International Journal of Neuroscience
ISSN: 0020-7454 (Print) 1543-5245 (Online) Journal homepage: http://www.tandfonline.com/loi/ines20
Obesity increases risk of anticoagulation reversal failure with prothrombin complex concentrate in those with intracranial hemorrhage Cherie Chu, Sheri Tokumaru, Kara Izumi & Kazuma Nakagawa To cite this article: Cherie Chu, Sheri Tokumaru, Kara Izumi & Kazuma Nakagawa (2014): Obesity increases risk of anticoagulation reversal failure with prothrombin complex concentrate in those with intracranial hemorrhage, International Journal of Neuroscience To link to this article: http://dx.doi.org/10.3109/00207454.2014.993034
Accepted author version posted online: 28 Nov 2014. Published online: 27 Dec 2014. Submit your article to this journal
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Date: 06 November 2015, At: 02:31
International Journal of Neuroscience, 2014; Early Online: 1–5 © 2014 Informa Healthcare USA, Inc. ISSN: 0020-7454 print / 1543-5245 online DOI: 10.3109/00207454.2014.993034
ORIGINAL ARTICLE
Obesity increases risk of anticoagulation reversal failure with prothrombin complex concentrate in those with intracranial hemorrhage Cherie Chu,1 Sheri Tokumaru,1 Kara Izumi,2 and Kazuma Nakagawa3 Downloaded by [University of Pennsylvania] at 02:31 06 November 2015
1
Department of Pharmacy Practice, Daniel K. Inouye College of Pharmacy, University of Hawaii at Hilo, Honolulu, HI, USA; 2 Department of Pharmacy, The Queen’s Medical Center, Honolulu, HI, USA; 3 Department of Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA, and Department of Neuroscience, The Queen’s Medical Center, Honolulu, HI, USA Background: Not all patients with warfarin-related acute intracranial hemorrhage (ICH) achieve full reversal of international normalized ratio (INR) after the first dose of weight-based prothrombin complex concentrate (PCC). We sought to identify factors associated with anticoagulation reversal failure after the first dose of PCC. Methods: Consecutive patients who were hospitalized with warfarin-related acute ICH at a tertiary center between 1 January 2010 and 31 December 2012 were studied. Anticoagulation reversal failure was defined as INR ≥ 1.5 after the first dose of PCC. Logistic regression was performed to determine the predictors of anticoagulation reversal failure. Results: Fifty-one patients with acute ICH received PCC for warfarin reversal using a weightbased protocol. Overall, 23 (45%) patients did not achieve full reversal of INR after the first dose. Those with anticoagulation reversal failure were obese (body mass index > 30 kg/m2 ) (41% vs. 14%, p = 0.03), had a higher initial INR (3.0 ± 1.4 vs. 2.0 ± 0.7, p = 0.001), and had a higher prevalence of initial INR >2.0 (22% vs. 67%, p = 0.001), compared with those who were successfully reversed. Multivariable logistic regression identified obesity (odds ratio 7.88, 95% CI 1.12 to 55.68) and initial INR >2.0 (odds ratio 12.49, 95% CI 2.27 to 68.87) as independent predictors of anticoagulation reversal failure. Conclusions: Obesity and elevated initial INR are independently associated with anticoagulation reversal failure using the weight-based PCC protocol in patients with warfarin-related acute ICH. Further studies are needed to determine more effective dosing protocols and individualized strategies for anticoagulation reversal after acute ICH, especially among obese patients. KEYWORDS: prothrombin complex concentrate, obesity, warfarin
Introduction Intracranial hemorrhage (ICH) in a setting of warfarinrelated coagulopathy is associated with high mortality and mobidity [1,2] and requires urgent anticoagulation reversal. The current guidelines recommend the use of prothrombin complex concentrate (PCC) when warfarin-associated major bleeding warrants rapid reversal [3–5]. Formulations of PCC contain clotting factors II, IX, X and varying amounts of factor VII [6]. Received 15 August 2014; revised 19 November 2014; accepted 25 November 2014 Correspondence: Cherie Chu, PharmD, University of Hawaii at Hilo, Daniel K. Inouye College of Pharmacy, 677 Ala Moana Blvd. Ste 1025, Honolulu, HI 96813, USA. Tel: (808) 389-1434. Fax: (808) 587-2699. E-mail: [email protected]
Advantages of using PCC over fresh frozen plasma (FFP) alone include the following: a low volume for infusion, rapid administration, fast onset of action, potential correction of international normalized ratio (INR) values within 30 min of administration, no requirement to obtain information on patient’s blood type, and the reduced risk of adverse reactions such as transfusionassociated acute lung injury [7–11]. Our institution uses Profilnine SDR (BDI Pharma, Columbia, SC), a three-factor PCC formulation that is a solvent detergent-treated concentrate of factors II, IX, X and low levels of factor VII. The factor VII to IX ratio of this formulation is no more than 35–100 units, whereas other four factor formulations, such as the newly approved KCentraR (CLS Behring, King of Prussia, PA), contain a factor VII to IX ratio of 10–25 units to 20–31 units. The exact dose of Profilnine SDR can be 1
2
C. Chu et al.
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Figure 1.
Prothrombin Complex Concentrate Guidelines.
calculated using the body weight, degree of INR prolongation and the desired level of correction [12]. However, this exact calculation method may be time-consuming and impractical, especially in the emergent clinical settings. Furthermore, this exact dose calculation strategy may be considered wasteful since some portion of the last PCC vial is often discarded. Various other methods of PCC dosing exist and are being practiced, although the consensus for exact dosing of PCC for the reversal of oral anticoagulants has not been established [4,12–14]. Our institution uses a simple weight-based protocol (Figure 1) utilizing Profilnine SDR to rapidly reverse warfarin-related coagulopathy in patients with acute ICH. This protocol was derived from the recommended weight-based dose of 25–50 units/kg [5] but was simplified to round up to the nearest vial size. This dosing regimen was selected due to clinical ease of administrating the whole vial, rather than partial vial, in emergency settings. However, based on our experience, not all patients achieve full reversal of INR after the first calculated dose. Therefore, we sought to identify clinical factors that are associated with anticoagulation reversal failure after the first calculated dose of PCC.
Methods This study was approved by the Queen’s Medical Center (QMC) Institutional Review Board and The University of Hawaii Human Studies Program prior to data collection. Consent was waived due to the retrospective nature of the study. At the time of this study, all available PCC formulations in the United States did not have Food and Drug Administration (FDA) approval for use as vitamin K antagonist reversal agents, and therefore used off-label for this indication. This was a retrospective study of consecutive patients with acute ICH and warfarin-related coagulopathy who were hospitalized at QMC between 1 January 2010 and 31 December 2012. QMC is a 505-bed medical center located in Honolulu, Hawaii, and is the only American
College of Surgeons-verified Trauma Center (Level II) in the Pacific Rim. Patients were included if they were over the age of 18 years; had an admitting diagnosis of traumatic or non-traumatic ICH, including epidural hematoma, subdural hematoma, subarachnoid hemorrhage and spontaneous intraparenchymal hemorrhage with verification by radiology report; were receiving warfarin therapy prior to admission; and received at least one dose of PCC. Patients were excluded if they received PCC for a non-ICH diagnosis. PCC doses were determined and administered per institutional protocol (Figure 1). The frequency of the use of FFP as adjunct therapy was also obtained. The decision to administer PCC was at the discretion of the treating physicians. Patient demographics, height, weight, body mass index (BMI), medical history including history of hypertension, diabetes mellitus, hyperlipidemia, atrial fibrillation/atrial flutter, prior stroke, peripheral vascular disease, coronary artery disease (CAD) or prior myocardial infarction (MI), venous thromboembolism (VTE), congestive heart failure, alcohol abuse, malignancy and liver disease, were obtained from the electronic medical record. The patients were considered to be obese if BMI was greater than or equal to 30 kg/m2 [15]. Medication history, including the concomitant use of aspirin, clopidogrel and antibiotics were also obtained. Patients were considered to have received appropriate number of PCC and FFP if they received the amount that was consistent with the institutional protocol (Figure 1). Initial INR and post-PCC INR values were obtained from the electronic medical record.
Statistical analysis Data were analyzed using commercially available statistical software (SPSS 22.0, Chicago, IL). The primary outcome was anticoagulation reversal failure, which was defined as INR ≥ 1.5 after the first calculated dose of PCC. Patient characteristics were summarized using descriptive statistics appropriate to variable type. Those who had successful reversal of INR were compared with those who had unsuccessful reversal using χ 2 test or Fisher’s Exact test for categorical data and two-tailed ttest for normally distributed, continuous variables. Multivariable analyses using a logistic regression model were performed to identify factors predictive of anticoagulation reversal failure. Variables with significance of p < 0.10 in the univariate analyses were incorporated in the model, with the exception of initial INR (continuous variable), weight (continuous variable), and BMI (continuous variable) since these variables were collinear to initial INR >2 (dichotomized variable) and obesity (dichotomized variable). Dichotomized variables of initial INR >2 and obesity were chosen to be entered in the International Journal of Neuroscience
INR reversal failure in obese
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Table 1.
3
Baseline characteristics of ICH patients.
No. of patients Age (years) Females Height (m) Weight (kg) Weight range, 80–90 kg BMI (kg/m2 ) Obesity Initial INR Initial INR >2 Mechanism of injury Traumatic ICH Spontaneous ICH Risk factors Hypertension Diabetes mellitus Hyperlipidemia Atrial fibrillation/atrial flutter Prior stroke Peripheral vascular disease Coronary artery disease or prior myocardial infarction Venous thromboembolism Congestive heart failure Smoking Alcohol abuse Malignancy Liver disease Medications Aspirin Clopidogrel Antibiotic use Appropriate PCC vials given Appropriate PCC + FFP given∗
Success
Failure
28 76 ± 13 12 (43) 1.68 ± 0.1 73 ± 18 5 (18) 26 ± 5 4 (14) 2.0 ± 0.7 9 (33)
23 69 ± 13 11 (48) 1.69 ± 0.12 84 ± 26 2 (9) 29 ± 8 9 (41) 3.0 ± 1.41 18 (78)
16 (57) 12 (43)
12 (52) 11 (48)
21 (75) 9 (32) 12 (43) 21 (75) 7 (25) 1 (4) 8 (29)
17 (74) 9 (39) 9 (39) 17 (74) 6 (26) 1 (4) 5 (22)
0.93 0.60 0.79 0.93 0.93 0.89 0.58
2 (7) 3 (11)
2 (9) 6 (26)
0.84 0.17
0 (0) 1 (4) 0 (0)
1 (4) 2 (9) 1 (4)
0.27 0.44 0.36
5 (18) 3 (11) 1 (4) 19 (68) 18 (64)
3 (13) 0 (0) 2 (9) 13 (57) 11 (48)
0.64 0.11 0.44 0.41 0.24
p 0.09 0.72 0.91 0.07 0.34 0.07 0.03 0.001 0.001 0.48
Patient characteristics comparing those who had an anticoagulation reversal success with those who had an anticoagulation reversal failure after the first calculated dose of prothrombin complex concentrate (PCC). Those who had successful anticoagulation reversal of INR were compared with those who had unsuccessful anticoagulation reversal. BMI: body mass index; Obesity: body mass index ≥ 30 kg/m2 ; INR: International Normalized Ratio. Appropriate PCC: correct number of PCC vials administered per institutional protocol. Data are n (%) or mean ± SD. ∗ Appropriate PCC + FFP given defined as appropriate PCC vials given and FFP was also administered.
final multivariable model to make the model more clinically useful. The odds ratio (OR) and 95% confidence interval (CI) were calculated from beta coefficients and their standard errors. Levels of p < 0.05 were considered statistically significant.
Results During the study period, 51 patients with acute ICH (55% from traumatic and 45% from spontaneous mechanism of injury) received PCC for rapid warfarin reversal using an institutional weight-based protocol. Overall, 23 out of 51 (45%) patients did not achieve full reversal of INR after the initial dosing. The range of baseline C
2014 Informa Healthcare USA, Inc.
INR for patients included was 1.2 to 7.1. In the univariate analyses, those with anticoagulation reversal failure were more likely to be obese (41% vs. 14%, p = 0.03), more likely to have a higher initial INR (3.0 ± 1.4 vs. 2.0 ± 0.7, p = 0.001) and higher prevalence of initial INR >2 (67% vs. 22%, p = 0.001), compared with those who were successfully reversed after the first dose (Table 1). In the multivariable logistic regression model, the independent predictors of anticoagulation reversal failure were obesity (OR 7.88, 95% CI: 1.12 to 55.68) and initial INR >2.0 (OR 12.49, 95% CI: 2.27 to 68.87) (Table 2). Overall, two patients (4%) developed acute VTE during hospitalization. Another patient was also documented to have chronic VTE in the upper extremity, which was present prior to admission. Thirteen patients
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Table 2. Multivariable model for failure of successful reversal (INR < 1.5). Fully adjusted model OR (95% CI)
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Obesity Age Gender Initial INR >2 Appropriate PCC Appropriate PCC + FFP∗∗
7.39 (1.12, 55.68)∗ 0.94 (0.88, 1.01) 0.35 (0.07, 1.69) 12.49 (2.27, 68.87)∗ 2.96 (0.12, 70.87) 0.19 (0.01, 4.39)
Fully adjusted multivariate model using variables with significance of p < 0.10 from the univariate analysis excluding weight, BMI and initial INR. Obesity: body mass index ≥ 30 kg/m2 ; INR: International Normalized Ratio. Appropriate PCC: correct number of PCC vials administered per institutional protocol. Data are Odds Ratios (OR) with 95% confidence interval (CI). ∗ Statistically significant OR. ∗∗ Appropriate PCC + FFP given defined as appropriate PCC vials given and FFP was also administered.
(25%) died during hospitalization, 12 of which were expected due to the severity of acute neurological injuries. One death was due to cardiac arrest, which occurred 15 days after admission and was not clinically felt to be related to the use of PCC.
Discussion This study demonstrated that obesity and elevated initial INR were independently associated with failure to reverse warfarin-related anticoagulation after first dose of simplified weight-based PCC dosing. Thrombotic events did occur but were relatively uncommon and comparable with other studies [14,16–18]. Association between higher baseline INR and reversal failure with PCC has been shown in other studies [19,20]. Since plasma factor levels and INR are inversely related, more factor replacement would be needed for adequate reversal with higher INR. Although the relationship between elevated initial INR and anticoagulation reversal failure has been reported, the impact of obesity on PCC dosing has not been well described. Most plausible explanation that naturally follows our observation of obesity and reversal failure is that the institutional guideline for PCC dosing limits patients weighing from 80–90 kg and more than 120 kg, to a dose less than the minimum recommended dose of 25 units/kg. Patients in these groups may have been potentially under-dosed. However, no patient weighed more than 120 kg and only two patients that failed to reverse fell in the 80–90 kg group, but were not obese. Therefore, we feel that our findings were not related to potential under-dosing due to the simplified protocol.
In addition, a study that looked at fixed dose PCC administration, using doses significantly less than the recommended 25 units/kg (6–17.9 units/kg), showed successful reversal to an INR less than 1.5 in 96% of their patients [12,19]. Similar to many drugs that are dosed by weight, there is no guideline for PCC dosing in a subset of obese patients. From a pharmacokinetic standpoint, plasma coagulation factors have a low volume of distribution, and their effect on INR is dependent on their distribution within the intravascular space [21]. Physiologically, blood volume does not increase proportionately to body mass, and thus theoretically, PCC dosing based on the ideal or adjusted bodyweight should theoretically be appropriate [20]. However, obese patients have been reported to have different baseline hemostatic and fibrinolytic systems compared with non-obese patients [22] and may hypothetically require more clotting factor replacement to reverse the effect of warfarin-related coagulopathy. Overall, we speculate the following three plausible explanations for our observation among obese patients: (1) Increased volume of distribution; (2) decreased time to distribution within the intravascular space; or (3) differences in baseline coagulation systems. The attempt to simplify a PCC dosing formula for clinical ease, in our case, resulted in a higher rate of reversal failure than reported in literature and especially affected obese patients. Due to lack of consensus in determining the most appropriate method of drug dosing for obese patients in general [23], we suggest that individualized PCC doses, in obese patients, should be based on a metric that accounts for varying proportions of muscle to fat [19] and variations in volume of distribution. This study has several limitations. Although the study population is representative of patients who received PCC at our institution using the institutional protocol, the results may not be generalizable to other institutions that use different PCC protocols. There was also incomplete data regarding INR after the second PCC dose was administered. Many of the patients who received additional PCC had second INRs checked many hours after the additional dose, therefore we feel that they do not truly reflect the effect of the additional dose of PCC. Pre-specified power calculations were not made, and thus the negative results do not prove a lack of association. The small sample size and retrospective nature of this study limit the conclusions drawn from this study to preliminary observations.
Conclusions Obesity and elevated initial INR are independently associated with anticoagulation reversal failure using the International Journal of Neuroscience
INR reversal failure in obese
weight-based PCC protocol in patients with warfarinrelated acute ICH. Further studies are needed to determine more effective dosing protocols and individualized strategies for anticoagulation reversal after acute ICH, especially among the obese patients.
Acknowledgements None.
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Declaration of Interest None of the authors was involved in commercial relationships in the form of financial support for personal financial interest during the time of this study. The authors alone are responsible for the content and writing of the paper.
References 1. Liotta EM, Prabhakaran S. Warfarin-associated intracerebral hemorrhage is increasing in prevalence in the United States. J Stroke Cerebrovasc Dis 2013;22(7):1151–5. 2. Sacco S, Marini C, Toni D, et al. Incidence and 10-year survival of intracerebral hemorrhage in a population-based registry. Stroke 2009;40(2):394–9. 3. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed. American College of Chest Physicians’ evidence-based clinical practice guidelines. Chest 2012;141(2 Suppl):e152S-84S. 4. Morgenstern LB, Hemphill JC, Anderson C, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2010;41(9):2108–29. 5. Baker RI, Coughlin PB, Gallus AS, et al. Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis. Med J Aust 2004;181(9): 492–7. 6. Leissinger CA, Blatt PM, Hoots WK, et al. Role of prothrombin complex concentrates in reversing warfarin anticoagulation: a review of the literature. Am J Hematol 2008;83(2): 137–43. 7. Boulis NM, Bobek MP, Schmaier A, et al. Use of factor IX complex in warfarin-related intracranial hemorrhage. Neurosurgery 1999;45(5):1113–18; discussion 8–9.
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8. Chapman SA, Irwin ED, Beal AL, et al. Prothrombin complex concentrate versus standard therapies for INR reversal in trauma patients receiving warfarin. Ann Pharmacother 2011;45(7–8):869–75. 9. Tran HA, Chunilal SD, Harper PL, et al. An update of consensus guidelines for warfarin reversal. Med J Aust 2013;198(4):198–9. 10. Pabinger I, Brenner B, Kalina U, et al. Prothrombin complex concentrate (Beriplex P/N) for emergency anticoagulation reversal: a prospective multinational clinical trial. J Thromb Haemost 2008;6(4):622–31. 11. Riess HB, Meier-Hellmann A, Motsch J, et al. Prothrombin complex concentrate (Octaplex) in patients requiring immediate reversal of oral anticoagulation. Thromb Res 2007;121(1):9–16. 12. Yasaka M, Sakata T, Naritomi H, et al. Optimal dose of prothrombin complex concentrate for acute reversal of oral anticoagulation. Thromb Res 2005;115(6):455–9. 13. van Aart L, Eijkhout HW, Kamphuis JS, et al. Individualized dosing regimen for prothrombin complex concentrate more effective than standard treatment in the reversal of oral anticoagulant therapy: an open, prospective randomized controlled trial. Thromb Res 2006;118(3):313–20. 14. Bershad EM, Suarez JI. Prothrombin complex concentrates for oral anticoagulant therapy-related intracranial hemorrhage: a review of the literature. Neurocrit Care 2010;12(3):403–13. 15. Flegal KM, Carroll MD, Ogden CL, et al. Prevalence and trends in obesity among US adults, 1999–2000. JAMA 2002;288(14):1723–7. 16. Cabral KP, Fraser GL, Duprey J, et al. Prothrombin complex concentrates to reverse warfarin-induced coagulopathy in patients with intracranial bleeding. Clin Neurol Neurosurg 2013;115(6):770–4. 17. Hickey M, Gatien M, Taljaard M, et al. Outcomes of urgent warfarin reversal with frozen plasma versus prothrombin complex concentrate in the emergency department. Circulation 2013;128(4):360–4. ¨ 18. Kohler M. Thrombogenicity of prothrombin complex concentrates. Thromb Res 1999;95(4, Suppl 1):S13–7. 19. Baggs JH, Patanwala AE, Williams EM, et al. Dosing of 3-factor prothrombin complex concentrate for international normalized ratio reversal. Ann Pharmacother 2012;46(1):51–6. 20. Switzer JA, Rocker J, Mohorn P, et al. Clinical experience with three-factor prothrombin complex concentrate to reverse warfarin anticoagulation in intracranial hemorrhage. Stroke 2012;43(9):2500–02. 21. Patanwala AE, Acquisto NM, Erstad BL. Prothrombin complex concentrate for critical bleeding. Ann Pharmacother 2011;45(7–8):990–9. 22. Mertens I, Van Gaal LF. Obesity, haemostasis and the fibrinolytic system. Obes Rev 2002;3(2):85–101. 23. Jacques KA, Erstad BL. Availability of information for dosing injectable medications in underweight or obese patients. Am J Health Syst Pharm 2010;67(22):1948–50.
ISSN: 0020-7454 (Print) 1543-5245 (Online) Journal homepage: http://www.tandfonline.com/loi/ines20
Obesity increases risk of anticoagulation reversal failure with prothrombin complex concentrate in those with intracranial hemorrhage Cherie Chu, Sheri Tokumaru, Kara Izumi & Kazuma Nakagawa To cite this article: Cherie Chu, Sheri Tokumaru, Kara Izumi & Kazuma Nakagawa (2014): Obesity increases risk of anticoagulation reversal failure with prothrombin complex concentrate in those with intracranial hemorrhage, International Journal of Neuroscience To link to this article: http://dx.doi.org/10.3109/00207454.2014.993034
Accepted author version posted online: 28 Nov 2014. Published online: 27 Dec 2014. Submit your article to this journal
Article views: 36
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View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ines20 Download by: [University of Pennsylvania]
Date: 06 November 2015, At: 02:31
International Journal of Neuroscience, 2014; Early Online: 1–5 © 2014 Informa Healthcare USA, Inc. ISSN: 0020-7454 print / 1543-5245 online DOI: 10.3109/00207454.2014.993034
ORIGINAL ARTICLE
Obesity increases risk of anticoagulation reversal failure with prothrombin complex concentrate in those with intracranial hemorrhage Cherie Chu,1 Sheri Tokumaru,1 Kara Izumi,2 and Kazuma Nakagawa3 Downloaded by [University of Pennsylvania] at 02:31 06 November 2015
1
Department of Pharmacy Practice, Daniel K. Inouye College of Pharmacy, University of Hawaii at Hilo, Honolulu, HI, USA; 2 Department of Pharmacy, The Queen’s Medical Center, Honolulu, HI, USA; 3 Department of Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA, and Department of Neuroscience, The Queen’s Medical Center, Honolulu, HI, USA Background: Not all patients with warfarin-related acute intracranial hemorrhage (ICH) achieve full reversal of international normalized ratio (INR) after the first dose of weight-based prothrombin complex concentrate (PCC). We sought to identify factors associated with anticoagulation reversal failure after the first dose of PCC. Methods: Consecutive patients who were hospitalized with warfarin-related acute ICH at a tertiary center between 1 January 2010 and 31 December 2012 were studied. Anticoagulation reversal failure was defined as INR ≥ 1.5 after the first dose of PCC. Logistic regression was performed to determine the predictors of anticoagulation reversal failure. Results: Fifty-one patients with acute ICH received PCC for warfarin reversal using a weightbased protocol. Overall, 23 (45%) patients did not achieve full reversal of INR after the first dose. Those with anticoagulation reversal failure were obese (body mass index > 30 kg/m2 ) (41% vs. 14%, p = 0.03), had a higher initial INR (3.0 ± 1.4 vs. 2.0 ± 0.7, p = 0.001), and had a higher prevalence of initial INR >2.0 (22% vs. 67%, p = 0.001), compared with those who were successfully reversed. Multivariable logistic regression identified obesity (odds ratio 7.88, 95% CI 1.12 to 55.68) and initial INR >2.0 (odds ratio 12.49, 95% CI 2.27 to 68.87) as independent predictors of anticoagulation reversal failure. Conclusions: Obesity and elevated initial INR are independently associated with anticoagulation reversal failure using the weight-based PCC protocol in patients with warfarin-related acute ICH. Further studies are needed to determine more effective dosing protocols and individualized strategies for anticoagulation reversal after acute ICH, especially among obese patients. KEYWORDS: prothrombin complex concentrate, obesity, warfarin
Introduction Intracranial hemorrhage (ICH) in a setting of warfarinrelated coagulopathy is associated with high mortality and mobidity [1,2] and requires urgent anticoagulation reversal. The current guidelines recommend the use of prothrombin complex concentrate (PCC) when warfarin-associated major bleeding warrants rapid reversal [3–5]. Formulations of PCC contain clotting factors II, IX, X and varying amounts of factor VII [6]. Received 15 August 2014; revised 19 November 2014; accepted 25 November 2014 Correspondence: Cherie Chu, PharmD, University of Hawaii at Hilo, Daniel K. Inouye College of Pharmacy, 677 Ala Moana Blvd. Ste 1025, Honolulu, HI 96813, USA. Tel: (808) 389-1434. Fax: (808) 587-2699. E-mail: [email protected]
Advantages of using PCC over fresh frozen plasma (FFP) alone include the following: a low volume for infusion, rapid administration, fast onset of action, potential correction of international normalized ratio (INR) values within 30 min of administration, no requirement to obtain information on patient’s blood type, and the reduced risk of adverse reactions such as transfusionassociated acute lung injury [7–11]. Our institution uses Profilnine SDR (BDI Pharma, Columbia, SC), a three-factor PCC formulation that is a solvent detergent-treated concentrate of factors II, IX, X and low levels of factor VII. The factor VII to IX ratio of this formulation is no more than 35–100 units, whereas other four factor formulations, such as the newly approved KCentraR (CLS Behring, King of Prussia, PA), contain a factor VII to IX ratio of 10–25 units to 20–31 units. The exact dose of Profilnine SDR can be 1
2
C. Chu et al.
Downloaded by [University of Pennsylvania] at 02:31 06 November 2015
Figure 1.
Prothrombin Complex Concentrate Guidelines.
calculated using the body weight, degree of INR prolongation and the desired level of correction [12]. However, this exact calculation method may be time-consuming and impractical, especially in the emergent clinical settings. Furthermore, this exact dose calculation strategy may be considered wasteful since some portion of the last PCC vial is often discarded. Various other methods of PCC dosing exist and are being practiced, although the consensus for exact dosing of PCC for the reversal of oral anticoagulants has not been established [4,12–14]. Our institution uses a simple weight-based protocol (Figure 1) utilizing Profilnine SDR to rapidly reverse warfarin-related coagulopathy in patients with acute ICH. This protocol was derived from the recommended weight-based dose of 25–50 units/kg [5] but was simplified to round up to the nearest vial size. This dosing regimen was selected due to clinical ease of administrating the whole vial, rather than partial vial, in emergency settings. However, based on our experience, not all patients achieve full reversal of INR after the first calculated dose. Therefore, we sought to identify clinical factors that are associated with anticoagulation reversal failure after the first calculated dose of PCC.
Methods This study was approved by the Queen’s Medical Center (QMC) Institutional Review Board and The University of Hawaii Human Studies Program prior to data collection. Consent was waived due to the retrospective nature of the study. At the time of this study, all available PCC formulations in the United States did not have Food and Drug Administration (FDA) approval for use as vitamin K antagonist reversal agents, and therefore used off-label for this indication. This was a retrospective study of consecutive patients with acute ICH and warfarin-related coagulopathy who were hospitalized at QMC between 1 January 2010 and 31 December 2012. QMC is a 505-bed medical center located in Honolulu, Hawaii, and is the only American
College of Surgeons-verified Trauma Center (Level II) in the Pacific Rim. Patients were included if they were over the age of 18 years; had an admitting diagnosis of traumatic or non-traumatic ICH, including epidural hematoma, subdural hematoma, subarachnoid hemorrhage and spontaneous intraparenchymal hemorrhage with verification by radiology report; were receiving warfarin therapy prior to admission; and received at least one dose of PCC. Patients were excluded if they received PCC for a non-ICH diagnosis. PCC doses were determined and administered per institutional protocol (Figure 1). The frequency of the use of FFP as adjunct therapy was also obtained. The decision to administer PCC was at the discretion of the treating physicians. Patient demographics, height, weight, body mass index (BMI), medical history including history of hypertension, diabetes mellitus, hyperlipidemia, atrial fibrillation/atrial flutter, prior stroke, peripheral vascular disease, coronary artery disease (CAD) or prior myocardial infarction (MI), venous thromboembolism (VTE), congestive heart failure, alcohol abuse, malignancy and liver disease, were obtained from the electronic medical record. The patients were considered to be obese if BMI was greater than or equal to 30 kg/m2 [15]. Medication history, including the concomitant use of aspirin, clopidogrel and antibiotics were also obtained. Patients were considered to have received appropriate number of PCC and FFP if they received the amount that was consistent with the institutional protocol (Figure 1). Initial INR and post-PCC INR values were obtained from the electronic medical record.
Statistical analysis Data were analyzed using commercially available statistical software (SPSS 22.0, Chicago, IL). The primary outcome was anticoagulation reversal failure, which was defined as INR ≥ 1.5 after the first calculated dose of PCC. Patient characteristics were summarized using descriptive statistics appropriate to variable type. Those who had successful reversal of INR were compared with those who had unsuccessful reversal using χ 2 test or Fisher’s Exact test for categorical data and two-tailed ttest for normally distributed, continuous variables. Multivariable analyses using a logistic regression model were performed to identify factors predictive of anticoagulation reversal failure. Variables with significance of p < 0.10 in the univariate analyses were incorporated in the model, with the exception of initial INR (continuous variable), weight (continuous variable), and BMI (continuous variable) since these variables were collinear to initial INR >2 (dichotomized variable) and obesity (dichotomized variable). Dichotomized variables of initial INR >2 and obesity were chosen to be entered in the International Journal of Neuroscience
INR reversal failure in obese
Downloaded by [University of Pennsylvania] at 02:31 06 November 2015
Table 1.
3
Baseline characteristics of ICH patients.
No. of patients Age (years) Females Height (m) Weight (kg) Weight range, 80–90 kg BMI (kg/m2 ) Obesity Initial INR Initial INR >2 Mechanism of injury Traumatic ICH Spontaneous ICH Risk factors Hypertension Diabetes mellitus Hyperlipidemia Atrial fibrillation/atrial flutter Prior stroke Peripheral vascular disease Coronary artery disease or prior myocardial infarction Venous thromboembolism Congestive heart failure Smoking Alcohol abuse Malignancy Liver disease Medications Aspirin Clopidogrel Antibiotic use Appropriate PCC vials given Appropriate PCC + FFP given∗
Success
Failure
28 76 ± 13 12 (43) 1.68 ± 0.1 73 ± 18 5 (18) 26 ± 5 4 (14) 2.0 ± 0.7 9 (33)
23 69 ± 13 11 (48) 1.69 ± 0.12 84 ± 26 2 (9) 29 ± 8 9 (41) 3.0 ± 1.41 18 (78)
16 (57) 12 (43)
12 (52) 11 (48)
21 (75) 9 (32) 12 (43) 21 (75) 7 (25) 1 (4) 8 (29)
17 (74) 9 (39) 9 (39) 17 (74) 6 (26) 1 (4) 5 (22)
0.93 0.60 0.79 0.93 0.93 0.89 0.58
2 (7) 3 (11)
2 (9) 6 (26)
0.84 0.17
0 (0) 1 (4) 0 (0)
1 (4) 2 (9) 1 (4)
0.27 0.44 0.36
5 (18) 3 (11) 1 (4) 19 (68) 18 (64)
3 (13) 0 (0) 2 (9) 13 (57) 11 (48)
0.64 0.11 0.44 0.41 0.24
p 0.09 0.72 0.91 0.07 0.34 0.07 0.03 0.001 0.001 0.48
Patient characteristics comparing those who had an anticoagulation reversal success with those who had an anticoagulation reversal failure after the first calculated dose of prothrombin complex concentrate (PCC). Those who had successful anticoagulation reversal of INR were compared with those who had unsuccessful anticoagulation reversal. BMI: body mass index; Obesity: body mass index ≥ 30 kg/m2 ; INR: International Normalized Ratio. Appropriate PCC: correct number of PCC vials administered per institutional protocol. Data are n (%) or mean ± SD. ∗ Appropriate PCC + FFP given defined as appropriate PCC vials given and FFP was also administered.
final multivariable model to make the model more clinically useful. The odds ratio (OR) and 95% confidence interval (CI) were calculated from beta coefficients and their standard errors. Levels of p < 0.05 were considered statistically significant.
Results During the study period, 51 patients with acute ICH (55% from traumatic and 45% from spontaneous mechanism of injury) received PCC for rapid warfarin reversal using an institutional weight-based protocol. Overall, 23 out of 51 (45%) patients did not achieve full reversal of INR after the initial dosing. The range of baseline C
2014 Informa Healthcare USA, Inc.
INR for patients included was 1.2 to 7.1. In the univariate analyses, those with anticoagulation reversal failure were more likely to be obese (41% vs. 14%, p = 0.03), more likely to have a higher initial INR (3.0 ± 1.4 vs. 2.0 ± 0.7, p = 0.001) and higher prevalence of initial INR >2 (67% vs. 22%, p = 0.001), compared with those who were successfully reversed after the first dose (Table 1). In the multivariable logistic regression model, the independent predictors of anticoagulation reversal failure were obesity (OR 7.88, 95% CI: 1.12 to 55.68) and initial INR >2.0 (OR 12.49, 95% CI: 2.27 to 68.87) (Table 2). Overall, two patients (4%) developed acute VTE during hospitalization. Another patient was also documented to have chronic VTE in the upper extremity, which was present prior to admission. Thirteen patients
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Table 2. Multivariable model for failure of successful reversal (INR < 1.5). Fully adjusted model OR (95% CI)
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Obesity Age Gender Initial INR >2 Appropriate PCC Appropriate PCC + FFP∗∗
7.39 (1.12, 55.68)∗ 0.94 (0.88, 1.01) 0.35 (0.07, 1.69) 12.49 (2.27, 68.87)∗ 2.96 (0.12, 70.87) 0.19 (0.01, 4.39)
Fully adjusted multivariate model using variables with significance of p < 0.10 from the univariate analysis excluding weight, BMI and initial INR. Obesity: body mass index ≥ 30 kg/m2 ; INR: International Normalized Ratio. Appropriate PCC: correct number of PCC vials administered per institutional protocol. Data are Odds Ratios (OR) with 95% confidence interval (CI). ∗ Statistically significant OR. ∗∗ Appropriate PCC + FFP given defined as appropriate PCC vials given and FFP was also administered.
(25%) died during hospitalization, 12 of which were expected due to the severity of acute neurological injuries. One death was due to cardiac arrest, which occurred 15 days after admission and was not clinically felt to be related to the use of PCC.
Discussion This study demonstrated that obesity and elevated initial INR were independently associated with failure to reverse warfarin-related anticoagulation after first dose of simplified weight-based PCC dosing. Thrombotic events did occur but were relatively uncommon and comparable with other studies [14,16–18]. Association between higher baseline INR and reversal failure with PCC has been shown in other studies [19,20]. Since plasma factor levels and INR are inversely related, more factor replacement would be needed for adequate reversal with higher INR. Although the relationship between elevated initial INR and anticoagulation reversal failure has been reported, the impact of obesity on PCC dosing has not been well described. Most plausible explanation that naturally follows our observation of obesity and reversal failure is that the institutional guideline for PCC dosing limits patients weighing from 80–90 kg and more than 120 kg, to a dose less than the minimum recommended dose of 25 units/kg. Patients in these groups may have been potentially under-dosed. However, no patient weighed more than 120 kg and only two patients that failed to reverse fell in the 80–90 kg group, but were not obese. Therefore, we feel that our findings were not related to potential under-dosing due to the simplified protocol.
In addition, a study that looked at fixed dose PCC administration, using doses significantly less than the recommended 25 units/kg (6–17.9 units/kg), showed successful reversal to an INR less than 1.5 in 96% of their patients [12,19]. Similar to many drugs that are dosed by weight, there is no guideline for PCC dosing in a subset of obese patients. From a pharmacokinetic standpoint, plasma coagulation factors have a low volume of distribution, and their effect on INR is dependent on their distribution within the intravascular space [21]. Physiologically, blood volume does not increase proportionately to body mass, and thus theoretically, PCC dosing based on the ideal or adjusted bodyweight should theoretically be appropriate [20]. However, obese patients have been reported to have different baseline hemostatic and fibrinolytic systems compared with non-obese patients [22] and may hypothetically require more clotting factor replacement to reverse the effect of warfarin-related coagulopathy. Overall, we speculate the following three plausible explanations for our observation among obese patients: (1) Increased volume of distribution; (2) decreased time to distribution within the intravascular space; or (3) differences in baseline coagulation systems. The attempt to simplify a PCC dosing formula for clinical ease, in our case, resulted in a higher rate of reversal failure than reported in literature and especially affected obese patients. Due to lack of consensus in determining the most appropriate method of drug dosing for obese patients in general [23], we suggest that individualized PCC doses, in obese patients, should be based on a metric that accounts for varying proportions of muscle to fat [19] and variations in volume of distribution. This study has several limitations. Although the study population is representative of patients who received PCC at our institution using the institutional protocol, the results may not be generalizable to other institutions that use different PCC protocols. There was also incomplete data regarding INR after the second PCC dose was administered. Many of the patients who received additional PCC had second INRs checked many hours after the additional dose, therefore we feel that they do not truly reflect the effect of the additional dose of PCC. Pre-specified power calculations were not made, and thus the negative results do not prove a lack of association. The small sample size and retrospective nature of this study limit the conclusions drawn from this study to preliminary observations.
Conclusions Obesity and elevated initial INR are independently associated with anticoagulation reversal failure using the International Journal of Neuroscience
INR reversal failure in obese
weight-based PCC protocol in patients with warfarinrelated acute ICH. Further studies are needed to determine more effective dosing protocols and individualized strategies for anticoagulation reversal after acute ICH, especially among the obese patients.
Acknowledgements None.
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Declaration of Interest None of the authors was involved in commercial relationships in the form of financial support for personal financial interest during the time of this study. The authors alone are responsible for the content and writing of the paper.
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