A 78-year-old woman with past medical history significant for atrial fibrillation (AF), hypertension, and endometrial cancer in remission after total abdominal hysterectomy presents to the emergency department with a one-day history of fatigue, dyspnea on exertion, and lightheadedness upon standing. She also reports passing two tarry black stools the evening prior to presentation, and another black stool the morning of admission to the hospital. She denies hematochezia or hematemesis. Ten years ago, the patient had an episode of upper gastrointestinal (GI) bleeding related to peptic ulcer disease in the setting of warfarin and aspirin therapy for carotid stenosis.
The patient is a former smoker with a 20 pack per year history. Her medications include apixaban 5 mg twice daily, aspirin 81 mg, amlodipine, atenolol, atorvastatin, digoxin, hydrochlorothiazide, and raloxifene. Her last dose of apixaban was 24 hours prior to presentation. On physical examination, the patient appears pale with conjunctival pallor. She is afebrile, blood pressure is 118/58 mm Hg, heart rate is 79 beats per minute, and oxygen saturation is 100% on room air. A soft systolic murmur is heard over the lower left sternal border. Her abdomen is soft and non-tender. Her rectal exam is significant for black, guaiac positive stool. A complete blood count is significant for a hemoglobin level of 8.2 g/dL (last hemoglobin three months prior to presentation was 14.8 g/dL). The prothrombin time is 16.7 seconds (reference range, 12.3-14.9 seconds), and her serum creatinine is within normal limits.
After the patient is started on a proton pump inhibitor (PPI) drip, an esophagogastroduodenoscopy (EGD) is performed, revealing a gastric ulcer containing a visible vessel oozing blood. The bleeding vessel is treated with an injection of epinephrine and gold probe cautery, following which hemostasis is achieved. H. pylori serologies are sent and are negative. Post-procedure hemoglobin level is 6.9 g/dL, and 1 unit packed red blood cells is transfused, with a rise in hemoglobin to 8.0 g/dL.
The correct answer is: B. Discontinue aspirin and restart anticoagulation therapy with apixaban 5 mg twice daily within 48-72 hours.
This is a case of upper GI bleeding in the setting of anticoagulation therapy. While the non-vitamin K antagonist oral anticoagulants (NOACs) offer improved protection in AF patients against stroke and systemic emboli relative to their vitamin K antagonist (VKA) counterparts, certain NOACs are associated with a higher incidence of GI bleeding compared to the VKAs, including dabigatran 150 mg twice daily (hazard ratio [HR] 1.50, 95% confidence interval [CI] 1.19-1.89), rivaroxaban 20 mg once daily (HR 1.42, 95% CI 1.22-1.66), and the higher-dose edoxaban regimen of 60/30 mg once daily (HR 1.23, 95% CI 1.02-1.50).1-3 In contrast, there is no increased rate of GI bleeding in patients taking apixaban versus warfarin (HR 0.89, 95% CI 0.70-1.15).4
Guidelines pertaining to NOAC management in the setting of GI bleeding are largely based on expert opinion, and further studies are needed to determine the optimal timing of restarting anticoagulation. Although option (D), restarting anticoagulation therapy with a reduced dose of apixaban 2.5 mg twice daily within 48-72 hours, would provide protection from thrombotic complications with an even greater reduction in risk of GI bleeding, the patient does not fit the profile for which this dose is approved – patients who are ≥80 years of age and either weigh below 60 kg or have a serum creatinine ≥1.5 mg/dL. An off-label use of a lower NOAC dose may be appropriate in patients who have experienced multiple GI bleeding events; however, there are no clinical data to support such dose adjustment strategies at this time.
Analysis of the patient's risk factors for bleeding, as well as consideration of the natural history of the bleeding source, is essential to stratify risk of re-bleeding. In this patient, an ulcer was identified and cauterized. If re-bleeding does not occur within 72 hours of treatment, one can assume relatively stable hemostasis of the vessel within the ulcer. According to one study of 393 patients undergoing endoscopic treatment for non-variceal upper GI bleeding, 66% of patients with high-risk lesions will re-bleed within one to three days.5 Resumption of anticoagulation can therefore be safely considered after the three-day window post-EGD has passed. According to expert opinion, if bleeding is more extensive, as may be the case after the resection of a large GI tumor, re-initiation of anticoagulation should be delayed for five to seven days.6
Important risk factors noted in pre-market and post-market studies for NOAC-associated GI bleeding include advanced age, prior history of GI bleeding, poor creatinine clearance, concomitant aspirin or non-steroidal anti-inflammatory drug (NSAID) use, smoking, and PPI use.2,7,8 In line with these observations, recent retrospective cohort studies suggest that the increased risk of GI bleeding in patients taking rivaroxaban or dabigatran is specific to patients over the age of 75.9,10 Since concomitant antiplatelet therapy increases the risk of bleeding in combination with oral anticoagulants,11,12 and there is no acute indication for concomitant aspirin therapy (e.g., recent acute coronary syndrome, arterial stent), aspirin could be discontinued to reduce the risk of bleeding. Furthermore, stopping aspirin would not be expected to reduce efficacy, as prior studies of aspirin + warfarin did not demonstrate added benefit of combination therapy compared to warfarin alone.13
The most important consideration in resuming anticoagulation therapy is balancing the risk of re-bleeding with the occurrence of a thromboembolic event. If the risk of recurrent bleeding is high – for example if the patient's source of bleeding is not found through endoscopy, colonoscopy, or small bowel evaluation; if the initial bleeding event cannot be controlled; or if a patient has multiple bleeding events on the NOAC despite dose adjustment and discontinuation of other factors that increase the risk of bleeding (e.g., concomitant antiplatelet of NSAIDs, excess alcohol), consideration should be given to LAA occlusion (E), ablation, or inferior vena cava filter placement. As this patient had no further bleeding post-EGD, aspirin could be discontinued, and additional interventions would not be warranted at this time.
Transitioning the patient to a VKA will not lower the chance of re-bleeding since apixaban and warfarin are associated with similar rates of GI bleeding, but warfarin carries an increased risk of intracranial hemorrhage.4 Additionally this patient previously experienced a GI bleed on warfarin (C).
It is important to note this patient's CHA2DS2-VASc score of 5 (1 point each for hypertension, vascular disease, and sex with 2 points for age > 75 years), which translates to a yearly stroke risk of 6.7% without anticoagulation therapy.14 GI bleeding may be managed with the use of blood products and the drug-specific reversal agents (idarucizumab for dabigatran and andexanet alfa for factor Xa inhibitors). GI bleeding events in anticoagulated patients are rarely life-threatening, and may signal underlying GI pathology that should be investigated.2,6,8,15 The aftermath of stroke is often irreversible and may significantly alter a patient's quality of life.
A recent Danish cohort study demonstrated that resumption of antithrombotic therapy after a GI bleeding event did not increase the risk of recurrent GI bleeding in patients taking a VKA, dabigatran, rivaroxaban, aspirin, clopidogrel, prasugrel, or ticagrelor, and patients who resumed oral anticoagulation therapy had lower all-cause mortality.16 Thus, when GI bleeding is controlled with adequate hemostasis and risk of re-bleeding is low, anticoagulation therapy should be restarted in the short term and not held until a repeat EGD to adequately prevent thromboembolism (A).
Given the lack of clear need for aspirin in addition to anticoagulant in this patient, the achievement of adequate hemostasis of a treatable source of bleeding, and the high risk of stroke in this patient, answer (B) – stopping aspirin and resuming apixaban at the standard dose – is the best option in this case.
References
- Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med 2009;361:1139-51.
- Sherwood MW, Nessel CC, Hellkamp AS, et al. Gastrointestinal Bleeding in Patients With Atrial Fibrillation Treated With Rivaroxaban or Warfarin. J Am Coll Cardiol 2015;66:2271-81.
- Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093-104.
- Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med 2011;365:981-92.
- Maggio D, Barkun AN, Martel M, Elouali S, Gralnek IM, Reason Investigators. Predictors of early rebleeding after endoscopic therapy bleeding secondary to high-risk lesions. Can J Gastroenterol 2013;27:454-8.
- Desai J, Granger CB, Weitz JI, Aisenberg J. Novel oral anticoagulants in gastroenterology practice. Gastrointest Endosc 2013;78:227-39.
- Tamayo S, Frank Peacock W, Patel M, et al. Characterizing major bleeding in patients with nonvalvular atrial fibrillation: a pharmacovigilance study of 27 467 patients taking rivaroxaban. Clin Cardiol 2015;38:63-8.
- Aisenberg J, Friedman KB, Desai J, et al. Gastrointestinal bleeding with Edoxaban versus Warfarin: Results from the ENGAGE AF-TIMI 48 Trial. Am Hear Assoc 2015;November:1-2.
- Abraham NS, Singh S, Alexander GC, et al. Comparative risk of gastrointestinal bleeding with dabigatran , rivaroxaban , and warfarin: population based cohort study. BMJ 2015;350:h1857.
- Avgil-Tsadok M, Jackevicius CA, Essebag V, et al. Dabigatran use in elderly patients with atrial fibrillation. Thromb Haemost 2016;115:1-9.
- Dans AL, Connolly SJ, Wallentin L, et al. Concomitant use of antiplatelet therapy with dabigatran or warfarin in the randomized evaluation of long-term anticoagulation therapy (RE-LY) trial. Circulation 2013;127(5):634-640.
- Delaney JA, Opatrny L, Brophy JM, Suissa S. Drug-drug interactions between antithrombotic medications and the risk of gastrointestinal bleeding. Can Medicat Assocation J 2007;177:7-11.
- Dentali F, Douketis JD, Lim W, Crowther M. Combined aspirin-oral anticoagulant therapy compared with oral anticoagulant therapy alone among patients at risk for cardiovascular disease: a meta-analysis of randomized trials. Arch Intern Med 2007;167:117-24.
- Lip GYH, Frison L, Halperin JL, Lane D a. Identifying patients at high risk for stroke despite anticoagulation: a comparison of contemporary stroke risk stratification schemes in an anticoagulated atrial fibrillation cohort. Stroke 2010;41:2731-8.
- Friedman KB, Kolb JM, Desai J, et al. How often does major gastrointestinal bleeding in patients receiving warfarin or dabigatran uncover cancer? The worldwide experience from the RE-LY trial. Digestive Disease Week. 2015.
- Staerk L, Lip GYH, Olesen JB, et al. Stroke and recurrent haemorrhage associated with antithrombotic treatment after gastrointestinal bleeding in patients with atrial fibrillation: nationwide cohort study. BMJ. 2015;351:1-11.
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