Proton Pump Inhibitors and Dabigatran Therapy: Impact on Gastric Bleeding and Dabigatran Plasma Levels

Abstract

Dabigatran etexilate, a direct thrombin inhibitor, is now frequently used for long-term pharmacological prevention of stroke or systemic embolism in patients with atrial fibrillation. However, such long-term dabigatran therapy (DT) significantly increases the risk of upper gastrointestinal (GI) bleeding. This increased risk of gastric bleeds might be reduced with gastroprotective agents, such as proton pump inhibitors (PPIs). PPIs coadministrated with dabigatran reduce the risk of upper GI bleeding in patients on long-term oral DT. Nevertheless, there is heated discussion regarding interactions between PPI and dabigatran that lead to decreases in dabigatran plasma levels. This article reviews up to date data about the risk of gastric bleeding on dabigatran, the impact of PPI on the reduction of gastric bleeding, and the interaction between PPI and dabigatran leading to decreased dabigatran plasma levels.

Keywords

dabigatran - proton pump inhibitors - atrial fibrillation - gastrointestinal bleeding - dabigatran levels

• References

• 1 Pistoia F, Sacco S, Tiseo C, Degan D, Ornello R, Carolei A. The epidemiology of atrial fibrillation and stroke. Cardiol Clin 2016; 34 (02) 255-268
• 2 Kirchhof P, Benussi S, Kotecha D. , et al; ESC Scientific Document Group. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016; 37 (38) 2893-2962
• 3 Connolly SJ, Ezekowitz MD, Yusuf S. , et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361 (12) 1139-1151
• 4 Vaughan Sarrazin MS, Jones M, Mazur A, Chrischilles E, Cram P. Bleeding rates in Veterans Affairs patients with atrial fibrillation who switch from warfarin to dabigatran. Am J Med 2014; 127 (12) 1179-1185
• 5 Chan EW, Lau WC, Leung WK. , et al. Prevention of dabigatran-related gastrointestinal bleeding with gastroprotective agents: a population-based study. Gastroenterology 2015; 149 (03) 586-95.e3
• 6 Bolek T, Samoš M, Škorňová I. , et al. Proton pump inhibition in patients treated with novel antithrombotic drugs: should we worry about thrombosis?. J Cardiovasc Pharmacol 2018; 72 (01) 71-76
• 7 Ruff CT, Giugliano RP, Braunwald E. , et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014; 383 (9921): 955-962
• 8 Eikelboom JW, Wallentin L, Connolly SJ. , et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial. Circulation 2011; 123 (21) 2363-2372
• 9 Hernandez I, Baik SH, Piñera A, Zhang Y. Risk of bleeding with dabigatran in atrial fibrillation. JAMA Intern Med 2015; 175 (01) 18-24
• 10 Riley TR, Gauthier-Lewis ML, Sanchez CK, Riley TT. Evaluation of bleeding events requiring hospitalization in patients with atrial fibrillation receiving dabigatran, warfarin, or antiplatelet therapy. J Pharm Pract 2017; 30 (02) 214-218
• 11 Maruyama K, Yamamoto T, Aoyagi H. , et al. Difference between the upper and the lower gastrointestinal bleeding in patients taking nonvitamin K oral anticoagulants. BioMed Res Int 2018; 2018: 7123607
• 12 Ray WA, Chung CP, Murray KT. , et al. Association of oral anticoagulants and proton pump inhibitor cotherapy with hospitalization for upper gastrointestinal tract bleeding. JAMA 2018; 320 (21) 2221-2230
• 13 Stangier J, Eriksson BI, Dahl OE. , et al. Pharmacokinetic profile of the oral direct thrombin inhibitor dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement. J Clin Pharmacol 2005; 45 (05) 555-563
• 14 Kishimoto W, Ishiguro N, Ludwig-Schwellinger E, Ebner T, Schaefer O. In vitro predictability of drug-drug interaction likelihood of P-glycoprotein-mediated efflux of dabigatran etexilate based on [I]2/IC50 threshold. Drug Metab Dispos 2014; 42 (02) 257-263
• 15 Pauli-Magnus C, Rekersbrink S, Klotz U, Fromm MF. Interaction of omeprazole, lansoprazole and pantoprazole with P-glycoprotein. Naunyn Schmiedebergs Arch Pharmacol 2001; 364 (06) 551-557
• 16 Ollier E, Hodin S, Basset T. , et al. In vitro and in vivo evaluation of drug-drug interaction between dabigatran and proton pump inhibitors. Fundam Clin Pharmacol 2015; 29 (06) 604-614
• 17 Liesenfeld KH, Lehr T, Dansirikul C. , et al. Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non-valvular atrial fibrillation from the RE-LY trial. J Thromb Haemost 2011; 9 (11) 2168-2175
• 18 Stangier J, Stähle H, Rathgen K, Fuhr R. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin Pharmacokinet 2008; 47 (01) 47-59
• 19 Bolek T, Samoš M, Stančiaková L. , et al. The impact of proton pump inhibition on dabigatran levels in patients with atrial fibrillation. Am J Ther 2019; 26 (03) e308-e313
• 20 Kuwayama T, Osanai H, Ajioka M. , et al. Influence of proton pump inhibitors on blood dabigatran concentrations in Japanese patients with non-valvular atrial fibrillation. J Arrhythm 2017; 33 (06) 619-623
• 21 Wedemeyer RS, Blume H. Pharmacokinetic drug interaction profiles of proton pump inhibitors: an update. Drug Saf 2014; 37 (04) 201-211
• 22 Bolek T, Samoš M, Škorňová I. , et al. Dabigatran levels in omeprazole versus pantoprazole-treated patients with atrial fibrillation: is there a difference?. Eur J Clin Pharmacol 2019; 75 (06) 875-877
• 23 Bolek T, Samoš M, Škorňová I. , et al. How to proceed with long-term anticoagulation in patient after total gastrectomy and atrial fibrillation?. Eur J Clin Pharmacol 2019; 75 (02) 285-286
• 24 Reilly PA, Lehr T, Haertter S. , et al; RE-LY Investigators. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol 2014; 63 (04) 321-328
• 25 Blandizzi C, Fornai M, Colucci R. , et al. Lansoprazole prevents experimental gastric injury induced by non-steroidal anti-inflammatory drugs through a reduction of mucosal oxidative damage. World J Gastroenterol 2005; 11 (26) 4052-4060