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Rapid Functional Decline After Dabigatran Toxicity in an Elderly Patient
Affiliations: 1Internal Medicine, University of Toledo Medical Center, Toledo, OH 2Resident Physician, University of Toledo, Toledo, OH 3Division of Geriatric Medicine, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX
Abstract: Warfarin has been the gold standard of stroke prevention in patients with atrial fibrillation; however, it requires constant laboratory monitoring to maintain therapeutic levels and has significant interactions with food and medications. Newer oral anticoagulants, such as dabigatran, have gained widespread use for the prevention of stroke in elderly individuals with atrial fibrillation. Unlike warfarin, dabigatran does not require constant monitoring to administer and effectively create therapeutic anticoagulation. However, there are drawbacks and complications that are associated with its use, including the fact that elderly patients with multiple comorbidities and dynamic health statuses are often underrepresented in clinical trials involving dabigatran, the lack of a clinically available measure to monitor therapeutic effect, and the lack of a rapid reversal agent. The authors discuss these and other issues involving dabigatran use and present the case of an 83-year-old patient who experienced rapid functional decline preceded by a massive upper gastrointestinal hemorrhage due to dabigatran toxicity.
Key words: Dabigatran, toxicity, gastrointestinal disorders, chronic kidney disease, warfarin.
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Warfarin has been the mainstay of stroke prevention in the setting of atrial fibrillation. Over the past 5 years, newer oral anticoagulants, such as dabigatran, have gained widespread use for the prevention of stroke in elderly patients with atrial fibrillation. However, in the absence of laboratory means of monitoring bleeding risk, elderly patients are at greater risk of such complications when prescribed dabigatran and other agents of its class. In this report, we describe our clinical experience of an 83-year-old man who presented with a massive gastrointestinal (GI) hemorrhage after using dabigatran. Information on the complications of dabigatran use in elderly patients is also provided.
Case Report
An 83-year-old man was brought to the emergency department for a massive upper GI bleed and hematemesis, acute anemia, anion gap metabolic acidosis, hypotension, and hyperkalemia. No history of GI bleed or stroke was noted at the time of admission. The patient’s comorbid conditions included hypertension, congestive heart failure, chronic kidney disease stage 3, coronary artery disease, atrial fibrillation, and large B-cell non-Hodgkin lymphoma with a history of chemotherapy. The patient had been taking dabigatran 150 mg twice daily for stroke prevention for 2 months in the setting of atrial fibrillation, with a CHADS2 stroke risk assessment score of 3. He had not been prescribed any other anticoagulation or antiplatelet therapy, including aspirin.
The patient presented with a hemoglobin level of 6.4 g/dL (normal, 14-17.5 g/dL) and a platelet count of 226 x 103/µL (normal, 150-350 x 103/µL.) Esophagogastroduodenoscopy (EGD) performed during hospital admission revealed evidence of a recent upper GI bleed. His baseline glomerular filtration rate (GFR) was 50 mL/min/1.73 m2, and his creatinine clearance level was less than 30 mL/min/1.73m2 (normal, 75-125 mL/min/1.73 m2) on admission. His renal function continued to worsen after admission; he underwent several sessions of hemodialysis to reduce the level of dabigatran. The patient’s hospital course was further complicated by sepsis secondary to a urinary tract infection and pneumonia. He developed respiratory failure, requiring a transfer to the intensive care unit (ICU) for mechanical ventilation. During his stay in the ICU, the patient’s hemoglobin dropped to 4.5 g/dL. His hemoglobin level stabilized, however, after receiving 11 units of packed red blood cells and 12 units of fresh frozen plasma. After a repeat EGD with endoclipping and cauterization, the patient remained stable. Despite intensive physical and occupational therapy over the course of the following 6 months, he had a poor return of function and a progressive decline in his activities of daily living (ADLs), requiring maximal assistance with bathing, walking, and toileting. The patient decided to undergo hospice care after being discharged from the hospital.
Discussion
Vitamin K antagonists, such as warfarin, require constant laboratory monitoring to maintain therapeutic levels. They also have significant interactions with food and beverages (eg, vitamin K–rich vegetables such as kale and spinach, cranberry juice), alcohol, and many medications and supplements (eg, aspirin, acetaminophen, certain antibiotics, fish oil), which can add to the difficulty in maintaining therapeutic levels in outpatients. Dabigatran is an oral direct thrombin inhibitor that was approved by the US Food and Drug Administration (FDA) in 2010. Unlike warfarin, dabigatran does not require constant monitoring to administer and effectively create therapeutic anticoagulation. Dabigatran has an 80% renal clearance,1 so appropriate dose adjustment is needed in response to changing renal function status in patients receiving the drug. Determining the appropriate dosage and avoiding bleeding toxicity can be difficult in elderly patients on multiple medications with high potential to impair renal function.
Since dabigatran’s approval for use in atrial fibrillation, clinicians have expressed concern with applying guidelines developed in ultra-selected clinical trial patient populations to the treatment of elderly patients with multiple comorbidities and dynamic health statuses, the latter of whom are often underrepresented in most clinical trials.2,3 Our patient, for example, had multiple comorbidities, including a history of large B-cell non-Hodgkin lymphoma and—more importantly, considering the renal clearance of dabigatran—chronic renal insufficiency. It is important to note that few elderly participants over the age of 80 years or those with a creatinine clearance of less than 50 mL/min/1.73 m2 were included in the often-quoted RE-LY (Randomized Evaluation of Long-Term Anticoagulant Therapy) trial.1 Of the more than 18,000 study participants, only 20% were over 80 years of age and only 5% had a creatinine clearance level of less than 50 mL/min/1.73 m2 despite the fact that more than 30% of individuals with atrial fibrillation are over 80 years of age and 33% have a creatinine clearance of less than 50 mL/min/1.73m2.1 Of note, as a patient’s creatinine clearance drops to below 30 mL/min/1.73m2, the half-life increases to 22 to 35 hours from its usual 12 to 17 hours in those with normal baseline renal function.4 Interestingly, the RE-LY trial excluded patients with a creatinine clearance of less than 30 mL/min/1.73 m2 and those with known anemia who have a hemoglobin level of less than 10 g/dL. Exclusion criteria in the RE-LY trial also included thrombocytopenia, severe valvular disease, history of stroke in the prior 2 weeks, history of disabling stroke in the prior 6 months, active liver disease, pregnancy, and recent or known bleeding. In reality, elderly patients often have a baseline history of thrombocytopenia, anemia, and/or chronic renal insufficiency.
Limitations of Dabigatran Therapy
Healthcare professionals should consider several issues before starting dabigatran in an elderly patient and should outline the limitations and risks associated with its use. The increased prevalence of multiple comorbidities, falls, gait disorders, dementia, and limited life expectancy in this population calls for circumspection and a frank risk-benefit discussion with patients.5 In particular, clinicians should discuss with patients and their caregivers cost factors, the lack of reversal therapy for dabigatran-induced bleeding, and the inability to monitor dabigatran levels. Such discussion will enable these individuals and their families to make an informed decision about the usage of dabigatran.
Monitoring. One drawback of dabigatran is the lack of a clinically available measure to monitor therapeutic effect as demonstrated in the case we reported. While prothrombin time and international normalized ratio (INR) have been used as standards to monitor warfarin levels, they are not nearly as useful for dabigatran. In the case of warfarin, appropriate reversal guidelines for holding the medication and using reversal agents exist; such guidelines do not exist for dabigatran.6-8 Had the case patient been on warfarin, the frequent monitoring of INR may have prevented the complication of a massive GI bleed. In the case of dabigatran, existing tools to measure drug concentration, including the chromogenic ecarin clotting time assay, are expensive and tend to be more reliable at lower dabigatran levels.9
Bleeding risk. While the overall rate of bleeding in the RE-LY trial was noninferior in patients taking dabigatran as compared with warfarin, the event rate of GI bleeding was higher at 150-mg doses of dabigatran.1 Later, a cohort study of 134,414 Medicare patients found reduced risk of ischemic stroke and mortality in patients, but an increased risk of major GI bleeding.10 Again, GI bleeding was seen more prominently at 150-mg doses of dabigatran. Additionally, in a recent retrospective cohort study comparing 1302 dabigatran users to 8102 warfarin users, dabigatran was associated with a higher incidence of major bleeding and GI bleeding, but a lower risk of intracranial hemorrhage compared with warfarin.8 In this study, the overall hazard ratio (HR) for GI bleeding among dabigatran users versus warfarin users was 1.85 (95% confidence interval [CI], 1.64-2.07).
Lack of reversal agents. Another concern that physicians have with the use of dabigatran is that there is currently no rapid reversal agent, especially in a scenario of intracranial or retroperitoneal hemorrhage or when surgery is emergently needed. In the case of severe bleeding, as in our patient, rapid reversal of anticoagulation is necessary. For vitamin K antagonists, fresh frozen plasma is available for rapid reversal. Although in development, no antidote for reversal of bleeding in dabigatran users exists.11 While hemorrhagic events are known complications of all anticoagulants, such as warfarin and dabigatran, the treatment options for bleeding due to dabigatran are limited.7,8,12 One such option is dialysis, as demonstrated in a 2010 study in which hemodialysis removed 62% to 68% of the dabigatran dose.13 Although dialysis is a possible option for therapy, it is known to decrease quality of life in the elderly patient and it creates its own risks.14 In a study of 3702 older adults on dialysis, for instance, 87% died or had a decrease in functional status within 12 months of starting dialysis.14 Our case patient underwent dialysis to correct the dabigatran overdose, but his recovery was poor, requiring 11 units of packed red blood cells, 12 units of fresh frozen plasma, a stay in the ICU, and a subsequent transfer to hospice due to a loss of ability to perform ADLs on follow-up visits.
Renal impairment risk. Having renal impairment has been shown to increase the susceptibility to bleeding complications and subsequent worsening of renal function in elderly patients taking dabigatran.8,15 Similar to the deteriorating renal status in our patient, a case report described a 66-year-old woman with GI bleeding after being on dabigatran 150 mg twice daily for 2 months and developed renal toxicity. She later became hemodialysis-dependent.15 After a hospital stay of 47 days, she was transferred to a nursing home, where she died 2 months later. It is important to note that when subgroup analysis is performed on elderly patients in the RE-LY trial, patients over the age of 75 with chronic kidney disease with a GFR of 30-50 ml/min were found to have a 5.3% per 100 patient-year rate of major bleeding. As in the clinical profile of our patient, higher risk of GI bleeding among dabigatran users compared with warfarin users is associated with being aged 75 years or older (HR, 1.85 [95% CI, 1.60-2.14]), having chronic kidney disease (HR, 1.81 [95% CI, 1.51-2.18]), and having multiple comorbidities (HR, 1.81 [95% CI, 1.56-2.11]), as Hernandez and colleagues8 showed.
Determining the Appropriateness of Dabigatran Use
As these limitations show, the importance of appropriate patient selection for dabigatran use cannot be overstated. However, assessing the risks and benefits of dabigatran in elderly patients is challenging because the clinical trials assessing the risks of dabigatran did not include—and sometimes excluded—patients with comorbid conditions commonly seen in the elderly population.
In our 83-year-old patient, the annual risk of stroke would be 5.9% using his previously mentioned CHADS2 risk assessment score of 3.16 The patient’s age and his history of hypertension and congestive heart failure contribute to his score. Although he had other comorbid conditions, including his history of non-Hodgkin lymphoma and renal impairment, none of his characteristics would exclude him from the RE-LY trial.1 The patient had no history of stroke or GI bleed, and his baseline hemoglobin level (outpatient value prior to presentation) and platelet count were 10.4 g/dL and 226 x 103/µL, respectively. There are many ways to estimate the likelihood of a GI bleed, but we recommend two bleeding risk tools that are particularly useful: (1) HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly [age ³65 years], drugs/alcohol concomitantly); and (2) ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation; anemia, severe renal disease, age ³75 years, previous hemorrhage, and history of hypertension). The patient’s HAS-BLED score of 1 (due to his age) places his bleeding risk at 3.4% annually, while his ATRIA score of 6 places him at a high risk (5.8%) of hemorrhage annually.17 This difference is accounted by placing a higher emphasis on age as a risk factor for hemorrhage and using a baseline hemoglobin level of less than 13 g/dL as a risk factor for men. Thus, the risks and benefits of anticoagulation in regard to bleeding risk range anywhere from 3.4% to 5.8%, creating a difficult situation for assessment and treatment if this difference is between a 5.8% chance of hemorrhage versus a 5.9% risk of stroke. According to the American College of Chest Physicians anticoagulation guidelines, when risks and benefits are similar, the indication for anti-
thrombotic prophylaxis is given a weak recommendation (Grade 2).18
Conclusion
Various factors provide reason to take caution when prescribing dabigatran in elderly individuals. Specifically, although no direct measure of dabigatran’s anticoagulation is available, routine monitoring of renal function in patients with chronic renal disease or in the elderly, who are susceptible to acute kidney injury, may be prudent. Further, physicians should also be careful to review prescriber information—especially those from the FDA—which continue to evolve as postmarket research and reports change guidelines for dabigatran. While deciding whether to choose dabigatran, it is also useful to carefully assess the risks and benefits of such a decision, using risk calculators when appropriate. In addition to these tools, it is important to remember that many patients were excluded from the RE-LY trial, including those with many of the risk factors that were present on both the HAS-BLED and ATRIA scores, such as advanced age and bleeding history. Interestingly, although patients with a creatinine clearance level of less than 30 mL/min/1.73 m2 were excluded from the study, prescriber information is provided for a dosage adjustment for patients with creatinine clearance levels between 15 and 30 mL/min/1.73 m2. These factors should not deter a healthcare provider from appropriately prescribing dabigatran to elderly patients, but it should serve to heighten awareness for both patients and prescribers.
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Disclosures: The authors report no relevant financial relationships.
Address correspondence to: Cletus U. Iwuagwu, MD, CMD, Ruppert Health Center, 3125 Transverse Drive, Toledo, OH 43614; cletus.iwuagwu@utoledo.edu
