Dabigatran-Induced Hemorrhage in an Elderly Man
Affiliations: 1Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, England; 2The Rotherham NHS Foundation Trust, Rotherham, England
Abstract: Dabigatran, a direct thrombin inhibitor, has been approved for stroke prophylaxis in patients with nonvalvular atrial fibrillation as an alternative to warfarin. Dabigatran produces a reliable and dose-dependent anticoagulation effect without the need for regular blood tests and dose adjustment. However, bleeding risk with dabigatran increases significantly with advancing age and renal impairment, and there is uncertainty surrounding the use of conventional coagulation assays in assessing its anticoagulant activity. Further, there is no specific agent that can reverse its activity in the context of bleeding. In this article, the authors track the hematological and coagulation parameters following resuscitation and attempted anticoagulation reversal in an elderly man. The authors also review the evidence base behind these therapeutic strategies along with interpretation of coagulation assays.
Key words: Dabigatran, anticoagulation, bleeding, warfarin.
Nonvalvular atrial fibrillation (NVAF) is associated with a five-fold increased risk of stroke1 and accounts for up to 20% of all ischemic strokes.2 Anticoagulation with vitamin K antagonists, namely warfarin, reduces this risk by up to two-thirds.3 However, the efficacy of warfarin is limited by multiple food and drug interactions, variable pharmacodynamics, and a narrow therapeutic window necessitating regular international normalized ratio (INR) monitoring and dose adjustment.4 For these reasons, a search for an alternative oral agent has ensued, leading to the development of dabigatran etexilate, a novel oral anticoagulant that selectively and reversibly inhibits thrombin, producing a reliable and dose-dependent anticoagulant effect, without the need for regular INR monitoring.
In the RE-LY (Randomized Evaluation of Long Term Anticoagulation Therapy) trial, patients with atrial fibrillation who took low-dose dabigatran (110 mg twice daily) had rates of stroke and systemic embolism that were similar to warfarin; however, dabigatran was associated with a lower risk of major bleeding at this dosage.5 When taken at the high dose (150 mg twice daily), dabigatran was associated with lower rates of stroke and systemic embolism but similar rates of major bleeding when compared with warfarin.5 However, there has been a growing controversy over the safety of dabigatran because unlike warfarin, dabigatran does not have an antidote to reverse its anticoagulation effects. In 2011, a total of 3781 serious adverse events associated with dabigatran were reported to the US Food and Drug Administration; of these, 2367 were reports of hemorrhage, and 542 cases resulted in death.6 These figures are likely to rise as the burden of NVAF among an aging population increases.7 There is a lack of evidence-based and clear guidance for clinicians dealing with dabigatran-induced bleeding. In this article, we discuss a case of dabigatran-induced gastrointestinal (GI) bleeding in an elderly man and provide a brief review of the existing literature regarding management of bleeding complications.
An 89-year-old man was admitted to the hospital because of confusion. He had a history of hypertension, osteoarthritis, and NVAF. His warfarin had recently been switched to dabigatran (150 mg twice daily) due to poor control of his INR. He also took ramipril and bendroflumethiazide. The initial physical examination was unremarkable. He scored 7 out of 10 on the Abbreviated Mental Test, suggesting mild cognitive impairment. Screening tests for his confusion were ordered. A chest radiograph was normal, and urinalysis revealed microscopic hematuria only. A complete blood count showed normocytic anemia (hemoglobin level, 9.2 g/dL; normal for men, 13.8-17.2 g/dL)with normal platelet and leucocyte counts. Laboratory tests showed mild renal impairment, including elevated urea nitrogen (42 mg/dL; normal, 6-20 mg/dL), elevated creatinine (1.4 mg/dL; normal for men, 0.7-1.3 mg/dL), and reduced glomerular filtration rate (GFR) of 41.8 mL/min/1.73m2 (GFR <60 mL/min/1.73m2 for >3 months may indicate chronic kidney disease). Routine coagulation assays were prolonged (prothrombin time [PT], 29 seconds; INR, 2.1; activated partial thromboplastin time [APTT], 77.7 seconds), and he had a fibrinogen level of 566 mg/dL (normal, 200-400 mg/dL). A gastroscopy was requested to further investigate his anemia.
Twelve hours after his admission, however, he developed profuse rectal bleeding associated with significant cardiovascular compromise (heart rate, 120 beats per minute; systolic blood pressure, 80/40 mm Hg). He was initially resuscitated with intravenous fluids. Repeat blood tests showed a drop in hemoglobin to 6.3 g/dL and increase in urea nitrogen and creatinine levels to 58.26 mg/dL and 1.75 mg/dL, respectively. His PT had increased to 32 seconds; his INR increased to 2.3; and his APTT increased to 81.4 seconds. Arterial blood gas analysis revealed a compensated metabolic acidosis, with a bicarbonate level of 17 mEq/Land a lactate level of 38.7 mg/dL. Intravenous proton pump inhibition was given for suspected upper GI bleeding, as was vitamin K 10 mg and 2500 units of prothrombin complex concentrate after the care team sought advice from a hematologist. The patient was transferred to the high dependency unit for close monitoring. He was transfused 3 units of fresh-frozen plasma and 4 units of whole blood. As shown in Table 1, coagulation parameters gradually improved; calcium and fibrinogen levels remained normal. The gastroscopy revealed a large bleeding duodenal ulcer that was injected with adrenaline. Testing for Helicobacter pylori was positive, and he was started on eradication therapy. The patient was transferred back to the medical ward with near normal coagulation and renal parameters. He was discharged from the hospital 2 weeks later without any anticoagulation or antiplatelet therapy.
This case highlights two factors associated with increased bleeding risk in patients taking dabigatran: older age and reduced renal function. These factors generally occur concomitantly, as increasing age is typically associated with declining renal function.8 The higher dose of dabigatran (150 mg twice daily) could be another factor in the patient’s condition, but it was shown in the RE-LY study to be more cost-effective than warfarin in patients with high risk of hemorrhage or high risk of stroke unless INR control with warfarin was excellent.9Because up to 80% of dabigatran is eliminated via the kidneys (20% biliary excretion), older individuals and those with renal impairment are more susceptible to drug accumulation and adverse events.10 The plasma half-life of dabigatran increases from 12 hours to 17 hours in patients with normal renal function, from 13 hours to 23 hours in patients with moderate renal impairment (GFR, 30-50 mL/min/1.73 m2), and from 22 hours to 35 hours in those with severe renal impairment (GFR <30 mL/min/1.73 m2).11 Indeed, data from the RE-LY trial confirmed increased rates of major bleeding as renal function declined, similar to that seen with warfarin (Table 2).5,12 A reduced dose of dabigatran 75 mg twice daily is suggested for patients with severe renal impairment (GFR, 15-30 mL/min/1.73 m2), and it is not recommended for those with a GFR of <15 mL/min/1.73 m2or those on dialysis.13 Our case patient had been taking high-dose dabigatran even though he had a reduced GFR because in the 12 months prior to his hospitalization, his GFR had been normal (ie, 60-70 mL/min/1.73 m2) according to the primary care physician and cardiologist who had ordered the change from warfarin to dabigatran.
Older age appears to be a risk factor for bleeding on dabigatran compared with warfarin (Table 2). Since 2011, dabigatran product information has added that renal function should be assessed at initiation of treatment and annually in patients older than 75 years or in those with a GFR of <50 mL/min/1.73 m2.13 Our case implicates acute chronic renal impairment in the accumulative anticoagulant effect of dabigatran, which precipitated GI bleeding from a peptic ulcer. Similar cases of upper GI bleeding have previously been reported.14-16 Interestingly, in the RE-LY study, while patients treated with dabigatran had lower rates of intracranial hemorrhage irrespective of age, rates of GI bleeding were significantly higher than in those taking warfarin (5.41% for dabigatran 110 mg, 6.13% dabigatran 150 mg vs 4.02% for warfarin, P<.004).5 Therefore, while dabigatran may help preserve some of the brain’s hemostatic protective mechanisms, it may have a separately detrimental effect on GI mucosa. The results of RE-LY also showed that concomitant use of aspirin was associated with a two-fold increased risk for all types of bleeding events, both for patients taking dabigatran or warfarin.1 It is also worth noting that dabigatran is metabolized by the P-glycoprotein enzyme, found primarily in the intestinal epithelium, hepatocytes, and renal tubular cells. Coadministration of drugs that inhibit this enzyme, including amiodarone, dronedarone, verapamil, clopidogrel, quinidine and ketoconazole, will increase the anticoagulant effect of dabigatran and predispose to bleeding episodes.13
Effect of Dabigatran on Coagulation Tests
Because the activation of thrombin is involved in the final step of the coagulation cascades, dabigatran affects assays that assess both the intrinsic and extrinsic pathways. Its anticoagulant effect is closely related to plasma concentrations, thus knowledge of when the last dose was administered is crucial to interpreting anticoagulation assays. PT and INR test the extrinsic coagulation pathway, and they are relatively insensitive to dabigatran activity. Therapeutic levels cause only modest prolongations (INR, approximately 1.6)17 and may falsely reassure clinicians of low anticoagulant activity; falsely elevated INR results with dabigatran have also been reported, particularly when using dabigatran with some point-of-care anticoagulation testing devices.18 The APTT targets the intrinsic pathway and is more sensitive than the PT/INR at therapeutic levels of dabigatran. However, this response flattens at higher plasma concentrations (>200 ng/mL),11 thus limiting its usefulness in situations of suspected overanticoagulation. Patients taking 150 mg twice daily for stroke prophylaxis may expect to see median peak plasma concentrations of approximately 180 ng/mL and APTT levels approximately twice that of controls.19 The thrombin clotting time (TT) is the most sensitive test to assess the effect of dabigatran because it directly measures the plasma activity of thrombin. Equipment is usually readily available in emergency settings and results can be obtained quickly; however, results between laboratories are not standardized due to differing test reagents, and at plasma concentrations less than 600 ng/mL, the TT test often exceeds the maximum measurements, again limiting its use in emergency settings.11 The most effective test in emergency situations is the Ecarin clotting time (ECT) because it is both sensitive and specific. Ecarin, a potent snake venom and prothrombin activator, is added to blood samples that are then assayed for the generation of fresh thrombin. As direct thrombin inhibitors inhibit this process, the ECT provides another direct measure of dabigatran activity.20 In addition, other anticoagulants, such as heparin or vitamin K antagonists, do not cause appreciable changes in ECT.21 However, ECT testing is not yet widely available, and normal or therapeutic reference ranges have not been uniformly standardized. Case literature on GI bleeding associated with dabigatran shows that routine assays, such as PT, INR, and APTT, are still the most commonly used to provide an estimation of anticoagulant activity and the response to treatment.13-15 If a TT result can be obtained, serial measurements that detect small changes in dabigatran’s effect may help guide further treatment.
Management of Bleeding
Management of bleeding in patients taking dabigatran depends largely on the severity of bleeding. Minor episodes may be dealt with by simply delaying or discontinuing therapy, while more serious episodes may require resuscitative interventions and attempts to reverse anticoagulant effects. General measures that should be considered when managing dabigatran-associated bleeding are listed in Table 3. Importance should be given to fluid resuscitation and ensuring renal perfusion given the drug’s predominant renal clearance.22
Dabigatran is lipophilic and, thus, is avidly adsorbed by activated charcoal. Oral administration of charcoal within 2 hours of ingestion may reduce gut absorption and peak plasma concentrations, while hemoperfusion can reduce plasma levels directly. Both of these methods have been studied in vitro using simulation techniques with good effect,23 but there is no current literature on its clinical application. Because only 35% of plasma dabigatran is protein-bound, it is readily dialyzable. An open-label study of six patients on dialysis for end-stage renal failure showed a drop of approximately two-thirds in plasma dabigatran concentration after 2 hours of dialysis.10 Although this appears to be a very useful way of rapidly clearing dabigatran in cases of severe overdose or bleeding, the process of obtaining vascular access for a large dialysis catheter in a potentially unstable and overanticoagulated patient is very challenging, particularly given clinical experience with respect to this is limited.22
Recombinant activated factor VII (rFVIIa) generates thrombin through the activation of factor X and has the potential to reverse many anticoagulants, including dabigatran. Animal models have shown that rFVIIa can reduce bleeding times in rats treated with dabigatran in a dose-dependent manner24; however, in another study, experimental intracranial hematoma expansion in mice showed no beneficial effects.25
In a 2011 review of the literature and guidelines, Ganetsky and colleagues22 concluded that, “the strength of the current evidence is insufficient to advocate for transfusion of rFVIIa and APCC as a first-line therapy for dabigatran-induced bleeding.”Similarly, studies assessing their effect on melagatran, an older direct thrombin inhibitor, produced conflicting results.26,27 Prothrombin complex concentrates (PCC) contain the vitamin K–dependent coagulation factors and can be divided into four-factor concentrates (ie, factors II, VII, IX and X) and three-factor concentrates (ie, factors II, IX, and X; significantly less of factor VII). Although more commonly used to rapidly reverse the effect of vitamin K antagonists, animal models have shown potential in dabigatran reversal. Activated PCC, which contains activated factor VII, reduced bleeding time in rat tail models treated with dabigatran,24 and four-factor PCC reduced intracranial hematoma expansion in mice.25
However, a randomized placebo-controlled crossover study in healthy human volunteers treated with dabigatran 150 mg twice daily failed to show correction of coagulation assays, including ECT, following administration of PCC.28 Vitamin K will not affect dabigatran activity, but it may be considered useful in patients with suspected coexisting nutritional vitamin K deficiency, liver disease, or concomitant use of warfarin. Fresh-frozen plasma has only shown minimal benefit in animal models,25 probably due to the fact that it contains relatively little thrombin; significantly large doses of thrombin are required before appreciable changes are detected in anticoagulant activity. Cryoprecipitate and tranexamic acid have not been studied specifically in association with dabigatran, but they are sometimes used when bleeding is complicated by consumption coagulopathy and antiplatelet use, respectively. In our case report, it is unclear whether coagulation assays normalized in response to the hemostatic agents given or to the gradual renal clearance of the drug.
Although there may be significant enthusiasm for the use of an alternative to warfarin, such as dabigatran, caution should be observed particularly in those with renal impairment and in the elderly (>75 years), as these patients are at risk of bleeding complications. Renal function should be screened before initiating treatment and monitored at least annually and probably at times of intercurrent illness. Inevitably, physicians will face the associated bleeding complications with increasing frequency. They should realize that although there is no readily available coagulation assay that accurately reflects dabigatran activity, some assays that are more commonly used can and are being used as an approximate measure; for example, APTT is a reasonable indicator of anticoagulant activity in the absence of ECT. Evidence for anticoagulation reversal is not only scarce, but also shows conflicting results, with no real consensus-based guidance available.Nevertheless, awareness of treatment options that have the potential to limit drug absorbency, increase renal clearance, and reverse anticoagulation activity may avoid delays in their implementation.
- Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991;22:983-988.
- Lip GY, Edwards SJ. Stroke prevention with aspirin, warfarin and ximelagatran in patients with nonvalvular atrial fibrillation: a systematic review and meta-analysis. Thromb Res. 2006;118(3):321-333.
- Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007;146(12):857-867.
- van der Meer FJ, Rosendaal FR, Vandenbroucke JP, Briët E. Bleeding complications in oral anticoagulant therapy. An analysis of risk factors. Arch Intern Med. 1993;153(13):1557-1562.
- Connolly SJ, Ezekowitz MD, Yusuf S, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation [published correction appears in N Engl J Med. 2010;363(19):1877]. N Engl J Med. 2009;361(12):1139-1151.
- Institute for Safe Medication Practices. Monitoring FDA MedWatch Reports: Anticoagulants the leading reported drug risk in 2011. www.ismp.org/QuarterWatch/pdfs/2011Q4.pdf. Published May 31, 2012. Accessed November 5, 2013.
- Savelieva I, Camm J. Update on atrial fibrillation: part I. Clin Cardiol. 2008;31(2):55-62.
- Coresh J, Astor B. Decreased kidney function in the elderly: clinical and preclinical, neither benign. Ann Intern Med. 2006;145(4):299-301.
- Shah S, Gage BF. Cost-effectiveness of dabigatran for stroke prevention in atrial fibrillation. Circulation. 2011;23:2562-2570.
- Stangier J, Rathgen K, Stähle H, Mazur D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etixilate: an open-label, parallel-group, single centre study. Clin Pharmacokinet. 2010;49(4):259-268.
- van Ryn J, Strangier J, Haertter S, et al. Dabigatran etixilate–a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost. 2010;103(6):1116-1127.
- Boehringer Ingelheim Pharmaceuticals Inc. Advisory Committee Briefing Document. US Food and Drug Administration Website. www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/cardiovascularandrenaldrugsadvisorycommittee/ucm226009.pdf. Published August 27, 2010. Accessed November 5, 2013.
- Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2013.
- Wychowski MK, Kouides PA. Dabigatran-induced gastrointestinal bleeding in an elderly patient with moderate renal impairment. Ann Pharmacother. 2012;46(4):e10.
- Fellows SE, Rosini JM, Curtis JA, Volz EG. Hemorrhagic gastritis with dabigatran in a patient with renal insufficiency. J Emerg Med. 2012;46(4):e10.
- Kernan L, Ito S, Shirazi F, Boesen K. Fatal gastrointestinal hemorrhage after a single dose of dabigatran. Clin Toxicol (Phila). 2012;50(7):571-573.
- Stangier J, Rathgen K, Stähle H, Gansser D, Roth W. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etixilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol. 2007:64(3):292-303.
- van Ryn J, Baruch L, Clemens A. Interpretation of point-of-care INR results in patients treated with dabigatran. Am J Med. 2012;125(4):417-420.
- Stangier J, Nehmiz G, Reilly P, et al. Pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran in a dose finding trial in atrial fibrillation. J Thromb Haemost. 2005;3(suppl 1):OR271.
- Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etixilate. Clin Pharmacokinet. 2008;47(5):285-295.
- Nowak G. Ecarin clotting time, a universal method to quantify direct thrombin inhibitors. Pathophysiol Haemost Thromb. 2003;33(4):173-183.
- Ganetsky M, Babu KM, Salhnick SD, Brown RS, Boyer EW. Dabigatran: review of pharmacology and management of bleeding complications of this novel oral anticoagulant. J Med Toxicol. 2011;7(4):281-287.
- van Ryn J, Sieger P, Kink-Eiband M, Gansser D, Clemens A. Adsorption of dabigatran etixilate in water or dabigatran in pooled human plasma by activated charcoal in vitro. Paper presented at: 51st ASH Annual Meeting and Exposition; December 5-8, 2013; New Orleans, LA. https://ash.confex.com/ash/2009/webprogram/Paper21383.html. Accessed November 5, 2013.
- van Ryn J, Ruehl D, Priepke H, Hauel N, Wienen W. Reversibility of the anticoagulant effect of high doses of the direct thrombin inhibitor dabigatran, by recombinant factor VIIA or activated prothrombin complex concentrate. Haematologica. 2008;93(s1):148.
- Zhou W, Schwarting S, Illanes S, et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran. Stroke. 2011;42(12):3594-3599.
- Woltz M, Levi M, Sarich TC, et al. Effect of recombinant factor VIIa on melagatran-induced inhibition of thrombin generation and platelet activity in healthy volunteers. Thromb Haemost. 2004;91(6):1090-1096.
- Sorensen B, Ingerslev J. A direct thrombin inhibitor studied by dynamic whole blood clot formation. Haemostatic response to ex-vivo addition of recombinant factor VIIa or activated prothrombin complex concentrate. Thromb Haemost. 2006;96(4):446-453.
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Disclosures: The authors report no relevant financial relationships.
Address correspondence to: Ali N. Ali, Sheffield Teaching Hospitals NHS Trust, Sheffield S5 7AU, England; email@example.com