A Patient Needing Concomitant P-gp Substrate and Inhibitor
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A 76-year-old woman with atrial fibrillation (CHADS2 score = 3) on warfarin presents to her cardiologist following multiple missed appointments at the anticoagulation clinic. She has had two visits to the Emergency Department over the past year for minor gastrointestinal bleeds in the setting of supratherapeutic INR. The patient is asymptomatic in clinic but confirms that she is unable to reliably attend the anticoagulation clinic appointments because the commute is too difficult for her.
The patient has history notable for permanent atrial fibrillation, hypertension, diabetes mellitus type 2, and stage III chronic renal insufficiency (CrCl 40 mL/min), without any prior history of TIA, stroke, coronary heart disease, or heart failure. Her outpatient medications include warfarin, dronedarone, atorvastatin, amlodipine and benazepril. Laboratory values in clinic are notable for INR 3.4 (goal 2-3).
After evaluation of the risks and benefits of various anticoagulation strategies in this patient, the cardiologist decides to discontinue warfarin and initiation dabigatran therapy for primary stroke prevention in the setting of non-compliance with warfarin.
Which of the following is the most appropriate strategy for initiation of dabigatran in this patient?
The correct answer is: C) Re-check INR and initiate half-dose dabigatran 75mg twice daily once INR < 2.0
This patient is currently receiving warfarin for anticoagulation based on her high-moderate risk of thromboembolic event (CHADS2 = 3; 5.9% risk of event per year without anticoagulation).1 The benefit of warfarin, however, is tempered by her non-compliance with INR monitoring as evidenced by the history of recurrent gastrointestinal bleeding in the setting of supratherapeutic INR. Thus, this patient may benefit from a trial with the newer anticoagulant agent dabigatran, which does not require INR monitoring. Dabigatran 150mg twice daily dosing has been shown in the RE-LY study to be associated with lower rates of stroke and systemic embolism with similar rates of bleeding when compared to warfarin.2
Cardiovascular substrates (X) and inhibitors (+) of P-glycoprotein. Strong inhibitors are indicated using (++). Relative potency was determined from literature review of both in vitro and clinical pharmacokinetic studies.
Relative potency was determined from review of studies of both in vitro and clinical pharmacokinetics. *Preliminary studies suggest that aspirin and avasimibe may induce P-gp expression, leading to reduced absorption of clopidogrel and digoxin, respectively. + No known interaction
Relevant to this patient, dabigatran is a substrate of P-gp whereas dronedarone is a strong P-gp inhibitor. Concomitant P-gp inhibition is an independent factor that has been demonstrated to cause increased serum dabigatran concentrations that can lead to excess anticoagulation and subsequent bleeding.4 Serum dabigatran levels were increased by up to 153% with co-administration of ketoconazole, up to 99% with dronedarone, and up to 58% with amiodarone; each of these drugs are known P-gp inhibitors.5
Impaired renal function has additionally been demonstrated to increase dabigatran concentration, with greater effects when combined with P-gp inhibition. As such, in patients who are taking a potent P-gp inhibitor current recommendations are to reduce the dose of dabigatran to 75mg twice daily in patients with moderate renal insufficiency (CrCl 30-50 mL/min), and to avoid dabigatran use in patients with severe renal impairment (CrCl 15-30 mL/min). In patients with end-stage renal failure (CrCl <15 mL/min), dabigatran should be avoided regardless of concomitant drug therapy.6
Finally, in patients undergoing conversion from warfarin to dabigatran, current recommendations are to discontinue warfarin and start dabigatran when the INR is below 2.0 in order to avoid excessive anticoagulation and increased risk of bleeding.6 Thus in this patient with moderate renal insufficiency currently taking a P-gp inhibitor and being converted from warfarin to the P-gp substrate dabigatran, a lower-dose of dabigatran (75mg twice daily) is warranted and should be initiated after INR levels are below 2.0 (ANSWER C). Full-dose dabigatran in the setting of concomitant P-gp inhibition with dronedarone would likely result in significantly elevated levels of dabigatran and increase the risk of bleeding (ANSWER B and D).
- Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001;285:2864-70.
- Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51.
- Wessler JD, Grip LT, Mendell J, Giugliano RP. The p-glycoprotein transport system and cardiovascular drugs. J Am Coll Cardiol 2013;61:2495-502.
- Douketis JD. Pharmacologic properties of the new oral anticoagulants: a clinician-oriented review with a focus on perioperative management. Curr Pharm Des 2010;16:3436-41.
- Walenga JM, Adiguzel C. Drug and dietary interactions of the new and emerging oral anticoagulants. Int J Clin Pract 2010;64:956-67.
- Package insert. Pradaxa (dabigatran etexilate). Ridgefield CBIP, Inc., 2010.