Letters

in time, we felt it prudent to hypothesize about rather than investigate how the changing landscape of pharmacy could have been a factor or a barrier in the pursuit of residency or fellowship training. In retrospect, it may have been effective to provide a historical perspective on progress of the profession between our survey and the earlier one, by Bucci et al.,1 specifically noting the proceedings of the March 1993 conference “Implementing Pharmaceutical Care” (conducted by ASHP and the ASHP Research and Education Foundation),2 held just six months before Bucci et al. conducted their survey. In 1993, the concept of pharmaceutical care was surfacing, and pharmacists were just beginning to assume responsibility for drug therapy outcomes. Interestingly, then-ASHP President Jannet M. Carmichael3 also shared her vision of the health care world as it would be in 2010, including how “the product focus of pharmacy has become a patient focus” and “nearly all drug information is available to all pharmacists at the touch of a few buttons.” Reflecting on our practice today, we agree that the recognized and respected value of pharmacists in the provision of patient-centered care may certainly play a role in the pursuit of residency and fellowship training. Given the many advances made in residency training, we also agree that there may have been additional factors not explicitly stated in the survey; this issue was discussed in the limitations section of our report. Competitiveness in the job market and the ability to gain additional qualifications are sound reasons for pharmacy students to pursue residency training and were not available, as stated, in the predetermined list provided. That said, some pharmacy positions do require specialized training or additional qualifications as a prerequisite for employment, so some students choose residency training to gain a competitive edge. After completion of our survey, one resident respondent sent us an e-mail stating that “the biggest barrier of all is simply burnout from pharmacy school.” Although this obstacle was not included in this study, we sought to identify what

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changes, if any, have occurred in the factors motivating pharmacy students to pursue residency and fellowship training through direct comparison of our survey results with those of Bucci et al.1 While the stated limitations were anticipated, our intention to perform statistical analysis required our survey to remain in the format of the earlier one. Ultimately, descriptive statistics were used, since the results of the previous survey were reported as percentages, without n values. The influence that different pharmacy schools would have on the pursuit of residency training is intriguing. In fact, this concept was a foundation for the Bucci et al.1 survey, as 80% of residency candidates were from only 20–30% of pharmacy schools at that time. Such a subanalysis would require a comparison of respondents based on the pharmacy school from which they graduated and not a comparison of the resident respondents from various residency program funding sources. Unfortunately, we did not collect this demographic information, which precluded our ability to compare results based on respondents’ pharmacy school affiliation. Although more women than men pursue residency training, an unpublished subanalysis of our data revealed that the top three most important factors to pursue residency or fellowship training were identical in ranking order for both sexes: the desire to (1) gain knowledge and experience, (2) attain specialized training, and (3) attain a prerequisite for certain jobs. The leading reasons selected

for why classmates chose not to pursue a residency or fellowship were also identical: financial obligations, job availability at graduation, and family obligations. As the landscapes of health care, pharmacy practice, and residency training continue to evolve, consideration of additional factors and barriers may warrant an updated, noncomparative study of these factors. 1. Bucci KK, Knapp KK, Ohri LK et al. Factors motivating pharmacy students to pursue residency and fellowship training. Am J Health-Syst Pharm. 1995; 52:2696-701. 2. Implementing pharmaceutical care. Proceedings of an invitational conference conducted by the American Society of Hospital Pharmacists and the ASHP Research and Education Foundation. Am J Hosp Pharm. 1993; 50:1585-656. 3. Carmichael JM. Comments on our vision of the future. Am J Hosp Pharm. 1993; 50:1642-5.

Bryan C. McCarthy Jr., Pharm.D., M.S., BCPS, Clinical Coordinator, Quality, Outcomes and Utilization University of Chicago Medicine Chicago, IL [email protected] Lynn Weber, Pharm.D., BCOP, Clinical Pharmacy Specialist, Hematology/Oncology, and Postgraduate Year 1 Residency Program Director Hennepin County Medical Center Minneapolis, MN

The authors have declared no potential conflicts of interest. DOI 10.2146/ajhp130687

Fatal dabigatran-associated bleeding

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e read with great interest the case presented by Schaeffer and Conway1 describing a fatal outcome with the use of dabigatran and would like to address several points about the patient’s medical management. We find it peculiar that the patient received the medications she did in the first

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place, given her advanced age, comorbidities, and high risk of major bleeding. We are surprised that there did not seem to be a pharmacist intervention at any point in the care of the patient. After the patient developed paroxysmal atrial fibrillation, she was prescribed warfarin sodium 10 mg daily for three

Letters

days while in the hospital. Harrison et al.2 found that patients given a 10-mg loading dose of warfarin sodium had more above-target International Normalized Ratio (INR) values than patients receiving 5 mg. On the third day, the INR for the current patient was 1.3, which prompted the physician to prescribe dabigatran 150 mg twice daily. However, given warfarin’s slow onset, responding to an INR of 1.3 was likely premature. Warfarin exhibits a long half-life of approximately 20–60 hours,3 and it is likely that much of the INR of 8.3 arising eight days later was due to warfarin as well as dabigatran. Hylek et al.4 found that INR decay back to baseline was significantly delayed in patients of advanced age, especially those age 80 years or older (the current patient was 78 years old). The patient’s CHADS2 score (estimate of stroke risk based on the presence of congestive heart failure, hypertension, age of >75 years, diabetes mellitus, and history of embolic stroke) (2 points) would predict a 4% risk of stroke per year,5 but the patient’s HAS-BLED score (estimate of bleeding risk based on the presence of hypertension, abnormal renal or liver function, previous stroke, bleeding history or predisposition, labile INR, age considered elderly, and concomitant excessive use of drugs or alcohol) would predict a 12.5% risk of major bleeding per year.6 Clearly, the risk outweighed the benefit. It is unfortunate the patient was given full-dose dabigatran, given her history of gastrointestinal bleeding. In the RE-LY trial, the dabigatran 150-mg group had significantly higher rates of major (life-threatening or non-life-threatening) gastrointestinal bleeding versus warfarintreated patients.7 Furthermore, relying on the patient’s discharge creatinine clearance (CLcr) of 93 mL/min likely provided the clinicians involved a false sense of security. The elderly are known to have decreased muscle mass, resulting in lower or normal baseline concentrations of serum creatinine.8 Also, in this presumed morbidly obese woman (her total body weight [TBW] was 193 kg), the use of TBW in the calculation of CLcr would

result in a substantially elevated CLcr value9; the authors made no mention of which weight was used in the calculation of CLcr. Dabigatran, a direct thrombin inhibitor, seemed a poor choice for anticoagulation given that there is currently no effective means of reversal other than hemodialysis. The oral factor Xa inhibitors (rivaroxaban, apixaban) may have been more logical choices, given that they act further up the common coagulation pathway and may be easier to reverse10 with means other than hemodialysis, which proved fatal in this patient. Indeed, the literature has noted successful reversal of rivaroxaban with the use of three-factor prothrombin complex concentrate.11 Further, the use of phytonadione should have been considered when managing the patient’s overanticoagulated state, as warfarin was likely still in the patient’s system. The miniscule amount of fresh frozen plasma given was also surprising; our institution gives at least 10 mL/kg; in this patient, at least four units would have been needed to promote coagulation12 and likely more, given her TBW. Also, only one unit of platelets was given, despite the patient having been treated with dipyridamole–aspirin; desmopressin could have been considered given the likelihood of some degree of uremia secondary to acute kidney injury. We agree with the authors that dabigatran was a significant contributor to this patient’s fatal bleeding event; however, we feel that (1) the benefits of anticoagulation were not outweighed by the risk of bleeding, (2) the patient conceivably had three different anticoagulants in her system at the time of bleeding, with dipyridamole–aspirin having no clearcut indication, (3) the choice of dabigatran 150 mg was poor, and (4) pharmacist intervention was lacking in this patient’s care. Had there been effective pharmacist intervention in this case, the outcome reported may have been avoided. 1. Schaeffer S, Conway SE. Fatal bleeding associated with dabigatran. Am J HealthSyst Pharm. 2013; 70:1651-2. Letter. 2. Harrison L, Johnston M, Massicotte PM et al. Comparison of 5-mg and 10-mg

loading doses in initiation of warfarin therapy. Ann Intern Med. 1997; 126:133-6. 3. Lexi-Drugs, version 1.13.0. Hudson, OH: Lexi-Comp.; 2013. 4. Hylek EM, Regan S, Go AS et al. Clinical predictors of prolonged delay in return of the International Normalized Ratio to within the therapeutic range after excessive anticoagulation with warfarin. Ann Intern Med. 2001; 135:393-400. 5. Gage BF, Waterman AD, Shannon W et al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA. 2001; 285:2864-70. 6. Pisters R, Lane DA, Nieuwlaat R et al. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Study. Chest. 2010; 138:1093-100. 7. Connolly SJ, Ezekowitz MD, Yusuf S et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009; 36:1139-51. 8. Drusano GL, Muncie HL, Hoopes JM et al. Commonly used methods of estimating creatinine clearance are inadequate for elderly debilitated nursing home patients. J Am Geriatr Soc. 1988; 36:437-41. 9. Winter MA, Guhr KN, Berg GM. Impact of various body weights and serum creatinine concentrations on the bias and accuracy of the Cockcroft-Gault equation. Pharmacotherapy. 2012; 32:604-12. 10. Dager WE. Developing a management plan for oral anticoagulant reversal. Am J Health-Syst Pharm. 2013; 70(suppl 1):S21-31. 11. Eerenberg ES, Kamphuisen PW, Sijpkens MK et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebocontrolled, crossover study in healthy subjects. Circulation. 2011; 124:1573-9. 12. Braunstein AH, Oberman HA. Transfusion of plasma components. Transfusion. 1984; 24:281-6.

Jeremiah Joson, Pharm.D., CGP, BCPS, Clinical and Outpatient Senior Pharmacist Kern Medical Center Bakersfield, CA [email protected] Van T. Nguyen, Pharm.D. Student Chicago College of Pharmacy Midwestern University Downers Grove, IL Rushabh Shah, M.D., Hospitalist San Joaquin Community Hospital Bakersfield, CA

The authors have declared no potential conflicts of interest. DOI 10.2146/ajhp130634

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Letters

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e described a catastrophic outcome in a patient with acute kidney injury who was treated with dabigatran and was unable to tolerate placement of a hemodialysis catheter. Dr. Joson and colleagues bring up several points related to anticoagulation therapy for atrial fibrillation (AF) specifically assessing the risks and benefits, choice of agent, and appropriate dosage. While we agree that the use of dabigatran in this patient case was a poor choice, a comprehensive review of optimal selection and use of anticoagulants in AF was beyond the scope of our report. The patient’s renal function was estimated using ideal body weight. Use of an oral anticoagulant in patients with a CHADS2 score of 2 (as in our patient) or higher is a strong recommendation (grade 1A) from the American College of Chest Physicians (ACCP) evidencebased clinical practice guidelines.1 These guidelines further state that HAS-BLED has not been extensively validated and can only be used to modestly predict major bleeding events. The ACCP guidelines suggest that assessment of bleeding risk may show that risk is outweighed when the patient has a weak indication for anticoagulation (i.e., CHADS2 score of 0 or 1). In addition, we calculated the patient’s HAS-BLED score at the time of anticoagulation initiation at a slightly lower risk of 8.9%, given that the renal dysfunction was not present at this time. Dr. Joson and colleagues also suggest that the patient should not have received full-dose dabigatran. According to the U.S. prescribing information, a dosage of 150 mg twice daily is recommended unless the creatinine clearance is 15–30 mL/min, in which case 75 mg twice daily should be used.2 No dosage reduction is recommended for patients at higher risk for bleeding, and an intermediate dose of 110 mg that resulted in lower bleeding rates in the RE-LY study has not been approved for use in the United States.2,3 We wholeheartedly agree that pharmacists have an essential role and pro-

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vide value in optimizing drug therapy. The case we described was managed in a small community hospital, and we were consulted at our poison center by personnel of the managing community hospital. It was not until after the patient had died that we learned of some essential case details—including prior warfarin use and the dose of fresh frozen plasma administered—that may have influenced our recommendations and patient care. We agree that warfarin sodium 10 mg for the first three days is too high a dosage for a 78-year-old woman with AF. A slow initial response with an International Normalized Ratio (INR) of 1.3 on day 4 was not a reason to require switching from warfarin to dabigatran. While we cannot fully exclude the fact that three days of warfarin therapy could have been a confounding factor, we feel that warfarin would have had a limited role, if any, on the laboratory values or clinical presentation during the second hospitalization. The patient’s INR at the second hospital admission was 8.3, measured nine days after the last warfarin dose. Using the upper end of warfarin’s halflife range, the patient would have cycled through 3.5 half-lives of warfarin at this time. The study by Hylek et al.4 evaluated INR decay rates for patients with INR values of >6. Since the INR was not monitored after warfarin discontinuation, it is unknown if the INR was ever above target due to warfarin. Thus, this study would not be applicable to the situation presented. Dabigatran is known to affect the INR in a relatively insensitive manner, and INR monitoring is not recommended for that drug.5 Four published cases of dabigatran-related bleeding in older adults with renal dysfunction have revealed elevated coagulation assays with INRs of 12, 14.5, and >10 and a prothrombin time of >60 seconds (none of these patients received warfarin).6-9 We stand by our conclusion that this case highlights the need for appropriate patient selection and warns of the im-

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practicability of hemodialysis as a treatment option. 1. Ageno W, Gallus AS, Wittkowsky A et al. Oral anticoagulation therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012; 141:e44S-88S. 2. Pradaxa (dabigatran) product information. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals; 2013 Apr. 3. Eikelboom JW, Wallentin L, Connolly SJ et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial. Circulation. 2011; 123:2363-72. 4. Hylek EM, Regan S, Go AS et al. Clinical predictors of prolonged delay in return of the International Normalized Ratio to within the therapeutic range after excessive anticoagulation with warfarin. Ann Intern Med. 2001; 135:393-400. 5. Van Ryn J, Stangier J, Haetter S et al. Dabigatran etexilate—a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulation activity. Thromb Haemost. 2010; 103:1116-27. 6. Cano EL, Miyares MA. Clinical challenges in a patient with dabigatran-induced fatal hemorrhage. Am J Geriatr Pharmacother. 2012; 10:160-3. 7. Béné J, Said W, Rannou M et al. Rectal bleeding and hemostatic disorders induced by dabigatran etexilate in 2 elderly patients. Ann Pharmacother. 2012; 46:e14. 8. Wychowski M, Kouides PA. Dabigatraninduced gastrointestinal bleeding in an elderly patient with moderate renal impairment. Ann Pharmacother. 2012; 46:e10. 9. Legrand M, Mateo J, Aribaud A et al. The use of dabigatran in elderly patients. Arch Intern Med. 2011; 171:1285-8.

Susan E. Conway, Pharm.D., Associate Professor Department of Pharmacy Clinical and Administrative Sciences College of Pharmacy University of Oklahoma Oklahoma City, OK [email protected]

The author has declared no potential conflicts of interest. DOI 10.2146/ajhp130735

Fatal dabigatran-associated bleeding.

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