May/June 2017

Clinical News: Anticoagulation Therapy After a Major Bleeding Event
By Inmaculada Hernandez, PharmD, PhD; Yuting Zhang, PhD; Paul K. L. Chin, PhD; and Samir Saba, MD
Today's Geriatric Medicine
Vol. 10 No. 3 P. 30

The most prevalent type of arrhythmia, atrial fibrillation (AF) is estimated to affect between 2 and 3 million individuals in the United States.1-3 AF is characterized by a disorganized electrical activity and contraction of the atrium. AF disrupts the blood flow, which can result in stagnant blood in the left atrial appendage and the formation of thrombus.4 Thrombi can embolize to the brain and block small arteries.5 This occlusion can trigger ischemic cerebrovascular events unless the blood supply is quickly restored.5 Hence, AF is associated with a five-fold increase in the risk of stroke, independent of age. In elderly patients, AF is the most important single cause of ischemic stroke.5

Anticoagulation therapy reduces the risk of stroke associated with AF by approximately 60%.6 However, anticoagulation is also associated with an increased risk of bleeding. Balancing the prevention of stroke and the risk of bleeding is especially difficult in the aftermath of a major bleeding event. Patients who experience a major bleed are at higher risk for bleeding again, but if anticoagulation therapy is not restarted, they also are at high risk of stroke and other thromboembolic events. The decision to resume anticoagulation after a major bleeding event is especially relevant in geriatric patients because age equal to or greater than 75 is a well-known risk factor for both bleeding and stroke. Thus, elderly patients who have survived a major bleeding event are at especially high risk of recurrent bleeding and high risk of stroke.7,8

Benefits of Restarting Anticoagulation Therapy After a Major Bleed
Researchers from the University of Pittsburgh (Pitt) conducted an observational study to evaluate the resumption of anticoagulation therapy in Medicare beneficiaries with AF who survived a major bleeding event.9 The study aimed to analyze which factors affect the probability of restarting anticoagulant therapy after a major bleeding event, and to compare the risk of stroke and death, and the risk of bleeding in patients who resumed anticoagulation therapy vs those who did not. The Pitt research team obtained 2010–2012 data from a 5% random sample of Medicare beneficiaries from the Centers for Medicare & Medicaid Services, after which they followed nearly 90,000 people who had filled prescriptions for two anticoagulants: warfarin, which has been used since 1954, and dabigatran, which was approved by the FDA in 2010.

More than 1,500 of those patients, whose average age was 80, suffered a major bleeding event that required hospitalization while using one of these drugs; nearly 50% restarted anticoagulation after the bleeding event. Specifically, 49% and 47% of the patients who bled on dabigatran and on warfarin restarted anticoagulation, respectively. Researchers also observed that patients who bled on warfarin were more likely to resume warfarin than patients who bled on dabigatran were to resume dabigatran (41% vs 28%, with p-value <0.001). Further, patients who bled on dabigatran were more likely to switch to warfarin than patients who bled on warfarin were to switch to dabigatran (17% vs 2%, p-value <0.001).

To identify factors that affected the resumption of anticoagulation therapy after a bleeding event, the Pitt researchers evaluated age, gender, race, eligibility for Medicaid coverage, clinical characteristics, anatomical location of the bleeding event, and measures that gauged the severity of the bleed. Older patients, those who experienced intracranial bleeding, received a blood transfusion, or were admitted to the intensive care unit were found to be less likely to resume anticoagulation after the bleeding event. Specifically, for patients who bled on dabigatran, the odds of resuming anticoagulation decreased by 26% for every five years increase in age. For patients who bled on warfarin, the odds of resuming warfarin compared with discontinuing anticoagulation therapy decreased by 11% for every five years increase in age.

In evaluating the benefit of anticoagulation restart after a bleeding event, the Pitt research team compared the risk of ischemic stroke, risk of death, combined risk of stroke or death, and the risk of bleeding between treatment groups. They found that the risk of dying from any cause or of having a stroke was 23% to 34% higher in patients who did not resume anticoagulation therapy, compared with those who did. Compared with patients who did not resume anticoagulation, resumption of anticoagulation therapy with dabigatran or warfarin was associated with 83% and 65% reduction, respectively, in the risk of all-cause mortality. The risk of bleeding did not differ between patients who restarted dabigatran and those who did not restart anticoagulation. The risk of having another major bleeding, however, was higher for patients who restarted warfarin after the initial bleeding event than for those who restarted dabigatran.

Clinical Implications
This observational study provides evidence of the benefit of restarting anticoagulation therapy after a major bleeding event. Specifically, the study demonstrated that the risk of dying from any cause or having a stroke was lower for patients who restarted anticoagulation after an initial bleeding event than for those who did not restart anticoagulation. This benefit of anticoagulation reinitiation contrasts with the observation that fewer than one-half of the study participants restarted anticoagulation after the initial bleeding event.

In their manuscript, the authors hypothesize that the reluctance to restart anticoagulation therapy among these patients may be caused by prescribers' aversion to the perceived high risk of recurrent bleeding events among patients who present with a major bleed. However, the results of this study showed that the risk of bleeding was not higher for patients who restarted dabigatran than for those who did not resume anticoagulation. For this reason, in the decision of whether to restart anticoagulation therapy in AF patients who have survived a major bleeding event, the benefits of stroke and death prevention appear to outweigh the risk of bleeding.

There appears to be greater aversion by clinicians to resuming anticoagulation in the elderly because of the perceived high risk of bleeding in patients who have survived a major bleeding event. This is reflected by the study finding that the likelihood of restarting anticoagulation decreased with age. However, this study shows the benefit of resuming anticoagulation therapy in a sample of Medicare beneficiaries whose average age was 80, which provides encouragement to clinicians to restart anticoagulation therapy in elderly patients who have survived a major bleeding event on anticoagulation.

— Inmaculada Hernandez, PharmD, PhD, is an assistant professor at the University of Pittsburgh School of Pharmacy. Her research focuses on measuring clinical and economic outcomes of newly approved pharmaceutical treatments.

— Yuting Zhang, PhD, is an associate professor at the University of Pittsburgh Graduate School of Public Health. Her research focuses on economic evaluations of health policy, health insurance markets, and health care reforms.

— Paul K. L. Chin, PhD, is a clinical pharmacologist at the University of Otago. His research interests include pharmacokinetics and therapeutic drug monitoring.

— Samir Saba, MD, is associate chief of cardiology, chief of cardiac electrophysiology at the University of Pittsburgh Medical Center, and an associate professor of cardiology at the University of Pittsburgh School of Medicine. His research interests include cardiac device therapy for heart failure, signal processing of intracardiac electrical signals for ischemia detection, molecular and genetic bases of arrhythmias, and effect of adherence to guidelines on patient outcomes.

References
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2. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the anticoagulation and risk factors in atrial fibrillation (atria) study. J Am Med Assoc. 2001;285(18):2370-2375.

3. Naccarelli GV, Varker H, Lin J, Schulman KL. Increasing prevalence of atrial fibrillation and flutter in the United States. Am J Cardiol. 2009;104(11):1534-1539.

4. Iwasaki YK, Nishida K, Kato T, Nattel S. Atrial fibrillation pathophysiology: implications for management. Circulation. 2011;124(20):2264-2274.

5. Hart RG, Halperin JL. Atrial fibrillation and stroke: concepts and controversies. Stroke. 2001;32(3):803-808.

6. 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.

7. Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010;138(5):1093-1100.

8. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest. 2010;137(2):263-272.

9. Hernandez I, Zhang Y, Brooks MM, Chin PK, Saba S. Anticoagulation use and clinical outcomes following major bleeding on dabigatran or warfarin in atrial fibrillation. Stroke. 2017;48(1):159-166.