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Original Article

Type and Timing of Reversal Agents in Patients Receiving Warfarin Who are Hospitalized for Major Bleeding

Jad Omran, MD1, Ben Nordhues MD2, Blake Buchert3, and Greg C. Flaker, MD, FACC4*


1Cardiovascular Medicine Department, University of Missouri Hospital and Clinics


2Internal Medicine Department, Mayo Clinic


3Vanderbilt University


4Cardiovascular Medicine department, University of Missouri Hospital and Clinics


Corresponding author


Greg C. Flaker, Cardiovascular Medicine department, University of Missouri Hospital and Clinics, CE 351 University of Missouri, Columbia Mo. 65212, 573-882-2296, Tel: 573-882-2296; Fax: 573-882-8450; E-mail: flakerg@health.missouri.edu


Received Date: 30 June 2014

Accepted Date: 23 July 2014

Published Date: 27 July 2014


Citation


Omran J, Nordhues B, Buchert B, Flaker GC (2014) Type and Timing of Reversal Agents in Patients Receiving Warfarin Who are Hospitalized for Major Bleeding. Enliven: Clin Cardiol Res 1(1): 001.

Copyright


@ 2014 Dr. Greg C. Flaker. This is an Open Access article published and distributed under the terms of the Creative Commons Attribution License, that permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.


Abstract


Background

In patients with warfarin-induced major bleeding, prompt administration of reversal agents increases coagulation factors and may allow early surgical correction of bleeding. However even with reversal agents, mortality is high. In this analysis the type and timing of reversal agents were evaluated


Methods

Review of warfarin treated non-trauma patients admitted to a University Hospital with ISTH defined major bleeding between October 2009 and January 2013.


Results

84 patients met entry criteria with a mean age 67.8 ± 14.3 years including 46 % females. The mean INR on admission was 3.6 ± 2.4. The site of major bleeding was central nervous system in 33 (39%), abdomen in 28 (33%), chest in 6 (7%) and other in 15 (18 %). Reversal agents including vitamin K, fresh frozen plasma (FFP), or prothrombin complex concentrate (PCC) were given to 83 patients. Forty patients required either major surgery (25 patients) or a therapeutic procedure (14 patients) to stop bleeding. Death occurred in 15 patients (18%) but the admission INR was not predictive of mortality (p=0.52, Kruskal-Wallis test). The INR was never completely corrected (INR<1.1) in 31 (37%) patients, 9 of whom died.


Conclusions

Patients with warfarin-induced major bleeding receive ineffective anticoagulation reversal, have delayed times to therapeutic procedures, and have a high mortality rate. Whether earlier administration of these agents or administration of newer agents would reduce hospital mortality requires further study.


Introduction


Major bleeding associated with warfarin has a high mortality rate [1]. Reversal agents including vitamin K, fresh frozen plasma (FFP) and, more recently, prothrombin complex concentrate (PCC), are recommended to rapidly correct the coagulopathy [2] and to allow early surgical treatment of the bleeding source. However, despite the use of reversal agents, mortality still remains high [3]. The reason for this lack of improvement is uncertain. One hypothesis is that delay in the administration of reversal agents or even administration of less effective reversal agents may contribute to the high mortality in warfarin treated patients who have major bleeding. This manuscript analyzes the type and timing of reversal agents used in these patients.


Methods

From October 2009 until January 1, 2013, 539 non-trauma patients who were admitted to a University Hospital with an ICD-9 code of hemorrhage, major bleeding, or coagulopathy were identified. Only those patients known to be receiving warfarin at the time of admission and those meeting ISTH criteria for major bleeding [4] were included in this analysis. Summary statistics were calculated and the Wilcoxon Rank Sum test was used to examine associations between mortality and age as well as admission INR, hemoglobin, and estimated glomerular filtration rate.


Results

A total of 84 patients met entry criteria. The mean age was 67.8 ± 14.3 years and 46% were female. The mean INR on admission was 3.6 ± 2.4. The site of bleeding was central nervous system (33 patients), abdominal (28 patients), chest (6 patients) and other site (15 cases). The mean hemoglobin on admission was 10.6 ± 2.8 gm/dl. The most common reversal agent used was a combination of vitamin K and fresh frozen plasma (Table 1). The average time from admission to administration of a reversal agent was 5.6 ± 8.1 hours. The admission service was a medical specialty in 39 patients and a surgical specialty in 45 patients. A total of 40 patients (30%) underwent either major surgery (25 patients) or other therapeutic procedure (14 patients) to stop bleeding. The average time from admission to corrective procedure was 17.8 ± 34.9 hours including one patient with a time to procedure of 168 hours.


Overall, only 61.9% of patients had their INR corrected during hospitalization. The mean number of days in the ICU was 6.3 ± 8 days; the mean hospital stay was 10.9 ± 9.2 days. A total of 15 patients died during the hospitalization. No significant (p < 0.05) association between mortality and age, admission INR, hemoglobin, or estimated glomerular filtration rate was noted (Table 1).


Discussion

A disadvantage of novel oral anticoagulant agents is the lack of a reversal agent. However, this study demonstrates a high mortality rate in patients with a modestly elevated INR, the majority of whom received a reversal agent for major bleeding. We report substantial delays in the administration of these agents and substantial delays in the time to surgical procedures required to stop bleeding. In addition, the use of PCC, which provides factors II, IX, and X (three factor) or II, VII, IX, X (four factor) and which now is the preferred reversal agent, was used infrequently in this study. The infrequent use of PCC for major bleeding in patients receiving anticoagulation has also been reported in a recent clinical trial [5].


Whether or not more timely administration of reversal agents or the use of more effective reversal agents will reduce mortality in warfarin treated patients with major bleeding should be the subject of future studies.


Reversal agent(s) Admission INR Time to Reversal Therapy (hours) Time to Procedure to Correct Bleed (hours) Mortality Rate

Vitamin K n=49

4.4 ± 2.8

4.9 ± 6.7

11.7 ± 8.3

18.4 %

Fresh Frozen Plasma(FFP) n=78

3.6 ± 2.4

5.3 ± 7.6

11.1 ± 10.0

17.9 %

Prothrombin Complex n=2

5.9 ± 4.5

0.6 ± 0.5

5.5

0 %

Vitamin K and FFP n=45

4.4 ± 2.8

4.2 ± 4.7

11.7 ± 8.3

17.8 %



References


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2. Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, et al. (2012) Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 141: e44S-88S.


3. Dowlatshahi D, Butcher K, Asdaghi N, Nahirniak S, Bernbaum M, et al. (2012) Poor Prognosis in Warfarin-Associated Intracranial Hemorrhage Despite Anticoagulation Reversal. Stroke 43:1812-1817.


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5. Majeed A, Hwang H, Connolly SJ, Eikelboom JW, Ezekowitz MD, et al. (2013) Management and Outcomes of Major Bleeding During Treatment with Dabigatran or Warfarin. Circulation 128: 2325-2332.