Odontology DOI 10.1007/s10266-015-0195-4
REVIEW ARTICLE
Managing dentoalveolar surgical procedures in patients taking new oral anticoagulants Stefano Sivolella • Marleen De Biagi • Giulia Brunello • Mario Berengo • Vittorio Pengo
Received: 21 May 2014 / Accepted: 1 December 2014 ! The Society of The Nippon Dental University 2015
Abstract The development of new orally administered anticoagulants, such as dabigatran, rivaroxaban, and apixaban, in the past few years has focused on avoiding some of the drawbacks associated with warfarin. This work aims to illustrate the main features of the most commonly used new oral anticoagulants, reviewing the current literature on the management of patients taking these drugs and needing oral and implant surgery, and discussing the currently proposed related guidelines. Keywords Dabigatran ! Rivaroxaban ! Apixaban ! Oral anticoagulants ! Oral surgery Introduction Various diseases and medical conditions can require oral anticoagulant therapy [1]. Vitamin K antagonists (VKAs), such as warfarin, are considered the treatment of choice for preventing thrombotic events, but this medication poses several problems, including the need to adjust the dosage frequently and monitor patients’ coagulation status, as well as multiple drug–drug and dietary interactions [2], and S. Sivolella ! M. De Biagi ! G. Brunello ! M. Berengo Department of Neurosciences, Institute of Clinical Dentistry, University of Padova, Via Venezia 90, 35129 Padua, Italy M. De Biagi (&) DDS, Resident, Institute of Clinical Dentistry, Azienda Ospedaliera, University of Padova, Via Venezia 90, 35129 Padua, Italy e-mail:
[email protected] V. Pengo Department of Cardiac Thoracic and Vascular Sciences, Padova University Hospital, Via Giustiniani 2, 35128 Padua, Italy
hence the development of novel oral anticoagulants (NOAs) designed to inhibit clotting cascade factors directly. These agents selectively block key factors in the coagulation cascade and prevent the conversion of fibrinogen into fibrin [3]. NOAs are at least as effective as warfarin, with the added advantages of a rapid onset of action; no need for bridging medication with other anticoagulant drugs such low-molecular-weight heparin [4]; a broad therapeutic index; a low potential for food and drug interactions; and a predictable anticoagulation effect that does away with the need for routine coagulation monitoring and enables the drug to be administered in fixed doses [1, 3–8]. Potential problems to consider when using NOAs concern: patients’ adherence to treatment and persistence (which is very important because NOAs have a short half-life); renal function; the management of major or life-threatening bleeding; the lack of a specific antidote; side-effects and potential drop-out rates; and costs (which are partially balanced by a lower outlay for laboratory tests) [7, 8]. This paper discusses NOAs (dabigatran, rivaroxaban, and apixaban, in particular) in relation to their use in dental practice involving oral surgery. The current management guidelines are also discussed.
Direct thrombin inhibitors Dabigatran Dabigatran etexilate is an oral, specific, and reversible, direct thrombin inhibitor used as an alternative to warfarin to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation, excluding patients with mechanical heart valves [9, 10]. In Europe
123
Odontology
(EU), it has also been approved for postoperative thromboprophylaxis in adult patients who have undergone elective total hip or total knee replacement surgery [1, 10]. Dabigatran has an advantage over indirect thrombin inhibitors, unfractionated heparin, and low-molecularweight heparin in that it inhibits the activity of both free and fibrin-bound thrombin [10, 11]. It is an inactive prodrug that requires metabolic activation. It has a rapid onset of action and a short half-life, enabling once- or twice-daily administration. Twenty percent of the absorbed drug undergoes hepatic metabolism, and the remaining 80 % is excreted unchanged via the renal system [8, 10]. Conventional tests such as prothrombin time (PT) or activated partial thromboplastin time (aPTT) are not ideal for assaying the effects of dabigatran [11], whereas diluted thrombin time (dTT), ecarin clotting time (ECT), and aPTT measured by Hemoclot" thrombin inhibitor assay (Hyphen BioMed, Neuville-sur-Oise, France) are sensitive tests for assessing its activity [2, 12]. Dabigatran acts as a substrate of the efflux transporter P-gp, so its concomitant use with strong P-gp inducers or P-gp inhibitors is best avoided [1, 10]. Co-administration with other anticoagulants and antiplatelet agents may increase the risk of bleeding [2]. Several important side-effects have been reported, including bleeding, dyspepsia, gastritis-like symptoms, and hypersensitivity reactions [1, 10]. Finally, one of the major concerns regarding dabigatran is the lack of an antidote for use in an emergency. Some researchers have recently identified a potential antidote—an antibody fragment aDabi-Fab—for reversing its anticoagulant effects [13].
Factor Xa inhibitors Rivaroxaban and apixaban Direct FXa inhibitors antagonize the active site of free FXa, clot-bound FXa, and prothrombinase complex-bound FXa, thus inhibiting thrombin activation. The orally administered direct FXa inhibitors available in the USA and Europe include rivaroxaban and apixaban [1, 11]. Rivaroxaban has been approved in the USA and EU for prophylaxis against venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery. It is also recommended for treating deep vein thrombosis (DVT) and pulmonary embolism (PE), and for preventing recurrent DVT and PE. This FXa inhibitor is indicated for reducing the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation. In combination with the antiplatelet agent aspirin (ASA), with or without the addition of thienopyridine (clopidogrel or ticlopidine), rivaroxaban has been approved for use in the
123
EU for preventing atherothrombotic events in adult patients who have experienced an acute coronary syndrome with elevated cardiac biomarkers [1, 14, 15]. Apixaban has been approved for use in the USA and the EU to reduce the risk of stroke and systemic embolism in adults suffering from non-valvular atrial fibrillation. It has also been approved in the EU, but not in the USA, for VTE prophylaxis in adult patients following elective hip or knee replacement surgery [16–18]. In 2013, the FDA and the European Medicines Agency agreed to review apixaban in other applications, for treating DVT and PE, and reducing the risk of recurrent DVT and PE [18]. Rivaroxaban and apixaban are active compounds with a rapid onset of action after oral ingestion and a high oral bioavailability [1, 7, 15, 16]. These drugs need to be used with caution in patients with severe renal impairment, and dose adjustments may become necessary if their plasma levels increase. They are not recommended for use in patients with severe liver impairment [16, 17]. The most appropriate and accurate way to quantify rivaroxaban is to use anti-Factor Xa chromogenic assays [6]. The drug reportedly has the effect of slightly prolonging conventional clotting times, in PT and PTT for instance [1, 2, 16, 19]. No routine coagulation test seems to be suitable for measuring apixaban levels [7]. Few drug–drug interactions have been reported to date. The co-administration of factor Xa inhibitors with CYP3A4 and P-gp inhibitors, or CYP3A4 and P-gp inducers should be avoided [16]. Due to the greater risk of bleeding, care has to be taken for patients treated concomitantly with any other drug affecting hemostasis, such as NSAIDs (nonsteroidal antiinflammatory drugs), ASA, or platelet aggregation inhibitors. An appropriate prophylactic treatment may be needed for such patients, particularly if they are at risk of ulcerative gastrointestinal disease [1, 7, 14, 16]. The most common adverse reactions seen in patients treated with FXa inhibitors are bleeding episodes, which may lead to posthemorrhagic anemia. Nausea is reportedly a common side effect too [14, 16]. Even though a specific antidote is not yet available, it has been established in vitro and in animal models that r-Antidote can reverse the anticoagulant activity of both direct and indirect FXa inhibitors, confirming its utility in patients requiring elective surgery or suffering from major bleeding [19, 20].
Periprocedural management of patients taking NOAs in oral surgery The periprocedural management of patients on chronic anticoagulation therapy is a common but nonetheless
Odontology
complex clinical problem, and how best to manage patients taking VKAs who require dental extractions has been investigated in depth. Most minor procedures can be handled safely while a patient taking VKAs is within a given target INR range [10, 21]. Recent guidelines indicate that, for the purposes of oral surgery, continuing VKA therapy and concurrently administering an oral prohemostatic agent are associated with a low risk (\5 %) of major bleeding, providing that the patient’s INR is not greater than 3.5 on the day of surgery [21–24]. On the other hand, temporarily withdrawing anticoagulant therapy seems to increase the risk of thrombosis [22, 23, 25]. In fact, the risk of bleeding during oral surgery can be minimized using oxidized cellulose (Surgicel, Johnson & Johnson Medical, New Brunwick, NJ, USA) or absorbable gelatin sponge (e.g. Spongostan, Johnson & Johnson Medical, USA) and sutures plus 5 % tranexamic acid mouthwashes four times a day for 2 days, or compressive gauze soaked in tranexamic acid [26, 27]. Using NOAs has the potential to simplify periprocedural patient management thanks to their relatively short elimination half-lives, rapid onset of action, predictable pharmacokinetic properties, and few interactions [1, 2, 24, 28]. Most published articles addressing the management of patients taking NOAs focus on the drugs’ pharmacological properties rather than on clinical data. All authors agree that there is no need for monitoring or dose adjustments, but no shared guidelines are currently available concerning any need to suspend NOA therapy and, if so, for how long before dental or implant surgery (Table 1) [1, 21, 29, 30]. Van Ryn et al. [12] suggested discontinuing dabigatran at least 24 h prior to any type of elective surgery, depending on the patient’s level of renal impairment and bleeding risk. In patients with a normal kidney function and exposed to a standard bleeding risk (e.g. for simple dental extractions), drug discontinuation 24 h before surgery reduces plasma levels to approximately 25 % of the steady-state trough levels, thus minimizing the bleeding risk [12]. In the event of emergency surgery, any need to reverse the effects of anticoagulants could be assessed by means of coagulation tests (dTT, ECT for dabigatran; antifactor Xa assay, PT) for rivaroxaban, but no routine coagulation tests seem to be appropriate for assaying apixaban [2, 7, 12]. The RE-LY trial provided data on periprocedural bleeding and thrombotic events in patients undergoing major or minor surgery while taking dabigatran: 4591 invasive procedures were documented, and approximately 460 of them were reportedly invasive dental procedures. The study showed similar rates of perioperative bleeding associated with both dosages of dabigatran considered (110 and 150 mg bid) and with warfarin. Discontinuing dabigatran (a mean 49 h before surgery) or warfarin (a mean
114 h before surgery) both resulted in a statistically similar incidence of thrombotic events. No precise details were provided on the type and duration of the dental procedures involved, the patients’ characteristics, and the timing of the anticoagulants’ discontinuation [31]. The few case reports in the literature of oral surgery performed in patients taking dabigatran demonstrate that single-tooth extractions can be managed without suspending the patient’s anticoagulant treatment, with no episodes of significant bleeding [32]. When multiple dental extractions were needed, on the other hand, temporarily suspending dabigatran therapy resulted in an adequate hemostasis, confirming previous findings [32, 33]. One case of significant postoperative bleeding was reported in a patient who underwent a full clearance of his remaining dentition while still taking dabigatran [32]. Firriolo and Hupp [1] proposed management recommendations similar to those adopted for enoxaparin, given that NOAs and low-molecular-weight heparins have a similar half-life. They consequently consider it unnecessary to discontinue NOA therapy for patients with a normal renal function and standard bleeding risk, especially if local hemostatic measures are used. However, oral and maxillofacial procedures characterized by a higher bleeding risk may require the temporary discontinuation of dabigatran at least 24 h before elective surgery [1]. Other Authors [2, 21, 34, 35] have also said that NOA therapy need not be suspended in dental patients due to undergo elective surgical procedures that carry a standard bleeding risk (e.g. single or multiple dental extractions involving up to 3 teeth, or up to 3 implants, scaling and root planing, probing, flap surgery, apex resection, alveoloplasty). It has also been suggested that surgery be performed as late as possible after the last intake of the drug, and that appropriate local hemostatic measures be used. In cases of elective dental surgery carrying a high bleeding risk, NOA therapy should be discontinued for 2–3 halflives before surgery, choosing the timing best suited to a given patient’s renal function [12, 24]. The potential for adverse bleeding events correlates with patients’ renal function. An altered metabolism of NOAs may affect their efficacy in these patients with chronic kidney disease (CKD), giving rise to a higher risk of bleeding. Severe gastrointestinal bleeding has been reported in patients with CKD taking dabigatran [36, 37]. On the other hand, when Harel et al. [38] examined the efficacy and safety of NOAs versus VKAs for atrial fibrillation and venous thromboembolism in patients with CKD in a systematic review and meta-analysis of randomized controlled trials, they found the two types of treatment similarly effective and safe. But no effective reversal agents are commercially available as yet for NOAs. In the event of hemorrhagic complications, the therapy should be stopped,
123
Odontology Table 1 Clinical guidelines for patients taking anticoagulants and requiring invasive dental procedures Authors, year
Continuation/suspension of NOA (and timing)
Perioperative measures
Postoperative measures
Breik et al. [32]
Do not suspend treatment
Divide the load of surgical procedures to reduce bleeding risk
Tranexamic acid rinse
Minimize surgical trauma
Van Diermen et al. [21]
Do not interrupt treatment
Do not prescribe NSAIDs or COX-2 inhibitors
Use coagulation agents Primary closure of surgical wound with absorbable suture
Provide written instructions
Divide the load of surgical procedures to reduce bleeding risk
Tranexamic acid rinse
Minimize surgical trauma
Provide written instructions
Do not prescribe NSAIDs or COX-2 inhibitors
Use coagulation agents Primary closure of surgical wound with absorbable suture Fakhri et al. [30]
Suspend for 2–4 days before and 2–3 days after surgery
Assess patient’s medical profile Use additional hemostatic agents
Provide bridging medication with heparins in cases of high thromboembolic risk Davis et al. [10]
Do not suspend for minor surgical procedures
Perform as late as possible after the last dose
Tranexamic acid rinse for 2–5 days
Discontinue 2–3 half-lives before major surgery
Local hemostatic measures
Avoid prescribing NSAIDs or ASA
Perform C10 h after latest administration
Restart when hemostasis is secure and risk of bleeding is deemed acceptably low
Pengo [7]
Withdraw treatment 1–3 days before surgery
Weitz et al. [35]
Do not suspend for dental extractions
Turpie et al. [34]
Do not suspend
Spyropoulos et al. [24]
Suspend 2–3 days before single extractions
Suspend 2–5 half-lives for moderate or high bleeding risk Avoid surgical intervention coinciding with peak drug activity (2–4 h after taking rivaroxaban)
Resume NOAs at 50 % of total daily dose for the 1st and 2nd days after surgery
Suspension 3–5 days before multiple extractions Firriolo and Hupp [1]
Do not suspend in case of standard bleeding risk and if renal function is normal
aPTT, TT test for dabigatran Anti-FXa assay, PT, aPTT for rivaroxaban
Prudent prescription of NSAIDs, opioid analgesics, and macrolide antibiotics
Suspend 1–5 days in cases of renal impairment Suspend at least 24 h before surgery at high bleeding risk
Adjunctive local hemostatic measures
Little [2]
Do not suspend
Consult patient’s physician
Van Ryn et al. [12]
Stop dabigatran 1–5 days before surgery depending on renal function and bleeding risk
Consult patient’s physician Local hemostatic measures
the source of bleeding should be investigated, and general hemostatic measures should be implemented [19]. Further treatments for bleeding complications include fluid resuscitation to increase renal blood flow, hemodynamic
123
support, and dialysis [10, 19, 33]. Fresh frozen plasma, recombinant factor VIIa, and prothrombin complex concentrates may help, though no data from clinical trials on this issue are currently available [3]. Given the short half-
Odontology
life of NOAs, this kind of support is required only until coagulation pathways have been restored to normal [19].
Conclusions NOAs have many advantages over other anticoagulant drugs. The periprocedural management of patients taking NOAs who are scheduled for dental surgery is based essentially on the drugs’ half-life and the patient’s renal conditions (creatinine clearance). When planning elective surgery or invasive procedures, it is important to balance the intervention-associated bleeding risk with the thrombotic risk associated with suspending anticoagulants in a given individual. The residual level of NOAs at which surgery might be ‘‘safe’’ is not yet known, and none of the available tests have correlated with bleeding risk. To the best of our knowledge, effective drug activity monitoring methods and antidotes are still lacking, making a totally safe surgical management difficult to achieve. There is still not enough information for dental practitioners coming from large-scale specific studies. The thromboembolic risk associated with suspending NOAs is probably comparable with the situation in patients taking VKAs. Clinical trials are needed on dental patients taking NOAs and requiring surgical procedures that carry different levels of bleeding risk (minor versus moderate or severe/life-threatening bleeding). Conflict of interest None of the participants in this study have any relationships that might be construed to give rise to potential conflicts of interest, nor any financial or personal relationships that might inappropriately influence (or bias) the study design and/or results. There is consequently no potential conflict of interest relating to individual authors’ commitments or financial support.
References 1. Firriolo FJ, Hupp WS. Beyond warfarin: the new generation of oral anticoagulants and their implications for the management of dental patients. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;113:431–41. 2. Little JW. New oral anticoagulants: will they replace warfarin? Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;113:575–80. 3. Nagarakanti R, Ellis CR. Dabigatran in clinical practice. Clin Ther. 2012;34:2051–60. 4. Jaffer AK. Anticoagulation management strategies for patients on warfarin who need surgery. Cleve Clin J Med. 2006;73(Suppl 1):S100–5. 5. Michota F. Transitions of care in anticoagulated patients. J Multidiscip Healthc. 2013;6:215–28. 6. Scaglione F. New oral anticoagulants: comparative pharmacology with vitamin K antagonists. Clin Pharmacokinet. 2013;52: 69–82. 7. Pengo V. Laboratory tests during direct oral anticoagulant treatment? Yes. Intern Emerg Med. 2013;8:371–2.
8. Weitz JI, Gross PL. New oral anticoagulants: which one should my patient use? Hematol Am Soc Hematol Educ Progr. 2012;2012:536–40. 9. Van de Werf F, Brueckmann M, Connolly SJ, Friedman J, Granger CB, Ha¨rtter S, Harper R, Kappetein AP, Lehr T, Mack MJ, Noack H, Eikelboom JW. A comparison of dabigatran etexilate with warfarin in patients with mechanical heart valves: the Randomized, phase II study to evaluate the safety and pharmacokinetics of oral dabigatran etexilate in patients after heart valve replacement (RE-ALIGN). Am Heart J. 2012; 163(931–7):e1. 10. Davis C, Robertson C, Shivakumar S, Lee M. Implications of dabigatran, a direct thrombin inhibitor, for oral surgery practice. J Can Dent Assoc. 2013;79:d74. 11. Aditya S. Oral and parenteral anticoagulants: new kids on the block. J Postgrad Med. 2012;58:275–85. 12. van Ryn J, Stangier J, Haertter S, Liesenfeld KH, Wienen W, Feuring M, Clemens A. Dabigatran etexilate—a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost. 2010;103:1116–27. 13. Schiele F, van Ryn J, Canada K, Newsome C, Sepulveda E, Park J, Nar H, Litzenburger T. A specific antidote for dabigatran: functional and structural characterization. Blood. 2013;121: 3554–62. 14. Xarelto": European medicines agency—EPAR—product information, 2013. http://www.ema.europa.eu/docs/en_GB/document_ library/EPAR_-_Product_Information/human/000944/WC5000571 08.pdf. Accessed 15 Aug 2013 (first published December 1, 2009). Accessed Sept 2014. 15. Xarelto": European medicines agency—assessment report, 2013. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Assessment_Report_-_Variation/human/000944/WC500144718. pdf. Accessed Sept 2014. 16. Eliquis": European medicines agency—EPAR—product information, 2013. http://www.ema.europa.eu/docs/en_GB/document_ library/EPAR_-_Product_Information/human/002148/WC50010 7728.pdf. Accessed Sept 2014. 17. Eliquis": European medicines agency—summary of opinion (post authorisation), 2012. http://www.ema.europa.eu/docs/en_ GB/document_library/Summary_of_opinion/human/002148/ WC500132869.pdf. Accessed Sept 2014. 18. Eliquis": FDA accepts for review ELIQUIS" (apixaban) supplemental new drug application for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and for the reduction in the risk of recurrent DVT and PE, 2013. http://news. bms.com/press-release/fda-accepts-review-eliquis-apixaban-supple mental-new-drug-application-treatment-deep-v. Accessed Sept 2014. 19. Pollack CV Jr. Managing bleeding in anticoagulated patients in the emergency care setting. J Emerg Med. 2013;45:467–77. 20. Lu G, DeGuzman FR, Hollenbach SJ, Karbarz MJ, Abe K, Lee G, Luan P, Hutchaleelaha A, Inagaki M, Conley PB, Phillips DR, Sinha U. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med. 2013;19:446–51. 21. van Diermen DE, van der Waal I, Hoogstraten J. Management recommendations for invasive dental treatment in patients using oral antithrombotic medication, including novel oral anticoagulants. Oral Surg Oral Med Oral Pathol Oral Radiol. 2013;116: 709–16. 22. Richards D. Guidelines for the management of patients who are taking oral anticoagulants and who require dental surgery. Evid Based Dent. 2008;9:5–6. 23. Douketis JD, Spyropoulos AC, Spencer FA, Mayr M, Jaffer AK, Eckman MH, Dunn AS, Kunz R. American college of chest
123
Odontology
24.
25.
26.
27.
28.
29.
30.
physicians. Perioperative management of antithrombotic therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e326S–50S. Spyropoulos AC, Douketis JD. How I treat anticoagulated patients undergoing an elective procedure or surgery. Blood. 2012;120:2954–62. Baglin TP, Cousins D, Keeling DM, Perry DJ, Watson HG. Safety indicators for inpatient and outpatient oral anticoagulant care: recommendations from the British Committee for Standards in Haematology and National Patient Safety Agency. Br J Haematol. 2007;136:26–9. Feldens CA, Vitolo MR, Drachler ML. Guidelines for the management of patients who are taking oral anticoagulants and who require dental surgery. Community Dent Oral Epidemiol. 2007;35:215–23. Mingarro-de-Leo´n A, Chaveli-Lo´pez B, Gavalda´-Esteve C. Dental management of patients receiving anticoagulant and/or antiplatelet treatment. J Clin Exp Dent. 2014;6:e155–61. Go´mez-Moreno G, Aguilar-Salvatierra A, Martı´n-Piedra MA, Guardia J, Calvo-Guirado JL, Cabrera M, Lo´pez-Gallardo C, Castillo T. Dabigatran and rivaroxaban, new oral anticoagulants. New approaches in dentistry. J Clin Exp Dent. 2010;2:e14–8. Palareti G, Ageno W, Ferrari A, Filippi A, Imberti D, Pengo V, Rubboli A, Toni D. Clinical management of rivaroxaban-treated patients. Expert Opin Pharmacother. 2013;14:655–67. Fakhri HR, Janket SJ, Jackson EA, Baird AE, Dinnocenzo R, Meurman JH. Tutorial in oral antithrombotic therapy: biology and dental implications. Med Oral Patol Oral Cir Bucal. 2013;18:e461–72.
123
31. Healey JS, Eikelboom J, Douketis J, Wallentin L, Oldgren J, Yang S, Themeles E, Heidbuchel H, Avezum A, Reilly P, Connolly SJ, Yusuf S, Ezekowitz M, RE-LY Investigators. Periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: results from the randomized evaluation of long-term anticoagulation therapy (RE-LY) randomized trial. Circulation. 2012;126:343–8. 32. Breik O, Cheng A, Sambrook PJ, Goss AN. Protocol in managing oral surgical patients taking dabigatran. Aust Dent J. 2014;59: 296–301. 33. Romond KK, Miller CS, Henry RG. Dental management considerations for a patient taking dabigatran etexilate: a case report. Oral Surg Oral Med Oral Pathol Oral Radiol. 2013;116:e191–5. 34. Turpie AG, Kreutz R, Llau J, Norrving B, Haas S. Management consensus guidance for the use of rivaroxaban—an oral, direct factor Xa inhibitor. Thromb Haemost. 2012;108:876–86. 35. Weitz JI, Quinlan DJ, Eikelboom JW. Periprocedural management and approach to bleeding in patients taking dabigatran. Circulation. 2012;126:2428–32. 36. Fellows SE, Rosini JM, Curtis JA, Volz EG. Hemorrhagic gastritis with dabigatran in a patient with renal insufficiency. J Emerg Med. 2013;44:e221–5. 37. Wychowski MK, Kouides PA. Dabigatran-induced gastrointestinal bleeding in an elderly patient with moderate renal impairment. Ann Pharmacother. 2012;46:e10. 38. Harel Z, Sholzberg M, Shah PS, Pavenski K, Harel S, Wald R, Bell CM, Perl J. Comparisons between novel oral anticoagulants and vitamin K antagonists in patients with CKD. J Am Soc Nephrol. 2014;25:431–42.
