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Appropriate Dosing of Novel Anticoagulants
An 80-year-old female with a history of atrial fibrillation on warfarin is seen by you in follow-up after her second emergency room visit for epistaxis in the setting of a supratherapeutic INR. As you review her laboratory data, you note that she is infrequently in therapeutic range despite careful monitoring, including home INR measurements. She expresses concern about her stroke risk while subtherapeutic and frustration with her repeated emergency room visits. She has seen commercials about other anticoagulants and is wondering whether there might be an alternative to warfarin.
Her medical history is notable only for non-valvular, paroxysmal atrial fibrillation and hypertension. She is currently managed with metoprolol succinate, hydrochlorothiazide, dronedarone, and warfarin. On exam, she is a well-appearing, petite female (5'4", 50kg) with an irregularly, irregular rhythm without murmurs. Laboratory studies from her recent emergency room visit showed a hemoglobin of 12.2 gm/dL and creatinine of 1.0 mg/dL, both stable from prior values. She has no history of liver disease. A 12-lead ECG reveals atrial fibrillation with a regular rate.
What would you recommend for anticoagulation in this patient?
Show Answer
The correct answer is: D. Reduced dosing of a novel oral anticoagulant (e.g. dabigatran 75mg twice daily, rivaroxaban 15mg once daily or apixaban 2.5mg twice daily).
Our patient has non-valvular atrial fibrillation with several risk factors for stroke, including age, gender, and a history of hypertension. With a CHADS2 score of 2 and CHA2DS2-VASc score of 4, she has a 4.0% annual risk of stroke. As such, the ACC/AHA/ESC/HRS guidelines would recommend continued anticoagulation for prevention of thromboembolism in the absence of any compelling contraindications (Class 1, level of evidence A).1
While it would not be incorrect to continue warfarin, her labs demonstrate infrequent time in therapeutic range despite initiating home INR testing. Furthermore, she has experienced repeated adverse events while supratherapeutic and has vocalized a preference for alternative therapy. In light of these factors, it would be reasonable to substitute a novel oral anticoagulant for warfarin.
Three novel oral anticoagulants (dabigatran, rivaroxaban, and apixaban) have been approved for use in non-valvular atrial fibrillation for prevention of thromboembolism based on studies demonstrating at least equivalent efficacy and safety when compared to warfarin.2-4 When choosing between these agents, it is important to take renal and hepatic function, age, and concomitant medications into consideration, as drug levels may vary by the degree of renal excretion, hepatic metabolism, and efflux transport by the P-glycoprotein (P-gp) system (see table below).5-8
Levels may be increased in patients with impaired renal function for drugs that undergo significant renal excretion. Clearance of dabigatran, a direct thrombin inhibitor, is primarily renal and therefore dose adjustments are recommended for renal impairment.8 Rivaroxaban, an oral factor Xa inhibitor, undergoes moderate renal excretion and also requires renal dose adjustment.7 Apixaban, another oral factor Xa inhibitor, has minimal renal clearance and only requires dose adjustment with renal dysfunction in presence of another risk factor for bleeding (e.g. low body weight or age ≥80 years).6 It should be noted that none of these medications were tested in patients with severe or end-stage renal disease and limited or no data are available for moderate-severe renal disease (creatinine clearance of 15-30 mL/min).
For drugs that undergo hepatic metabolism, drug levels may be increased in patients with significant hepatic impairment. Furthermore, levels may be increased or decreased, respectively, by simultaneous use of inhibitors or inducers of the specific cytochrome P450. Both rivaroxaban and apixaban are metabolized by the liver (primarily by CYP 3A4) and therefore, use is not recommended in patients with severe ± moderate hepatic impairment. Additionally, concomitant use of medications that simultaneously induce or inhibit both CYP 3A4 and P-gp transport are either discouraged or require anticoagulant dose adjustment. Strong dual inducers of CYP 3A4 and P-gp include rifampin, carbamazepine, phenytoin, and St. John's wort. Strong dual inhibitors of CYP 3A4 and P-gp include ketoconazole, itraconazole, HIV protease inhibitors (e.g. ritonavir), cyclosporin, and clarithromycin.9
Finally, P-gp is a membrane transporter found in the intestine, liver, and kidneys, as well as in endothelial cells at the blood-brain barrier. Alteration of P-gp activity can influence drug absorption, elimination, and central nervous system penetration for substrates of the transporter, which includes all three novel oral anticoagulants. In general, inhibitors of P-gp increase serum concentrations of substrate and concomitant use may require dose adjustment. Inhibitors of the P-gp transporter include dronedarone, cyclosporine, ketoconazole, HIV protease inhibitors, tacrolimus, and verapamil.9
With a creatinine of 1.0 mg/dL, our petite (50kg), elderly patient has moderate renal impairment with a creatinine clearance of 35 mL/min using the Cockcroft-Gault equation. She has no known liver disease. Importantly, she is on dronedarone, an inhibitor of the P-gp transporter with only moderate effects on CYP 3A4. Based on her reduced creatinine clearance (30-50 mL/min) and dronedarone use, a dabigatran dose of 75mg twice daily would be recommended. It should be noted, however, that concerns have been raised about the use of dabigatran in elderly patients (age ≥80 years).10 While dronedarone inhibits P-gp, it is only a moderate inhibitor of CYP 3A4and therefore is not contraindicated with rivaroxaban or apixaban. However, given her renal impairment the correct dosing for rivaroxaban is 15mg once daily. With two risk factors (age ≥80 and weight ≤60kg), the recommended apixaban dosing is 2.5mg twice daily.
|
Anticoagulant |
Renal Excretion |
Hepatic Metabolism |
P-gp* Substrate |
Dosing Recommendations |
Additional Comments |
|
Dabigatran8 |
Yes
|
No |
Yes |
Based on Renal Function: CrCl 30-50 mL/min with potent P-gp inhibitor (dronedarone or ketoconazole): 75mg twice daily CrCl 15-30 mL/min†: 75mg twice daily CrCl <15 mL/min or dialysis: use not recommended Hepatic Impairment: |
Caution is recommended with use in patients ≥80 years
|
|
Rivaroxaban7 |
Yes |
Yes |
Yes |
Based on Renal Function: CrCl 15-50 mL/min†: 15mg once daily CrCl <15 mL/min or dialysis: use not recommended Hepatic Impairment: |
Avoid strong dual inducers or inhibitors of P-gp and CYP 3A4 (e.g. ketoconazole, HIV protease inhibitors, rifampin, carbemazepine, phenytoin) |
|
Apixaban6 |
Yes |
Yes |
Yes |
5mg twice daily: no dose adjustment factors present 2.5mg twice daily: With at least two of the following: Age ≥80 years, weight ≤60kg, Cr ≥1.5 mg/dL 2.5mg twice daily: With a strong dual inhibitor of P-gp and CYP 3A4 (e.g. ketoconazole, HIV protease inhibitors, clarithromycin) Hepatic Impairment: |
No safety data for CrCl <15mL/min or dialysis |
*P-gp, P-glycoprotein; †CrCl <15-30 mL/min not studied
References
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- Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. The New England journal of medicine. 2011;365:883-891
- Wessler JD, Grip LT, Mendell J, Giugliano RP. The p-glycoprotein transport system and cardiovascular drugs. Journal of the American College of Cardiology. 2013;61:2495-2502
- Eliquis® prescribing information. 12/2012
- Xarelto® prescribing information. 08/2013
- Pradaxa® prescribing information. 04/2013
- FDA. Drug interactions & labeling. 09/2011
- Harper P, Young L, Merriman E. Bleeding risk with dabigatran in the frail elderly. The New England journal of medicine. 2012;366:864-866
