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Clinical Crossroads |

Antiplatelet and Anticoagulant Therapy in Patients With Gastrointestinal Bleeding:  An 86-Year-Old Woman With Peptic Ulcer Disease

Majid A. Almadi, MBBS, FRCPC, MSc(Epi); Alan Barkun, MDCM, FRCPC, MSc(Epi); James Brophy, MEng, MD, FRCPC, PhD
JAMA. 2011;306(21):2367-2374. doi:10.1001/jama.2011.1653.
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Bleeding in the upper gastrointestinal tract is a common medical problem, with an incidence of 48 to 160 cases per 1000 adults per year and a mortality rate of 5% to 14%. The risk of gastrointestinal bleeding is increased with the use of antiplatelet medications including aspirin and clopidogrel, as well as warfarin or a combination of these medications. The recurrence rate for bleeding in patients who continue to take aspirin after an episode of peptic ulcer disease–related bleeding can reach up to 300 cases per 1000 person-years and varies by age, sex, and the use of nonsteroidal anti-inflammatory medications. Using the case of Ms S, an 86-year-old woman who presented to the emergency department with an episode of nonvariceal upper gastrointestinal tract bleeding, we address the management of patients who are receiving antiplatelet or anticoagulation therapy who present with gastrointestinal bleeding, including when to restart antiplatelet or anticoagulation therapy, interventions to reduce the risk of bleeding recurrence, and the potential for drug interactions between clopidogrel and proton pump inhibitors.

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GI bleed while receiving anticoagulation threrapy
Posted on December 3, 2011
Erik R. Taylor, Third Year Pharmacy Student
Roseman Univeristy of Health Sciences,
Conflict of Interest: None Declared
Admittance to hospitals due to upper gastrointestinal (GI) bleeds has a prevalence of up to 160 cases per 100,000. (1) The presence of H. pylori carries the single-largest risk, having been proven causative in up to 70% of cases.(2) Other significant risk factors include NSAID use, increasing age, heavy alcohol consumption, smoking, chronic liver or renal disease, and male sex. (2) During an acute upper GI bleed, aspirin and anticoagulation therapy should be withheld until hemostasis is achieved. Aspirin resumed upon hemostasis (confirmed endoscopically) has a mortality benefit in patients with cardiovascular (CV) or cerebrovascular disease following a GI bleed, while not significantly affecting the rate of recurrent GI bleed. (3) Several trials have demonstrated the effectiveness of utilizing proton- pump inhibitors (PPI) to prevent recurrent GI bleeds, especially following H. pylori eradication when present. (4,5) Similar to the antiplatelet therapy, warfarin titration should commence upon hemostasis. The necessity for anticoagulation bridging in patients with atrial fibrillation has not been proven to outweigh the increased risk of bleeding. Evidence is limited in this area however, an interruption of anticoagulation of five or less days was shown to incur only a 0.4% incidence of stroke, with a jump to 2.2% after seven days therefore it is reasonable to avoid bridging therapy unless the patient is at high risk for stroke and expected to require a prolonged time period to reach a therapeutic INR (6) Dabigatran as an alternative to warfarin has shown an increased risk of major GI bleed (odds ratio: 1.5, P<0.05) thus would not be the optimal choice in this patient population. (7)
Observational studies raised concern regarding PPIs decreasing the effectiveness of clopidogrel by decreasing the conversion to its active form, thus inhibiting its CV benefit. In 2010 the COGENT trial tested this hypothesis and revealed the combination of clopidogrel and aspirin with omeprazole did reduce GI events and did not affect CV events in comparison to the combination without omeprazole, consequently diminishing concern of a clinically significant pharmacokinetic drug interaction.(8)
Following H. pylori eradication (if present), the recurrence of peptic ulcers with aspirin therapy is 1.9% after 6 months. (4) Using a PPI after eradication, the rate of recurrence becomes 1.6% at 12 months. As Ms. S is taking both antiplatelet and anticoagulation therapy, it would be important for her to utilize the gastroprotective effects of a PPI for as long as she is at an increased risk of bleed, proven benefits have been shown up to a year. (5)
For Ms. S., I recommend H. pylori testing. As previously mentioned, eradication of H. Pylori would greatly reduce her rate of ulcer recurrence. After hemostasis, she should be restarted on aspirin for primary prevention due to her age and gender. (10) In addition, her warfarin should be titrated to goal INR of 2-3, as dictated by her 4% stroke risk (CHADS2 score of 2) due to atrial fibrillation. A PPI should be initiated and continued for at least a year, pending future research on long-term PPI therapy. (5)
(1) Lewis J, Bilker W, Bresinger C, et al. Hospitalization and mortality rates from peptic ulcer disease and GI bleeding in the 1990s: relationship to sales of nonsteroidal anti-inflammatory drugs and acid suppression medications. Am J Gastroenterol 2002;97:2540-9. (2) Lassen A, Hallas J, Schaffalitzky O. Complicated and uncomplicated peptic ulcers in a Danish county 1993-2002: a population-based cohort study. Am J Gastroenterol 2006;101:945-53. (3) Sung J, Lau J, Ching J, et al. Continuation of low-dose aspirin therapy in peptic ulcer bleeding: a randomized trial. Ann Intern Med. 2010 Jan;152(1):1-9. (4) Chan F, Chung S, Suen B, et al. Preventing recurrent upper gastrointestinal bleeding in patients with helicobacter pylori infection who are taking low-dose aspirin or naproxen. N Engl J Med 2001;344(13):967 -73. (5) Chuen K, Lam S, Chu K, et al. Lansoprazole for the prevention of recurrences of ulcer complications from long-term low-dose aspirin use. N Engl J Med 2002;346(26):2033-8. (6) Garcia D, Regan S, Henault L, et al. Risk of thromboembolism with short-term interruption of warfarin therapy. Arch Intern Med 2008;168(1):63-9. (7) Connolly S, Ezekowitz M, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51. (8) Bhatt D, Cryer B, Contant C, et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med 2010;363(20):1909-17. (9) Ridker P, Cook N, Lee I, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med 2005;352(13):1293-1304.
Conflict of Interest: None declared
Adapting to change: the need to periodically revisit therapeutic decisions
Posted on November 16, 2011
Scott K Aberegg, MD, MPH
SKA Critical Care Services, LLC
Conflict of Interest: None Declared
Ms. S has a serious complication associated with primary prevention with warfarin and aspirin. Decisions about their ongoing use hinge on the risks and benefits of treatment versus no treatment, and her values and preferences, all of which can change over time. A hospitalization or complication represents an opportunity to re-evaluate the suitability of these and all therapies in light of new information or changing preferences. This is such an opportunity. Ms. S has approximately 6 years of life remaining (http://www.ssa.gov/oact/STATS/table4c6.html). Based on evidence from two decades of clinical trials (from which Ms. S would have been excluded on the basis of recent ulcer bleeding), her absolute annual risk of stroke is apporximately 3% [1-3]. This can be reduced by approximately 2% per year with warfarin. Thus, her lifetime risk of stroke is 18%, and can be reduced to 6% if she takes warfarin for the rest of her life. Alternatively, by foregoing warfarin, Ms. S has approximately an 88% chance of not having a warfarin-preventable stroke during the remainder of her life [3a], and her short-term risk of stroke from AF without warfarin is negligibly low. We cannot calculate her Framingham score, but her remaining lifetime risk of a myocardial infarction is probably less than 2%, which confines any benefit from prophylactic aspirin to much less than that[4].
In patients with healed ulcers, the risk of recurrent bleeding at one year associated with aspirin use is 15%, and this is reduced to about 2% with proton pump inhibitors (PPIs)[5]. The risk of recurrent bleeding in patients with unhealed ulcers, and those not taking aspirin is less well defined, but is probably low with PPIs and appropriate follow-up [6]. While warfarin itself is not a risk factor for peptic ulcer disease (PUD), its use can increase the severity of bleeding.
Ms. S suffered a fall as a result of this hemorrhage. While she remains physically active at 86, she is at risk of a debilitating hip fracture or intracranial hemorrhage from falling. Also, her new baseline hematocrit is lower than before this episode, making her more susceptible complications if bleeding recurrs. The vignette does not provide information about her home environment but it is noteworthy that predictive models, such as the CHADS2 and HAS-BLED scores do not account for the risk of falling and other factors that must be considered in the risk assessment of individual patients[7, 8].
Given these considerations, the immediate short term risk of warfarin -preventable stroke and aspirin-preventable MI during healing of her ulcer, treatment of H. pylori (if indicated), and reassessment of her hematocrit and any evidence of recurrent bleeding, is very low (<1%). Ms. S may therefore wish to forego treatment with both aspirin and warfarin during this time. Moreover, depending on her individual values and preferences, she may wish to reconsider ongoing warfarin therapy altogether at this time or at some point in the future if she decides that her remaining lifetime risk of stroke does not justify the ongoing risk and inconvenience of warfarin therapy.
Reference List
1. Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S, et al. Apixaban in Patients with Atrial Fibrillation. New England Journal of Medicine 2011; 364(9):806-817.
2. Ezekowitz MD, Bridgers SL, James KE, Carliner NH, Colling CL, Gornick CC, et al. Warfarin in the Prevention of Stroke Associated with Nonrheumatic Atrial Fibrillation. New England Journal of Medicine 1992; 327(20):1406-1412.
3. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. New England Journal of Medicine 2011; 365(10):883-891.
3a. Armstrong K, Schwartz JS, Fitzgerald G, Putt M, Ubel PA. Effect of framing as gain versus loss on understanding and hypothetical treatment choices: survival and mortality curves. Med Decis Making 2002; 22(1):76- 83.
4. Ridker PM, Cook NR, Lee IM, Gordon D, Gaziano JM, Manson JE, et al. A Randomized Trial of Low-Dose Aspirin in the Primary Prevention of Cardiovascular Disease in Women. New England Journal of Medicine 2005; 352(13):1293-1304.
5. Lai KC, Lam SK, Chu KM, Wong BCY, Hui WM, Hu WHC, et al. Lansoprazole for the Prevention of Recurrences of Ulcer Complications from Long-Term Low-Dose Aspirin Use. New England Journal of Medicine 2002; 346(26):2033-2038.
6. Gralnek IM, Barkun AN, Bardou M. Management of Acute Bleeding from a Peptic Ulcer. New England Journal of Medicine 2008; 359(9):928-937.
7. Gage BF, van Walraven C, Pearce L, Hart RG, Koudstaal PJ, Boode BSP, et al. Selecting Patients With Atrial Fibrillation for Anticoagulation. Circulation 2004; 110(16):2287-2292.
8. Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJGM, Lip GYH. A Novel User-Friendly Score (HAS-BLED) To Assess 1-Year Risk of Major Bleeding in Patients With Atrial Fibrillation. Chest 2010; 138(5):1093- 1100.
Conflict of Interest: None declared
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