Cost of Bleeding in Trauma and Complex Cardiac Surgery

Clinical Therapeutics/Volume 37, Number 9, 2015

Cost of Bleeding in Trauma and Complex Cardiac Surgery

Arthur Zbrozek, MSc, MBA, RPh

; and Glenn Magee, MBA

1

CSL Behring, King of Prussia, Pennsylvania; and

Premier Research Services, Charlotte, North Carolina

Purpose: Trauma and complex cardiac surgery are associated with a high risk of bleeding complications. The difference in costs between patients who require bleeding control measures and those who do not is poorly understood. Our goal was to assess the cost of care and outcomes for patients in these settings.

Methods: Patients 418 years of age, who were discharged between January 2010 and December 2012, were retrospectively identified in the Premier Hospital Database based on International Classifi ca-tion of Disease, Ninth Revisioncodes. These patients were categorized as having received blood products (“bleeding patients”) or not (“nonbleeding patients”). Patients with costs and length of stay (LOS) of zero were excluded. Differences in treatment costs and outcomes were assessed using univariate analysis and multivariate modeling.

Findings:Bleeding trauma patients (n¼8800) had a 150% higher total cost of care (P o 0.001; 146% after excluding costs of agents used for bleeding control, Po0.001), an 81.3% longer hospital LOS (Po0.001), and a 65.2% longer intensive care unit (ICU) LOS (P o 0.001) than nonbleeding patients (n ¼ 53,727). Bleeding complex cardiac surgery patients (n¼ 82,832) had a 133.2% higher total cost of care (P o 0.001; 128.7% after excluding costs of agents used for bleeding control, P o 0.001), a 155.6% longer hospital LOS (P o 0.001), and an 89.3% longer ICU LOS (Po0.001) than nonbleeding patients (n¼380,902).

Implications: Trauma and cardiac surgery patients who experienced bleeding and received allogeneic blood product transfusions had significantly worse outcomes, including longer LOS, greater inpatient mortality, and higher costs of care (even when excluding costs of agents used for bleeding control) than those who did not. (Clin Ther.2015;37:1966– 1974) _& 2015 The Authors. Published by Elsevier HS Journals, Inc.

Key words: blood transfusion, cardiac surgery, patient outcomes, pharmacoeconomics, trauma.

INTRODUCTION

The true cost of allogeneic blood products, such as fresh frozen plasma (FFP), red blood cells (RBCs), and cryoprecipitate, is an issue that is poorly understood and not well documented in the literature.1 It is a complex matter, because costs have to take into account not only the direct acquisition cost of the product, but also the associated indirect costs, such as blood collection, testing, distribution, and storage.2 Furthermore, the total cost should also take into account all costs associated with hospital stay and the treatment of any adverse events and poor outcomes associated with blood product transfusion. Blood products have been associated with a number of adverse events, including transfusion-associated circu-latory overload (TACO), transfusion-related acute lung injury (TRALI), pathogen transmission, allergic reactions, and even increased mortality,3–5and there is a dose-dependent correlation between allogeneic blood product transfusion and adverse outcomes in trauma patients.6 Patients who receive allogeneic blood product transfusions have been shown to require longer hospital stays,6 which significantly increases the cost of their treatment; it has been estimated that hospital stay accounts for 465% of all transfusion-related costs.7

In addition, the cost of blood products themselves is rising. This can be attributed to a number of factors, including increased demand, tighter restrictions on blood donor eligibility, and increasing laboratory testing and treatment of blood to keep it free from infectious diseases and bacteria.2,8,9 For example, the introduction of pathogen reduction technology, such as treatment of plasma with amotosalen or riboflavin, can more than triple the cost of a unit of blood.10

Accepted for publication June 4, 2015.

http://dx.doi.org/10.1016/j.clinthera.2015.06.007 0149-2918/$ - see front matter

&2015 The Authors. Published by Elsevier HS Journals, Inc. This is an open access article under the CC BY-NC-ND license

(http://creativecommons.org/licenses/by-nc-nd/4.0/).

The clinical settings of complex cardiac surgery and trauma are known to be associated with high rates of transfusion. Up to 15% of the US blood supply is transfused in the setting of cardiac surgery,11 and approximately 1 in 10 trauma patients experience significant hemorrhaging,12 which results in a high transfusion rate in this setting. Hemorrhage is associated with poor outcomes, such as increased morbidity, mortality, and even death,13–15which leads to an increased use of resources by these patients during hospitalization.

To determine the cost implications of allogeneic blood product transfusion in trauma and complex cardiac surgery, we assessed the cost of care and outcomes for patients in these 2 clinical settings based on bleeding status (ie, bleeding patients vs nonbleeding patients). PATIENTS AND METHODS

Trauma and Cardiac Surgery

In this retrospective analysis, patients 418 years old discharged between January 1, 2010 and Decem-ber 31, 2012 were identified in the US Premier Hospital Database based on selectInternational Clas-sification Disease, Ninth Revision (ICD-9) procedure codes within the trauma or complex cardiac surgical population definitions (Appendix). The Premier Hospital Database is a Health Insurance Portability and Accountability Act compliant dataset and is considered exempt from approval from an institutional review board based upon the Code of Federal Regulation, §46.101b(4), from the United States Department of Health and Human Services.

Complex cardiac patients included those who underwent operations of the valves, septa, or vessels of the heart, as well as those with incision or excision of the aorta or other thoracic vessels. Trauma patients included those with a diagnosis code that indicated internal injuries to the heart, lung, or other specified internal organs. A listing of the codes used to identify patients is presented in the Appendix. Patients were then categorized as bleeding or nonbleeding, based on specific ICD-9 codes and blood product use (patients who received at least 1 U of blood products [RBCs, FFP, cryoprecipitate, or platelets] were characterized as bleeding). Use of the following agents for bleeding control was extracted from the database: RBCs, FFP, platelets, cryoprecipitate, recombinant activated factor VII, and hetastarch. Patients who received blood products before the day of surgery or patients with

costs and a hospital length of stay (LOS) of zero were excluded. The following information relating to pa-tient demographic characteristics was extracted from the database: age, gender, race, ethnicity, comorbid-ities and comorbidity score, and hospital costs. Prod-ucts and services that might have influenced the use of blood products in bleeding patients, including fibrin sealants, tranexamic acid, protamine, and the use of an intraoperative cell saver, were identified and used as effect modifiers in multivariate analyses. All costs were based on hospital-reported costs for procedures, medications, other therapies, and laboratory costs taken directly from chargemaster-detailed use.

The primary outcome was hospital cost per patient (both including and excluding costs of agents used for bleeding control); secondary outcomes included hospital LOS, intensive care unit (ICU) admission and LOS, inpatient mortality, hospital readmission, and adverse events (including TACO, TRALI, thromboembolic events, pulmonary edema, and acute respiratory distress). Statistical Analysis

Differences in outcomes between bleeding and nonbleeding patients were assessed using both uni-variate analysis and multiuni-variate regression models. Statistical significance for univariate comparisons was assessed using χ2 tests for categorical variables and Student’sttests for continuous variables. Multivariate analysis was used to calculate odds ratios for inpatient mortality, 30-day readmission for bleeding, and ICU admission; confidence limits for these parameters were generated using the Wald test. A fully specified model was developed that included all covariates that dem-onstrated significant differences in univariate compar-isons from patient demographic and hospital characteristic variables, as well as the Charlson Co-morbidity Index score and ICU admission. All models used backward elimination with aPvalue ofo0.1 to determine variable inclusion in the final model. RESULTS

Trauma

A total of 62,527 trauma patients were identified for inclusion in the study; of these, 8800 received at least 1 U of blood products (bleeding patients), and 53,727 did not (nonbleeding patients). Baseline pa-tient characteristics are shown inTable I.

In the bleeding patients group, 56.2% (n¼4942) of patients received RBCs (mean [SD] 4.8 [6.7] U),

44.3% (n¼3893) received FFP (mean 6.4 [10.1] U), 2.7% (n ¼ 240) received cryoprecipitate (mean 9.6 [2.9] U), and 13.5% (n ¼ 1180) received platelets (mean 2.9 [3.9] U). Mean costs for these blood products per transfused patient were $1112 for RBCs, $578 for FFP, $1463 for cryoprecipitate, and $1486 for platelets (Table II).

Multivariate models adjusting for patient demo-graphic characteristics demonstrated that, when the costs of agents used for bleeding control were in-cluded, bleeding patients had a 150% higher total cost of care ($46,033 vs $18,434; P o 0.001) than non-bleeding patients (Figure 1;Table III). When the costs of agents used for bleeding control were excluded, bleeding patients had a 146% higher total cost of care ($45,375 vs $18,441;Po0.001).

Bleeding patients had a 81.3% longer LOS (13.6 days vs 7.5 days; P o 0.001). They were also 3.53 times as likely to be admitted to the ICU (Po0.001), 3.75 times as likely to be readmitted for bleeding within 30 days (Po0.001), and 4.09 times as likely to die in hospital (P o 0.001). The mortality rate

differed significantly between the 2 groups (10.72% bleeding patients vs 3.14% nonbleeding patients;Po 0.001). Compared with nonbleeding patients, bleeding patients had higher rates of thromboembolic events (7.84% vs 6.70%; P o 0.001), TACO (2.00% vs 0.76%; P o 0.001), and TRALI (0.13% vs 0.01%; Po0.001). The incidence of acute respiratory distress did not differ between the 2 groups (0.31% vs 0.33%; P ¼ 0.730), and no cases of pulmonary edema were observed in either group.

Cardiac Surgery

A total of 463,734 patients (82,832 bleeding; 380,902 nonbleeding) were included. Baseline demo-graphic patient characteristics are shown in Table I. Bleeding patients were older (465 years: 62.3% vs 49.8%; P o 0.001), sicker (Charlson Comorbidity Index 43: 22.5% vs 15.4%; P o 0.001), and had higher rates of cerebrovascular disease (10.2% vs 4.3%; _{P o} 0.001) and peripheral vascular disease (18.2% vs 9.4%; P o 0.001) than nonbleeding patients.

Table I. Baseline characteristics of trauma and complex cardiac surgery patients

Trauma Complex Cardiac Surgery

Characteristic Nonbleeding Patients (n¼53,727) Bleeding Patients (n ¼8800) P Value Nonbleeding Patients (n¼380,902) Bleeding Patients (n ¼82,832) PValue Gender, n (%) Female 13,764 (25.6) 2461 (28.0) o0.001 122,739 (32.2) 30,399 (36.7) o0.001 Male 39,947 (74.4) 6329 (71.9) 258,125 (67.8) 52,403 (63.3) Unknown 16 (0.0) 10 (0.1) 38 (0.0) 30 (0.0) Age, y, mean (SD) 55.8 (22.7) 54.4 (22.7) o0.001 64.3 (12.3) 67.4 (11.9) o0.001 Race, n (%) Black 7242 (13.5) 1142 (13.0) 30,753 (8.1) 5894 (7.1) o0.001 White 35,408 (65.9) 5715 (64.9) 0.005 271,218 (71.2) 59,047 (71.3) Other 11,077 (20.6) 1943 (22.1) 78,931 (20.7) 17,891 (21.6) Ethnicity, n (%) Hispanic 1348 (2.5) 271 (3.1) 5838 (1.5) 1166 (1.4) o0.001 Non-Hispanic 42,650 (79.4) 6857 (77.9) 301,971 (79.3) 64,941 (78.4) Other 9729 (18.1) 1672 (19.0) o0.001 73,093 (19.2) 16,725 (20.2)

CCI score, mean (SD) [median]

1.3 (2.0) [0] 1.4 (2.0) [0] 0.005 1.9 (1.7)[1] 2.3 (1.9)[2] o0.001

CCI¼Charlson Comorbidity Index.

Clinical Therapeutics

Table II. Agents used for bleeding control in trauma and complex cardiac surgery patients

Trauma Complex Cardiac Surgery

Characteristics Nonbleeding Patients (n¼53,727) Bleeding Patients (n¼8800) Nonbleeding Patients (n¼380,902) Bleeding Patients (n¼82,832) n (%) Mean (SD) Median Cost per Recipient

($) n (%)

Mean (SD) Median Dose per Recipient

(U)

Mean (SD) Median Cost per Recipient

($) PValue n (%)

Mean (SD) Median Cost per Recipient

($) n (%)

Mean (SD) Median Dose per Recipient

(U)

Mean (SD) Median Cost per Recipient

($) PValue PRBCs — — 4942 (56.2) 4.81 (6.65) 3.0 1112 (2001) 582 — — 42,691 (51.5) 4.51 (4.90) 3.0 1034 (1450) 627 FFP — — 3893 (44.3) 6.43 (10.08) 4.0 578 (1183) 252 — — 30,118 (36.4) 4.22 (5.45) 0.0 323 (591) 192 Platelets — — 1180 (13.5) 2.89 (3.91) 2.0 1486 (2427) 742 — — 22,914 (27.7) 2.95 (4.77) 0.0 1281 (1583) 830 Cryoprecipitate — — 240 (2.7) 9.64 (12.72) 7.0 1463 (2295) 759 — — 4892 (5.9) 5.53 (6.81) 5.0 968 (1481) 563 rFVIIa — — 190 (2.2) 5.77 (6.49) 3.5 7549 (8352) 4895 — — 1551 (1.9) 4.91 (6.65) 3.0 7349 (14,691) 4453 Hetastarch — — 1264 (14.4) 1.67 (1.50) 1.0 51 (77) 29 — — 25,148 (30.4) 1.74 (1.47) 1.0 45 (54) 30 Fibrin sealants 128 (0.2) 97 (1.1) — o0.001 2320 (0.6) 2474 (3.0) — o0.001 600 (430) 513 897 (1066) 676 0.011 581 (446) 507 669 (601) 505 o0.001 Tranexamic acid 39 (0.1) 52 (0.6) — o0.001 1472 (0.4) 2187 (2.6) — o0.001 168 (202) 111 255 (421) 147 0.200 452 (318) 531 193 (254) 67 o0.001 Protamine 420 (0.8) 341 (3.9) — o0.001 58,470 (15.4) 55,575 (67.1) — o0.001 23 (25) 14 30 (38) 20 0.002 36 (35) 27 38 (41) 27 o0.001 Intraoperative cell saver 375 (0.7) 506 (5.8) — o0.001 0.462 24,377 (6.4) 26,928 (32.5) — o0.001 385 (637) 150 422 (849) 152 495 (803) 228 415 (653) 215 o0.001

FFP¼fresh frozen plasma; PRBCs¼packed red blood cells; rFVIIa¼recombinant activated factor VII.

A . Zbrozek and G. Magee r 2015 1969

In the bleeding patients group, 51.5% (n¼42,691) of patients received RBCs (mean [SD] 4.5 [4.9] U), 36.4% (n¼30,118) received FFP (mean 4.2 [5.5] U), 5.9% (n ¼ 4892) received cryoprecipitate (mean 5.5 [6.8] U), and 27.7% (n ¼ 22,914) received platelets (mean 3.0 [4.8] U). Mean costs for these blood products per transfused patient were $1034 for RBCs, $323 for FFP, $968 for cryoprecipitate, and $1281 for platelets (Table II).

Multivariate models that adjusted for patient dem-ographic characteristics demonstrated that, in bleed-ing patients, the total cost of hospital stay was 133.2% higher when the costs of agents used for bleeding control were included ($50,344 vs $21,590; Po0.001) and 128.7% higher when these costs were excluded ($49,378 vs $21,590; P o 0.001) than in nonbleeding patients (Figure 1;Table III).

Bleeding patients were 4.54 times as likely to be admitted to the ICU, 3.40 times as likely to die, and 4.59 times as likely to be readmitted for bleeding within 30 days (all P o 0.001). They also had a 49.1% longer hospital LOS (P o 0.001) than non-bleeding patients. Mortality was significantly higher in bleeding patients than in nonbleeding patients (5.30% vs 1.43%; P o0.001). Bleeding patients also experi-enced higher rates of a number of adverse events, including TACO (6.38% vs 1.80%; P o 0.001), TRALI (0.07% vs 0.01%; P o 0.001), and acute respiratory distress (0.36% vs 0.22%;Po0.001). In contrast, more nonbleeding patients experienced thromboembolic events than bleeding patients (46.12% vs 29.92%; Po0.001).

DISCUSSION

Our study showed that, in the settings of both trauma and complex cardiac surgery, bleeding patients had significantly worse outcomes than nonbleeding patients. Bleeding patients had longer hospital and ICU LOS, greater inpatient mortality, and higher total costs of care, even when the costs of agents used for bleeding control were excluded. In addition, bleeding patients were more likely to be readmitted to the hospital than nonbleeding patients.

The true total cost of allogeneic blood products is difficult to define, because it must take into account all aspects of the blood collection, production, and administration process. A 2007 study by Shander et al.2 suggested that there were 9 cost areas that must be taken into account, ranging from the costs

T able III. T rauma and complex cardiac surger y patient outcomes, adjusted for patient characteristics LO S and Cost An alysis Nonbl eeding Patients (n ¼ 53,7 2 7 ) Bleedin g Patients (n ¼ 8800) Dif ference (% increase) P V alue Nonb leeding Pat ients (n ¼ 380, 902) Bleedi ng Pat ients (n ¼ 82, 832) Di fference (% increase) P V alue LOS, days, mean (S D) 7. 5 (9. 1) 13.6 (1 4.5) 8 1.3 o 0.00 1 4 .5 (5.0) 11 .5 (1 0.0) 155. 6 o 0.0 0 1 Pat ients with ICU stay , n (%) 20,6 5 1 (38.4 ) 6526 (7 4.2) 93.2 o 0.00 1 1 8 7,39 3 (49.2) 75 ,1 73 (90.8 ) 84. 6 o 0.0 0 1 ICU stay , days, mean (SD) 4.6 (6. 1) 7. 6 (9.7) 65.2 o 0.00 1 2 .8 (3.5) 5.3 (7 .3) 89. 3 o 0.0 0 1 Total patient cos t, $, mean (SD) 1 8,434 (2 4,34 7) 46,0 33 (50,4 49) 150.0 o 0.00 1 2 1 ,59 0 (1 8 ,594) 50, 34 4 (40,4 04) 1 33. 2 o 0.0 0 1 Total patient cos t excluding blood product s o r bloo d manag eme nt, $, mean (SD) 1 8,44 1 (2 4,34 7) 45,3 75 (49,7 62) 146.0 o 0.00 1 2 1 ,59 0 (1 8 ,594) 49,3 7 8 (39,8 22) 128. 7 o 0.0 0 1 Prob ability of Ev ent * Odds Ratio (95% CI) P V alue Odds Ratio (95 % C I) P V alue Inp atient mor tality 4.09 (3.7 4 – 4. 48) o 0.00 1 3.40 (3.25 – 3.55 ) o 0.0 0 1 30-day readmission for blee ding 3. 7 5 (3.08 – 4.58 ) o 0.00 1 4.59 (4.26 – 4.96 ) o 0.0 0 1 ICU adm issio n 3.5 3 (3.2 1 – 3.5 3) o 0.00 1 4.54 (3. 1 0 – 6.80) o 0.0 0 1 CI ¼ con fi dence inter val; ICU ¼ intensive care unit; LO S ¼ length of stay . * Occur ring in bleeding ver sus nonbleeding patients. Clinical Therapeutics 1970 Volume 37 Number 9

incurred by blood donors to the cost of organizing and maintaining nationwide and/or international hemovigilance programs. The authors estimated that, taking into account only 3 of the 9 described cost elements (cost of producing blood components for transfusion, transfusion logistics, and the treatment of transfusion-transmitted disease and associated adverse outcomes), the real cost of blood per unit in 2007 was a minimum of $1400.2Other estimates for the price of blood components per unit have ranged from $350.49 to $780.59.16–18 However, the costs are difficult to compare across studies, because each of these studies was performed in a different clinical setting, and varying methods were used to calculate the total.

A large proportion of the total cost of blood products can be attributed to costs incurred post-transfusion, such as the treatment of adverse events and hospital LOS. On average, bleeding patients in the present study stayed in hospital for 4 days longer than nonbleeding patients, an increase in LOS of 38.9%. Of the patients who were admitted to the ICU, bleeding patients stayed an average of 2 days longer than nonbleeding patients. The impact of transfusion on hospital LOS was shown previously, with 1 UK study estimating that hospital LOS accounted for 66% of total costs.7 A 2008 study of patients with

acute coronary syndrome found that total treatment costs per patient increased by $2080 for each transfusion event.19 Further analysis of these data showed that the majority of this increased cost could be attributed to increased hospital LOS. Another economic study of patients who underwent colorectal cancer resection showed that total hospital charges of transfused patients were significantly higher than those of nontransfused patients ($28,101 vs $15,978; P o 0.0001), and that charges were shown to increase by 2.0% per unit of RBCs and/or platelets transfused after adjustment for confounding factors.20 In addition, hospital LOS was significantly longer in the transfused group (16.7 days vs 10.3 days; P o 0.0001), and was shown to increase by 1.3% for every unit of RBCs and/or platelets transfused.

A number of previous studies showed that the transfusion of allogeneic blood products is associated with a number of adverse events, including TACO, TRALI, allergic reactions, and the transmission of pathogens.4,21–23 In the present study, bleeding car-diac surgery and trauma patients who received trans-fusions experienced significantly higher rates of TACO and TRALI than those who did not receive tranfusions. Studies showed that avoidance of blood

60000 50000 46033 18434 P<0.001 50344 21590 P<0.001 40000 30000 Cost in US$ 20000 10000 0

Bleeding Patients Nonbleeding Patients Trauma

Bleeding Patients Nonbleeding Patients Complex cardiac surgery

Figure 1. Comparison of total hospital costs for bleeding and nonbleeding patients in trauma and complex cardiac surgery.

product transfusion reduced the risk of complica-tions,24 and although data are limited, patient blood management programs were shown to reduce transfusion and improve patient outcomes.25 One recent study showed that the implementation of a blood product conservation initiative in the setting of cardiac surgery reduced postoperative morbidity and mortality, reduced health care costs, and improved resource utilization.26 Furthermore, the implemen-tation of hemostatic therapy algorithms based on point-of-care (POC)-guided coagulation management was shown to reduce blood product transfusion in different clinical settings.27–30In the setting of cardiac surgery, one such study compared a POC-guided algorithm with conventional therapy (whereby hemo-static therapy was driven by laboratory coagulation testing).27 Patients randomized to the POC algorithm group received fewer FFP and platelet transfusions, had shorter ICU LOS, experienced fewer adverse events, and had a lower mortality rate than patients in the conventional therapy group.27

Therefore, we hypothesize that the use of patient blood management strategies may improve clinical outcomes by focusing not only on the reduction of blood product transfusion, but also on minimizing blood loss.25 Preoperatively, this consists of identifying patients at risk of bleeding as soon as possible, and ensuring any necessary treatment is promptly administered. Intraoperatively, the use of meticulous hemostasis, surgical, and anesthetic techniques can all help to minimize blood loss. For example, maintaining physiologic body temperature during surgery can reduce blood loss and transfusion requirements.31,32 Goal-directed therapy can reduce postoperative blood loss,28 and when used in combination with a transfusion algorithm, POC-guided coagulation therapy in the setting of cardiac surgery has been shown to reduce both transfusion requirements and costs.28,33,34

Our study had limitations similar to other obser-vational studies. ICD-9 codes were used to determine patient inclusion; identification of comorbidities and coding practices might differ among hospitals. Sim-ilarly, data regarding use and costs relies on hospitals reporting from their chargemaster records. Finally, our results only considered the variables identified, and the unobserved differences, including differences in the types of surgeries or trauma types, might affect the outcomes considered.

Our study showed that, in the settings of trauma and complex cardiac surgery, bleeding patients who subsequently receive allogeneic blood product trans-fusions have poorer outcomes, which results in higher costs and longer hospital LOS. Minimizing blood loss or prompt resolution of bleeding with targeted ther-apy is likely to reduce additional risks and costs incurred by patients with trauma or who are under-going complex cardiac surgery. These concerns are important both to care providers and to hospital administrators, whose cost perspectives we took. These professionals both worry, to varying degrees, about quality of care and the effects on hospital finances. Procedure-related outcomes generating addi-tional costs and LOS without reimbursement adjust-ments bode poorly for the finances of the entire provider institution. Further, the results of this study provide break-even estimates for administrators and clinicians to use when evaluating the costs of therapies designed to avoid surgical bleeding.

ACKNOWLEDGMENTS

Both authors designed this study and prepared the article, and approved the_final article. Medical writing assistance for this study was provided by Meridian HealthComms, funded by CSL Behring. The input of Joanna Whyte, while at CSL Behring Global Health Economics, is acknowledged.

CONFLICTS OF INTEREST

Art Zbrozek is an employee of CSL Behring. Glenn Magree is an employee of Premier Research Services, which received funding from CSL Behring to conduct this study. The authors have indicated that they have no other conflicts of interest regarding the content of this article.

SUPPLEMENTAL MATERIAL

Supplementary data associated with this article can be found in the online version at http://dx.doi.org/ 10.1016/j.clinthera.2015.06.007.

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Address correspondence to: Arthur Zbrozek, MSc, MBA, RPh CSL Behring, 1020 1st Avenue, King of Prussia, PA 19406. E-mail: art. [email protected]

Clinical Therapeutics