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

Drug Substrate Inhibitor Antiarrhythmic Agents     Amiodarone   ++ Bepridil X   Dronedarone   ++ Digoxin X   Felodipine   + Propafenone   + Quinidine X ++ Verapamil X ++ Anticoagulant Agents     Apixaban X   Dabigatran X   Rivaroxaban X   Edoxaban X   Warfarin X + Antihypertensive agents     Aliskiren X   Captopril   + Carvedilol   ++ Celiprolol X   Diltiazem X + Felodipine   + Isradipine   + Labetalol X   Losartan X + Mibefradil   + Nadolol X   Nicardipine   ++ Nifedipine   + Propranolol X + Reserpine   + Talinolol X + Telmisartan   + Timolol X   Antihypertensive agents     Aspirin*     Clopidogrel X   Dipyridamole   + Prasugrel+     Ticagrelor X + Statins     Atorvastatin X ++ Lovastatin X   Other     Avasimibe*     Ranolazine   + Ambrisentan X

The concern in this patient is the concomitant use of both a P-glycoprotein (P-gp) substrate and a P-gp inhibitor. P-gp is a membrane transport system that mediates the export of drugs from cells located in the small intestine, blood-brain barrier, hepatocytes, and kidney proximal tubules. Many cardiovascular drugs have recently been described to have clinically relevant interactions with the P-gp system, acting as substrates, inducers, or inhibitors of P-gp.³ Dose adjustment is therefore often necessary when prescribing a P-gp substrate along with a P-gp inhibitor in order to avoid elevated drug levels. The following table presents the cardiovascular substrates and inhibitors of P-gp.

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).

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References

1. 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.
2. 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.
3. Wessler JD, Grip LT, Mendell J, Giugliano RP. The p-glycoprotein transport system and cardiovascular drugs. J Am Coll Cardiol 2013;61:2495-502.
4. 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.
5. Walenga JM, Adiguzel C. Drug and dietary interactions of the new and emerging oral anticoagulants. Int J Clin Pract 2010;64:956-67.
6. Package insert. Pradaxa (dabigatran etexilate). Ridgefield CBIP, Inc., 2010.