated by CYP3A4. CYP3A4 inhibitors can decrease the metabolism of apixaban, increasing both AUC and Cmax. Conversely, CYP3A4 inducers can increase the metablism of apixaban, decreasing AUC and Cmax
  3. Agents that interfere with both P-gp and CYP3A4 are likely to cause more significant interactions with apixaban than agents that interfere with P-gp or CYP3A4 alone.
Drug Class Examples (based on human in vivo data)1 Known or Probable Effect US PI Recommendations UW Medicine
Suggested Management Guidelines2
Combined P-gp inhibitor and strong inhibitor of CYP3A4 cobicistat, conivaptan, indinavir, itraconazole*, ketoconazole**, posaconazole, ritonavir*, saquinavir, telaprevir, telithromycin
* cited as example in US PI

** cited as example in US PI, with pharmacokinetic data cited

Significant increase in apixaban concentration Reduce apixaban dose to 2.5mg twice daily.
In patients already taking 2.5mg twice daily, avoid coadministration		 CONSIDER ALTERNATIVE THERAPY
Combined P-gp inhibitor and moderate CYP3A4 inhibitor OR strong CYP3A4 inhibitor alone amiodarone, azithromycin, clarithromycin*, cyclosporine, diltiazem*, dronedarone, erythromycin, fluconazole grapefruit, lapatinib, mifepristone, naproxen**, nefazodone, nicardipine, ranolazine, tamoxifen, ticagrelor, verapamil, voriconazole

* pharmacokinetic data cited in US PI

 Moderate increase in apixaban concentrations in patients with normal renal function.
Potentially significant increase in apixaban concentrations in patients with severe renal insufficiency		 No dose adjustment recommended USE WITH CAUTION in patients with normal renal function.

CONSIDER ALTERNATIVE THERAPY in patients with severe renal insufficiency (CrCl < 30ml/min), age > 80 yrs, or low body weight (< 60 kg)
Combined P-gp inducer and strong CYP3A4 inducer carbamazepine*, dexamethasone, rifampin**, St Johns wort*

* cited as example in US PI
** cited as example in US PI, with pharmacokinetic data cited

Significant reduction in apixaban concentration
Effect may persist for several weeks after discontinuation of stong inducers of P-gp and/or CYP3A4		 Avoid use AVOID USE
Inducers of P-gp tipranavir Not specifically addressed AVOID USE
Strong inducers of CYP3A4 bosentan, efavirenz, etravirine, fosphenytoin, nafcillin, nevirapine, phenobarbital3, phenytoin*, primidone, rifabutin, rifapentine

* cited as example of combined P-gp inducer and strong CYP3A4 inducer in US PI

 Avoid use of phenytoin AVOID USE

1based on human in vivo data, in Cytochrome P450 Enzymes and Transports Table, from Hansten PD and Horn JR. The Top 100 Drug Interactions: A Guide to Patient Management, 2014 ed, H&H Publications, Freeland WA 2014.

2based on probable effects on apixaban, taking into consideration known characteristics of the precipitant drug according to human in vivo data

3avoid apixaban use in patients on long-term phenobarbital; the UW Medicine Phenobarbital Protocol for Alcohol Withdrawal Syndrome is a short course, lessening the risk of inducing apixaban metabolism as it typically takes at least 5-7 days to produce maximal induction

Therapeutic Monitoring

Apixaban is not intended to be monitored using routine coagulation testing. Its fixed dosing is not intended to be adjusted on the basis of any coagulation laboratory parameter.

As a result of Factor Xa inhibition, apixaban prolongs clotting tests such as prothrombin time (PT)/ INR, and activated partial thromboplastin time (aPTT). Changes observed in these clotting tests at the expected therapeutic dose, however, are small, subject to a high degree of variability, and not useful in monitoring the anticoagulation effect of apixaban.

Learn more about Apixaban Assay (APIXN1)

 

Peri-Procedural Management of Apixaban

CrCl T 1/2 Standard Risk of Bleeding High Risk of Bleeding
(major surgery, spinal puncture or placement of spinal/epidural catheter, and other situations in which complete hemostasis is required)
Time of last dose of apixaban before procedure (peri-procedural bridging is generally not required)
> 80 ml/min 12 hrs at least 24 hours at least 48 hours
50-79 ml/min 14.6 hrs
30-49 ml/min 17.6 hrs at least 48 hours at least 72 hours
15-29 ml/min 17.3 hrs
< 15 ml/min no data consider measuring drug activity with apixaban assay to determine absence of drug effect

* ASRA 4th edition 2018: hold 72 hours for all patients prior to neuraxial procedures, without consider of the effect of renal function on elimination half-life and clearance

 

Reversal and Management of Bleeding

There is now an FDA-approved reversal agent for apixaban, see andexanet alfa and Guidelines For Reversal of Anticoagulants.

Mild Bleeding

  • Delay the next dose or discontinue therapy

Moderate to Severe Bleeding

  • Symptomatic treatment
  • Mechanical compression
  • Surgical intervention
  • Fluid replacement and hemodynamic support
  • Blood product transfusion
  • Oral charcoal may block the continued absorption from the gut even if charcoal is given 6 hours after ingestion of apixaban.
  • NOTE: Not dialyzable

Life Threatening Bleeding

  • Measures above
  • Last resort: PCC (Kcentra) and andexanet alfa when this product becomes available.

 

Relevant Clinical Trials

Stroke Prevention in Atrial Fibrillation

Apixaban vs. Warfarin – Granger CB, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365(11):981-992. (ARISTOTLE)

Apixaban vs. Aspirin – Connolly SJ, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011; 364(9):806-817. (AVERROES)

Treatment of DVT/PE

Hip Replacement 

Knee Replacement

 

Management Plan

The direct oral anticoagulants (DOACs; apixaban, betrixaban, dabigatran, edoxaban, rivaroxaban) do not require the specialized long-term monitoring and management services provided by the UW Medicine Anticoagulation Clinics. UW Medicine Anticoagulation Services provides the following on a consultative basis:

  1. consults to providers regarding DOAC drug selection, dosing, drug interactions, and peri-procedural issues
  2. support and instructions to patients and providers for switching patients among the various oral agents
  3. DOAC patient education, both telephonic and in person

Guidelines for long-term management of DOACs, developed by UW Medicine Anticoagulation Services and intended to be used by MDs/RNs/MAs in primary or specialty care clinics, are available below.

Guidelines for DOAC Management

Patient Education

Patient education materials, specific to each DOAC and developed by UW Medicine Anticoagulation Services, are available on this website in the Patient Education tab.


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