Research and Reports Evaluating Warfarin Management by Pharmacists in a Community Teaching Hospital Allison A. Chilipko, Daryn K. Norwood Objective: The purpose of this study was to evaluate warfarin management by pharmacists compared with physicians through an inpatient anticoagulation management service (AMS). Design: Retrospective cohort study. Setting: Community teaching hospital. Patients, Participants: Patients were randomly selected from the Inpatient AMS from January 1, 2009 to January 1, 2011. Patients were included if they were 18 of age years or older and received warfarin for at least three days and excluded for indefinite warfarin discontinuation or an indication following orthopedic surgery. A total of 179 patients were included in each group. Interventions: The electronic medical record was reviewed for demographics, warfarin indication and goal range, international normalized ratios (INRs), albumin, drug-drug interactions, bleeding, and thrombotic rates. Main Outcome Measures: Primary endpoints included mean time to therapeutic INR, mean time within goal, frequency of supratherapeutic INRs, bleeding, thrombotic rates, and mean INR on discharge. Results: There was no statistically significant difference in the time required to reach a therapeutic INR; 3.17 vs. 2.65 days (95% confidence interval -0.09-1.13; P = 0.093). However, the pharmacist group resulted in a lower frequency of supratherapeutic INRs and significantly more time within goal range. Conclusion: Similar results were observed for pharmacistmanaged and physician-managed patients for INR monitoring and outcome rates. However, the pharmacistmanaged patients demonstrated a lower incidence of supratherapeutic INRs and significantly more time within goal. Key Words: Anticoagulation, International normalized ratio, Joint Commission, Pharmacist, Pharmacokinetics, Warfarin.
Abbreviations: AE = Adverse events, Afib = Atrial
fibrillation, AMS = Anticoagulation management service, CT = Computed tomography, DVT = Deep venous thrombosis, FDA = Food and Drug Administration, FFP = Fresh frozen plasma, Hgb = Hemoglobin, INR = International normalized ratio, NNT = Number needed to treat, NPSG = National Patient Safety Goal, PE = Pulmonary embolism, PI = Performance improvement, PMS = Pharmacokinetics Monitoring Service, Scr = Serum creatinine, TTR = Time in therapeutic range. Consult Pharm 2014;29:95-103.
Introduction In 2008, National Patient Safety Goal (NPSG) 03.05.01 was adopted by the Joint Commission to reduce the likelihood of patient harm associated with the use of anticoagulation.1 As outlined within this goal, the institution should maintain an anticoagulation management program to decrease adverse drug reactions associated with administration, monitoring, and counseling. The NPSG also required facilities to develop a protocol for recommending initial and maintenance warfarin doses based on individual patient risk factors (i.e., albumin, age, presence of drug-drug interactions, etc.) and to establish a policy for monitoring anticoagulation therapy.1 To achieve compliance with this goal, our community teaching hospital initiated an inpatient anticoagulation management service (AMS) in 2008. This community teaching hospital supports approximately 290 beds, specializing in cardiovascular surgery, stroke, diabetes care, and orthopedic and hand surgery. To optimize safe medication use, the pharmacy department supports a Pharmacokinetics Monitoring Service (PMS) and Drug Information telephone line. Through this service, clinical pharmacists monitor patients on a daily basis to track pertinent vital signs, laboratory data, imaging results, and microbiological cultures for antimicrobial stewardship, appropriate renal dose adjustment, and intravenous to oral conversion. Routinely monitored medications
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Research and Reports include vancomycin, aminoglycosides, enoxaparin, phenytoin, ketorolac, tramadol, and restricted antimicrobials. In addition, pharmacists also are involved with seeing patients with the various acute care teams on the general medicine service and in the intensive care unit. For anticoagulation management, the role of the clinical pharmacist was limited within the scope of the PMS prior to 2008. The pharmacist would review the abnormal laboratory report and follow up on patients with international normalized ratios (INRs) greater than 4.0. However, beyond recommending changes in therapy, pharmacists were not empowered to manage therapy “per protocol.” To further minimize the risk of adverse events (AEs), the second author of this paper developed and obtained approval for the AMS. This new service was intended to allow the pharmacy department to significantly expand the existing scope of anticoagulation monitoring by incorporating the AMS within the PMS in 2008. After starting this service, the pharmacists followed all patients receiving warfarin therapy during their inpatient stay. On each sheet, the pharmacist records patient weight, age, and ethnicity; warfarin indication and goal INR range; home warfarin dose; and albumin, if available. On a daily basis, the pharmacist records the patient’s INR, hemoglobin (Hgb), hematocrit, platelets, and inpatient warfarin dose in addition to screening for bridge therapy with heparin or enoxaparin, vitamin K administration, and the presence of significant drug-drug interactions. For physician-managed patients, the pharmacist may intervene to recommend a dose change based on INR trend or suggest the need for bridge therapy. Ultimately, the AMS allows warfarin dosing by pharmacy when requested by the prescriber. If pharmacy services are ordered, the pharmacist is then responsible for managing the patient’s therapy (i.e., writing warfarin orders and/or ordering appropriate laboratory work, and providing patient education for those who newly start warfarin). The pharmacist will document these interventions in an initial progress note with subsequent progress notes every 72 hours. For continuing quality improvement, the service is evaluated every six months through a pharmacy performance improvement (PI) initiative.
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Other institutions have adopted a similar philosophy to include the pharmacy department in efforts to reduce AEs.2-6 In a study by Jennings et al., pharmacist involvement in anticoagulation management led to a reduction in thromboses (4.6%-3.9%), major bleeds (8.7%-3.3%), and minor bleeds (4.6%-3.5%) from 2004 to 2006.5 The number needed to treat (NNT) to prevent one thrombotic event was 25.8 patients, compared with 30.6 patients and 37.1 patients to avoid one major and minor bleed, respectively.5 Additional literature stems from a study by Biscup-Horn et al. for the cardiac surgery unit.6 AMS development resulted in a 17% decrease in postoperative length of stay (13.9 vs. 11.6 days; P = 0.015), when comparing pre-implementation with post-implementation.6 The service also showed a reduction in postsurgical supratherapeutic INR values (13.4% vs. 7.2%; P = 0.036) and postoperative bleeding (3.1% vs. 1.3%; P = 0.22).6 While the majority of published literature regarding pharmacist-driven anticoagulation management was conducted in larger medical centers, these studies vary according to endpoints and pharmacist involvement. Also, they evaluate pre- and post-implementation without direct comparison both with and without a pharmacist. Therefore, the objective of the current study was to evaluate INR trends and event rates from physician-managed patients versus pharmacist-managed patients to assess the impact of the AMS at our facility.
Methods Study Design A retrospective cohort study was conducted to compare pharmacist-managed patients with those receiving standard care through physician management. The authors obtained Institutional Review Board approval from the health systems research institute. The study was designed to include more patients than the existing PI in providing a more comprehensive evaluation of patient outcomes over a longer time period. Patient cases were randomly selected from January 1, 2009, to January 1, 2011.
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Patient Population Eligible patients were randomly identified from the patients followed through the AMS from January 1, 2009 to January 1, 2011. To qualify for retrospective study inclusion, patients needed to be 18 years of age or older and receiving warfarin for at least three consecutive days during their admission. Patients in the physician-managed group were also selected randomly with the same inclusion criteria to equal the same number of patients managed by pharmacists. Patients were excluded if warfarin was discontinued indefinitely during their hospital stay or if they were receiving warfarin for prevention of venous thromboembolism following orthopedic surgery. This latter group was excluded since they are given a lower INR goal (INR 1.5-2.0) at our facility, and the majority of warfarin prescribing is done by the orthopedic physician assistants with limited pharmacy involvement as this population often has a duration of stay ≤ 3 days. Data Collection For patients who met inclusion criteria, the electronic medical chart was reviewed to evaluate patient demographics, indication for anticoagulation, goal INR range, consecutive INRs during hospitalization, length of stay, INR on discharge, need for vitamin K administration, and first outpatient INR at the Anticoagulation Clinic. To recognize potential confounders and account for any discrepancies between the groups, investigators also collected the patient’s albumin level on admission and potential for drug-drug interactions that may influence the INR. A low albumin may increase sensitivity to warfarin and potentially increase the risk for developing a supratherapeutic INR. A supratherapeutic INR was defined as any INR value greater than the therapeutic range defined by the indication for anticoagulation. For instance, any INR > 3.0 would be considered supratherapeutic for a goal INR of 2.0-3.0. Also, drug-drug interactions may lead to a more labile INR. Drug-drug interactions were organized into three categories: drugs that increase bleeding risk, drugs that increase the INR, and drugs that decrease the INR (Table 1). The drugs listed in Table 1 include those
routinely tracked for all patients receiving warfarin by the AMS. This table is not meant to include all potential interactions with warfarin and only reflective of the information used internally on our monitoring form for managing warfarin therapy. Therefore, only medications on the formulary at our facility are listed. Other rarely used medications (prasugrel or aspirin/extended-release dipyridamole) were added, as needed at the discretion of the pharmacist. Bridge therapy with heparin or enoxaparin (or other parental anticoagulants) was included with the daily monitoring of warfarin dosing. The data collection process also incorporated the number of drugs within each category as well as the number of patients with drug-drug interactions in more than one category. Subtherapeutic INRs were not collected, as the goal of the NPSG is to reduce the likelihood of patient harm associated with the use of anticoagulation. Therefore, our study focused on bleed risk from anticoagulation. While the number of subtherapeutic INRs may serve more utility in the outpatient setting, in the inpatient setting, the incidence of thrombotic events was used to determine any AEs associated with subtherapeutic INRs. To evaluate the future impact of oral direct thrombin inhibitors, the number of patients who would potentially qualify for dabigatran was determined from the sample population. A patient was deemed to be potentially appropriate for dabigatran if the patient was receiving anticoagulation for nonvalvular atrial fibrillation (Afib) and had a creatinine clearance greater than 15 milliliters/ minute. Given the Food and Drug Administration’s (FDA’s) approval of dabigatran during the course of the study period, all patients were evaluated for dabigatran eligibility, regardless of time of hospital admission, to provide a preliminary analysis of the potential effect of dabigatran on the AMS. Dabigatran was the only FDA-approved oral alternative to warfarin at the time of this study. The occurrence of bleeding and thrombotic events was collected from the following parameters: Bleeding was defined by patient-reported symptoms, need for transfusion with packed red blood cells or use of fresh frozen plasma (FFP), positive stool guiac results, and/or
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Table 1. Drug-Drug Interaction Categories* ↑ Bleed Risk
↑ INR
↓ INR
Aspirin Clopidogrel Celecoxib/Nonsteroidal Anti-Inflammatory Drugs
Allopurinol Amiodarone/Dronedarone Azithromycin/Clarithromycin
Carbamazepine Nafcillin/Dicloxacillin Phenobarbital
Ketorolac
Fluconazole/Metronidazole Simvastatin Sulfamethoxazole-Trimethoprim Moxifloxacin/Ciprofloxacin Tramadol Steroids Acetaminophen > 2 g/day
Phenytoin Rifampin Ritonavir
* Drug-drug interactions recorded by the AMS (only the more common types of interactions are listed). Abbreviations: AMS = Anticoagulation management service, INR = International normalized ratio.
a decrease in the Hgb by ≥ 2 g/dL in 24 hours. An acute thrombotic event was documented by positive Doppler Duplex findings for deep venous thrombosis (DVT), positive chest computed tomography (CT) or lung ventilation perfusion scan results for pulmonary embolism (PE), and/ or positive head CT scan for stroke. Thrombotic events were defined as new events occurring after warfarin therapy was instituted for patients newly starting on warfarin during hospital admission or acute thromboses in patients already receiving warfarin prior to admission. Extension of an existing thrombosis or documentation of chronic or old thromboses was not counted as a new thrombotic event.
Outcomes Primary endpoints focused on INR trends, bleeding and thrombotic event outcomes, and duration of pharmacy dosing in conjunction with total length of hospitalization. The mean time to reach a therapeutic INR, mean time spent within goal range, and mean INR on discharge were compared between groups. The mean time to reach a therapeutic INR was defined as the number of days to reach a therapeutic INR in patients newly starting on warfarin during their hospital stay who presented with a
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subtherapeutic INR on admission, or who had warfarin held because of a supratherapeutic INR value. Mean time spent within INR goal range was calculated as the number of consecutive days during the hospital admission when the patient had a therapeutic INR. Additionally, the frequency of supratherapeutic INRs was identified both before and after pharmacy management as opposed to the cumulative incidence for physician-managed patients. Time in therapeutic range (TTR) was not collected as this measure is often more reflective of outpatient monitoring for anticoagulation. Including TTR for inpatient anticoagulation may be misleading as INR monitoring frequency is often daily and may be falsely weighted in one direction versus another depending on whether the patient was admitted with a therapeutic INR or was started on warfarin during the admission. Furthermore, the TTR value is also limited in the inpatient setting, as many patients initiated on warfarin during their admission are often discharged once the INR became therapeutic. Given these concerns, the authors collected mean time (days) to reach a therapeutic INR, mean time (days) spent within goal range, mean INR on discharge, and frequency of supratherapeutic INRs for both groups.
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Secondary outcomes included frequency of vitamin K administration, mean INR at outpatient follow-up, and potential patient suitability for dabigatran. Eligibility was determined, based on indication for anticoagulation and renal function, to estimate the number of patients who could possibly be transitioned from warfarin and subsequent changes in service volume.
Statistical Analysis The choice of statistical test was made based on the nature of the outcome to enable the recognition of statistically significant differences between the pharmacist-managed and physician-managed patients. Chi-square testing was used for the following categorical outcomes: bleeding and thrombotic events, supratherapeutic INR incidence, vitamin K administration, and dabigatran candidacy. A two-tailed unpaired Student’s t-test with 95% confidence interval (CI) was calculated for continuous endpoints: mean time to therapeutic INR and mean INR on admission, discharge, and follow-up. A P-value less than 0.05 represented a statistically significant difference. SAS version 9.1.3 (SAS Institute, Cary, NC) was used for all statistical analysis.
Results Demographics At baseline, the pharmacist-managed and physicianmanaged groups were similar, with significant differences only in male gender and number of hemodialysis patients (Table 2). There were significantly more males in the physician-managed (n = 97, 54%) than the pharmacistmanaged (n = 74, 41%) group; P = 0.015, whereas there were significantly more hemodialysis patients in the pharmacist-managed (n = 40, 22%) vs. the physicianmanaged (n = 23, 12%) group; P = 0.018. Anticoagulation Indication and Goal INR Range In both groups more than half of the patients were receiving warfarin prior to admission: 125 patients in the pharmacist-managed (70%) vs. 108 patients in the physician-managed (60%) group (Table 2). The most
frequent indication for anticoagulation was Afib. An INR goal of 2.0-3.0 was targeted for more than 90% of the patients in both groups. Given the prevalence of Afib, close to one-third of the patients in the pharmacist-managed (n = 57, 32%) and physician-managed (n = 71, 40%) group may have been eligible for dabigatran. This eligibility estimate was based solely on the number of patients in either treatment arm with a creatinine clearance > 15 mL/min and who were receiving warfarin for nonvalvular Afib. However, since completing this study, our internal PI data have shown approximately 80 patients on dabigatran annually in 2011 and 2012 compared with approximately 100 patients on rivaroxaban in 2012. Despite the increased use of other oral anticoagulants, the inpatient anticoagulation service has continued to manage 379 patients on warfarin in 2011 and 444 patients on warfarin in 2012.
Albumin and Drug-Drug Interactions Albumin levels were comparable between the groups with a mean albumin of 3.1 ± 0.6 g/dL (129/179 patients) and 3.2 ± 0.5 g/dL (111/179 patients) in the pharmacistmanaged and physician-managed groups, respectively (95% CI -0.215-0.077; P = 0.350). Given this similarity, differences in albumin level and warfarin sensitivity did not account for inter-group differences in patient outcomes. All patients were subject to at least one drug interaction between warfarin and one of the agents listed in Table 1. There was no significant difference between the groups for the number of patients subject to drug-drug interactions in one of the three categories or in all three categories. However, significantly more patients in the physician-managed group (n = 112, 63%) demonstrated drug-drug interactions in two of the three categories compared with the pharmacist-managed group (n = 92, 51%; P = 0.033). Within each of the three categories, there was no difference between the number of patients for the pharmacist-managed and physician-managed groups. Length of Stay The physician-managed group had a significantly shorter mean length of stay (6.7 ± 4.6 days) versus the pharmacistmanaged group (8.1 ± 6.1 days, 95% CI 0.35-2.60; P = 0.01).
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Table 2. Baseline Demographics Physician-Managed (n = 179)
P-value
97 (54)
0.015*
105 (59) 63 (35) 11 (6) 67 ± 13.5 23 (13)
0.449 1.000 0.062 0.710 0.018*
75 (42) 70 (39) 19 (10) 7 (4) 5 (3) 3 (2)
77 (43) 57 (32) 14 (8) 11 (6) 11 (6) 9 (5)
0.831 0.151 0.834 0.333 0.125 0.078
168 (94) 5 (3) 6 (3)
163 (91) 6 (3) 10 (6)
0.317 0.759 0.306
Pharmacist-Managed (n = 179) 74 (41) Male Gender, n (%) Race/Ethnicity, n (%) 112 (63) African-American 63 (35) Caucasian 4 (2) Other 67 ± 14.9 Mean Age (yrs) ± SD 40 (22) Hemodialysis, n (%) Indication for Anticoagulation, n (%) Afib DVT/PE Afib and DVT/PE Afib and valve replacement Other+ Valve INR Goal Range, n (%) 2.0-3.0 2.5-3.5 Other#
* Denotes a statistically significant difference; P-value < 0.05. + Other indications include cardiac thrombus (n = 3) and peripheral vascular disease (n = 2) for the pharmacist-managed group and cardiac thrombus (n = 2), peripheral vascular disease (n = 7), and history of stroke (n = 2) for the physician-managed group. # Other goal ranges include INR 2.0-2.5 (n = 4), INR 1.5-2.0 (n = 1), and INR 2.5-3.0 (n = 1) for pharmacist-managed patients and INR 2.0-2.5 (n = 6), INR 1.5-1.8 (n = 2), INR 1.5-2.0 (n = 1), and INR 3.0-3.5 (n = 1) for physician-managed patients. Abbreviations: Afib = Atrial fibrillation, DVT = Deep venous thrombosis, INR = International normalized ratio, PE = Pulmonary embolism, SCr = Serum creatinine, SD = Standard deviation.
For the pharmacist-managed group, pharmacy involvement was requested for more than 50% of the patients’ stay over approximately 5.5 days.
Inpatient INR Monitoring No statistically significant differences were noted between groups for mean time to therapeutic INR and mean time
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within goal range (Table 3). The physician-managed group, however, did have a non-statistically significant trend toward a shorter time to reach a therapeutic INR than the pharmacist-managed group (2.65 ± 1.24 [physician] vs. 3.17 ± 2.23 days [pharmacy], 95% CI -0.09-1.13; P = 0.093). However, the pharmacist-managed patients spent a statistically significant greater amount of time
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Table 3. Inpatient and Outpatient INR Monitoring
During Hospital Stay Mean time to therapeutic INR (days) ± SD Mean time within INR goal (days) ± SD On Discharge Mean INR ± SD At Follow-Up Mean INR ± SD
Pharmacist-Managed
Physician-Managed
P-value
3.17 ± 2.23
2.65 ± 1.24
0.093 (95% CI: -0.09-1.13)
2.84 ± 2.5
2.20 ± 1.4
0.017* (95% CI: 0.12-1.17)
2.11 ± 0.6
2.09 ± 0.8
0.750 (95% CI: -0.124-0.171)
2.37 ± 1.3
2.08 ± 0.8
0.293 (95% CI: -0.144-0.996)
*Denotes a statistically significant difference; P-value < 0.05. Abbreviations: CI = Confidence interval, INR = International normalized ratio, SD = Standard deviation.
within goal range versus the physician-managed patients (2.84 ± 2.5 [pharmacy] vs. 2.20 ± 1.4 days [physician], 95% CI 0.12-1.17; P = 0.017). For further evaluation, we analyzed the pharmacy-managed patients into two separate groups, pre- and post- the request for pharmacy dosing when reviewing supratherapeutic INRs. A supratherapeutic INR was experienced by 36 patients (20%) in the pharmacist-managed group prior to the request for pharmacy dosing. This number increased to 53 patients (30%) after the request for pharmacy dosing; however, 24 of these patients (45%) were supratherapeutic before pharmacist management. Otherwise stated, almost half of the patients who experienced supratherapeutic INRs after the request for pharmacy dosing had a history of elevated INRs prior to the request for pharmacy dosing. For the physicianmanaged group, 43 patients (24%) experienced an elevated INR during their admission. Thus, after pharmacy dosing, the pharmacist-managed group demonstrated a lower incidence of supratherapeutic INRs (n = 29, 16%) compared with the physician-managed group. Despite the incidence of supratherapeutic INRs prior to the request for pharmacy dosing, no difference was found between the
groups for mean duration of INR elevation (1.61 ± 1.0 [pharmacy] vs. 1.84 days ± 1.0 [physician], 95% CI -0.673-0.207; P = 0.16). On discharge, the mean INR was comparable for both groups (2.11 ± 0.6 [pharmacy] vs. 2.09 ± 0.8 [physician], 95% CI -0.1240.171; P = 0.75).
Bleeding and Thrombotic Events The overall incidence of bleeding was comparable between pharmacist-managed (42/179, 23%) and physicianmanaged patients (46/179, 26%). When stratifying bleeding rates, there was no significant difference between groups for patient-reported symptoms, stool guaic results, FFP or vitamin K administration, or need for transfusion. The incidence of bleeding did not lead to mortality in either group. Of those patients who received vitamin K or FFP, most cases were given prior to a procedure or surgical intervention rather than to reverse the INR or mitigate bleeding. However, significantly more patients in the physician-managed group (18/179, 10%) were noted to have a Hgb decrease (≥ 2 g/dL in 24 hours) than in the pharmacist-managed group (4/179, 2%); P = 0.002.
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Research and Reports No patients in either group experienced a thrombotic event during their stay.
Outpatient INR Follow-Up Following hospital discharge, 34 patients in the pharmacistmanaged group and 16 patients in the physician-managed group were seen at the hospital’s anticoagulation clinic. There was no difference between groups in the mean INR at follow-up regardless of who was managing the patient during the preceding hospital stay (INR = 2.37 for pharmacist-managed patients vs. INR = 2.08 for physicianmanaged patients, CI -0.144-0.996; P = 0.293).
Discussion For INR values, notable differences between the groups were observed during the hospital stay despite similarity between the groups on discharge and at outpatient followup. The pharmacist-managed group illustrated a longer time spent within INR goal. Furthermore, after pharmacy dosing was initiated, the pharmacist-managed patients experienced a lower incidence of supratherapeutic INRs when compared with before pharmacy dosing or the physician-managed group. In regard to event outcomes, bleeding rates were not significantly different for the two groups. No thromboses occurred in either group. Given the respective length of inpatient admission for each arm, pharmacy dosing was requested for more than half the length of the patients’ hospital stay. Comparable management was evident for the pharmacist-managed and physician-managed patients. Given the statistically significant differences favoring the pharmacy-managed group, the results suggest an overall trend toward more optimal management in the pharmacist group. Furthermore, it appears that pharmacy dosing was potentially requested for more complicated patient cases as evidenced by the greater number of hemodialysis patients and longer length of stay for this group. Comparing our data to previous literature is difficult as many of the available studies often focus on different endpoints given the nature of the service or the population being studied. For instance, the two articles reviewed in
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the introduction evaluated anticoagulation management in general cardiac or cardiac surgery populations; therefore, endpoints such as postoperative bleeding were included.5,6 Another study did review the impact of a pharmacistdirected anticoagulation service in an 802-bed urban teaching hospital and level 1 trauma center.7 However this study included 500 patients and focused more on transitions of care metrics, elevated INRs (> 5), thrombosis, and major bleeding. These factors were grouped together to result in a composite safety endpoint. The safety endpoint reduction favored the pharmacy group. Since this study was in a level 1 trauma center, comparing the incidence of bleeding or thrombosis with our community teaching hospital would be difficult. There were no thrombotic events observed in our study in either arm, and overall bleeding was comparable between the two groups; however, the physician group experienced more supratherapeutic INRs and more patients with a drop in Hgb ≥ 2 g/dL in a 24-hour period. However, it would be difficult to determine whether this drop in Hgb resulted from heme-concentration or an actual bleed. In our trial, pharmacist-managed patients were within their therapeutic goal more often than their physician-managed counterparts. Finally, a recent consensus statement supports the role of the pharmacist in managing therapy in the acute care setting and suggests many of the same markers for validating outcomes: frequency of elevated INRs, bleed rates, and thrombosis.8 While benchmark data are not available given the variation in patient populations, our study appears to be consistent with many of the recommendations presented in this consensus statement.
Strengths and Limitations In evaluating the internal and external validity of this study, strengths and weaknesses of the design and execution must be considered with regard to potential impact upon results and conclusions. Strengths of the current study include a reasonable sample size, expansion and extension beyond the existing PI data, data collection for multiple primary and secondary outcomes, and anticipatory measures to control for potential confounders with regard to albumin and drug-drug interactions. However,
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limitations that may preclude extrapolation of these findings include the retrospective versus prospective study design and thus reliance on prior electronic medical record documentation. Pharmacy monitoring and potential intervention for the physician-managed patients through the PMS may underestimate the potential inter-group differences given indirect/direct pharmacy involvement with both treatment sets.
Conclusion In contrast to existing literature, this study directly compares two treatment groups as opposed to illustrating a difference in patient outcomes before and after AMS implementation. No dosing protocol was used for this study as dosing protocols for warfarin are controversial given the number of variables (antibiotics, drug interactions, changes in diet, frequency of medication changes, etc.) that need to be considered when dosing warfarin. Particularly in the inpatient setting, these variables may be even more multi-factorial compared with the outpatient setting as medications and the health status of the patient may change more frequently. As described in the current study, pharmacist- and physician-managed patients demonstrated similarity with regard to anticoagulation management and outcome rates. While the physician group showed a trend toward shorter time to reach a therapeutic INR, the pharmacist group reached statistical significance in having more time within the goal INR range. Moreover, the pharmacist group was associated with a lower incidence of supratherapeutic INR values. Resulting data from this project have been utilized to continue to reduce adverse drug events associated with anticoagulation by maintaining the service and continually evaluating its ongoing progress and development.
Allison A. Chilipko, PharmD, BCPS, CGP, is a clinical pharmacist, internal medicine, MedStar Union Memorial Hospital, Baltimore, Maryland. At the time that this project was completed she was a PGY-2 pharmacy resident in internal medicine, MedStar Union Memorial Hospital. Daryn K. Norwood, PharmD, BCPS, CGP, FASCP, is program director, PGY-2 internal medicine pharmacy residency, and clinical pharmacist, internal medicine, MedStar Union Memorial Hospital. For correspondence: Daryn K. Norwood, PharmD, BCPS, CGP, FASCP, Department of Pharmacy, MedStar Union Memorial Hospital Pharmacy, 201 East University Parkway, Baltimore, MD 21218; Phone: 410-554-2769; Fax: 410-554-2576; E-mail: [email protected]. Acknowledgements: The authors would like to acknowledge Maureen M. Connors, PharmD, BCPS, AAHIVP, for her support of the project, research insight, and assistance with statistical analysis. Disclosure: No funding was received for the development of this manuscript. The authors have no potential conflicts of interest. © 2014 American Society of Consultant Pharmacists, Inc. All rights reserved. Doi:10.4140/TCP.n.2014.95
References 1. The Joint Commission, National Patient Safety Goals Web site. http:// www.jointcommission.org/assets/1/18/NPSG_Chapter_Jan2013_HAP. pdf. Accessed June 12, 2013. 2. Airee A, Guirguis AB, Mohammad RA. Clinical outcomes and pharmacists’ acceptance of a community hospital’s anticoagulation management service utilizing decentralized clinical staff pharmacists. Ann Pharmacother 2009;43:621-8. 3. Donovan JL, Drake JA, Whittaker P et al. Pharmacy-managed anticoagulation: assessment of in-hospital efficacy and evaluation of financial impact and community acceptance. J Thromb Thrombolys 2006;22:23-30. 4. Rudd KM, Dier JG. Comparison of two different models of anticoagulation management services with usual medical care. Pharmacotherapy 2010;30:330-8. 5. Jennings HR, Miller EC, Williams TS et al. Reducing anticoagulant medication adverse events and avoidable patient harm. Joint Comm J Qual Im 2008;34:196-200. 6. Biscup-Horn PJ, Streiff MB, Ulbrich TR et al. Impact of an inpatient anticoagulation management service on clinical outcomes. Ann Pharmacother 2008;42:777-82. 7. Schillig J, Kaatz S, Hudson M et al. Clinical and safety impact of an inpatient pharmacist-directed anticoagulation service. J Hosp Med 2011;6:322-8. 8. Nutesci EA, Wittkowsky AK, Burnett A et al. Delivery of optimized inpatient anticoagulation therapy: consensus statement from the anticoagulation forum. Ann Pharmacother 2013;47:714-24.
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Abbreviations: AE = Adverse events, Afib = Atrial
fibrillation, AMS = Anticoagulation management service, CT = Computed tomography, DVT = Deep venous thrombosis, FDA = Food and Drug Administration, FFP = Fresh frozen plasma, Hgb = Hemoglobin, INR = International normalized ratio, NNT = Number needed to treat, NPSG = National Patient Safety Goal, PE = Pulmonary embolism, PI = Performance improvement, PMS = Pharmacokinetics Monitoring Service, Scr = Serum creatinine, TTR = Time in therapeutic range. Consult Pharm 2014;29:95-103.
Introduction In 2008, National Patient Safety Goal (NPSG) 03.05.01 was adopted by the Joint Commission to reduce the likelihood of patient harm associated with the use of anticoagulation.1 As outlined within this goal, the institution should maintain an anticoagulation management program to decrease adverse drug reactions associated with administration, monitoring, and counseling. The NPSG also required facilities to develop a protocol for recommending initial and maintenance warfarin doses based on individual patient risk factors (i.e., albumin, age, presence of drug-drug interactions, etc.) and to establish a policy for monitoring anticoagulation therapy.1 To achieve compliance with this goal, our community teaching hospital initiated an inpatient anticoagulation management service (AMS) in 2008. This community teaching hospital supports approximately 290 beds, specializing in cardiovascular surgery, stroke, diabetes care, and orthopedic and hand surgery. To optimize safe medication use, the pharmacy department supports a Pharmacokinetics Monitoring Service (PMS) and Drug Information telephone line. Through this service, clinical pharmacists monitor patients on a daily basis to track pertinent vital signs, laboratory data, imaging results, and microbiological cultures for antimicrobial stewardship, appropriate renal dose adjustment, and intravenous to oral conversion. Routinely monitored medications
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Research and Reports include vancomycin, aminoglycosides, enoxaparin, phenytoin, ketorolac, tramadol, and restricted antimicrobials. In addition, pharmacists also are involved with seeing patients with the various acute care teams on the general medicine service and in the intensive care unit. For anticoagulation management, the role of the clinical pharmacist was limited within the scope of the PMS prior to 2008. The pharmacist would review the abnormal laboratory report and follow up on patients with international normalized ratios (INRs) greater than 4.0. However, beyond recommending changes in therapy, pharmacists were not empowered to manage therapy “per protocol.” To further minimize the risk of adverse events (AEs), the second author of this paper developed and obtained approval for the AMS. This new service was intended to allow the pharmacy department to significantly expand the existing scope of anticoagulation monitoring by incorporating the AMS within the PMS in 2008. After starting this service, the pharmacists followed all patients receiving warfarin therapy during their inpatient stay. On each sheet, the pharmacist records patient weight, age, and ethnicity; warfarin indication and goal INR range; home warfarin dose; and albumin, if available. On a daily basis, the pharmacist records the patient’s INR, hemoglobin (Hgb), hematocrit, platelets, and inpatient warfarin dose in addition to screening for bridge therapy with heparin or enoxaparin, vitamin K administration, and the presence of significant drug-drug interactions. For physician-managed patients, the pharmacist may intervene to recommend a dose change based on INR trend or suggest the need for bridge therapy. Ultimately, the AMS allows warfarin dosing by pharmacy when requested by the prescriber. If pharmacy services are ordered, the pharmacist is then responsible for managing the patient’s therapy (i.e., writing warfarin orders and/or ordering appropriate laboratory work, and providing patient education for those who newly start warfarin). The pharmacist will document these interventions in an initial progress note with subsequent progress notes every 72 hours. For continuing quality improvement, the service is evaluated every six months through a pharmacy performance improvement (PI) initiative.
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Other institutions have adopted a similar philosophy to include the pharmacy department in efforts to reduce AEs.2-6 In a study by Jennings et al., pharmacist involvement in anticoagulation management led to a reduction in thromboses (4.6%-3.9%), major bleeds (8.7%-3.3%), and minor bleeds (4.6%-3.5%) from 2004 to 2006.5 The number needed to treat (NNT) to prevent one thrombotic event was 25.8 patients, compared with 30.6 patients and 37.1 patients to avoid one major and minor bleed, respectively.5 Additional literature stems from a study by Biscup-Horn et al. for the cardiac surgery unit.6 AMS development resulted in a 17% decrease in postoperative length of stay (13.9 vs. 11.6 days; P = 0.015), when comparing pre-implementation with post-implementation.6 The service also showed a reduction in postsurgical supratherapeutic INR values (13.4% vs. 7.2%; P = 0.036) and postoperative bleeding (3.1% vs. 1.3%; P = 0.22).6 While the majority of published literature regarding pharmacist-driven anticoagulation management was conducted in larger medical centers, these studies vary according to endpoints and pharmacist involvement. Also, they evaluate pre- and post-implementation without direct comparison both with and without a pharmacist. Therefore, the objective of the current study was to evaluate INR trends and event rates from physician-managed patients versus pharmacist-managed patients to assess the impact of the AMS at our facility.
Methods Study Design A retrospective cohort study was conducted to compare pharmacist-managed patients with those receiving standard care through physician management. The authors obtained Institutional Review Board approval from the health systems research institute. The study was designed to include more patients than the existing PI in providing a more comprehensive evaluation of patient outcomes over a longer time period. Patient cases were randomly selected from January 1, 2009, to January 1, 2011.
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Patient Population Eligible patients were randomly identified from the patients followed through the AMS from January 1, 2009 to January 1, 2011. To qualify for retrospective study inclusion, patients needed to be 18 years of age or older and receiving warfarin for at least three consecutive days during their admission. Patients in the physician-managed group were also selected randomly with the same inclusion criteria to equal the same number of patients managed by pharmacists. Patients were excluded if warfarin was discontinued indefinitely during their hospital stay or if they were receiving warfarin for prevention of venous thromboembolism following orthopedic surgery. This latter group was excluded since they are given a lower INR goal (INR 1.5-2.0) at our facility, and the majority of warfarin prescribing is done by the orthopedic physician assistants with limited pharmacy involvement as this population often has a duration of stay ≤ 3 days. Data Collection For patients who met inclusion criteria, the electronic medical chart was reviewed to evaluate patient demographics, indication for anticoagulation, goal INR range, consecutive INRs during hospitalization, length of stay, INR on discharge, need for vitamin K administration, and first outpatient INR at the Anticoagulation Clinic. To recognize potential confounders and account for any discrepancies between the groups, investigators also collected the patient’s albumin level on admission and potential for drug-drug interactions that may influence the INR. A low albumin may increase sensitivity to warfarin and potentially increase the risk for developing a supratherapeutic INR. A supratherapeutic INR was defined as any INR value greater than the therapeutic range defined by the indication for anticoagulation. For instance, any INR > 3.0 would be considered supratherapeutic for a goal INR of 2.0-3.0. Also, drug-drug interactions may lead to a more labile INR. Drug-drug interactions were organized into three categories: drugs that increase bleeding risk, drugs that increase the INR, and drugs that decrease the INR (Table 1). The drugs listed in Table 1 include those
routinely tracked for all patients receiving warfarin by the AMS. This table is not meant to include all potential interactions with warfarin and only reflective of the information used internally on our monitoring form for managing warfarin therapy. Therefore, only medications on the formulary at our facility are listed. Other rarely used medications (prasugrel or aspirin/extended-release dipyridamole) were added, as needed at the discretion of the pharmacist. Bridge therapy with heparin or enoxaparin (or other parental anticoagulants) was included with the daily monitoring of warfarin dosing. The data collection process also incorporated the number of drugs within each category as well as the number of patients with drug-drug interactions in more than one category. Subtherapeutic INRs were not collected, as the goal of the NPSG is to reduce the likelihood of patient harm associated with the use of anticoagulation. Therefore, our study focused on bleed risk from anticoagulation. While the number of subtherapeutic INRs may serve more utility in the outpatient setting, in the inpatient setting, the incidence of thrombotic events was used to determine any AEs associated with subtherapeutic INRs. To evaluate the future impact of oral direct thrombin inhibitors, the number of patients who would potentially qualify for dabigatran was determined from the sample population. A patient was deemed to be potentially appropriate for dabigatran if the patient was receiving anticoagulation for nonvalvular atrial fibrillation (Afib) and had a creatinine clearance greater than 15 milliliters/ minute. Given the Food and Drug Administration’s (FDA’s) approval of dabigatran during the course of the study period, all patients were evaluated for dabigatran eligibility, regardless of time of hospital admission, to provide a preliminary analysis of the potential effect of dabigatran on the AMS. Dabigatran was the only FDA-approved oral alternative to warfarin at the time of this study. The occurrence of bleeding and thrombotic events was collected from the following parameters: Bleeding was defined by patient-reported symptoms, need for transfusion with packed red blood cells or use of fresh frozen plasma (FFP), positive stool guiac results, and/or
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Table 1. Drug-Drug Interaction Categories* ↑ Bleed Risk
↑ INR
↓ INR
Aspirin Clopidogrel Celecoxib/Nonsteroidal Anti-Inflammatory Drugs
Allopurinol Amiodarone/Dronedarone Azithromycin/Clarithromycin
Carbamazepine Nafcillin/Dicloxacillin Phenobarbital
Ketorolac
Fluconazole/Metronidazole Simvastatin Sulfamethoxazole-Trimethoprim Moxifloxacin/Ciprofloxacin Tramadol Steroids Acetaminophen > 2 g/day
Phenytoin Rifampin Ritonavir
* Drug-drug interactions recorded by the AMS (only the more common types of interactions are listed). Abbreviations: AMS = Anticoagulation management service, INR = International normalized ratio.
a decrease in the Hgb by ≥ 2 g/dL in 24 hours. An acute thrombotic event was documented by positive Doppler Duplex findings for deep venous thrombosis (DVT), positive chest computed tomography (CT) or lung ventilation perfusion scan results for pulmonary embolism (PE), and/ or positive head CT scan for stroke. Thrombotic events were defined as new events occurring after warfarin therapy was instituted for patients newly starting on warfarin during hospital admission or acute thromboses in patients already receiving warfarin prior to admission. Extension of an existing thrombosis or documentation of chronic or old thromboses was not counted as a new thrombotic event.
Outcomes Primary endpoints focused on INR trends, bleeding and thrombotic event outcomes, and duration of pharmacy dosing in conjunction with total length of hospitalization. The mean time to reach a therapeutic INR, mean time spent within goal range, and mean INR on discharge were compared between groups. The mean time to reach a therapeutic INR was defined as the number of days to reach a therapeutic INR in patients newly starting on warfarin during their hospital stay who presented with a
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subtherapeutic INR on admission, or who had warfarin held because of a supratherapeutic INR value. Mean time spent within INR goal range was calculated as the number of consecutive days during the hospital admission when the patient had a therapeutic INR. Additionally, the frequency of supratherapeutic INRs was identified both before and after pharmacy management as opposed to the cumulative incidence for physician-managed patients. Time in therapeutic range (TTR) was not collected as this measure is often more reflective of outpatient monitoring for anticoagulation. Including TTR for inpatient anticoagulation may be misleading as INR monitoring frequency is often daily and may be falsely weighted in one direction versus another depending on whether the patient was admitted with a therapeutic INR or was started on warfarin during the admission. Furthermore, the TTR value is also limited in the inpatient setting, as many patients initiated on warfarin during their admission are often discharged once the INR became therapeutic. Given these concerns, the authors collected mean time (days) to reach a therapeutic INR, mean time (days) spent within goal range, mean INR on discharge, and frequency of supratherapeutic INRs for both groups.
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Secondary outcomes included frequency of vitamin K administration, mean INR at outpatient follow-up, and potential patient suitability for dabigatran. Eligibility was determined, based on indication for anticoagulation and renal function, to estimate the number of patients who could possibly be transitioned from warfarin and subsequent changes in service volume.
Statistical Analysis The choice of statistical test was made based on the nature of the outcome to enable the recognition of statistically significant differences between the pharmacist-managed and physician-managed patients. Chi-square testing was used for the following categorical outcomes: bleeding and thrombotic events, supratherapeutic INR incidence, vitamin K administration, and dabigatran candidacy. A two-tailed unpaired Student’s t-test with 95% confidence interval (CI) was calculated for continuous endpoints: mean time to therapeutic INR and mean INR on admission, discharge, and follow-up. A P-value less than 0.05 represented a statistically significant difference. SAS version 9.1.3 (SAS Institute, Cary, NC) was used for all statistical analysis.
Results Demographics At baseline, the pharmacist-managed and physicianmanaged groups were similar, with significant differences only in male gender and number of hemodialysis patients (Table 2). There were significantly more males in the physician-managed (n = 97, 54%) than the pharmacistmanaged (n = 74, 41%) group; P = 0.015, whereas there were significantly more hemodialysis patients in the pharmacist-managed (n = 40, 22%) vs. the physicianmanaged (n = 23, 12%) group; P = 0.018. Anticoagulation Indication and Goal INR Range In both groups more than half of the patients were receiving warfarin prior to admission: 125 patients in the pharmacist-managed (70%) vs. 108 patients in the physician-managed (60%) group (Table 2). The most
frequent indication for anticoagulation was Afib. An INR goal of 2.0-3.0 was targeted for more than 90% of the patients in both groups. Given the prevalence of Afib, close to one-third of the patients in the pharmacist-managed (n = 57, 32%) and physician-managed (n = 71, 40%) group may have been eligible for dabigatran. This eligibility estimate was based solely on the number of patients in either treatment arm with a creatinine clearance > 15 mL/min and who were receiving warfarin for nonvalvular Afib. However, since completing this study, our internal PI data have shown approximately 80 patients on dabigatran annually in 2011 and 2012 compared with approximately 100 patients on rivaroxaban in 2012. Despite the increased use of other oral anticoagulants, the inpatient anticoagulation service has continued to manage 379 patients on warfarin in 2011 and 444 patients on warfarin in 2012.
Albumin and Drug-Drug Interactions Albumin levels were comparable between the groups with a mean albumin of 3.1 ± 0.6 g/dL (129/179 patients) and 3.2 ± 0.5 g/dL (111/179 patients) in the pharmacistmanaged and physician-managed groups, respectively (95% CI -0.215-0.077; P = 0.350). Given this similarity, differences in albumin level and warfarin sensitivity did not account for inter-group differences in patient outcomes. All patients were subject to at least one drug interaction between warfarin and one of the agents listed in Table 1. There was no significant difference between the groups for the number of patients subject to drug-drug interactions in one of the three categories or in all three categories. However, significantly more patients in the physician-managed group (n = 112, 63%) demonstrated drug-drug interactions in two of the three categories compared with the pharmacist-managed group (n = 92, 51%; P = 0.033). Within each of the three categories, there was no difference between the number of patients for the pharmacist-managed and physician-managed groups. Length of Stay The physician-managed group had a significantly shorter mean length of stay (6.7 ± 4.6 days) versus the pharmacistmanaged group (8.1 ± 6.1 days, 95% CI 0.35-2.60; P = 0.01).
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Table 2. Baseline Demographics Physician-Managed (n = 179)
P-value
97 (54)
0.015*
105 (59) 63 (35) 11 (6) 67 ± 13.5 23 (13)
0.449 1.000 0.062 0.710 0.018*
75 (42) 70 (39) 19 (10) 7 (4) 5 (3) 3 (2)
77 (43) 57 (32) 14 (8) 11 (6) 11 (6) 9 (5)
0.831 0.151 0.834 0.333 0.125 0.078
168 (94) 5 (3) 6 (3)
163 (91) 6 (3) 10 (6)
0.317 0.759 0.306
Pharmacist-Managed (n = 179) 74 (41) Male Gender, n (%) Race/Ethnicity, n (%) 112 (63) African-American 63 (35) Caucasian 4 (2) Other 67 ± 14.9 Mean Age (yrs) ± SD 40 (22) Hemodialysis, n (%) Indication for Anticoagulation, n (%) Afib DVT/PE Afib and DVT/PE Afib and valve replacement Other+ Valve INR Goal Range, n (%) 2.0-3.0 2.5-3.5 Other#
* Denotes a statistically significant difference; P-value < 0.05. + Other indications include cardiac thrombus (n = 3) and peripheral vascular disease (n = 2) for the pharmacist-managed group and cardiac thrombus (n = 2), peripheral vascular disease (n = 7), and history of stroke (n = 2) for the physician-managed group. # Other goal ranges include INR 2.0-2.5 (n = 4), INR 1.5-2.0 (n = 1), and INR 2.5-3.0 (n = 1) for pharmacist-managed patients and INR 2.0-2.5 (n = 6), INR 1.5-1.8 (n = 2), INR 1.5-2.0 (n = 1), and INR 3.0-3.5 (n = 1) for physician-managed patients. Abbreviations: Afib = Atrial fibrillation, DVT = Deep venous thrombosis, INR = International normalized ratio, PE = Pulmonary embolism, SCr = Serum creatinine, SD = Standard deviation.
For the pharmacist-managed group, pharmacy involvement was requested for more than 50% of the patients’ stay over approximately 5.5 days.
Inpatient INR Monitoring No statistically significant differences were noted between groups for mean time to therapeutic INR and mean time
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within goal range (Table 3). The physician-managed group, however, did have a non-statistically significant trend toward a shorter time to reach a therapeutic INR than the pharmacist-managed group (2.65 ± 1.24 [physician] vs. 3.17 ± 2.23 days [pharmacy], 95% CI -0.09-1.13; P = 0.093). However, the pharmacist-managed patients spent a statistically significant greater amount of time
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Table 3. Inpatient and Outpatient INR Monitoring
During Hospital Stay Mean time to therapeutic INR (days) ± SD Mean time within INR goal (days) ± SD On Discharge Mean INR ± SD At Follow-Up Mean INR ± SD
Pharmacist-Managed
Physician-Managed
P-value
3.17 ± 2.23
2.65 ± 1.24
0.093 (95% CI: -0.09-1.13)
2.84 ± 2.5
2.20 ± 1.4
0.017* (95% CI: 0.12-1.17)
2.11 ± 0.6
2.09 ± 0.8
0.750 (95% CI: -0.124-0.171)
2.37 ± 1.3
2.08 ± 0.8
0.293 (95% CI: -0.144-0.996)
*Denotes a statistically significant difference; P-value < 0.05. Abbreviations: CI = Confidence interval, INR = International normalized ratio, SD = Standard deviation.
within goal range versus the physician-managed patients (2.84 ± 2.5 [pharmacy] vs. 2.20 ± 1.4 days [physician], 95% CI 0.12-1.17; P = 0.017). For further evaluation, we analyzed the pharmacy-managed patients into two separate groups, pre- and post- the request for pharmacy dosing when reviewing supratherapeutic INRs. A supratherapeutic INR was experienced by 36 patients (20%) in the pharmacist-managed group prior to the request for pharmacy dosing. This number increased to 53 patients (30%) after the request for pharmacy dosing; however, 24 of these patients (45%) were supratherapeutic before pharmacist management. Otherwise stated, almost half of the patients who experienced supratherapeutic INRs after the request for pharmacy dosing had a history of elevated INRs prior to the request for pharmacy dosing. For the physicianmanaged group, 43 patients (24%) experienced an elevated INR during their admission. Thus, after pharmacy dosing, the pharmacist-managed group demonstrated a lower incidence of supratherapeutic INRs (n = 29, 16%) compared with the physician-managed group. Despite the incidence of supratherapeutic INRs prior to the request for pharmacy dosing, no difference was found between the
groups for mean duration of INR elevation (1.61 ± 1.0 [pharmacy] vs. 1.84 days ± 1.0 [physician], 95% CI -0.673-0.207; P = 0.16). On discharge, the mean INR was comparable for both groups (2.11 ± 0.6 [pharmacy] vs. 2.09 ± 0.8 [physician], 95% CI -0.1240.171; P = 0.75).
Bleeding and Thrombotic Events The overall incidence of bleeding was comparable between pharmacist-managed (42/179, 23%) and physicianmanaged patients (46/179, 26%). When stratifying bleeding rates, there was no significant difference between groups for patient-reported symptoms, stool guaic results, FFP or vitamin K administration, or need for transfusion. The incidence of bleeding did not lead to mortality in either group. Of those patients who received vitamin K or FFP, most cases were given prior to a procedure or surgical intervention rather than to reverse the INR or mitigate bleeding. However, significantly more patients in the physician-managed group (18/179, 10%) were noted to have a Hgb decrease (≥ 2 g/dL in 24 hours) than in the pharmacist-managed group (4/179, 2%); P = 0.002.
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Research and Reports No patients in either group experienced a thrombotic event during their stay.
Outpatient INR Follow-Up Following hospital discharge, 34 patients in the pharmacistmanaged group and 16 patients in the physician-managed group were seen at the hospital’s anticoagulation clinic. There was no difference between groups in the mean INR at follow-up regardless of who was managing the patient during the preceding hospital stay (INR = 2.37 for pharmacist-managed patients vs. INR = 2.08 for physicianmanaged patients, CI -0.144-0.996; P = 0.293).
Discussion For INR values, notable differences between the groups were observed during the hospital stay despite similarity between the groups on discharge and at outpatient followup. The pharmacist-managed group illustrated a longer time spent within INR goal. Furthermore, after pharmacy dosing was initiated, the pharmacist-managed patients experienced a lower incidence of supratherapeutic INRs when compared with before pharmacy dosing or the physician-managed group. In regard to event outcomes, bleeding rates were not significantly different for the two groups. No thromboses occurred in either group. Given the respective length of inpatient admission for each arm, pharmacy dosing was requested for more than half the length of the patients’ hospital stay. Comparable management was evident for the pharmacist-managed and physician-managed patients. Given the statistically significant differences favoring the pharmacy-managed group, the results suggest an overall trend toward more optimal management in the pharmacist group. Furthermore, it appears that pharmacy dosing was potentially requested for more complicated patient cases as evidenced by the greater number of hemodialysis patients and longer length of stay for this group. Comparing our data to previous literature is difficult as many of the available studies often focus on different endpoints given the nature of the service or the population being studied. For instance, the two articles reviewed in
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the introduction evaluated anticoagulation management in general cardiac or cardiac surgery populations; therefore, endpoints such as postoperative bleeding were included.5,6 Another study did review the impact of a pharmacistdirected anticoagulation service in an 802-bed urban teaching hospital and level 1 trauma center.7 However this study included 500 patients and focused more on transitions of care metrics, elevated INRs (> 5), thrombosis, and major bleeding. These factors were grouped together to result in a composite safety endpoint. The safety endpoint reduction favored the pharmacy group. Since this study was in a level 1 trauma center, comparing the incidence of bleeding or thrombosis with our community teaching hospital would be difficult. There were no thrombotic events observed in our study in either arm, and overall bleeding was comparable between the two groups; however, the physician group experienced more supratherapeutic INRs and more patients with a drop in Hgb ≥ 2 g/dL in a 24-hour period. However, it would be difficult to determine whether this drop in Hgb resulted from heme-concentration or an actual bleed. In our trial, pharmacist-managed patients were within their therapeutic goal more often than their physician-managed counterparts. Finally, a recent consensus statement supports the role of the pharmacist in managing therapy in the acute care setting and suggests many of the same markers for validating outcomes: frequency of elevated INRs, bleed rates, and thrombosis.8 While benchmark data are not available given the variation in patient populations, our study appears to be consistent with many of the recommendations presented in this consensus statement.
Strengths and Limitations In evaluating the internal and external validity of this study, strengths and weaknesses of the design and execution must be considered with regard to potential impact upon results and conclusions. Strengths of the current study include a reasonable sample size, expansion and extension beyond the existing PI data, data collection for multiple primary and secondary outcomes, and anticipatory measures to control for potential confounders with regard to albumin and drug-drug interactions. However,
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limitations that may preclude extrapolation of these findings include the retrospective versus prospective study design and thus reliance on prior electronic medical record documentation. Pharmacy monitoring and potential intervention for the physician-managed patients through the PMS may underestimate the potential inter-group differences given indirect/direct pharmacy involvement with both treatment sets.
Conclusion In contrast to existing literature, this study directly compares two treatment groups as opposed to illustrating a difference in patient outcomes before and after AMS implementation. No dosing protocol was used for this study as dosing protocols for warfarin are controversial given the number of variables (antibiotics, drug interactions, changes in diet, frequency of medication changes, etc.) that need to be considered when dosing warfarin. Particularly in the inpatient setting, these variables may be even more multi-factorial compared with the outpatient setting as medications and the health status of the patient may change more frequently. As described in the current study, pharmacist- and physician-managed patients demonstrated similarity with regard to anticoagulation management and outcome rates. While the physician group showed a trend toward shorter time to reach a therapeutic INR, the pharmacist group reached statistical significance in having more time within the goal INR range. Moreover, the pharmacist group was associated with a lower incidence of supratherapeutic INR values. Resulting data from this project have been utilized to continue to reduce adverse drug events associated with anticoagulation by maintaining the service and continually evaluating its ongoing progress and development.
Allison A. Chilipko, PharmD, BCPS, CGP, is a clinical pharmacist, internal medicine, MedStar Union Memorial Hospital, Baltimore, Maryland. At the time that this project was completed she was a PGY-2 pharmacy resident in internal medicine, MedStar Union Memorial Hospital. Daryn K. Norwood, PharmD, BCPS, CGP, FASCP, is program director, PGY-2 internal medicine pharmacy residency, and clinical pharmacist, internal medicine, MedStar Union Memorial Hospital. For correspondence: Daryn K. Norwood, PharmD, BCPS, CGP, FASCP, Department of Pharmacy, MedStar Union Memorial Hospital Pharmacy, 201 East University Parkway, Baltimore, MD 21218; Phone: 410-554-2769; Fax: 410-554-2576; E-mail: [email protected]. Acknowledgements: The authors would like to acknowledge Maureen M. Connors, PharmD, BCPS, AAHIVP, for her support of the project, research insight, and assistance with statistical analysis. Disclosure: No funding was received for the development of this manuscript. The authors have no potential conflicts of interest. © 2014 American Society of Consultant Pharmacists, Inc. All rights reserved. Doi:10.4140/TCP.n.2014.95
References 1. The Joint Commission, National Patient Safety Goals Web site. http:// www.jointcommission.org/assets/1/18/NPSG_Chapter_Jan2013_HAP. pdf. Accessed June 12, 2013. 2. Airee A, Guirguis AB, Mohammad RA. Clinical outcomes and pharmacists’ acceptance of a community hospital’s anticoagulation management service utilizing decentralized clinical staff pharmacists. Ann Pharmacother 2009;43:621-8. 3. Donovan JL, Drake JA, Whittaker P et al. Pharmacy-managed anticoagulation: assessment of in-hospital efficacy and evaluation of financial impact and community acceptance. J Thromb Thrombolys 2006;22:23-30. 4. Rudd KM, Dier JG. Comparison of two different models of anticoagulation management services with usual medical care. Pharmacotherapy 2010;30:330-8. 5. Jennings HR, Miller EC, Williams TS et al. Reducing anticoagulant medication adverse events and avoidable patient harm. Joint Comm J Qual Im 2008;34:196-200. 6. Biscup-Horn PJ, Streiff MB, Ulbrich TR et al. Impact of an inpatient anticoagulation management service on clinical outcomes. Ann Pharmacother 2008;42:777-82. 7. Schillig J, Kaatz S, Hudson M et al. Clinical and safety impact of an inpatient pharmacist-directed anticoagulation service. J Hosp Med 2011;6:322-8. 8. Nutesci EA, Wittkowsky AK, Burnett A et al. Delivery of optimized inpatient anticoagulation therapy: consensus statement from the anticoagulation forum. Ann Pharmacother 2013;47:714-24.
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