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Dabigatran-induced esophagitis: A frequently overlooked adverse effect

2016; Elsevier BV; Volume: 212; Linguagem: Inglês

10.1016/j.ijcard.2016.03.178

1874-1754

Nixiao Zhang, Xiushi Suzy Liu, Guangping Li, Tong Liu,

Cardiac electrophysiology and arrhythmias

Atrial fibrillation (AF) is known to increase the risk of ischemic stroke and other thromboembolic events in patients with atrial fibrillation. For a long time, warfarin was the only available oral anticoagulant. Conventionally it was considered effective and widely prescribed for the prevention of thromboembolic events in patients with AF. However, routine laboratory monitoring on international normalized ratio (INR) and inevitable dose adjustments, potential interactions with several drugs and food, presented significant inconvenience and challenge in managing patients taking warfarin on daily medical practice [ [1] Ziff O.J. Camm A.J. Individualized approaches to thromboprophylaxis in atrial fibrillation. Am. Heart J. 2016; 173: 143-158 Crossref PubMed Scopus (12) Google Scholar ]. Dabigatran etexilate, a new direct thrombin inhibitor, has been shown to be non-inferior to warfarin in protecting patients with atrial fibrillation (AF) from suffering ischemic stroke and treating patients who are afflicted with systemic thromboembolism [ 2 Phan K. Wang N. Pison L. Kumar N. Hitos K. Thomas S.P. Meta-analysis of dabigatran vs warfarin in patients undergoing catheter ablation for atrial fibrillation. Int. J. Cardiol. 2015; 189: 199-203 Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar , 3 Providencia R. Albenque J.P. Combes S. Bouzeman A. Casteigt B. Combes N. et al. Safety and efficacy of dabigatran versus warfarin in patients undergoing catheter ablation of atrial fibrillation: a systematic review and meta-analysis. Heart. 2014; 100: 324-335 Crossref PubMed Scopus (70) Google Scholar ]. It is a potent, reversible and direct competitive inhibitor of thrombin which is administered orally as a prodrug (dabigatran etexilate) and is converted to active dabigatran following its digestion from the small intestinal mucosa [ 4 Bytzer P. Connolly S.J. Yang S. Ezekowitz M. Formella S. Reilly P.A. et al. Analysis of upper gastrointestinal adverse events among patients given dabigatran in the RE-LY trial. Clin. Gastroenterol. Hepatol. 2013; 11 (e241–245): 246-252 Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar , 5 Connolly S.J. Ezekowitz M.D. Yusuf S. Eikelboom J. Oldgren J. Parekh A. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 2009; 361: 1139-1151 Crossref PubMed Scopus (8841) Google Scholar , 6 Shibagaki K. Taniguchi H. Goto D. Kobayashi K. Kinoshita Y. Dabigatran-induced asymptomatic esophageal mucosal injury. Gastrointest. Endosc. 2016; 83: 472-474 Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar ]. As published in The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) [ [4] Bytzer P. Connolly S.J. Yang S. Ezekowitz M. Formella S. Reilly P.A. et al. Analysis of upper gastrointestinal adverse events among patients given dabigatran in the RE-LY trial. Clin. Gastroenterol. Hepatol. 2013; 11 (e241–245): 246-252 Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar ] trial, the only adverse effect (AE) that was significantly more common in dabigatran patients than in warfarin patients was dyspepsia (defined as upper abdominal pain, abdominal pain, abdominal discomfort, epigastric discomfort, and dyspepsia). Recent accumulating case studies and observational reports have drawn more and more attention to the higher risk of dabigatran induced esophagitis compared to warfarin [ 4 Bytzer P. Connolly S.J. Yang S. Ezekowitz M. Formella S. Reilly P.A. et al. Analysis of upper gastrointestinal adverse events among patients given dabigatran in the RE-LY trial. Clin. Gastroenterol. Hepatol. 2013; 11 (e241–245): 246-252 Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar , 6 Shibagaki K. Taniguchi H. Goto D. Kobayashi K. Kinoshita Y. Dabigatran-induced asymptomatic esophageal mucosal injury. Gastrointest. Endosc. 2016; 83: 472-474 Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar , 7 Liu E. Shehata M. Liu T. Amorn A. Cingolani E. Kannarkat V. et al. Prevention of esophageal thermal injury during radiofrequency ablation for atrial fibrillation. J. Interv. Card. Electrophysiol. 2012; 35: 35-44 Crossref PubMed Scopus (33) Google Scholar , 8 Okada M. Okada K. Exfoliative esophagitis and esophageal ulcer induced by dabigatran. Endoscopy. 2012; 44 (UCTN): E23-E24 PubMed Google Scholar , 9 Ootani A. Hayashi Y. Miyagi Y. Dabigatran-induced esophagitis. Clin. Gastroenterol. Hepatol. 2014; 12: e55-e56 Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar , 10 Singh S. Savage L. Klein M. Thomas C. Severe necrotic oesophageal and gastric ulceration associated with dabigatran. BMJ Case Rep. 2013; 2013 Google Scholar , 11 Toya Y. Nakamura S. Tomita K. Matsuda N. Abe K. Abiko Y. et al. Dabigatran-induced esophagitis: the prevalence and endoscopic characteristics. J. Gastroenterol. Hepatol. 2016; 31: 610-614 Crossref PubMed Scopus (41) Google Scholar ]. Generally speaking the incidence of drug-induced esophageal injury has been estimated to be only 3.9 per 100,000 persons per year [ 11 Toya Y. Nakamura S. Tomita K. Matsuda N. Abe K. Abiko Y. et al. Dabigatran-induced esophagitis: the prevalence and endoscopic characteristics. J. Gastroenterol. Hepatol. 2016; 31: 610-614 Crossref PubMed Scopus (41) Google Scholar , 12 Kikendall J.W. Friedman A.C. Oyewole M.A. Fleischer D. Johnson L.F. Pill-induced esophageal injury. Case reports and review of the medical literature. Dig. Dis. Sci. 1983; 28: 174-182 Crossref PubMed Scopus (229) Google Scholar ]. In the case of dabigatran, a recently published study showed that nonbleeding upper gastrointestinal adverse events without investigators confirming the mucosal changes accounted for 16.9% of participants with dabigatran; gastroesophageal reflux disease (GERD)-related events were predominant [ 4 Bytzer P. Connolly S.J. Yang S. Ezekowitz M. Formella S. Reilly P.A. et al. Analysis of upper gastrointestinal adverse events among patients given dabigatran in the RE-LY trial. Clin. Gastroenterol. Hepatol. 2013; 11 (e241–245): 246-252 Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar , 11 Toya Y. Nakamura S. Tomita K. Matsuda N. Abe K. Abiko Y. et al. Dabigatran-induced esophagitis: the prevalence and endoscopic characteristics. J. Gastroenterol. Hepatol. 2016; 31: 610-614 Crossref PubMed Scopus (41) Google Scholar ]. Meanwhile, Toya et al. reported the prevalence of dabigatran-induced esophagitis (DIE) in 20% of participants based on endoscopic confirmation [ [11] Toya Y. Nakamura S. Tomita K. Matsuda N. Abe K. Abiko Y. et al. Dabigatran-induced esophagitis: the prevalence and endoscopic characteristics. J. Gastroenterol. Hepatol. 2016; 31: 610-614 Crossref PubMed Scopus (41) Google Scholar ]. Therefore, it is reasonable to suspect that the presence of dabigatran induced esophagitis could be overlooked in asymptomatic patients who don't undergo endoscopic inspection. Staying vigilant for such side effects probably is not unjustified in clinical practice.