Effect of pharmacy management on turnaround time of 4-factor prothrombin complex concentrate

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1 PHARMACY MANAGEMENT AJHP RESIDENTS EDITION Effect of pharmacy management on turnaround time of 4-factor prothrombin complex concentrate Eileen Langstraat, Pharm.D., BCPS, Department of Pharmacy, Kaiser Permanente, Rockville, MD. Ashley Martinelli, Pharm.D., BCCCP, Department of Pharmacy, Univeristy of Maryland Medical Center, Baltimore, MD. Brian Spoelhof, Pharm.D., BCPS, Department of Pharmacy, Lahey Hospital, Burlington, MA. Shailly Shah, Pharm.D., M.S., BCPS, Department of Pharmacy, Emory University Hospital Midtown, Atlanta, GA. Address correspondence to Dr. Martinelli Copyright 2017, American Society of Health-System Pharmacists, Inc. All rights reserved /17/0901-0S61. DOI /ajhp Purpose. The change in turnaround time of 4-factor prothrombin complex concentrate (PCC) when managed by the pharmacy department compared to blood bank management was evaluated. Methods. A retrospective analysis evaluated blood bank versus pharmacy management of PCC. Blood bank management was evaluated from November 2014 to November 2015, and pharmacy management was evaluated from December 2015 to July Chart review was performed on all patients who received PCC during these study periods. The primary outcome was the difference in median time from order entry to administration between management groups. Comparisons were made for the appropriateness of clinical use, length of stay, and discharge status. The primary outcome was analyzed using a Mann Whitney U test. Secondary outcomes were analyzed using the chi-square test or Fisher s exact test. Descriptive statistics were utilized to analyze secondary outcomes. Results. Forty-three patients received PCC in the blood bank group, and 22 patients received PCC in the pharmacy group. Median turnaround time of PCC was lower in the pharmacy group (43 minutes; interquartile range [IQR], minutes) compared to the blood bank group (62 minutes; IQR; minutes; p = 0.032). PCC use was clinically appropriate for 55% of patients (n = 12) in the pharmacy group compared with 37% of patients (n = 16) in the blood bank group (p = 0.182). There were no significant differences between the blood bank and pharmacy groups with regard to hospital length of stay or in-hospital mortality. Conclusion. Conversion of PCC management from the blood bank to the pharmacy was associated with a significant decrease in time to PCC administration. Keywords: blood coagulation factors, hospital medication errors, prothrombin complex concentrates, warfarin Am J Health-Syst Pharm. 2017; 74(suppl 3):S61-6 Four-factor prothrombin complex concentrate (PCC; Kcentra, CSL Behring, King of Prussia, PA) is a blood-derived product containing clotting factors II, VII, IX, and X. 1 It is approved by the Food and Drug Administration (FDA) for the rapid reversal of vitamin K antagonist (VKA)- induced coagulopathy in serious bleeding events, such as intracranial hemorrhage (ICH), or when an urgent surgery or invasive procedure is necessary, based on evidence showing safety and efficacy compared with fresh frozen plasma. 2-8 Additionally, PCC has been investigated for use as a reversal agent for the factor Xa inhibitors, although it is currently not FDA approved for this indication. 9 The American College of Chest Physicians, 10 the Neurocritical Care Society, and the Society of Critical Care Medicine 11 have published clinical practice guidelines for antithrombotic therapy and prevention of thrombosis. These guidelines recommend the use of AM J HEALTH-SYST PHARM VOLUME 74 SUPPLEMENT 3 SEPTEMBER 1, 2017 S61

2 AJHP RESIDENTS EDITION PHARMACY MANAGEMENT PCC in combination with intravenous phytonadione for rapid anticoagulation reversal in patients with VKAassociated major bleeding or the potential for significant blood loss from urgent surgical intervention. Literature and guidelines emphasize timeliness of anticoagulation reversal with PCC because, in patients with life-threatening bleeding, delays in reversal have been associated with increased mortality; however, no specific recommendation of time from patient presentation to PCC administration is provided A singlecenter, retrospective study including 56 patients with ICH found that a reversal time of less than 200 minutes was associated with a significantly smaller increase in ICH volume on repeat computerized tomography scan compared with patients reversed with PCC beyond 200 minutes after presentation. 14 Currently, no best-practice model for the evaluation, preparation, and distribution is available to expedite appropriate PCC administration. An evaluation of a pharmacy-led, blood factors stewardship program showed that pharmacy management of blood factors was associated with increased appropriate use of blood factors. 15 That study also found that pharmacy stewardship of blood products led to cost savings. Pharmacy management offers several advantages including increased familiarity with calculations to ensure proper dosing, clinical pharmacist evaluation, and the potential for decreased time to product administration to the patient. Additionally, accurate dose preparation is complicated because the number of units per vial varies among different lots of the same product. 1,2 Institutions may choose to administer the exact volume corresponding to the ordered dose or round the final dose to the nearest vial size. If the chosen procedure is not done systematically, there could be a discrepancy between the units of PCC actually administered versus the amount recorded in the medical record and subsequently charged. Eileen R. Langstraat, Pharm.D., BCPS, is the postgraduate year 2 (PGY2) medication-use safety pharmacy resident at The Johns Hopkins Hospital. She received her bachelor of arts degree in biochemistry from Saint Mary s College of Maryland in 2009 and her doctor of pharmacy degree from Shenandoah University in Dr. Langstraat completed an ASHP-accredited postgraduate year 1 pharmacy residency at Johns Hopkins Bayview Medical Center in Her current research interests include medication safety and medication-use process quality improvement. Following the completion of her PGY2 medication-use safety residency, Dr. Langstraat will be the pharmacy medication and patient safety coordinator at Kaiser Permanente, Rockville, Maryland. We conducted a study at the Johns Hopkins Bayview Medical Center, a 527-bed academic medical center that transitioned management of all blood factors from the blood bank to the pharmacy department on December 1, The institution has an anticoagulation clinic, is a comprehensive stroke center, and is a level II trauma center, which has a neurocritical care unit with neurosurgery on site. Clinical pharmacy services are available throughout the hospital, including in the emergency department, neurocritical care unit, and the anticoagulation clinic. This study focused on the impact of the transition of PCC from blood bank management to pharmacy management specifically because of the emergent nature of its use and because of its complicated dosing requirements. Activated PCC (Feiba, Shire, Lexington, MA) is also available at our facility but was not included in this study because of a lack of product utilization during the time frames of interest. Before the transition, orders for PCC were processed through the blood bank and not transmitted directly to pharmacy. Ordering was limited to a list of approved providers or to other prescribers after consultation with a 24-hour transfusion medicine service. After the order was received and verified, the blood bank dispensed the number of factor IX units rounded to the nearest vial. A blood bank or pharmacy staff member would transfer the product to the pharmacy for sterile preparation before delivery to the bedside for administration. Under this process, the pharmacy received no orders for PCC, and no labels or medication administration record documentation was created. All orders were documented in nursing notes when administered. The implementation of a new electronic medical record (EMR) afforded the institution the opportunity to simplify this process by moving it entirely to pharmacy management, including blood factor storage, and to standardize order evaluation for clinical appropriateness. A standardized process for clinical evaluation, dose rounding, preparation, and distribution of PCC orders was developed jointly by the departments of pharmacy, transfusion medicine, emergency medicine, neurocritical care, trauma, and hematology. Furthermore, a guideline approved by the pharmacy and therapeutics committee was developed to expedite emergent reversal of anticoagulation in ICH. When the guideline was followed, the requirement for transfusion medicine approval was waived. The primary purpose of the study was to evaluate the change in time from order placement to administra- S62 AM J HEALTH-SYST PHARM VOLUME 74 SUPPLEMENT 3 SEPTEMBER 1, 2017

3 PHARMACY MANAGEMENT AJHP RESIDENTS EDITION tion of PCC when managed by the pharmacy department compared with previous management by blood bank and preparation by pharmacy. The secondary objective of the study was to compare appropriateness of clinical use of PCC between these management groups. Methods This was a retrospective, observational, single-center, qualityimprovement project that was approved by the investigational review board. Patients were included in the study if they were at least 18 years of age and were administered PCC between the time points of interest. Patients for the blood bank management group received PCC between November 2014 and November Patients for the pharmacy management group received PCC between December 2015 and July The institution moved to a new EMR system on December 1, 2015; therefore, time points of interest for each group were selected based on when the transition from blood bank to pharmacy management occurred (also on December 1, 2015) as well as when the change to the new EMR occurred. Patients for the blood bank group were identified utilizing an automated search of the blood bank s electronic record system for PCC use during the time points of interest. Patients were identified for the pharmacy group by performing an automated search of the EMR for PCC administration during the time points of interest. Individual patient charts were then reviewed for data collection. Recorded patient variables included patient demographics, ordered PCC dose, administered PCC dose, phytonadione ordered dose and administration route, order entry and administration times for PCC and phytonadione, initial and post-pcc International Normalized Ratio (INR), length of stay, and mortality. For patients receiving warfarin, all INR results within the 48 hours after PCC administration were also collected. Demographics collected included age, sex, race, weight, indication for PCC administration, initial INR, prescribed anticoagulant, and indication for anticoagulant use. The per-protocol PCC dose was calculated retrospectively for each patient in the study using the patient s initial INR and the patient weight that was utilized for the PCC order, and comparisons were made between this calculated per-protocol dose and the administered dose. The weight entered in the hospital computer system at the time of PCC ordering was used. This may have been an estimated weight depending on patient location and clinical status. The primary outcome of the study was turnaround time for PCC, which was defined as the length of time in minutes from the time of PCC order entry to the recorded start of PCC administration. Secondary outcomes were appropriateness of clinical use, length of stay, and inhouse mortality. Appropriateness of clinical use of PCC was defined a priori as adhering to the approved indication (ICH or major bleeding in a patient taking a reversible anticoagulant, and INR > 1.4 if the patient is taking warfarin), dose precision, and i.v. phytonadione administration within 2 hours of PCC in patients receiving warfarin. Approved indication for PCC use was defined as the occurrence of a major bleeding event or requirement of urgent invasive procedure in a patient receiving anticoagulation therapy with warfarin or a factor Xa inhibitor. Major bleeding was defined as presence of ICH or other life-threatening bleeding warranting anticoagulation reversal as per the provider s clinical judgement. Dose precision was defined as 10% difference between ordered and calculated doses. One-time PCC doses were those in our institution s evidencebased dosing protocol 1,10,11 : 25 units/ kg i.v. (maximum, 2,500 units) for an INR of >1.4 and <4, 35 units/kg i.v. (maximum, 3,500 units) for an INR of 4 and <6, and 50 units/kg i.v. (maximum 5,000 units) for an INR of 6. Phytonadione order turnaround time was defined as the duration in minutes from order entry to pharmacist verification, and it was collected to set a reference for pharmacy processing time for both periods of interest. Categorical variables were analyzed using a chi-square test. Continuous variables were analyzed using a Mann Whitney U test. Descriptive statistics used median with interquartile ranges (IQR) and percentages. The a priori level of significance was A power analysis was not conducted. Statistical calculations were performed using SPSS Statistics, version 22 (IBM Analytics, Armonk, NY). Results A total of 65 patients were identified for inclusion in the study (Table 1). The blood bank group and pharmacy group included 43 and 22 patients, respectively. Patients did not differ significantly in age, sex, or other assessed baseline characteristics. The majority of patients in both groups were taking warfarin for anticoagulation. Three patients in the blood bank group (7%) were taking rivaroxaban and 1 patient (2%) was taking dabigatran. The median initial INR was 2.7 for the blood bank group compared with 2.6 for the pharmacy group. The majority of patients in both groups received PCC for anticoagulation reversal in the setting of an ICH (Table 2). The median turnaround time of PCC was shorter in the pharmacy group (43 minutes; IQR, minutes) compared with the blood bank group (62 minutes; IQR, minutes) (p = 0.032). Median turnaround time for phytonadione was similar for the blood bank group (45 minutes; IQR, minutes) and the pharmacy group (47 minutes; IQR, minutes) (p = 0.545). The median time to verification of phytonadione orders was 2 minutes (IQR, 1 6 minutes) in the blood bank group and 2 minutes (IQR, 0 5 minutes) in the pharmacy group (p = 0.24). PCC was used appropriately for 12 patients (55%) in the pharmacy group AM J HEALTH-SYST PHARM VOLUME 74 SUPPLEMENT 3 SEPTEMBER 1, 2017 S63

4 AJHP RESIDENTS EDITION PHARMACY MANAGEMENT Table 1. Patient Characteristics Variable a compared with 16 patients (37%) in the blood bank group (Table 3). The most common reason that a PCC administration did not qualify as appropriate use was the presence of a >10% difference between the calculated and administered PCC doses, followed by failure to administer 10 mg of i.v. phytonadione within 2 hours of PCC administration. After PCC administration, INR results within the first 24 hours were similar between groups for those patients with warfarin-induced coagulopathy. The median postdose INR after PCC administration was 1.2 for both groups. All surviving patients in the pharmacy group (1 died before follow-up) and 39 patients in the blood bank group (91%) achieved successful Blood Bank Group (n = 43) reversal of anticoagulation, as indicated by a postdose INR of <1.4 after PCC administration. In the 48 hours after PCC administration, 10 patients in the blood bank group (23%) and 1 patient in the pharmacy group (5%) had a repeat INR of >1.4 (p = 0.066). There were no significant differences between the blood bank and pharmacy groups with regard to hospital length of stay or in-hospital mortality. Discussion The best practice for management of PCC is not currently known. Available evidence suggests that pharmacy management of blood factors may be beneficial for reducing unnecessary or inappropriate PCC use. 15 Additionally, Pharmacy Group (n = 22) p Median age (yr, IQR) 78 (66 83) 82 (75 85) No. (%) women 21 (49) 11 (50) No. (%) Caucasian 34 (79) 14 (64) 0.18 Median weight (kg, IQR) 76.7 ( ) 76.7 ( ) No. (%) treated with warfarin 34 (79) 20 (91) No. (%) with atrial fibrillation 25 (58) 18 (82) Median initial INR (IQR) 2.7 ( ) 2.6 ( ) a IQR = interquartile range, INR = International Normalized Ratio. Table 2. Indications For 4-Factor Prothrombin Complex Concentrate Indication No. (%) Patients With Indication Blood Bank Group (n = 43) Pharmacy Group (n = 22) Intracranial hemorrhage 34 (79) 16 (73) Surgery 2 (5) 1 (5) Gastrointestinal bleeding 3 (7) 2 (9) Hemophilia 2 (5) 0 Hemoptysis 2 (5) 0 Emergent surgery with liver dysfunction 0 1 (5) Acute chest wall hematoma 0 1 (5) Unspecified petechial hemorrhages 0 1 (5) decreased time to PCC administration has been correlated with a decrease in bleeding volume in ICH, which suggests a possible correlation with improved outcomes overall. 14 Our study compared PCC management by the blood bank with PCC management by pharmacy and found several differences. Management of PCC by pharmacy at this institution was associated with a significant decrease in time from order entry to patient administration. Comparatively, turnaround time for phytonadione did not differ significantly between groups. Because pharmacy was responsible for clinical review, verification, preparation, and dispensing of phytonadione throughout both study time periods, this suggests that pharmacy dispensing processes did not differ significantly during the different time periods. Previous studies have shown that rapid correction of elevated INRs in serious bleeding events reduces mortality. 12,13 Another study correlated shorter time to PCC administration with a significant decrease in hematoma expansion. 14 Our current study did not show significant differences between groups with regard to mortality or hospital length of stay. This was a small study that was underpowered to find such differences in a patient population at known risk for increased mortality. There was also no significant difference between groups in the first post-pcc INR, but there were S64 AM J HEALTH-SYST PHARM VOLUME 74 SUPPLEMENT 3 SEPTEMBER 1, 2017

5 PHARMACY MANAGEMENT AJHP RESIDENTS EDITION Table 3. Appropriateness of Use of 4-Factor Prothrombin Complex Concentrate (PCC) Appropriateness Criterion a more patients in the blood bank group whose INR did not remain below 1.4 in the 48 hours after PCC administration. This difference may be attributed to the lower frequency of appropriate phytonadione administration in the blood bank group. The frequency of appropriate PCC did not differ significantly between the 2 groups. In both groups, some patients received doses that deviated more than 10% from the correct dose per protocol. This is an inherent problem associated with PCC because the product contains variable amounts of factor IX. An increase in the number of patients who received phytonadione 10 mg was noted in the pharmacy group. This was likely due to a standardized order set containing both agents and education provided to pharmacists. The decision to permit only 10% variance between ordered and dispensed doses was made before the transition to pharmacy. This was arbitrarily set based on acceptable rounding rules. There are no data available to guide this practice, and perhaps this limitation is too stringent. Some institutions currently practice a fixeddose protocol for PCC. Variable dosing has been compared with fixed dosing, with no significant difference found between groups in INR reduction. 16 Klein et al. 17 also demonstrated that a fixed-dose strategy of PCC 1,500 units was associated with a high rate of INR reversal with no adverse events. A newer study demonstrated that having a fixed dosing protocol did not improve time to PCC administration and necessitated subsequent doses of PCC to achieve a target INR. 18 Simplifying a complex ordering and dispensing process may have benefits, but the overall clinical outcomes of simplification are not known at this time. There were several limitations to this quality-improvement study. The study included a small sample size, encompassing a total of 65 patients. This prevented determination of differences in clinical outcomes between groups, such as length of stay and mortality. The study time frame was also a limitation, because staff training may be different depending on the time of year. There were also possible differences in workload and staffing that cannot be accounted for between the 2 groups. The limited study duration for the pharmacy group contributed to the small sample size of the pharmacy group compared with the blood bank group. This study did not examine adverse events associated with PCC use (e.g., thrombolytic events), which would have been helpful for evaluation of how inappropriate PCC use affects adverse event occurrence. We did not collect the administration of blood products, such as fresh frozen plasma, packed red blood cells, No. (%) Patients With Treatment Meeting Criterion Blood Bank Group (n = 43) Pharmacy Group (n = 22) p Patient taking reversible anticoagulant b 37 (86) 20 (91) Patient has ICH or acute major bleeding 36 (84) 21 (95) Initial INR >1.4 c 34 (79) 21 (95) Phytonadione 10 mg i.v. given when indicated 33 (77) 21 (95) <10% difference between ordered and calculated PCC doses 23 (53) 14 (64) All criteria met 16 (37) 12 (55) a ICH = intracranial hemorrhage, INR = International Normalized Ratio. b Reversible anticoagulants includes warfarin, rivaroxaban, and apixaban. c INR >1.4 during treatment with warfarin or use of other reversible anticoagulant. and platelets, because our focus was specific to blood factors within the pharmacy processes. Additionally, the time to measurement of the first INR was not collected (rather, the first INR post-pcc). Because this was a singlecenter study at an academic medical center, these results may not be applicable to all hospital settings where PCC is utilized. Additionally, there was the possibility of clinical pharmacist intervention on PCC orders during the blood bank time frame, which could potentially confound results. Conclusion Conversion of PCC management from the blood bank to the pharmacy was associated with a significant decrease in time to PCC administration. Acknowledgments The authors acknowledge Nicole Kiehle, Pharm.D., BCPS, for her thoughtful review of this manuscript and suggested edits. Disclosures The authors have declared no potential conflicts of interest. Previous affiliations When this project was conducted, all authors were affiliated with Johns Hopkins Bayview Medical Center, Baltimore, MD. References 1. Kcentra (prothrombin complex concentrate [human]) package insert. Kankakee, IL: CSL Behring LLC; AM J HEALTH-SYST PHARM VOLUME 74 SUPPLEMENT 3 SEPTEMBER 1, 2017 S65

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