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Impact of an Oral Antineoplastic Renewal Clinic on Medication Possession Ratio and Cost-Savings
Evaluation of oral antineoplastic agent (OAN) adherence patterns have identified correlations between nonadherence or over-adherence and poorer disease-related outcomes. Multiple studies have focused on imatinib use in chronic myeloid leukemia (CML) due to its continuous, long-term use. A study by Ganesan and colleagues found that nonadherence to imatinib showed a significant decrease in 5-year event-free survival between 76.7% of adherent participants compared with 59.8% of nonadherent participants.1 This study found that 44% of patients who were adherent to imatinib achieved complete cytogenetic response vs only 26% of patients who were nonadherent. In another study of imatinib for CML, major molecular response (MMR) was strongly correlated with adherence and no patients with adherence < 80% were able to achieve MMR.2 Similarly, in studies of tamoxifen for breast cancer, < 80% adherence resulted in a 10% decrease in survival when compared to those who were more adherent.3,4
In addition to the clinical implications of nonadherence, there can be a significant cost associated with suboptimal use of these medications. The price of a single dose of OAN medication may cost as much as $440.5
The benefits of multidisciplinary care teams have been identified in many studies.6,7 While studies are limited in oncology, pharmacists provide vital contributions to the oncology multidisciplinary team when managing OANs as these health care professionals have expert knowledge of the medications, potential adverse events (AEs), and necessary monitoring parameters.8 In one study, patients seen by the pharmacist-led oral chemotherapy management program experienced improved clinical outcomes and response to therapy when compared with preintervention patients (early molecular response, 88.9% vs 54.8%, P = .01; major molecular response, 83.3% vs 57.6%, P = .06).9 During the study, 318 AEs were reported, leading to 235 pharmacist interventions to ameliorate AEs and improve adherence.
The primary objective of this study was to measure the impact of a pharmacist-driven OAN renewal clinic on medication adherence. The secondary objective was to estimate cost-savings of this new service.
Methods
Prior to July 2014, several limitations were identified related to OAN prescribing and monitoring at the Richard L. Roudebush Veterans Affairs Medical Center in Indianapolis, Indiana (RLRVAMC). The prescription ordering process relied primarily on the patient to initiate refills, rather than the prescriber OAN prescriptions also lacked consistency for number of refills or quantities dispensed. Furthermore, ordering of antineoplastic products was not limited to hematology/oncology providers. Patients were identified with significant supply on hand at the time of medication discontinuation, creating concerns for medication waste, tolerability, and nonadherence.
As a result, opportunities were identified to improve the prescribing process, recommended monitoring, toxicity and tolerability evaluation, medication reconciliation, and medication adherence. In July of 2014, the RLRVAMC adopted a new chemotherapy order entry system capable of restricting prescriptions to hematology/oncology providers and limiting dispensed quantities and refill amounts. A comprehensive pharmacist driven OAN renewal clinic was implemented on September 1, 2014 with the goal of improving long-term adherence and tolerability, in addition to minimizing medication waste.
Patients were eligible for enrollment in the clinic if they had a cancer diagnosis and were concomitantly prescribed an OAN outlined in Table 1. All eligible patients were automatically enrolled in the clinic when they were deemed stable on their OAN by a hematology/oncology pharmacy specialist. Stability was defined as ≤ Grade 1 symptoms associated with the toxicities of OAN therapy managed with or without intervention as defined by the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Once enrolled in the renewal clinic, patients were called by an oncology pharmacy resident (PGY2) 1 week prior to any OAN refill due date. Patients were asked a series of 5 adherence and tolerability questions (Table 2) to evaluate renewal criteria for approval or need for further evaluation. These questions were developed based on targeted information and published reports on monitoring adherence.10,11 Criteria for renewal included: < 10% self-reported missed doses of the OAN during the previous dispensing period, no hospitalizations or emergency department visits since most recent hematology/oncology provider appointment, no changes to concomitant medication therapies, and no new or worsening medication-related AEs. Patients meeting all criteria were given a 30-day supply of OAN. Prescribing, dispensing, and delivery of OAN were facilitated by the pharmacist. Patient cases that did not meet criteria for renewal were escalated to the hematology/oncology provider or oncology clinical pharmacy specialist for further evaluation.
Study Design and Setting
This was a pre/post retrospective cohort, quality improvement study of patients enrolled in the RLRVAMC OAN pharmacist renewal clinic. The study was deemed exempt from institutional review board (IRB) by the US Department of Veterans Affairs (VA) Research and Development Department.
Study Population
Patients were included in the preimplementation group if they had received at least 2 prescriptions of an eligible OAN. Therapy for the preimplementation group was required to be a monthly duration > 21 days and between the dates of September 1, 2013 and August 31, 2014. Patients were included in the postimplementation group if they had received at least 2 prescriptions of the studied OANs between September 1, 2014 and January 31, 2015. Patients were excluded if they had filled < 2 prescriptions of OAN; were managed by a non-VA oncologist or hematologist; or received an OAN other than those listed in Table 1.
Data Collection
For all patients in both the pre- and postimplementation cohorts, a standardized data collection tool was used to collect the following via electronic health record review by a PGY2 oncology resident: age, race, gender, oral antineoplastic agent, refill dates, days’ supply, estimated unit cost per dose cancer diagnosis, distance from the RLRVAMC, copay status, presence of hospitalizations/ED visits/dosage reductions, discontinuation rates, reasons for discontinuation, and total number of current prescriptions. The presence or absence of dosage reductions were collected to identify concerns for tolerability, but only the original dose for the preimplementation group and dosage at time of clinic enrollment for the postimplementation group was included in the analysis.
Outcomes and Statistical Analyses
The primary outcome was medication adherence defined as the median medication possession ratio (MPR) before and after implementation of the clinic. Secondary outcomes included the proportion of patients who were adherent from before implementation to after implementation and estimated cost-savings of this clinic after implementation. MPR was used to estimate medication adherence by taking the cumulative day supply of medication on hand divided by the number of days on therapy.12 Number of days on therapy was determined by taking the difference on the start date of the new medication regimen and the discontinuation date of the same regimen. Patients were grouped by adherence into one of the following categories: < 0.8, 0.8 to 0.89, 0.9 to 1, and > 1.1. Patients were considered adherent if they reported taking ≥ 90% (MPR ≥ 0.9) of prescribed doses, adopted from the study by Anderson and colleagues.12 A patient with an MPR > 1, likely due to filling prior to the anticipated refill date, was considered 100% adherent (MPR = 1). If a patient switched OAN during the study, both agents were included as separate entities.
A conservative estimate of cost-savings was made by multiplying the RLRVAMC cost per unit of medication at time of initial prescription fill by the number of units taken each day multiplied by the total days’ supply on hand at time of therapy discontinuation. Patients with an MPR < 1 at time of therapy discontinuation were assumed to have zero remaining units on hand and zero cost savings was estimated. Waste, for purposes of cost-savings, was calculated for all MPR values > 1. Additional supply anticipated to be on hand from dose reductions was not included in the estimated cost of unused medication.
Descriptive statistics compared demographic characteristics between the pre- and postimplementation groups. MPR data were not normally distributed, which required the use of nonparametric Mann-Whitney U tests to compare pre- and postMPRs. Pearson χ2 compared the proportion of adherent patients between groups while descriptive statistics were used to estimate cost savings. Significance was determined based on a P value < .05. IBM SPSS Statistics software was used for all statistical analyses. As this was a complete sample of all eligible subjects, no sample size calculation was performed.
Results
In the preimplementation period, 246 patients received an OAN and 61 patients received an OAN in the postimplementation period (Figure 1). Of the 246 patients in the preimplementation period, 98 were eligible and included in the preimplementation group. Similarly, of the 61 patients in the postimplementation period, 35 patients met inclusion criteria for the postimplementation group. The study population was predominantly male with an average age of approximately 70 years in both groups (Table 3). More than 70% of the population in each group was White. No statistically significant differences between groups were identified. The most commonly prescribed OAN in the preimplementation group were abiraterone, imatinib, and enzalutamide (Table 3). In the postimplementation group, the most commonly prescribed agents were abiraterone, imatinib, pazopanib, and dasatinib. No significant differences were observed in prescribing of individual agents between the pre- and postimplementation groups or other characteristics that may affect adherence including patient copay status, number of concomitant medications, and driving distance from the RLRVAMC.
Thirty-six (36.7%) patients in the preimplementation group were considered nonadherent (MPR < 0.9) and 18 (18.4%) had an MPR < 0.8. Fifteen (15.3%) patients in the preimplementation clinic were considered overadherent (MPR > 1.1). Forty-seven (47.9%) patients in the preimplementation group were considered adherent (MPR 0.9 - 1.1) while all 35 (100%) patients in the postimplementation group were considered adherent (MPR 0.9 - 1.1). No non- or overadherent patients were identified in the postimplementation group (Figure 2). The median MPR for all patients in the preimplementation group was 0.94 compared with 1.06 (P < .001) in the postimplementation group.
Thirty-five (35.7%) patients had therapy discontinued or held in the preimplementation group compared with 2 (5.7%) patients in the postimplementation group (P < .001). Reasons for discontinuation in the preimplementation group included disease progression (n = 27), death (n = 3), lost to follow up (n = 2), and intolerability of therapy (n = 3). Both patients that discontinued therapy in the postimplementation group did so due to disease progression. Of the 35 patients who had their OAN discontinued or held in the preimplementation group, 14 patients had excess supply on hand at time of discontinuation. The estimated value of the unused medication was $37,890. Nine (25%) of the 35 patients who discontinued therapy had a dosage reduction during the course of therapy and the additional supply was not included in the cost estimate. Similarly, 1 of the 2 patients in the postimplementation group had their OAN discontinued during study. The cost of oversupply of medication at the time of therapy discontinuation was estimated at $1,555. No patients in the postimplementation group had dose reductions. After implementation of the OAN renewal clinic, the total cost savings between pre ($37,890) and postimplementation ($1,555) groups was $36,355.
Discussion
OANs are widely used therapies, with more than 25 million doses administered per year in the United States alone.12 The use of these agents will continue to grow as more targeted agents become available and patients request more convenient treatment options. The role for hematology/oncology clinical pharmacy services must adapt to this increased usage of OANs, including increasing pharmacist involvement in medication education, adherence and tolerability assessments, and proactive drug interaction monitoring.However, additional research is needed to determine optimal management strategies.
Our study aimed to compare OAN adherence among patients at a tertiary care VA hospital before and after implementation of a renewal clinic. The preimplementation population had a median MPR of 0.94 compared with 1.06 in the postimplementation group (P < .001). Although an ideal MPR is 1.0, we aimed for a slightly higher MPR to allow a supply buffer in the event of prescription delivery delays, as more than 90% of prescriptions are mailed to patients from a regional mail-order pharmacy. Importantly, the median MPRs do not adequately convey the impact from this clinic. The proportion of patients who were considered adherent to OANs increased from 47.9% in the preimplementation to 100% in the postimplementation period. These finding suggest that the clinical pharmacist role to assess and encourage adherence through monitoring tolerability of these OANs improved the overall medication taking experience of these patients.
Upon initial evaluation of adherence pre- and postimplementation, median adherence rates in both groups appeared to be above goal at 0.94 and 1.06 respectively. Patients in the postimplementation group intentionally received a 5- to 7-day supply buffer to account for potential prescription delivery delays due to holidays and inclement weather. This would indicate that the patients in the postimplementation group would have 15% oversupply due to the 5-day supply buffer. After correcting for patients with confounding reasons for excess (dose reductions, breaks in treatment, etc.), the median MPR in the prerefill clinic group decreased to 0.9 and the MPR in the postrefill clinic group increased slightly to 1.08. Although the median adherence rate in both the pre- and postimplementation groups were above goal of 0.90, 36% of the patients in the preimplementation group were considered nonadherent (MPR < 0.9) compared with no patients in the postimplementation group. Therefore, our intervention to improve patient adherence appeared to be beneficial at our institution.
In addition to improving adherence, one of the goals of the renewal clinic was to minimize excess supply at the time of therapy discontinuation. This was accomplished by aligning medication fills with medical visits and objective monitoring, as well as limiting supply to no more than 30 days. Of the patients in the postimplementation group, only 1 patient had remaining medication at the time of therapy discontinuation compared with 14 patients in the preimplementation group. The estimated cost savings from excess supply was $36,335. Limiting the amount of unused supply not only saves money for the patient and the institution, but also decreases opportunity for improper hazardous waste disposal and unnecessary exposure of hazardous materials to others.
Our results show the pharmacist intervention in the coordination of renewals improved adherence, minimized medication waste, and saved money. The cost of pharmacist time participating in the refill clinic was not calculated. Each visit was completed in approximately 5 minutes, with subsequent documentation and coordination taking an additional 5 to 10 minutes. During the launch of this service, the oncology pharmacy resident provided all coverage of the clinic. Oversite of the resident was provided by hematology/oncology clinical pharmacy specialists. We have continued to utilize pharmacy resident coverage since that time to meet education needs and keep the estimated cost per visit low. Another option in the case that pharmacy residents are not available would be utilization of a pharmacy technician, intern, or professional student to conduct the adherence and tolerability phone assessments. Our escalation protocol allows intervention by clinical pharmacy specialist and/or other health care providers when necessary. Trainees have only required basic training on how to use the protocol.
Limitations
Due to this study’s retrospective design, an inherent limitation is dependence on prescriber and refill records for documentation of initiation and discontinuation dates. Therefore, only the association of impact of pharmacist intervention on medication adherence can be determined as opposed to causation. We did not take into account discrepancies in day supply secondary to ‘held’ therapies, dose reductions, or doses supplied during an inpatient admission, which may alter estimates of MPR and cost-savings data. Patients in the postimplementation group intentionally received a 5 to 7-day supply buffer to account for potential prescription delivery delays due to holidays and inclement weather. This would indicate that the patients in the postimplementation group would have 15% oversupply due to the 5-day supply buffer, thereby skewing MPR values. This study did not account for cost avoidance resulting from early identification and management of toxicity. Finally, the postimplementation data only spans 4 months and a longer duration of time is needed to more accurately determine sustainability of renewal clinic interventions and provide comprehensive evaluation of cost-avoidance.
Conclusion
Implementation of an OAN renewal clinic was associated with an increase in MPR, improved proportion of patients considered adherent, and an estimated $36,335 cost-savings. However, prospective evaluation and a longer study duration are needed to determine causality of improved adherence and cost-savings associated with a pharmacist-driven OAN renewal clinic.
1. Ganesan P, Sagar TG, Dubashi B, et al. Nonadherence to imatinib adversely affects event free survival in chronic phase chronic myeloid leukemia. Am J Hematol 2011; 86: 471-474. doi:10.1002/ajh.22019
2. Marin D, Bazeos A, Mahon FX, et al. Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol 2010; 28: 2381-2388. doi:10.1200/JCO.2009.26.3087
3. McCowan C, Shearer J, Donnan PT, et al. Cohort study examining tamoxifen adherence and its relationship to mortality in women with breast cancer. Br J Cancer 2008; 99: 1763-1768. doi:10.1038/sj.bjc.6604758
4. Lexicomp Online. Sunitinib. Hudson, Ohio: Lexi-Comp, Inc; August 20, 2019.
5. Babiker A, El Husseini M, Al Nemri A, et al. Health care professional development: Working as a team to improve patient care. Sudan J Paediatr. 2014;14(2):9-16.
6. Spence MM, Makarem AF, Reyes SL, et al. Evaluation of an outpatient pharmacy clinical services program on adherence and clinical outcomes among patients with diabetes and/or coronary artery disease. J Manag Care Spec Pharm. 2014;20(10):1036-1045. doi:10.18553/jmcp.2014.20.10.1036
7. Holle LM, Puri S, Clement JM. Physician-pharmacist collaboration for oral chemotherapy monitoring: Insights from an academic genitourinary oncology practice. J Oncol Pharm Pract 2015; doi:10.1177/1078155215581524
8. Muluneh B, Schneider M, Faso A, et al. Improved Adherence Rates and Clinical Outcomes of an Integrated, Closed-Loop, Pharmacist-Led Oral Chemotherapy Management Program. Journal of Oncology Practice. 2018;14(6):371-333. doi:10.1200/JOP.17.00039.
9. Font R, Espinas JA, Gil-Gil M, et al. Prescription refill, patient self-report and physician report in assessing adherence to oral endocrine therapy in early breast cancer patients: a retrospective cohort study in Catalonia, Spain. British Journal of Cancer. 2012 ;107(8):1249-1256. doi:10.1038/bjc.2012.389.
10. Anderson KR, Chambers CR, Lam N, et al. Medication adherence among adults prescribed imatinib, dasatinib, or nilotinib for the treatment of chronic myeloid leukemia. J Oncol Pharm Practice. 2015;21(1):19–25. doi:10.1177/1078155213520261
11. Weingart SN, Brown E, Bach PB, et al. NCCN Task Force Report: oral chemotherapy. J Natl Compr Canc Netw. 2008;6(3): S1-S14.
Evaluation of oral antineoplastic agent (OAN) adherence patterns have identified correlations between nonadherence or over-adherence and poorer disease-related outcomes. Multiple studies have focused on imatinib use in chronic myeloid leukemia (CML) due to its continuous, long-term use. A study by Ganesan and colleagues found that nonadherence to imatinib showed a significant decrease in 5-year event-free survival between 76.7% of adherent participants compared with 59.8% of nonadherent participants.1 This study found that 44% of patients who were adherent to imatinib achieved complete cytogenetic response vs only 26% of patients who were nonadherent. In another study of imatinib for CML, major molecular response (MMR) was strongly correlated with adherence and no patients with adherence < 80% were able to achieve MMR.2 Similarly, in studies of tamoxifen for breast cancer, < 80% adherence resulted in a 10% decrease in survival when compared to those who were more adherent.3,4
In addition to the clinical implications of nonadherence, there can be a significant cost associated with suboptimal use of these medications. The price of a single dose of OAN medication may cost as much as $440.5
The benefits of multidisciplinary care teams have been identified in many studies.6,7 While studies are limited in oncology, pharmacists provide vital contributions to the oncology multidisciplinary team when managing OANs as these health care professionals have expert knowledge of the medications, potential adverse events (AEs), and necessary monitoring parameters.8 In one study, patients seen by the pharmacist-led oral chemotherapy management program experienced improved clinical outcomes and response to therapy when compared with preintervention patients (early molecular response, 88.9% vs 54.8%, P = .01; major molecular response, 83.3% vs 57.6%, P = .06).9 During the study, 318 AEs were reported, leading to 235 pharmacist interventions to ameliorate AEs and improve adherence.
The primary objective of this study was to measure the impact of a pharmacist-driven OAN renewal clinic on medication adherence. The secondary objective was to estimate cost-savings of this new service.
Methods
Prior to July 2014, several limitations were identified related to OAN prescribing and monitoring at the Richard L. Roudebush Veterans Affairs Medical Center in Indianapolis, Indiana (RLRVAMC). The prescription ordering process relied primarily on the patient to initiate refills, rather than the prescriber OAN prescriptions also lacked consistency for number of refills or quantities dispensed. Furthermore, ordering of antineoplastic products was not limited to hematology/oncology providers. Patients were identified with significant supply on hand at the time of medication discontinuation, creating concerns for medication waste, tolerability, and nonadherence.
As a result, opportunities were identified to improve the prescribing process, recommended monitoring, toxicity and tolerability evaluation, medication reconciliation, and medication adherence. In July of 2014, the RLRVAMC adopted a new chemotherapy order entry system capable of restricting prescriptions to hematology/oncology providers and limiting dispensed quantities and refill amounts. A comprehensive pharmacist driven OAN renewal clinic was implemented on September 1, 2014 with the goal of improving long-term adherence and tolerability, in addition to minimizing medication waste.
Patients were eligible for enrollment in the clinic if they had a cancer diagnosis and were concomitantly prescribed an OAN outlined in Table 1. All eligible patients were automatically enrolled in the clinic when they were deemed stable on their OAN by a hematology/oncology pharmacy specialist. Stability was defined as ≤ Grade 1 symptoms associated with the toxicities of OAN therapy managed with or without intervention as defined by the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Once enrolled in the renewal clinic, patients were called by an oncology pharmacy resident (PGY2) 1 week prior to any OAN refill due date. Patients were asked a series of 5 adherence and tolerability questions (Table 2) to evaluate renewal criteria for approval or need for further evaluation. These questions were developed based on targeted information and published reports on monitoring adherence.10,11 Criteria for renewal included: < 10% self-reported missed doses of the OAN during the previous dispensing period, no hospitalizations or emergency department visits since most recent hematology/oncology provider appointment, no changes to concomitant medication therapies, and no new or worsening medication-related AEs. Patients meeting all criteria were given a 30-day supply of OAN. Prescribing, dispensing, and delivery of OAN were facilitated by the pharmacist. Patient cases that did not meet criteria for renewal were escalated to the hematology/oncology provider or oncology clinical pharmacy specialist for further evaluation.
Study Design and Setting
This was a pre/post retrospective cohort, quality improvement study of patients enrolled in the RLRVAMC OAN pharmacist renewal clinic. The study was deemed exempt from institutional review board (IRB) by the US Department of Veterans Affairs (VA) Research and Development Department.
Study Population
Patients were included in the preimplementation group if they had received at least 2 prescriptions of an eligible OAN. Therapy for the preimplementation group was required to be a monthly duration > 21 days and between the dates of September 1, 2013 and August 31, 2014. Patients were included in the postimplementation group if they had received at least 2 prescriptions of the studied OANs between September 1, 2014 and January 31, 2015. Patients were excluded if they had filled < 2 prescriptions of OAN; were managed by a non-VA oncologist or hematologist; or received an OAN other than those listed in Table 1.
Data Collection
For all patients in both the pre- and postimplementation cohorts, a standardized data collection tool was used to collect the following via electronic health record review by a PGY2 oncology resident: age, race, gender, oral antineoplastic agent, refill dates, days’ supply, estimated unit cost per dose cancer diagnosis, distance from the RLRVAMC, copay status, presence of hospitalizations/ED visits/dosage reductions, discontinuation rates, reasons for discontinuation, and total number of current prescriptions. The presence or absence of dosage reductions were collected to identify concerns for tolerability, but only the original dose for the preimplementation group and dosage at time of clinic enrollment for the postimplementation group was included in the analysis.
Outcomes and Statistical Analyses
The primary outcome was medication adherence defined as the median medication possession ratio (MPR) before and after implementation of the clinic. Secondary outcomes included the proportion of patients who were adherent from before implementation to after implementation and estimated cost-savings of this clinic after implementation. MPR was used to estimate medication adherence by taking the cumulative day supply of medication on hand divided by the number of days on therapy.12 Number of days on therapy was determined by taking the difference on the start date of the new medication regimen and the discontinuation date of the same regimen. Patients were grouped by adherence into one of the following categories: < 0.8, 0.8 to 0.89, 0.9 to 1, and > 1.1. Patients were considered adherent if they reported taking ≥ 90% (MPR ≥ 0.9) of prescribed doses, adopted from the study by Anderson and colleagues.12 A patient with an MPR > 1, likely due to filling prior to the anticipated refill date, was considered 100% adherent (MPR = 1). If a patient switched OAN during the study, both agents were included as separate entities.
A conservative estimate of cost-savings was made by multiplying the RLRVAMC cost per unit of medication at time of initial prescription fill by the number of units taken each day multiplied by the total days’ supply on hand at time of therapy discontinuation. Patients with an MPR < 1 at time of therapy discontinuation were assumed to have zero remaining units on hand and zero cost savings was estimated. Waste, for purposes of cost-savings, was calculated for all MPR values > 1. Additional supply anticipated to be on hand from dose reductions was not included in the estimated cost of unused medication.
Descriptive statistics compared demographic characteristics between the pre- and postimplementation groups. MPR data were not normally distributed, which required the use of nonparametric Mann-Whitney U tests to compare pre- and postMPRs. Pearson χ2 compared the proportion of adherent patients between groups while descriptive statistics were used to estimate cost savings. Significance was determined based on a P value < .05. IBM SPSS Statistics software was used for all statistical analyses. As this was a complete sample of all eligible subjects, no sample size calculation was performed.
Results
In the preimplementation period, 246 patients received an OAN and 61 patients received an OAN in the postimplementation period (Figure 1). Of the 246 patients in the preimplementation period, 98 were eligible and included in the preimplementation group. Similarly, of the 61 patients in the postimplementation period, 35 patients met inclusion criteria for the postimplementation group. The study population was predominantly male with an average age of approximately 70 years in both groups (Table 3). More than 70% of the population in each group was White. No statistically significant differences between groups were identified. The most commonly prescribed OAN in the preimplementation group were abiraterone, imatinib, and enzalutamide (Table 3). In the postimplementation group, the most commonly prescribed agents were abiraterone, imatinib, pazopanib, and dasatinib. No significant differences were observed in prescribing of individual agents between the pre- and postimplementation groups or other characteristics that may affect adherence including patient copay status, number of concomitant medications, and driving distance from the RLRVAMC.
Thirty-six (36.7%) patients in the preimplementation group were considered nonadherent (MPR < 0.9) and 18 (18.4%) had an MPR < 0.8. Fifteen (15.3%) patients in the preimplementation clinic were considered overadherent (MPR > 1.1). Forty-seven (47.9%) patients in the preimplementation group were considered adherent (MPR 0.9 - 1.1) while all 35 (100%) patients in the postimplementation group were considered adherent (MPR 0.9 - 1.1). No non- or overadherent patients were identified in the postimplementation group (Figure 2). The median MPR for all patients in the preimplementation group was 0.94 compared with 1.06 (P < .001) in the postimplementation group.
Thirty-five (35.7%) patients had therapy discontinued or held in the preimplementation group compared with 2 (5.7%) patients in the postimplementation group (P < .001). Reasons for discontinuation in the preimplementation group included disease progression (n = 27), death (n = 3), lost to follow up (n = 2), and intolerability of therapy (n = 3). Both patients that discontinued therapy in the postimplementation group did so due to disease progression. Of the 35 patients who had their OAN discontinued or held in the preimplementation group, 14 patients had excess supply on hand at time of discontinuation. The estimated value of the unused medication was $37,890. Nine (25%) of the 35 patients who discontinued therapy had a dosage reduction during the course of therapy and the additional supply was not included in the cost estimate. Similarly, 1 of the 2 patients in the postimplementation group had their OAN discontinued during study. The cost of oversupply of medication at the time of therapy discontinuation was estimated at $1,555. No patients in the postimplementation group had dose reductions. After implementation of the OAN renewal clinic, the total cost savings between pre ($37,890) and postimplementation ($1,555) groups was $36,355.
Discussion
OANs are widely used therapies, with more than 25 million doses administered per year in the United States alone.12 The use of these agents will continue to grow as more targeted agents become available and patients request more convenient treatment options. The role for hematology/oncology clinical pharmacy services must adapt to this increased usage of OANs, including increasing pharmacist involvement in medication education, adherence and tolerability assessments, and proactive drug interaction monitoring.However, additional research is needed to determine optimal management strategies.
Our study aimed to compare OAN adherence among patients at a tertiary care VA hospital before and after implementation of a renewal clinic. The preimplementation population had a median MPR of 0.94 compared with 1.06 in the postimplementation group (P < .001). Although an ideal MPR is 1.0, we aimed for a slightly higher MPR to allow a supply buffer in the event of prescription delivery delays, as more than 90% of prescriptions are mailed to patients from a regional mail-order pharmacy. Importantly, the median MPRs do not adequately convey the impact from this clinic. The proportion of patients who were considered adherent to OANs increased from 47.9% in the preimplementation to 100% in the postimplementation period. These finding suggest that the clinical pharmacist role to assess and encourage adherence through monitoring tolerability of these OANs improved the overall medication taking experience of these patients.
Upon initial evaluation of adherence pre- and postimplementation, median adherence rates in both groups appeared to be above goal at 0.94 and 1.06 respectively. Patients in the postimplementation group intentionally received a 5- to 7-day supply buffer to account for potential prescription delivery delays due to holidays and inclement weather. This would indicate that the patients in the postimplementation group would have 15% oversupply due to the 5-day supply buffer. After correcting for patients with confounding reasons for excess (dose reductions, breaks in treatment, etc.), the median MPR in the prerefill clinic group decreased to 0.9 and the MPR in the postrefill clinic group increased slightly to 1.08. Although the median adherence rate in both the pre- and postimplementation groups were above goal of 0.90, 36% of the patients in the preimplementation group were considered nonadherent (MPR < 0.9) compared with no patients in the postimplementation group. Therefore, our intervention to improve patient adherence appeared to be beneficial at our institution.
In addition to improving adherence, one of the goals of the renewal clinic was to minimize excess supply at the time of therapy discontinuation. This was accomplished by aligning medication fills with medical visits and objective monitoring, as well as limiting supply to no more than 30 days. Of the patients in the postimplementation group, only 1 patient had remaining medication at the time of therapy discontinuation compared with 14 patients in the preimplementation group. The estimated cost savings from excess supply was $36,335. Limiting the amount of unused supply not only saves money for the patient and the institution, but also decreases opportunity for improper hazardous waste disposal and unnecessary exposure of hazardous materials to others.
Our results show the pharmacist intervention in the coordination of renewals improved adherence, minimized medication waste, and saved money. The cost of pharmacist time participating in the refill clinic was not calculated. Each visit was completed in approximately 5 minutes, with subsequent documentation and coordination taking an additional 5 to 10 minutes. During the launch of this service, the oncology pharmacy resident provided all coverage of the clinic. Oversite of the resident was provided by hematology/oncology clinical pharmacy specialists. We have continued to utilize pharmacy resident coverage since that time to meet education needs and keep the estimated cost per visit low. Another option in the case that pharmacy residents are not available would be utilization of a pharmacy technician, intern, or professional student to conduct the adherence and tolerability phone assessments. Our escalation protocol allows intervention by clinical pharmacy specialist and/or other health care providers when necessary. Trainees have only required basic training on how to use the protocol.
Limitations
Due to this study’s retrospective design, an inherent limitation is dependence on prescriber and refill records for documentation of initiation and discontinuation dates. Therefore, only the association of impact of pharmacist intervention on medication adherence can be determined as opposed to causation. We did not take into account discrepancies in day supply secondary to ‘held’ therapies, dose reductions, or doses supplied during an inpatient admission, which may alter estimates of MPR and cost-savings data. Patients in the postimplementation group intentionally received a 5 to 7-day supply buffer to account for potential prescription delivery delays due to holidays and inclement weather. This would indicate that the patients in the postimplementation group would have 15% oversupply due to the 5-day supply buffer, thereby skewing MPR values. This study did not account for cost avoidance resulting from early identification and management of toxicity. Finally, the postimplementation data only spans 4 months and a longer duration of time is needed to more accurately determine sustainability of renewal clinic interventions and provide comprehensive evaluation of cost-avoidance.
Conclusion
Implementation of an OAN renewal clinic was associated with an increase in MPR, improved proportion of patients considered adherent, and an estimated $36,335 cost-savings. However, prospective evaluation and a longer study duration are needed to determine causality of improved adherence and cost-savings associated with a pharmacist-driven OAN renewal clinic.
Evaluation of oral antineoplastic agent (OAN) adherence patterns have identified correlations between nonadherence or over-adherence and poorer disease-related outcomes. Multiple studies have focused on imatinib use in chronic myeloid leukemia (CML) due to its continuous, long-term use. A study by Ganesan and colleagues found that nonadherence to imatinib showed a significant decrease in 5-year event-free survival between 76.7% of adherent participants compared with 59.8% of nonadherent participants.1 This study found that 44% of patients who were adherent to imatinib achieved complete cytogenetic response vs only 26% of patients who were nonadherent. In another study of imatinib for CML, major molecular response (MMR) was strongly correlated with adherence and no patients with adherence < 80% were able to achieve MMR.2 Similarly, in studies of tamoxifen for breast cancer, < 80% adherence resulted in a 10% decrease in survival when compared to those who were more adherent.3,4
In addition to the clinical implications of nonadherence, there can be a significant cost associated with suboptimal use of these medications. The price of a single dose of OAN medication may cost as much as $440.5
The benefits of multidisciplinary care teams have been identified in many studies.6,7 While studies are limited in oncology, pharmacists provide vital contributions to the oncology multidisciplinary team when managing OANs as these health care professionals have expert knowledge of the medications, potential adverse events (AEs), and necessary monitoring parameters.8 In one study, patients seen by the pharmacist-led oral chemotherapy management program experienced improved clinical outcomes and response to therapy when compared with preintervention patients (early molecular response, 88.9% vs 54.8%, P = .01; major molecular response, 83.3% vs 57.6%, P = .06).9 During the study, 318 AEs were reported, leading to 235 pharmacist interventions to ameliorate AEs and improve adherence.
The primary objective of this study was to measure the impact of a pharmacist-driven OAN renewal clinic on medication adherence. The secondary objective was to estimate cost-savings of this new service.
Methods
Prior to July 2014, several limitations were identified related to OAN prescribing and monitoring at the Richard L. Roudebush Veterans Affairs Medical Center in Indianapolis, Indiana (RLRVAMC). The prescription ordering process relied primarily on the patient to initiate refills, rather than the prescriber OAN prescriptions also lacked consistency for number of refills or quantities dispensed. Furthermore, ordering of antineoplastic products was not limited to hematology/oncology providers. Patients were identified with significant supply on hand at the time of medication discontinuation, creating concerns for medication waste, tolerability, and nonadherence.
As a result, opportunities were identified to improve the prescribing process, recommended monitoring, toxicity and tolerability evaluation, medication reconciliation, and medication adherence. In July of 2014, the RLRVAMC adopted a new chemotherapy order entry system capable of restricting prescriptions to hematology/oncology providers and limiting dispensed quantities and refill amounts. A comprehensive pharmacist driven OAN renewal clinic was implemented on September 1, 2014 with the goal of improving long-term adherence and tolerability, in addition to minimizing medication waste.
Patients were eligible for enrollment in the clinic if they had a cancer diagnosis and were concomitantly prescribed an OAN outlined in Table 1. All eligible patients were automatically enrolled in the clinic when they were deemed stable on their OAN by a hematology/oncology pharmacy specialist. Stability was defined as ≤ Grade 1 symptoms associated with the toxicities of OAN therapy managed with or without intervention as defined by the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Once enrolled in the renewal clinic, patients were called by an oncology pharmacy resident (PGY2) 1 week prior to any OAN refill due date. Patients were asked a series of 5 adherence and tolerability questions (Table 2) to evaluate renewal criteria for approval or need for further evaluation. These questions were developed based on targeted information and published reports on monitoring adherence.10,11 Criteria for renewal included: < 10% self-reported missed doses of the OAN during the previous dispensing period, no hospitalizations or emergency department visits since most recent hematology/oncology provider appointment, no changes to concomitant medication therapies, and no new or worsening medication-related AEs. Patients meeting all criteria were given a 30-day supply of OAN. Prescribing, dispensing, and delivery of OAN were facilitated by the pharmacist. Patient cases that did not meet criteria for renewal were escalated to the hematology/oncology provider or oncology clinical pharmacy specialist for further evaluation.
Study Design and Setting
This was a pre/post retrospective cohort, quality improvement study of patients enrolled in the RLRVAMC OAN pharmacist renewal clinic. The study was deemed exempt from institutional review board (IRB) by the US Department of Veterans Affairs (VA) Research and Development Department.
Study Population
Patients were included in the preimplementation group if they had received at least 2 prescriptions of an eligible OAN. Therapy for the preimplementation group was required to be a monthly duration > 21 days and between the dates of September 1, 2013 and August 31, 2014. Patients were included in the postimplementation group if they had received at least 2 prescriptions of the studied OANs between September 1, 2014 and January 31, 2015. Patients were excluded if they had filled < 2 prescriptions of OAN; were managed by a non-VA oncologist or hematologist; or received an OAN other than those listed in Table 1.
Data Collection
For all patients in both the pre- and postimplementation cohorts, a standardized data collection tool was used to collect the following via electronic health record review by a PGY2 oncology resident: age, race, gender, oral antineoplastic agent, refill dates, days’ supply, estimated unit cost per dose cancer diagnosis, distance from the RLRVAMC, copay status, presence of hospitalizations/ED visits/dosage reductions, discontinuation rates, reasons for discontinuation, and total number of current prescriptions. The presence or absence of dosage reductions were collected to identify concerns for tolerability, but only the original dose for the preimplementation group and dosage at time of clinic enrollment for the postimplementation group was included in the analysis.
Outcomes and Statistical Analyses
The primary outcome was medication adherence defined as the median medication possession ratio (MPR) before and after implementation of the clinic. Secondary outcomes included the proportion of patients who were adherent from before implementation to after implementation and estimated cost-savings of this clinic after implementation. MPR was used to estimate medication adherence by taking the cumulative day supply of medication on hand divided by the number of days on therapy.12 Number of days on therapy was determined by taking the difference on the start date of the new medication regimen and the discontinuation date of the same regimen. Patients were grouped by adherence into one of the following categories: < 0.8, 0.8 to 0.89, 0.9 to 1, and > 1.1. Patients were considered adherent if they reported taking ≥ 90% (MPR ≥ 0.9) of prescribed doses, adopted from the study by Anderson and colleagues.12 A patient with an MPR > 1, likely due to filling prior to the anticipated refill date, was considered 100% adherent (MPR = 1). If a patient switched OAN during the study, both agents were included as separate entities.
A conservative estimate of cost-savings was made by multiplying the RLRVAMC cost per unit of medication at time of initial prescription fill by the number of units taken each day multiplied by the total days’ supply on hand at time of therapy discontinuation. Patients with an MPR < 1 at time of therapy discontinuation were assumed to have zero remaining units on hand and zero cost savings was estimated. Waste, for purposes of cost-savings, was calculated for all MPR values > 1. Additional supply anticipated to be on hand from dose reductions was not included in the estimated cost of unused medication.
Descriptive statistics compared demographic characteristics between the pre- and postimplementation groups. MPR data were not normally distributed, which required the use of nonparametric Mann-Whitney U tests to compare pre- and postMPRs. Pearson χ2 compared the proportion of adherent patients between groups while descriptive statistics were used to estimate cost savings. Significance was determined based on a P value < .05. IBM SPSS Statistics software was used for all statistical analyses. As this was a complete sample of all eligible subjects, no sample size calculation was performed.
Results
In the preimplementation period, 246 patients received an OAN and 61 patients received an OAN in the postimplementation period (Figure 1). Of the 246 patients in the preimplementation period, 98 were eligible and included in the preimplementation group. Similarly, of the 61 patients in the postimplementation period, 35 patients met inclusion criteria for the postimplementation group. The study population was predominantly male with an average age of approximately 70 years in both groups (Table 3). More than 70% of the population in each group was White. No statistically significant differences between groups were identified. The most commonly prescribed OAN in the preimplementation group were abiraterone, imatinib, and enzalutamide (Table 3). In the postimplementation group, the most commonly prescribed agents were abiraterone, imatinib, pazopanib, and dasatinib. No significant differences were observed in prescribing of individual agents between the pre- and postimplementation groups or other characteristics that may affect adherence including patient copay status, number of concomitant medications, and driving distance from the RLRVAMC.
Thirty-six (36.7%) patients in the preimplementation group were considered nonadherent (MPR < 0.9) and 18 (18.4%) had an MPR < 0.8. Fifteen (15.3%) patients in the preimplementation clinic were considered overadherent (MPR > 1.1). Forty-seven (47.9%) patients in the preimplementation group were considered adherent (MPR 0.9 - 1.1) while all 35 (100%) patients in the postimplementation group were considered adherent (MPR 0.9 - 1.1). No non- or overadherent patients were identified in the postimplementation group (Figure 2). The median MPR for all patients in the preimplementation group was 0.94 compared with 1.06 (P < .001) in the postimplementation group.
Thirty-five (35.7%) patients had therapy discontinued or held in the preimplementation group compared with 2 (5.7%) patients in the postimplementation group (P < .001). Reasons for discontinuation in the preimplementation group included disease progression (n = 27), death (n = 3), lost to follow up (n = 2), and intolerability of therapy (n = 3). Both patients that discontinued therapy in the postimplementation group did so due to disease progression. Of the 35 patients who had their OAN discontinued or held in the preimplementation group, 14 patients had excess supply on hand at time of discontinuation. The estimated value of the unused medication was $37,890. Nine (25%) of the 35 patients who discontinued therapy had a dosage reduction during the course of therapy and the additional supply was not included in the cost estimate. Similarly, 1 of the 2 patients in the postimplementation group had their OAN discontinued during study. The cost of oversupply of medication at the time of therapy discontinuation was estimated at $1,555. No patients in the postimplementation group had dose reductions. After implementation of the OAN renewal clinic, the total cost savings between pre ($37,890) and postimplementation ($1,555) groups was $36,355.
Discussion
OANs are widely used therapies, with more than 25 million doses administered per year in the United States alone.12 The use of these agents will continue to grow as more targeted agents become available and patients request more convenient treatment options. The role for hematology/oncology clinical pharmacy services must adapt to this increased usage of OANs, including increasing pharmacist involvement in medication education, adherence and tolerability assessments, and proactive drug interaction monitoring.However, additional research is needed to determine optimal management strategies.
Our study aimed to compare OAN adherence among patients at a tertiary care VA hospital before and after implementation of a renewal clinic. The preimplementation population had a median MPR of 0.94 compared with 1.06 in the postimplementation group (P < .001). Although an ideal MPR is 1.0, we aimed for a slightly higher MPR to allow a supply buffer in the event of prescription delivery delays, as more than 90% of prescriptions are mailed to patients from a regional mail-order pharmacy. Importantly, the median MPRs do not adequately convey the impact from this clinic. The proportion of patients who were considered adherent to OANs increased from 47.9% in the preimplementation to 100% in the postimplementation period. These finding suggest that the clinical pharmacist role to assess and encourage adherence through monitoring tolerability of these OANs improved the overall medication taking experience of these patients.
Upon initial evaluation of adherence pre- and postimplementation, median adherence rates in both groups appeared to be above goal at 0.94 and 1.06 respectively. Patients in the postimplementation group intentionally received a 5- to 7-day supply buffer to account for potential prescription delivery delays due to holidays and inclement weather. This would indicate that the patients in the postimplementation group would have 15% oversupply due to the 5-day supply buffer. After correcting for patients with confounding reasons for excess (dose reductions, breaks in treatment, etc.), the median MPR in the prerefill clinic group decreased to 0.9 and the MPR in the postrefill clinic group increased slightly to 1.08. Although the median adherence rate in both the pre- and postimplementation groups were above goal of 0.90, 36% of the patients in the preimplementation group were considered nonadherent (MPR < 0.9) compared with no patients in the postimplementation group. Therefore, our intervention to improve patient adherence appeared to be beneficial at our institution.
In addition to improving adherence, one of the goals of the renewal clinic was to minimize excess supply at the time of therapy discontinuation. This was accomplished by aligning medication fills with medical visits and objective monitoring, as well as limiting supply to no more than 30 days. Of the patients in the postimplementation group, only 1 patient had remaining medication at the time of therapy discontinuation compared with 14 patients in the preimplementation group. The estimated cost savings from excess supply was $36,335. Limiting the amount of unused supply not only saves money for the patient and the institution, but also decreases opportunity for improper hazardous waste disposal and unnecessary exposure of hazardous materials to others.
Our results show the pharmacist intervention in the coordination of renewals improved adherence, minimized medication waste, and saved money. The cost of pharmacist time participating in the refill clinic was not calculated. Each visit was completed in approximately 5 minutes, with subsequent documentation and coordination taking an additional 5 to 10 minutes. During the launch of this service, the oncology pharmacy resident provided all coverage of the clinic. Oversite of the resident was provided by hematology/oncology clinical pharmacy specialists. We have continued to utilize pharmacy resident coverage since that time to meet education needs and keep the estimated cost per visit low. Another option in the case that pharmacy residents are not available would be utilization of a pharmacy technician, intern, or professional student to conduct the adherence and tolerability phone assessments. Our escalation protocol allows intervention by clinical pharmacy specialist and/or other health care providers when necessary. Trainees have only required basic training on how to use the protocol.
Limitations
Due to this study’s retrospective design, an inherent limitation is dependence on prescriber and refill records for documentation of initiation and discontinuation dates. Therefore, only the association of impact of pharmacist intervention on medication adherence can be determined as opposed to causation. We did not take into account discrepancies in day supply secondary to ‘held’ therapies, dose reductions, or doses supplied during an inpatient admission, which may alter estimates of MPR and cost-savings data. Patients in the postimplementation group intentionally received a 5 to 7-day supply buffer to account for potential prescription delivery delays due to holidays and inclement weather. This would indicate that the patients in the postimplementation group would have 15% oversupply due to the 5-day supply buffer, thereby skewing MPR values. This study did not account for cost avoidance resulting from early identification and management of toxicity. Finally, the postimplementation data only spans 4 months and a longer duration of time is needed to more accurately determine sustainability of renewal clinic interventions and provide comprehensive evaluation of cost-avoidance.
Conclusion
Implementation of an OAN renewal clinic was associated with an increase in MPR, improved proportion of patients considered adherent, and an estimated $36,335 cost-savings. However, prospective evaluation and a longer study duration are needed to determine causality of improved adherence and cost-savings associated with a pharmacist-driven OAN renewal clinic.
1. Ganesan P, Sagar TG, Dubashi B, et al. Nonadherence to imatinib adversely affects event free survival in chronic phase chronic myeloid leukemia. Am J Hematol 2011; 86: 471-474. doi:10.1002/ajh.22019
2. Marin D, Bazeos A, Mahon FX, et al. Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol 2010; 28: 2381-2388. doi:10.1200/JCO.2009.26.3087
3. McCowan C, Shearer J, Donnan PT, et al. Cohort study examining tamoxifen adherence and its relationship to mortality in women with breast cancer. Br J Cancer 2008; 99: 1763-1768. doi:10.1038/sj.bjc.6604758
4. Lexicomp Online. Sunitinib. Hudson, Ohio: Lexi-Comp, Inc; August 20, 2019.
5. Babiker A, El Husseini M, Al Nemri A, et al. Health care professional development: Working as a team to improve patient care. Sudan J Paediatr. 2014;14(2):9-16.
6. Spence MM, Makarem AF, Reyes SL, et al. Evaluation of an outpatient pharmacy clinical services program on adherence and clinical outcomes among patients with diabetes and/or coronary artery disease. J Manag Care Spec Pharm. 2014;20(10):1036-1045. doi:10.18553/jmcp.2014.20.10.1036
7. Holle LM, Puri S, Clement JM. Physician-pharmacist collaboration for oral chemotherapy monitoring: Insights from an academic genitourinary oncology practice. J Oncol Pharm Pract 2015; doi:10.1177/1078155215581524
8. Muluneh B, Schneider M, Faso A, et al. Improved Adherence Rates and Clinical Outcomes of an Integrated, Closed-Loop, Pharmacist-Led Oral Chemotherapy Management Program. Journal of Oncology Practice. 2018;14(6):371-333. doi:10.1200/JOP.17.00039.
9. Font R, Espinas JA, Gil-Gil M, et al. Prescription refill, patient self-report and physician report in assessing adherence to oral endocrine therapy in early breast cancer patients: a retrospective cohort study in Catalonia, Spain. British Journal of Cancer. 2012 ;107(8):1249-1256. doi:10.1038/bjc.2012.389.
10. Anderson KR, Chambers CR, Lam N, et al. Medication adherence among adults prescribed imatinib, dasatinib, or nilotinib for the treatment of chronic myeloid leukemia. J Oncol Pharm Practice. 2015;21(1):19–25. doi:10.1177/1078155213520261
11. Weingart SN, Brown E, Bach PB, et al. NCCN Task Force Report: oral chemotherapy. J Natl Compr Canc Netw. 2008;6(3): S1-S14.
1. Ganesan P, Sagar TG, Dubashi B, et al. Nonadherence to imatinib adversely affects event free survival in chronic phase chronic myeloid leukemia. Am J Hematol 2011; 86: 471-474. doi:10.1002/ajh.22019
2. Marin D, Bazeos A, Mahon FX, et al. Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol 2010; 28: 2381-2388. doi:10.1200/JCO.2009.26.3087
3. McCowan C, Shearer J, Donnan PT, et al. Cohort study examining tamoxifen adherence and its relationship to mortality in women with breast cancer. Br J Cancer 2008; 99: 1763-1768. doi:10.1038/sj.bjc.6604758
4. Lexicomp Online. Sunitinib. Hudson, Ohio: Lexi-Comp, Inc; August 20, 2019.
5. Babiker A, El Husseini M, Al Nemri A, et al. Health care professional development: Working as a team to improve patient care. Sudan J Paediatr. 2014;14(2):9-16.
6. Spence MM, Makarem AF, Reyes SL, et al. Evaluation of an outpatient pharmacy clinical services program on adherence and clinical outcomes among patients with diabetes and/or coronary artery disease. J Manag Care Spec Pharm. 2014;20(10):1036-1045. doi:10.18553/jmcp.2014.20.10.1036
7. Holle LM, Puri S, Clement JM. Physician-pharmacist collaboration for oral chemotherapy monitoring: Insights from an academic genitourinary oncology practice. J Oncol Pharm Pract 2015; doi:10.1177/1078155215581524
8. Muluneh B, Schneider M, Faso A, et al. Improved Adherence Rates and Clinical Outcomes of an Integrated, Closed-Loop, Pharmacist-Led Oral Chemotherapy Management Program. Journal of Oncology Practice. 2018;14(6):371-333. doi:10.1200/JOP.17.00039.
9. Font R, Espinas JA, Gil-Gil M, et al. Prescription refill, patient self-report and physician report in assessing adherence to oral endocrine therapy in early breast cancer patients: a retrospective cohort study in Catalonia, Spain. British Journal of Cancer. 2012 ;107(8):1249-1256. doi:10.1038/bjc.2012.389.
10. Anderson KR, Chambers CR, Lam N, et al. Medication adherence among adults prescribed imatinib, dasatinib, or nilotinib for the treatment of chronic myeloid leukemia. J Oncol Pharm Practice. 2015;21(1):19–25. doi:10.1177/1078155213520261
11. Weingart SN, Brown E, Bach PB, et al. NCCN Task Force Report: oral chemotherapy. J Natl Compr Canc Netw. 2008;6(3): S1-S14.
Impact of an Oral Antineoplastic Renewal Clinic on Medication Possession Ratio and Cost-Savings
Evaluation of oral antineoplastic agent (OAN) adherence patterns have identified correlations between nonadherence or over-adherence and poorer disease-related outcomes. Multiple studies have focused on imatinib use in chronic myeloid leukemia (CML) due to its continuous, long-term use. A study by Ganesan and colleagues found that nonadherence to imatinib showed a significant decrease in 5-year event-free survival between 76.7% of adherent participants compared with 59.8% of nonadherent participants.1 This study found that 44% of patients who were adherent to imatinib achieved complete cytogenetic response vs only 26% of patients who were nonadherent. In another study of imatinib for CML, major molecular response (MMR) was strongly correlated with adherence and no patients with adherence < 80% were able to achieve MMR.2 Similarly, in studies of tamoxifen for breast cancer, < 80% adherence resulted in a 10% decrease in survival when compared to those who were more adherent.3,4
In addition to the clinical implications of nonadherence, there can be a significant cost associated with suboptimal use of these medications. The price of a single dose of OAN medication may cost as much as $440.5
The benefits of multidisciplinary care teams have been identified in many studies.6,7 While studies are limited in oncology, pharmacists provide vital contributions to the oncology multidisciplinary team when managing OANs as these health care professionals have expert knowledge of the medications, potential adverse events (AEs), and necessary monitoring parameters.8 In one study, patients seen by the pharmacist-led oral chemotherapy management program experienced improved clinical outcomes and response to therapy when compared with preintervention patients (early molecular response, 88.9% vs 54.8%, P = .01; major molecular response, 83.3% vs 57.6%, P = .06).9 During the study, 318 AEs were reported, leading to 235 pharmacist interventions to ameliorate AEs and improve adherence.
The primary objective of this study was to measure the impact of a pharmacist-driven OAN renewal clinic on medication adherence. The secondary objective was to estimate cost-savings of this new service.
Methods
Prior to July 2014, several limitations were identified related to OAN prescribing and monitoring at the Richard L. Roudebush Veterans Affairs Medical Center in Indianapolis, Indiana (RLRVAMC). The prescription ordering process relied primarily on the patient to initiate refills, rather than the prescriber OAN prescriptions also lacked consistency for number of refills or quantities dispensed. Furthermore, ordering of antineoplastic products was not limited to hematology/oncology providers. Patients were identified with significant supply on hand at the time of medication discontinuation, creating concerns for medication waste, tolerability, and nonadherence.
As a result, opportunities were identified to improve the prescribing process, recommended monitoring, toxicity and tolerability evaluation, medication reconciliation, and medication adherence. In July of 2014, the RLRVAMC adopted a new chemotherapy order entry system capable of restricting prescriptions to hematology/oncology providers and limiting dispensed quantities and refill amounts. A comprehensive pharmacist driven OAN renewal clinic was implemented on September 1, 2014 with the goal of improving long-term adherence and tolerability, in addition to minimizing medication waste.
Patients were eligible for enrollment in the clinic if they had a cancer diagnosis and were concomitantly prescribed an OAN outlined in Table 1. All eligible patients were automatically enrolled in the clinic when they were deemed stable on their OAN by a hematology/oncology pharmacy specialist. Stability was defined as ≤ Grade 1 symptoms associated with the toxicities of OAN therapy managed with or without intervention as defined by the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Once enrolled in the renewal clinic, patients were called by an oncology pharmacy resident (PGY2) 1 week prior to any OAN refill due date. Patients were asked a series of 5 adherence and tolerability questions (Table 2) to evaluate renewal criteria for approval or need for further evaluation. These questions were developed based on targeted information and published reports on monitoring adherence.10,11 Criteria for renewal included: < 10% self-reported missed doses of the OAN during the previous dispensing period, no hospitalizations or emergency department visits since most recent hematology/oncology provider appointment, no changes to concomitant medication therapies, and no new or worsening medication-related AEs. Patients meeting all criteria were given a 30-day supply of OAN. Prescribing, dispensing, and delivery of OAN were facilitated by the pharmacist. Patient cases that did not meet criteria for renewal were escalated to the hematology/oncology provider or oncology clinical pharmacy specialist for further evaluation.
Study Design and Setting
This was a pre/post retrospective cohort, quality improvement study of patients enrolled in the RLRVAMC OAN pharmacist renewal clinic. The study was deemed exempt from institutional review board (IRB) by the US Department of Veterans Affairs (VA) Research and Development Department.
Study Population
Patients were included in the preimplementation group if they had received at least 2 prescriptions of an eligible OAN. Therapy for the preimplementation group was required to be a monthly duration > 21 days and between the dates of September 1, 2013 and August 31, 2014. Patients were included in the postimplementation group if they had received at least 2 prescriptions of the studied OANs between September 1, 2014 and January 31, 2015. Patients were excluded if they had filled < 2 prescriptions of OAN; were managed by a non-VA oncologist or hematologist; or received an OAN other than those listed in Table 1.
Data Collection
For all patients in both the pre- and postimplementation cohorts, a standardized data collection tool was used to collect the following via electronic health record review by a PGY2 oncology resident: age, race, gender, oral antineoplastic agent, refill dates, days’ supply, estimated unit cost per dose cancer diagnosis, distance from the RLRVAMC, copay status, presence of hospitalizations/ED visits/dosage reductions, discontinuation rates, reasons for discontinuation, and total number of current prescriptions. The presence or absence of dosage reductions were collected to identify concerns for tolerability, but only the original dose for the preimplementation group and dosage at time of clinic enrollment for the postimplementation group was included in the analysis.
Outcomes and Statistical Analyses
The primary outcome was medication adherence defined as the median medication possession ratio (MPR) before and after implementation of the clinic. Secondary outcomes included the proportion of patients who were adherent from before implementation to after and estimated cost-savings of this clinic after implementation. MPR was used to estimate medication adherence by taking the cumulative day supply of medication on hand divided by the number of days on therapy.12 Number of days on therapy was determined by taking the difference on the start date of the new medication regimen and the discontinuation date of the same regimen. Patients were grouped by adherence into one of the following categories: < 0.8, 0.8 to 0.89, 0.9 to 1, and > 1.1. Patients were considered adherent if they reported taking ≥ 90% (MPR ≥ 0.9) of prescribed doses, adopted from the study by Anderson and colleagues.12 A patient with an MPR > 1, likely due to filling prior to the anticipated refill date, was considered 100% adherent (MPR = 1). If a patient switched OAN during the study, both agents were included as separate entities.
A conservative estimate of cost-savings was made by multiplying the RLRVAMC cost per unit of medication at time of initial prescription fill by the number of units taken each day multiplied by the total days’ supply on hand at time of therapy discontinuation. Patients with an MPR < 1 at time of therapy discontinuation were assumed to have zero remaining units on hand and zero cost savings was estimated. Waste, for purposes of cost-savings, was calculated for all MPR values > 1. Additional supply anticipated to be on hand from dose reductions was not included in the estimated cost of unused medication.
Descriptive statistics compared demographic characteristics between the pre- and postimplementation groups. MPR data were not normally distributed, which required the use of nonparametric Mann-Whitney U tests to compare pre- and postMPRs. Pearson χ2 compared the proportion of adherent patients between groups while descriptive statistics were used to estimate cost savings. Significance was determined based on a P value < .05. IBM SPSS Statistics software was used for all statistical analyses. As this was a complete sample of all eligible subjects, no sample size calculation was performed.
Results
In the preimplementation period, 246 patients received an OAN and 61 patients received an OAN in the postimplementation period (Figure 1). Of the 246 patients in the preimplementation period, 98 were eligible and included in the preimplementation group. Similarly, of the 61 patients in the postimplementation period, 35 patients met inclusion criteria for the postimplementation group. The study population was predominantly male with an average age of approximately 70 years in both groups (Table 3). More than 70% of the population in each group was White. No statistically significant differences between groups were identified. The most commonly prescribed OAN in the preimplementation group were abiraterone, imatinib, and enzalutamide (Table 3). In the postimplementation group, the most commonly prescribed agents were abiraterone, imatinib, pazopanib, and dasatinib. No significant differences were observed in prescribing of individual agents between the pre- and postimplementation groups or other characteristics that may affect adherence including patient copay status, number of concomitant medications, and driving distance from the RLRVAMC.
Thirty-six (36.7%) patients in the preimplementation group were considered nonadherent (MPR < 0.9) and 18 (18.4%) had an MPR < 0.8. Fifteen (15.3%) patients in the preimplementation clinic were considered overadherent (MPR > 1.1). Forty-seven (47.9%) patients in the preimplementation group were considered adherent (MPR 0.9 - 1.1) while all 35 (100%) patients in the postimplementation group were considered adherent (MPR 0.9 - 1.1). No non- or overadherent patients were identified in the postimplementation group (Figure 2). The median MPR for all patients in the preimplementation group was 0.94 compared with 1.06 (P < .001) in the postimplementation group.
Thirty-five (35.7%) patients had therapy discontinued or held in the preimplementation group compared with 2 (5.7%) patients in the postimplementation group (P < .001). Reasons for discontinuation in the preimplementation group included disease progression (n = 27), death (n = 3), lost to follow up (n = 2), and intolerability of therapy (n = 3). Both patients that discontinued therapy in the postimplementation group did so due to disease progression. Of the 35 patients who had their OAN discontinued or held in the preimplementation group, 14 patients had excess supply on hand at time of discontinuation. The estimated value of the unused medication was $37,890. Nine (25%) of the 35 patients who discontinued therapy had a dosage reduction during the course of therapy and the additional supply was not included in the cost estimate. Similarly, 1 of the 2 patients in the postimplementation group had their OAN discontinued during study. The cost of oversupply of medication at the time of therapy discontinuation was estimated at $1,555. No patients in the postimplementation group had dose reductions. After implementation of the OAN renewal clinic, the total cost savings between pre ($37,890) and postimplementation ($1,555) groups was $36,355.
Discussion
OANs are widely used therapies, with more than 25 million doses administered per year in the United States alone.12 The use of these agents will continue to grow as more targeted agents become available and patients request more convenient treatment options. The role for hematology/oncology clinical pharmacy services must adapt to this increased usage of OANs, including increasing pharmacist involvement in medication education, adherence and tolerability assessments, and proactive drug interaction monitoring.However, additional research is needed to determine optimal management strategies.
Our study aimed to compare OAN adherence among patients at a tertiary care VA hospital before and after implementation of a renewal clinic. The preimplementation population had a median MPR of 0.94 compared with 1.06 in the postimplementation group (P < .001). Although an ideal MPR is 1.0, we aimed for a slightly higher MPR to allow a supply buffer in the event of prescription delivery delays, as more than 90% of prescriptions are mailed to patients from a regional mail-order pharmacy. Importantly, the median MPRs do not adequately convey the impact from this clinic. The proportion of patients who were considered adherent to OANs increased from 47.9% in the preimplementation to 100% in the postimplementation period. These finding suggest that the clinical pharmacist role to assess and encourage adherence through monitoring tolerability of these OANs improved the overall medication taking experience of these patients.
Upon initial evaluation of adherence pre- and postimplementation, median adherence rates in both groups appeared to be above goal at 0.94 and 1.06 respectively. Patients in the postimplementation group intentionally received a 5- to 7-day supply buffer to account for potential prescription delivery delays due to holidays and inclement weather. This would indicate that the patients in the postimplementation group would have 15% oversupply due to the 5-day supply buffer. After correcting for patients with confounding reasons for excess (dose reductions, breaks in treatment, etc.), the median MPR in the prerefill clinic group decreased to 0.9 and the MPR in the postrefill clinic group increased slightly to 1.08. Although the median adherence rate in both the pre- and postimplementation groups were above goal of 0.90, 36% of the patients in the preimplementation group were considered nonadherent (MPR < 0.9) compared with no patients in the postimplementation group. Therefore, our intervention to improve patient adherence appeared to be beneficial at our institution.
In addition to improving adherence, one of the goals of the renewal clinic was to minimize excess supply at the time of therapy discontinuation. This was accomplished by aligning medication fills with medical visits and objective monitoring, as well as limiting supply to no more than 30 days. Of the patients in the postimplementation group, only 1 patient had remaining medication at the time of therapy discontinuation compared with 14 patients in the preimplementation group. The estimated cost savings from excess supply was $36,335. Limiting the amount of unused supply not only saves money for the patient and the institution, but also decreases opportunity for improper hazardous waste disposal and unnecessary exposure of hazardous materials to others.
Our results show the pharmacist intervention in the coordination of renewals improved adherence, minimized medication waste, and saved money. The cost of pharmacist time participating in the refill clinic was not calculated. Each visit was completed in approximately 5 minutes, with subsequent documentation and coordination taking an additional 5 to 10 minutes. During the launch of this service, the oncology pharmacy resident provided all coverage of the clinic. Oversite of the resident was provided by hematology/oncology clinical pharmacy specialists. We have continued to utilize pharmacy resident coverage since that time to meet education needs and keep the estimated cost per visit low. Another option in the case that pharmacy residents are not available would be utilization of a pharmacy technician, intern, or professional student to conduct the adherence and tolerability phone assessments. Our escalation protocol allows intervention by clinical pharmacy specialist and/or other health care providers when necessary. Trainees have only required basic training on how to use the protocol.
Limitations
Due to this study’s retrospective design, an inherent limitation is dependence on prescriber and refill records for documentation of initiation and discontinuation dates. Therefore, only the association of impact of pharmacist intervention on medication adherence can be determined as opposed to causation. We did not take into account discrepancies in day supply secondary to ‘held’ therapies, dose reductions, or doses supplied during an inpatient admission, which may alter estimates of MPR and cost-savings data. Patients in the postimplementation group intentionally received a 5 to 7-day supply buffer to account for potential prescription delivery delays due to holidays and inclement weather. This would indicate that the patients in the postimplementation group would have 15% oversupply due to the 5-day supply buffer, thereby skewing MPR values. This study did not account for cost avoidance resulting from early identification and management of toxicity. Finally, the postimplementation data only spans 4 months and a longer duration of time is needed to more accurately determine sustainability of renewal clinic interventions and provide comprehensive evaluation of cost-avoidance.
Conclusion
Implementation of an OAN renewal clinic was associated with an increase in MPR, improved proportion of patients considered adherent, and an estimated $36,335 cost-savings. However, prospective evaluation and a longer study duration are needed to determine causality of improved adherence and cost-savings associated with a pharmacist-driven OAN renewal clinic.
1. Ganesan P, Sagar TG, Dubashi B, et al. Nonadherence to imatinib adversely affects event free survival in chronic phase chronic myeloid leukemia. Am J Hematol 2011; 86: 471-474. doi:10.1002/ajh.22019
2. Marin D, Bazeos A, Mahon FX, et al. Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol 2010; 28: 2381-2388. doi:10.1200/JCO.2009.26.3087
3. McCowan C, Shearer J, Donnan PT, et al. Cohort study examining tamoxifen adherence and its relationship to mortality in women with breast cancer. Br J Cancer 2008; 99: 1763-1768. doi:10.1038/sj.bjc.6604758
4. Lexicomp Online. Sunitinib. Hudson, Ohio: Lexi-Comp, Inc; August 20, 2019.
5. Babiker A, El Husseini M, Al Nemri A, et al. Health care professional development: Working as a team to improve patient care. Sudan J Paediatr. 2014;14(2):9-16.
6. Spence MM, Makarem AF, Reyes SL, et al. Evaluation of an outpatient pharmacy clinical services program on adherence and clinical outcomes among patients with diabetes and/or coronary artery disease. J Manag Care Spec Pharm. 2014;20(10):1036-1045. doi:10.18553/jmcp.2014.20.10.1036
7. Holle LM, Puri S, Clement JM. Physician-pharmacist collaboration for oral chemotherapy monitoring: Insights from an academic genitourinary oncology practice. J Oncol Pharm Pract 2015; doi:10.1177/1078155215581524
8. Muluneh B, Schneider M, Faso A, et al. Improved Adherence Rates and Clinical Outcomes of an Integrated, Closed-Loop, Pharmacist-Led Oral Chemotherapy Management Program. Journal of Oncology Practice. 2018;14(6):371-333. doi:10.1200/JOP.17.00039.
9. Font R, Espinas JA, Gil-Gil M, et al. Prescription refill, patient self-report and physician report in assessing adherence to oral endocrine therapy in early breast cancer patients: a retrospective cohort study in Catalonia, Spain. British Journal of Cancer. 2012 ;107(8):1249-1256. doi:10.1038/bjc.2012.389.
10. Anderson KR, Chambers CR, Lam N, et al. Medication adherence among adults prescribed imatinib, dasatinib, or nilotinib for the treatment of chronic myeloid leukemia. J Oncol Pharm Practice. 2015;21(1):19–25. doi:10.1177/1078155213520261
11. Weingart SN, Brown E, Bach PB, et al. NCCN Task Force Report: oral chemotherapy. J Natl Compr Canc Netw. 2008;6(3): S1-S14.
Evaluation of oral antineoplastic agent (OAN) adherence patterns have identified correlations between nonadherence or over-adherence and poorer disease-related outcomes. Multiple studies have focused on imatinib use in chronic myeloid leukemia (CML) due to its continuous, long-term use. A study by Ganesan and colleagues found that nonadherence to imatinib showed a significant decrease in 5-year event-free survival between 76.7% of adherent participants compared with 59.8% of nonadherent participants.1 This study found that 44% of patients who were adherent to imatinib achieved complete cytogenetic response vs only 26% of patients who were nonadherent. In another study of imatinib for CML, major molecular response (MMR) was strongly correlated with adherence and no patients with adherence < 80% were able to achieve MMR.2 Similarly, in studies of tamoxifen for breast cancer, < 80% adherence resulted in a 10% decrease in survival when compared to those who were more adherent.3,4
In addition to the clinical implications of nonadherence, there can be a significant cost associated with suboptimal use of these medications. The price of a single dose of OAN medication may cost as much as $440.5
The benefits of multidisciplinary care teams have been identified in many studies.6,7 While studies are limited in oncology, pharmacists provide vital contributions to the oncology multidisciplinary team when managing OANs as these health care professionals have expert knowledge of the medications, potential adverse events (AEs), and necessary monitoring parameters.8 In one study, patients seen by the pharmacist-led oral chemotherapy management program experienced improved clinical outcomes and response to therapy when compared with preintervention patients (early molecular response, 88.9% vs 54.8%, P = .01; major molecular response, 83.3% vs 57.6%, P = .06).9 During the study, 318 AEs were reported, leading to 235 pharmacist interventions to ameliorate AEs and improve adherence.
The primary objective of this study was to measure the impact of a pharmacist-driven OAN renewal clinic on medication adherence. The secondary objective was to estimate cost-savings of this new service.
Methods
Prior to July 2014, several limitations were identified related to OAN prescribing and monitoring at the Richard L. Roudebush Veterans Affairs Medical Center in Indianapolis, Indiana (RLRVAMC). The prescription ordering process relied primarily on the patient to initiate refills, rather than the prescriber OAN prescriptions also lacked consistency for number of refills or quantities dispensed. Furthermore, ordering of antineoplastic products was not limited to hematology/oncology providers. Patients were identified with significant supply on hand at the time of medication discontinuation, creating concerns for medication waste, tolerability, and nonadherence.
As a result, opportunities were identified to improve the prescribing process, recommended monitoring, toxicity and tolerability evaluation, medication reconciliation, and medication adherence. In July of 2014, the RLRVAMC adopted a new chemotherapy order entry system capable of restricting prescriptions to hematology/oncology providers and limiting dispensed quantities and refill amounts. A comprehensive pharmacist driven OAN renewal clinic was implemented on September 1, 2014 with the goal of improving long-term adherence and tolerability, in addition to minimizing medication waste.
Patients were eligible for enrollment in the clinic if they had a cancer diagnosis and were concomitantly prescribed an OAN outlined in Table 1. All eligible patients were automatically enrolled in the clinic when they were deemed stable on their OAN by a hematology/oncology pharmacy specialist. Stability was defined as ≤ Grade 1 symptoms associated with the toxicities of OAN therapy managed with or without intervention as defined by the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Once enrolled in the renewal clinic, patients were called by an oncology pharmacy resident (PGY2) 1 week prior to any OAN refill due date. Patients were asked a series of 5 adherence and tolerability questions (Table 2) to evaluate renewal criteria for approval or need for further evaluation. These questions were developed based on targeted information and published reports on monitoring adherence.10,11 Criteria for renewal included: < 10% self-reported missed doses of the OAN during the previous dispensing period, no hospitalizations or emergency department visits since most recent hematology/oncology provider appointment, no changes to concomitant medication therapies, and no new or worsening medication-related AEs. Patients meeting all criteria were given a 30-day supply of OAN. Prescribing, dispensing, and delivery of OAN were facilitated by the pharmacist. Patient cases that did not meet criteria for renewal were escalated to the hematology/oncology provider or oncology clinical pharmacy specialist for further evaluation.
Study Design and Setting
This was a pre/post retrospective cohort, quality improvement study of patients enrolled in the RLRVAMC OAN pharmacist renewal clinic. The study was deemed exempt from institutional review board (IRB) by the US Department of Veterans Affairs (VA) Research and Development Department.
Study Population
Patients were included in the preimplementation group if they had received at least 2 prescriptions of an eligible OAN. Therapy for the preimplementation group was required to be a monthly duration > 21 days and between the dates of September 1, 2013 and August 31, 2014. Patients were included in the postimplementation group if they had received at least 2 prescriptions of the studied OANs between September 1, 2014 and January 31, 2015. Patients were excluded if they had filled < 2 prescriptions of OAN; were managed by a non-VA oncologist or hematologist; or received an OAN other than those listed in Table 1.
Data Collection
For all patients in both the pre- and postimplementation cohorts, a standardized data collection tool was used to collect the following via electronic health record review by a PGY2 oncology resident: age, race, gender, oral antineoplastic agent, refill dates, days’ supply, estimated unit cost per dose cancer diagnosis, distance from the RLRVAMC, copay status, presence of hospitalizations/ED visits/dosage reductions, discontinuation rates, reasons for discontinuation, and total number of current prescriptions. The presence or absence of dosage reductions were collected to identify concerns for tolerability, but only the original dose for the preimplementation group and dosage at time of clinic enrollment for the postimplementation group was included in the analysis.
Outcomes and Statistical Analyses
The primary outcome was medication adherence defined as the median medication possession ratio (MPR) before and after implementation of the clinic. Secondary outcomes included the proportion of patients who were adherent from before implementation to after and estimated cost-savings of this clinic after implementation. MPR was used to estimate medication adherence by taking the cumulative day supply of medication on hand divided by the number of days on therapy.12 Number of days on therapy was determined by taking the difference on the start date of the new medication regimen and the discontinuation date of the same regimen. Patients were grouped by adherence into one of the following categories: < 0.8, 0.8 to 0.89, 0.9 to 1, and > 1.1. Patients were considered adherent if they reported taking ≥ 90% (MPR ≥ 0.9) of prescribed doses, adopted from the study by Anderson and colleagues.12 A patient with an MPR > 1, likely due to filling prior to the anticipated refill date, was considered 100% adherent (MPR = 1). If a patient switched OAN during the study, both agents were included as separate entities.
A conservative estimate of cost-savings was made by multiplying the RLRVAMC cost per unit of medication at time of initial prescription fill by the number of units taken each day multiplied by the total days’ supply on hand at time of therapy discontinuation. Patients with an MPR < 1 at time of therapy discontinuation were assumed to have zero remaining units on hand and zero cost savings was estimated. Waste, for purposes of cost-savings, was calculated for all MPR values > 1. Additional supply anticipated to be on hand from dose reductions was not included in the estimated cost of unused medication.
Descriptive statistics compared demographic characteristics between the pre- and postimplementation groups. MPR data were not normally distributed, which required the use of nonparametric Mann-Whitney U tests to compare pre- and postMPRs. Pearson χ2 compared the proportion of adherent patients between groups while descriptive statistics were used to estimate cost savings. Significance was determined based on a P value < .05. IBM SPSS Statistics software was used for all statistical analyses. As this was a complete sample of all eligible subjects, no sample size calculation was performed.
Results
In the preimplementation period, 246 patients received an OAN and 61 patients received an OAN in the postimplementation period (Figure 1). Of the 246 patients in the preimplementation period, 98 were eligible and included in the preimplementation group. Similarly, of the 61 patients in the postimplementation period, 35 patients met inclusion criteria for the postimplementation group. The study population was predominantly male with an average age of approximately 70 years in both groups (Table 3). More than 70% of the population in each group was White. No statistically significant differences between groups were identified. The most commonly prescribed OAN in the preimplementation group were abiraterone, imatinib, and enzalutamide (Table 3). In the postimplementation group, the most commonly prescribed agents were abiraterone, imatinib, pazopanib, and dasatinib. No significant differences were observed in prescribing of individual agents between the pre- and postimplementation groups or other characteristics that may affect adherence including patient copay status, number of concomitant medications, and driving distance from the RLRVAMC.
Thirty-six (36.7%) patients in the preimplementation group were considered nonadherent (MPR < 0.9) and 18 (18.4%) had an MPR < 0.8. Fifteen (15.3%) patients in the preimplementation clinic were considered overadherent (MPR > 1.1). Forty-seven (47.9%) patients in the preimplementation group were considered adherent (MPR 0.9 - 1.1) while all 35 (100%) patients in the postimplementation group were considered adherent (MPR 0.9 - 1.1). No non- or overadherent patients were identified in the postimplementation group (Figure 2). The median MPR for all patients in the preimplementation group was 0.94 compared with 1.06 (P < .001) in the postimplementation group.
Thirty-five (35.7%) patients had therapy discontinued or held in the preimplementation group compared with 2 (5.7%) patients in the postimplementation group (P < .001). Reasons for discontinuation in the preimplementation group included disease progression (n = 27), death (n = 3), lost to follow up (n = 2), and intolerability of therapy (n = 3). Both patients that discontinued therapy in the postimplementation group did so due to disease progression. Of the 35 patients who had their OAN discontinued or held in the preimplementation group, 14 patients had excess supply on hand at time of discontinuation. The estimated value of the unused medication was $37,890. Nine (25%) of the 35 patients who discontinued therapy had a dosage reduction during the course of therapy and the additional supply was not included in the cost estimate. Similarly, 1 of the 2 patients in the postimplementation group had their OAN discontinued during study. The cost of oversupply of medication at the time of therapy discontinuation was estimated at $1,555. No patients in the postimplementation group had dose reductions. After implementation of the OAN renewal clinic, the total cost savings between pre ($37,890) and postimplementation ($1,555) groups was $36,355.
Discussion
OANs are widely used therapies, with more than 25 million doses administered per year in the United States alone.12 The use of these agents will continue to grow as more targeted agents become available and patients request more convenient treatment options. The role for hematology/oncology clinical pharmacy services must adapt to this increased usage of OANs, including increasing pharmacist involvement in medication education, adherence and tolerability assessments, and proactive drug interaction monitoring.However, additional research is needed to determine optimal management strategies.
Our study aimed to compare OAN adherence among patients at a tertiary care VA hospital before and after implementation of a renewal clinic. The preimplementation population had a median MPR of 0.94 compared with 1.06 in the postimplementation group (P < .001). Although an ideal MPR is 1.0, we aimed for a slightly higher MPR to allow a supply buffer in the event of prescription delivery delays, as more than 90% of prescriptions are mailed to patients from a regional mail-order pharmacy. Importantly, the median MPRs do not adequately convey the impact from this clinic. The proportion of patients who were considered adherent to OANs increased from 47.9% in the preimplementation to 100% in the postimplementation period. These finding suggest that the clinical pharmacist role to assess and encourage adherence through monitoring tolerability of these OANs improved the overall medication taking experience of these patients.
Upon initial evaluation of adherence pre- and postimplementation, median adherence rates in both groups appeared to be above goal at 0.94 and 1.06 respectively. Patients in the postimplementation group intentionally received a 5- to 7-day supply buffer to account for potential prescription delivery delays due to holidays and inclement weather. This would indicate that the patients in the postimplementation group would have 15% oversupply due to the 5-day supply buffer. After correcting for patients with confounding reasons for excess (dose reductions, breaks in treatment, etc.), the median MPR in the prerefill clinic group decreased to 0.9 and the MPR in the postrefill clinic group increased slightly to 1.08. Although the median adherence rate in both the pre- and postimplementation groups were above goal of 0.90, 36% of the patients in the preimplementation group were considered nonadherent (MPR < 0.9) compared with no patients in the postimplementation group. Therefore, our intervention to improve patient adherence appeared to be beneficial at our institution.
In addition to improving adherence, one of the goals of the renewal clinic was to minimize excess supply at the time of therapy discontinuation. This was accomplished by aligning medication fills with medical visits and objective monitoring, as well as limiting supply to no more than 30 days. Of the patients in the postimplementation group, only 1 patient had remaining medication at the time of therapy discontinuation compared with 14 patients in the preimplementation group. The estimated cost savings from excess supply was $36,335. Limiting the amount of unused supply not only saves money for the patient and the institution, but also decreases opportunity for improper hazardous waste disposal and unnecessary exposure of hazardous materials to others.
Our results show the pharmacist intervention in the coordination of renewals improved adherence, minimized medication waste, and saved money. The cost of pharmacist time participating in the refill clinic was not calculated. Each visit was completed in approximately 5 minutes, with subsequent documentation and coordination taking an additional 5 to 10 minutes. During the launch of this service, the oncology pharmacy resident provided all coverage of the clinic. Oversite of the resident was provided by hematology/oncology clinical pharmacy specialists. We have continued to utilize pharmacy resident coverage since that time to meet education needs and keep the estimated cost per visit low. Another option in the case that pharmacy residents are not available would be utilization of a pharmacy technician, intern, or professional student to conduct the adherence and tolerability phone assessments. Our escalation protocol allows intervention by clinical pharmacy specialist and/or other health care providers when necessary. Trainees have only required basic training on how to use the protocol.
Limitations
Due to this study’s retrospective design, an inherent limitation is dependence on prescriber and refill records for documentation of initiation and discontinuation dates. Therefore, only the association of impact of pharmacist intervention on medication adherence can be determined as opposed to causation. We did not take into account discrepancies in day supply secondary to ‘held’ therapies, dose reductions, or doses supplied during an inpatient admission, which may alter estimates of MPR and cost-savings data. Patients in the postimplementation group intentionally received a 5 to 7-day supply buffer to account for potential prescription delivery delays due to holidays and inclement weather. This would indicate that the patients in the postimplementation group would have 15% oversupply due to the 5-day supply buffer, thereby skewing MPR values. This study did not account for cost avoidance resulting from early identification and management of toxicity. Finally, the postimplementation data only spans 4 months and a longer duration of time is needed to more accurately determine sustainability of renewal clinic interventions and provide comprehensive evaluation of cost-avoidance.
Conclusion
Implementation of an OAN renewal clinic was associated with an increase in MPR, improved proportion of patients considered adherent, and an estimated $36,335 cost-savings. However, prospective evaluation and a longer study duration are needed to determine causality of improved adherence and cost-savings associated with a pharmacist-driven OAN renewal clinic.
Evaluation of oral antineoplastic agent (OAN) adherence patterns have identified correlations between nonadherence or over-adherence and poorer disease-related outcomes. Multiple studies have focused on imatinib use in chronic myeloid leukemia (CML) due to its continuous, long-term use. A study by Ganesan and colleagues found that nonadherence to imatinib showed a significant decrease in 5-year event-free survival between 76.7% of adherent participants compared with 59.8% of nonadherent participants.1 This study found that 44% of patients who were adherent to imatinib achieved complete cytogenetic response vs only 26% of patients who were nonadherent. In another study of imatinib for CML, major molecular response (MMR) was strongly correlated with adherence and no patients with adherence < 80% were able to achieve MMR.2 Similarly, in studies of tamoxifen for breast cancer, < 80% adherence resulted in a 10% decrease in survival when compared to those who were more adherent.3,4
In addition to the clinical implications of nonadherence, there can be a significant cost associated with suboptimal use of these medications. The price of a single dose of OAN medication may cost as much as $440.5
The benefits of multidisciplinary care teams have been identified in many studies.6,7 While studies are limited in oncology, pharmacists provide vital contributions to the oncology multidisciplinary team when managing OANs as these health care professionals have expert knowledge of the medications, potential adverse events (AEs), and necessary monitoring parameters.8 In one study, patients seen by the pharmacist-led oral chemotherapy management program experienced improved clinical outcomes and response to therapy when compared with preintervention patients (early molecular response, 88.9% vs 54.8%, P = .01; major molecular response, 83.3% vs 57.6%, P = .06).9 During the study, 318 AEs were reported, leading to 235 pharmacist interventions to ameliorate AEs and improve adherence.
The primary objective of this study was to measure the impact of a pharmacist-driven OAN renewal clinic on medication adherence. The secondary objective was to estimate cost-savings of this new service.
Methods
Prior to July 2014, several limitations were identified related to OAN prescribing and monitoring at the Richard L. Roudebush Veterans Affairs Medical Center in Indianapolis, Indiana (RLRVAMC). The prescription ordering process relied primarily on the patient to initiate refills, rather than the prescriber OAN prescriptions also lacked consistency for number of refills or quantities dispensed. Furthermore, ordering of antineoplastic products was not limited to hematology/oncology providers. Patients were identified with significant supply on hand at the time of medication discontinuation, creating concerns for medication waste, tolerability, and nonadherence.
As a result, opportunities were identified to improve the prescribing process, recommended monitoring, toxicity and tolerability evaluation, medication reconciliation, and medication adherence. In July of 2014, the RLRVAMC adopted a new chemotherapy order entry system capable of restricting prescriptions to hematology/oncology providers and limiting dispensed quantities and refill amounts. A comprehensive pharmacist driven OAN renewal clinic was implemented on September 1, 2014 with the goal of improving long-term adherence and tolerability, in addition to minimizing medication waste.
Patients were eligible for enrollment in the clinic if they had a cancer diagnosis and were concomitantly prescribed an OAN outlined in Table 1. All eligible patients were automatically enrolled in the clinic when they were deemed stable on their OAN by a hematology/oncology pharmacy specialist. Stability was defined as ≤ Grade 1 symptoms associated with the toxicities of OAN therapy managed with or without intervention as defined by the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Once enrolled in the renewal clinic, patients were called by an oncology pharmacy resident (PGY2) 1 week prior to any OAN refill due date. Patients were asked a series of 5 adherence and tolerability questions (Table 2) to evaluate renewal criteria for approval or need for further evaluation. These questions were developed based on targeted information and published reports on monitoring adherence.10,11 Criteria for renewal included: < 10% self-reported missed doses of the OAN during the previous dispensing period, no hospitalizations or emergency department visits since most recent hematology/oncology provider appointment, no changes to concomitant medication therapies, and no new or worsening medication-related AEs. Patients meeting all criteria were given a 30-day supply of OAN. Prescribing, dispensing, and delivery of OAN were facilitated by the pharmacist. Patient cases that did not meet criteria for renewal were escalated to the hematology/oncology provider or oncology clinical pharmacy specialist for further evaluation.
Study Design and Setting
This was a pre/post retrospective cohort, quality improvement study of patients enrolled in the RLRVAMC OAN pharmacist renewal clinic. The study was deemed exempt from institutional review board (IRB) by the US Department of Veterans Affairs (VA) Research and Development Department.
Study Population
Patients were included in the preimplementation group if they had received at least 2 prescriptions of an eligible OAN. Therapy for the preimplementation group was required to be a monthly duration > 21 days and between the dates of September 1, 2013 and August 31, 2014. Patients were included in the postimplementation group if they had received at least 2 prescriptions of the studied OANs between September 1, 2014 and January 31, 2015. Patients were excluded if they had filled < 2 prescriptions of OAN; were managed by a non-VA oncologist or hematologist; or received an OAN other than those listed in Table 1.
Data Collection
For all patients in both the pre- and postimplementation cohorts, a standardized data collection tool was used to collect the following via electronic health record review by a PGY2 oncology resident: age, race, gender, oral antineoplastic agent, refill dates, days’ supply, estimated unit cost per dose cancer diagnosis, distance from the RLRVAMC, copay status, presence of hospitalizations/ED visits/dosage reductions, discontinuation rates, reasons for discontinuation, and total number of current prescriptions. The presence or absence of dosage reductions were collected to identify concerns for tolerability, but only the original dose for the preimplementation group and dosage at time of clinic enrollment for the postimplementation group was included in the analysis.
Outcomes and Statistical Analyses
The primary outcome was medication adherence defined as the median medication possession ratio (MPR) before and after implementation of the clinic. Secondary outcomes included the proportion of patients who were adherent from before implementation to after and estimated cost-savings of this clinic after implementation. MPR was used to estimate medication adherence by taking the cumulative day supply of medication on hand divided by the number of days on therapy.12 Number of days on therapy was determined by taking the difference on the start date of the new medication regimen and the discontinuation date of the same regimen. Patients were grouped by adherence into one of the following categories: < 0.8, 0.8 to 0.89, 0.9 to 1, and > 1.1. Patients were considered adherent if they reported taking ≥ 90% (MPR ≥ 0.9) of prescribed doses, adopted from the study by Anderson and colleagues.12 A patient with an MPR > 1, likely due to filling prior to the anticipated refill date, was considered 100% adherent (MPR = 1). If a patient switched OAN during the study, both agents were included as separate entities.
A conservative estimate of cost-savings was made by multiplying the RLRVAMC cost per unit of medication at time of initial prescription fill by the number of units taken each day multiplied by the total days’ supply on hand at time of therapy discontinuation. Patients with an MPR < 1 at time of therapy discontinuation were assumed to have zero remaining units on hand and zero cost savings was estimated. Waste, for purposes of cost-savings, was calculated for all MPR values > 1. Additional supply anticipated to be on hand from dose reductions was not included in the estimated cost of unused medication.
Descriptive statistics compared demographic characteristics between the pre- and postimplementation groups. MPR data were not normally distributed, which required the use of nonparametric Mann-Whitney U tests to compare pre- and postMPRs. Pearson χ2 compared the proportion of adherent patients between groups while descriptive statistics were used to estimate cost savings. Significance was determined based on a P value < .05. IBM SPSS Statistics software was used for all statistical analyses. As this was a complete sample of all eligible subjects, no sample size calculation was performed.
Results
In the preimplementation period, 246 patients received an OAN and 61 patients received an OAN in the postimplementation period (Figure 1). Of the 246 patients in the preimplementation period, 98 were eligible and included in the preimplementation group. Similarly, of the 61 patients in the postimplementation period, 35 patients met inclusion criteria for the postimplementation group. The study population was predominantly male with an average age of approximately 70 years in both groups (Table 3). More than 70% of the population in each group was White. No statistically significant differences between groups were identified. The most commonly prescribed OAN in the preimplementation group were abiraterone, imatinib, and enzalutamide (Table 3). In the postimplementation group, the most commonly prescribed agents were abiraterone, imatinib, pazopanib, and dasatinib. No significant differences were observed in prescribing of individual agents between the pre- and postimplementation groups or other characteristics that may affect adherence including patient copay status, number of concomitant medications, and driving distance from the RLRVAMC.
Thirty-six (36.7%) patients in the preimplementation group were considered nonadherent (MPR < 0.9) and 18 (18.4%) had an MPR < 0.8. Fifteen (15.3%) patients in the preimplementation clinic were considered overadherent (MPR > 1.1). Forty-seven (47.9%) patients in the preimplementation group were considered adherent (MPR 0.9 - 1.1) while all 35 (100%) patients in the postimplementation group were considered adherent (MPR 0.9 - 1.1). No non- or overadherent patients were identified in the postimplementation group (Figure 2). The median MPR for all patients in the preimplementation group was 0.94 compared with 1.06 (P < .001) in the postimplementation group.
Thirty-five (35.7%) patients had therapy discontinued or held in the preimplementation group compared with 2 (5.7%) patients in the postimplementation group (P < .001). Reasons for discontinuation in the preimplementation group included disease progression (n = 27), death (n = 3), lost to follow up (n = 2), and intolerability of therapy (n = 3). Both patients that discontinued therapy in the postimplementation group did so due to disease progression. Of the 35 patients who had their OAN discontinued or held in the preimplementation group, 14 patients had excess supply on hand at time of discontinuation. The estimated value of the unused medication was $37,890. Nine (25%) of the 35 patients who discontinued therapy had a dosage reduction during the course of therapy and the additional supply was not included in the cost estimate. Similarly, 1 of the 2 patients in the postimplementation group had their OAN discontinued during study. The cost of oversupply of medication at the time of therapy discontinuation was estimated at $1,555. No patients in the postimplementation group had dose reductions. After implementation of the OAN renewal clinic, the total cost savings between pre ($37,890) and postimplementation ($1,555) groups was $36,355.
Discussion
OANs are widely used therapies, with more than 25 million doses administered per year in the United States alone.12 The use of these agents will continue to grow as more targeted agents become available and patients request more convenient treatment options. The role for hematology/oncology clinical pharmacy services must adapt to this increased usage of OANs, including increasing pharmacist involvement in medication education, adherence and tolerability assessments, and proactive drug interaction monitoring.However, additional research is needed to determine optimal management strategies.
Our study aimed to compare OAN adherence among patients at a tertiary care VA hospital before and after implementation of a renewal clinic. The preimplementation population had a median MPR of 0.94 compared with 1.06 in the postimplementation group (P < .001). Although an ideal MPR is 1.0, we aimed for a slightly higher MPR to allow a supply buffer in the event of prescription delivery delays, as more than 90% of prescriptions are mailed to patients from a regional mail-order pharmacy. Importantly, the median MPRs do not adequately convey the impact from this clinic. The proportion of patients who were considered adherent to OANs increased from 47.9% in the preimplementation to 100% in the postimplementation period. These finding suggest that the clinical pharmacist role to assess and encourage adherence through monitoring tolerability of these OANs improved the overall medication taking experience of these patients.
Upon initial evaluation of adherence pre- and postimplementation, median adherence rates in both groups appeared to be above goal at 0.94 and 1.06 respectively. Patients in the postimplementation group intentionally received a 5- to 7-day supply buffer to account for potential prescription delivery delays due to holidays and inclement weather. This would indicate that the patients in the postimplementation group would have 15% oversupply due to the 5-day supply buffer. After correcting for patients with confounding reasons for excess (dose reductions, breaks in treatment, etc.), the median MPR in the prerefill clinic group decreased to 0.9 and the MPR in the postrefill clinic group increased slightly to 1.08. Although the median adherence rate in both the pre- and postimplementation groups were above goal of 0.90, 36% of the patients in the preimplementation group were considered nonadherent (MPR < 0.9) compared with no patients in the postimplementation group. Therefore, our intervention to improve patient adherence appeared to be beneficial at our institution.
In addition to improving adherence, one of the goals of the renewal clinic was to minimize excess supply at the time of therapy discontinuation. This was accomplished by aligning medication fills with medical visits and objective monitoring, as well as limiting supply to no more than 30 days. Of the patients in the postimplementation group, only 1 patient had remaining medication at the time of therapy discontinuation compared with 14 patients in the preimplementation group. The estimated cost savings from excess supply was $36,335. Limiting the amount of unused supply not only saves money for the patient and the institution, but also decreases opportunity for improper hazardous waste disposal and unnecessary exposure of hazardous materials to others.
Our results show the pharmacist intervention in the coordination of renewals improved adherence, minimized medication waste, and saved money. The cost of pharmacist time participating in the refill clinic was not calculated. Each visit was completed in approximately 5 minutes, with subsequent documentation and coordination taking an additional 5 to 10 minutes. During the launch of this service, the oncology pharmacy resident provided all coverage of the clinic. Oversite of the resident was provided by hematology/oncology clinical pharmacy specialists. We have continued to utilize pharmacy resident coverage since that time to meet education needs and keep the estimated cost per visit low. Another option in the case that pharmacy residents are not available would be utilization of a pharmacy technician, intern, or professional student to conduct the adherence and tolerability phone assessments. Our escalation protocol allows intervention by clinical pharmacy specialist and/or other health care providers when necessary. Trainees have only required basic training on how to use the protocol.
Limitations
Due to this study’s retrospective design, an inherent limitation is dependence on prescriber and refill records for documentation of initiation and discontinuation dates. Therefore, only the association of impact of pharmacist intervention on medication adherence can be determined as opposed to causation. We did not take into account discrepancies in day supply secondary to ‘held’ therapies, dose reductions, or doses supplied during an inpatient admission, which may alter estimates of MPR and cost-savings data. Patients in the postimplementation group intentionally received a 5 to 7-day supply buffer to account for potential prescription delivery delays due to holidays and inclement weather. This would indicate that the patients in the postimplementation group would have 15% oversupply due to the 5-day supply buffer, thereby skewing MPR values. This study did not account for cost avoidance resulting from early identification and management of toxicity. Finally, the postimplementation data only spans 4 months and a longer duration of time is needed to more accurately determine sustainability of renewal clinic interventions and provide comprehensive evaluation of cost-avoidance.
Conclusion
Implementation of an OAN renewal clinic was associated with an increase in MPR, improved proportion of patients considered adherent, and an estimated $36,335 cost-savings. However, prospective evaluation and a longer study duration are needed to determine causality of improved adherence and cost-savings associated with a pharmacist-driven OAN renewal clinic.
1. Ganesan P, Sagar TG, Dubashi B, et al. Nonadherence to imatinib adversely affects event free survival in chronic phase chronic myeloid leukemia. Am J Hematol 2011; 86: 471-474. doi:10.1002/ajh.22019
2. Marin D, Bazeos A, Mahon FX, et al. Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol 2010; 28: 2381-2388. doi:10.1200/JCO.2009.26.3087
3. McCowan C, Shearer J, Donnan PT, et al. Cohort study examining tamoxifen adherence and its relationship to mortality in women with breast cancer. Br J Cancer 2008; 99: 1763-1768. doi:10.1038/sj.bjc.6604758
4. Lexicomp Online. Sunitinib. Hudson, Ohio: Lexi-Comp, Inc; August 20, 2019.
5. Babiker A, El Husseini M, Al Nemri A, et al. Health care professional development: Working as a team to improve patient care. Sudan J Paediatr. 2014;14(2):9-16.
6. Spence MM, Makarem AF, Reyes SL, et al. Evaluation of an outpatient pharmacy clinical services program on adherence and clinical outcomes among patients with diabetes and/or coronary artery disease. J Manag Care Spec Pharm. 2014;20(10):1036-1045. doi:10.18553/jmcp.2014.20.10.1036
7. Holle LM, Puri S, Clement JM. Physician-pharmacist collaboration for oral chemotherapy monitoring: Insights from an academic genitourinary oncology practice. J Oncol Pharm Pract 2015; doi:10.1177/1078155215581524
8. Muluneh B, Schneider M, Faso A, et al. Improved Adherence Rates and Clinical Outcomes of an Integrated, Closed-Loop, Pharmacist-Led Oral Chemotherapy Management Program. Journal of Oncology Practice. 2018;14(6):371-333. doi:10.1200/JOP.17.00039.
9. Font R, Espinas JA, Gil-Gil M, et al. Prescription refill, patient self-report and physician report in assessing adherence to oral endocrine therapy in early breast cancer patients: a retrospective cohort study in Catalonia, Spain. British Journal of Cancer. 2012 ;107(8):1249-1256. doi:10.1038/bjc.2012.389.
10. Anderson KR, Chambers CR, Lam N, et al. Medication adherence among adults prescribed imatinib, dasatinib, or nilotinib for the treatment of chronic myeloid leukemia. J Oncol Pharm Practice. 2015;21(1):19–25. doi:10.1177/1078155213520261
11. Weingart SN, Brown E, Bach PB, et al. NCCN Task Force Report: oral chemotherapy. J Natl Compr Canc Netw. 2008;6(3): S1-S14.
1. Ganesan P, Sagar TG, Dubashi B, et al. Nonadherence to imatinib adversely affects event free survival in chronic phase chronic myeloid leukemia. Am J Hematol 2011; 86: 471-474. doi:10.1002/ajh.22019
2. Marin D, Bazeos A, Mahon FX, et al. Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol 2010; 28: 2381-2388. doi:10.1200/JCO.2009.26.3087
3. McCowan C, Shearer J, Donnan PT, et al. Cohort study examining tamoxifen adherence and its relationship to mortality in women with breast cancer. Br J Cancer 2008; 99: 1763-1768. doi:10.1038/sj.bjc.6604758
4. Lexicomp Online. Sunitinib. Hudson, Ohio: Lexi-Comp, Inc; August 20, 2019.
5. Babiker A, El Husseini M, Al Nemri A, et al. Health care professional development: Working as a team to improve patient care. Sudan J Paediatr. 2014;14(2):9-16.
6. Spence MM, Makarem AF, Reyes SL, et al. Evaluation of an outpatient pharmacy clinical services program on adherence and clinical outcomes among patients with diabetes and/or coronary artery disease. J Manag Care Spec Pharm. 2014;20(10):1036-1045. doi:10.18553/jmcp.2014.20.10.1036
7. Holle LM, Puri S, Clement JM. Physician-pharmacist collaboration for oral chemotherapy monitoring: Insights from an academic genitourinary oncology practice. J Oncol Pharm Pract 2015; doi:10.1177/1078155215581524
8. Muluneh B, Schneider M, Faso A, et al. Improved Adherence Rates and Clinical Outcomes of an Integrated, Closed-Loop, Pharmacist-Led Oral Chemotherapy Management Program. Journal of Oncology Practice. 2018;14(6):371-333. doi:10.1200/JOP.17.00039.
9. Font R, Espinas JA, Gil-Gil M, et al. Prescription refill, patient self-report and physician report in assessing adherence to oral endocrine therapy in early breast cancer patients: a retrospective cohort study in Catalonia, Spain. British Journal of Cancer. 2012 ;107(8):1249-1256. doi:10.1038/bjc.2012.389.
10. Anderson KR, Chambers CR, Lam N, et al. Medication adherence among adults prescribed imatinib, dasatinib, or nilotinib for the treatment of chronic myeloid leukemia. J Oncol Pharm Practice. 2015;21(1):19–25. doi:10.1177/1078155213520261
11. Weingart SN, Brown E, Bach PB, et al. NCCN Task Force Report: oral chemotherapy. J Natl Compr Canc Netw. 2008;6(3): S1-S14.
Implementation and Evaluation of a 90-Minute Rituximab Infusion Protocol at the Richard L. Roudebush VA Medical Center
Rituximab is a genetically engineered chimeric immunoglobulin G1 monoclonal antibody. It functions by binding to the CD20 antigen on the surface of B-cell lymphocytes, leading to complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity.1 The US Food and Drug Administration approved this therapy to treat patients with B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia, along with other nonmalignant indications, including pemphigus vulgaris and rheumatoid arthritis (RA). Historically, a significant amount of time and labor on behalf of medical personnel has been required to administer rituximab according to the original manufacturer’s labeling due to the boxed warning associated with infusion-related reactions (IRRs).2
Originally, the elongated infusion times that were recommended for rituximab were largely due to the perceived risk of serious infusion-related adverse drug reactions. Slower infusion times should reduce the risk of a reaction and are considered to be a good option for those patients who are at a high risk of having a severe IRRs to rituximab. Examples of high-risk patients from previous studies include those with significant cardiovascular disease, a circulating lymphocyte count ≤ 5,000/µL at the start of infusion, and those who have previously had a reaction to rituximab.3-5 In appropriate patients, research has shown a decreasing incidence of all-grade IRRs for patients who are prescribed rituximab as they receive more doses of the drug.2,6 The ability to identify suitable patients for 90-minute infusions of rituximab and the prospect of better health system resource utilization has led investigators to study the effects of shortened infusion times.
The RATE trial addressed this subject with a phase 3 safety study on the effects of a 90-minute rituximab infusion for patients with previously untreated diffuse large B-cell and follicular lymphoma.3 The patients in this study received their first dose of rituximab using the traditional infusion approach. If it was well-tolerated, they received subsequent rituximab infusions using a 90-minute protocol. Only 1.1% of patients who had previously received a rituximab infusion developed a grade 3 or 4 IRR when receiving a faster infusion of the drug for the first time.3 This result led to the addition of instructions for a 90-minute infusion to the package insert.2
In contrast to the RATE trial, the RATE-RA trial evaluated the incidence of IRRs in patients who received rituximab for nonmalignant indications. This study assessed patients with RA receiving rituximab for > 120 minutes. The authors reported 0.6% of the patients in the study developed a grade 3 or 4 IRR associated with the first 120-minute infusion of the medication.5 The researchers concluded that rituximab can be administered at a faster rate during second and subsequent infusions in patients who have been shown to tolerate traditional infusions without increasing the risk or severity of IRRs.5
The US Department of Veterans Affairs (VA) Richard L. Roudebush VA Medical Center (RLRVAMC) in Indianapolis, Indiana, uses traditional directions for the infusion of rituximab due to perceived tolerability and safety concerns specifically in a veteran population—even while other VA medical centers have implemented shortened infusion protocols. This also is despite the fact that available research shows rapid infusions of the drug are well tolerated in a variety of community settings.7,8 Anticipated benefits of implementing a protocol include savings in chair time at the institution’s infusion clinic along with increased nursing and patient satisfaction. This project was conducted to prepare, implement, and assess the safety of a 90-minute rituximab protocol at the RLRVAMC.
Methods
Proactive measures were required before and during the implementation of the 90-minute protocol to ensure patient safety and staff satisfaction. Updates to the RLRVAMC policy for the management of medical emergencies within the infusion center were reviewed and approved by the acute care committee and nursing leadership. A protocol was developed to identify eligible patients, outline the hypersensitivity protocol, instruct pharmacy personnel on admixture preparation, and provide a titration schedule based on dose. Order sets also were created to assist health care providers (HCPs) with the prescribing of rituximab for nonantineoplastic indications. Educational materials were crafted to assist with order verification, product preparation, labeling, and programming of infusion pumps. Live education was provided for physicians, pharmacists, and nurses to ensure smooth implementation of the protocol and appropriate management of medical emergencies based on the updated policy.
Study Design
Nursing staff in the infusion clinic were surveyed once before a live education session and again after the conclusion of the study. The purpose of the survey was to assess the prior experience and current comfort level of the nursing staff with administering rituximab over 90 minutes. Nurses were asked the following questions: (1) Do you have prior experience administering rituximab via 90-minute infusion; and (2) do you feel comfortable administering rituximab via 90-minute infusion?
A weekly report of patients who received rituximab between November 1, 2018 through April 1, 2019 at the RLRVAMC was generated. HCPs were alerted to eligible patients based on protocol requirements. The HCPs then made the final determination and entered orders accordingly.
This study was a retrospective chart review of all who patients received a rapid infusion of rituximab. Patients who were included if they were aged ≥ 18 years, received rituximab infusions in the RLRVAMC infusion clinic, had an absolute lymphocyte count ≤ 5,000/mm3 at the time of their rapid infusions, had no significant baseline cardiovascular disease or respiratory compromise, and had no prior grade 3 or 4 rituximab IRRs as defined by Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.9 This study was a quality improvement initiative and considered exempt by the institutional review board. All data were deidentified and secured to ensure patient privacy.
The primary endpoint for this study was the incidence of grade 3 or 4 IRRs associated with the rapid infusion of rituximab. Secondary endpoints included the proportion of patients who experienced a grade 3 or 4 infusion reaction, who received proper treatment according to the institution’s hypersensitivity protocol, savings in infusion clinic chair time, and nursing satisfaction with education and implementation of the rapid infusion rituximab protocol.
The following data were collected for all included patients: demographics, lactic acid dehydrogenase level, white blood cell count, and absolute lymphocyte count prior to rituximab infusion, indication for treatment, dose of rituximab for 90-minute infusion, date of infusion, starting time, ending time, number of previous rituximab infusions within the past 3 months, symptoms of infusion reactions during rituximab infusion, and grade of any infusion reactions that occurred.
Estimated savings in infusion clinic chair time was calculated by taking the difference in time between each completed rapid infusion and the estimated amount of time it would have taken for each patient to receive a traditional infusion. The estimated amount of time for traditional infusion was determined by following the institution’s protocol for administering rituximab to patients who previously tolerated their first dose of the drug (eg, 100 mg/h starting rate and increasing by 100 mg/h every 30 minutes to a maximum infusion rate of 400 mg/h). All endpoints were analyzed using descriptive statistics.
Results
Between November 1, 2018 and April 1, 2019, 11 patients received a total of 24 rapid infusions of rituximab. The majority of patients included in the study were older males, and the most common indication for rapid infusion was follicular lymphoma (Table 1).
Primary Endpoint
All patients who received a rapid infusion of rituximab were reviewed in the analysis of the primary and secondary endpoints. Among the 24 rapid infusions of rituximab, 1 infusion was stopped due to the patient experiencing a grade 3 IRR according to criteria from CTCAE Version 5.0. The patient was found to have dysphagia at baseline and experienced severe symptoms in the days following the first infusion that put the patient at high risk for subsequent infusion related concerns. Eligibility criteria for the 90-minute protocol were updated based on these findings. No patient experienced a grade 4 or 5 IRR. The remaining 23 infusions were well tolerated by the patients with no clinically significant events.
Secondary Endpoints
The patient who experienced a grade 3 IRR to rituximab received proper treatment by infusion clinic nurses according to the RLRVAMC hypersensitivity protocol. Patients who received rapid infusions of rituximab had a mean length of infusion of 95.0 minutes. This was in contrast to the mean time of each patient’s previous nonrapid infusion of 134.3 minutes. The difference between the 2 values equated to a savings in infusion clinic chair mean time of 39.3 minutes per patient.
Nurses were asked whether they had prior experience administering rituximab via 90-minute infusion and whether they felt comfortable administering a 90-minute rituximab infusion. Before the live education session, none of the nurses surveyed had prior experience or felt comfortable administering rituximab over 90 minutes. When the nurses were surveyed poststudy, all reported that they were experienced administering rituximab and felt comfortable with the process (Table 2).
Discussion
The infusion of rituximab has been associated with significant challenges related to the time and labor required. Although a vast number of institutions across the country now infuse the medication over an abbreviated time, HCP concerns for patient safety and appropriate use of hypersensitivity protocol in a veteran population delayed implementation at RLRVAMC. The results from this quality improvement initiative highlight the positive impact of the proactive measures that were used to implement the rapid infusion protocol for rituximab on improving HCP prescribing rates, nursing satisfaction, and appropriate management of IRRs.
Rapid infusion saved on average 39.3 minutes per patient in infusion clinic chair time. Each successful rapid infusion of rituximab potentially opened additional time in clinic for ≥ 1 patients to receive an infusion therapy. The RLRVAMC usually operated at maximum capacity, so the ability to accommodate more patients helped decrease hospital admittances for time-sensitive infusions.
The initial criteria used to screen patients to determine whether a rapid infusion of rituximab would be appropriate was based on inclusion and exclusion criteria for past studies on the same subject.3-5 The incidence of hypersensitivity reactions associated with study participants who received rapid rituximab infusions also resembles past research done on the subject, which is important to note due to prior misconceptions of staff at the institution of a higher risk of reaction in this specific veteran population. One patient with RA experienced a grade 3 IRR in this study. Although this patient met the original inclusion criteria, the patient had baseline dysphagia, and following the first infusion, reported to the emergency department (ED) with symptoms of delayed anaphylaxis. In this case, the order for rapid infusion was placed in advance and the prescriber was unaware of the ED visit. Based on this event, eligibility criteria for 90-minute rituximab infusions were updated to include additional information specifying that candidates for a rapid infusion also may have no baseline airway compromise. This hypersensitivity reaction also highlighted the need for decision support technology to assist HCPs in patient selection as well as empowering nursing and pharmacy staff to identify concerns once they place orders.
Over the course of the study, investigators assisted the HCPs with preparation of orders for the rapid infusion of rituximab for antineoplastic indications. Due to feasibility issues with this practice moving forward, order sets containing rituximab were updated to include a 90-minute option. This created a more standardized process that allowed HCPs to screen potential patients on their own. The expectation is that HCPs will be more likely to order 90-minute infusions for eligible patients in the future with this efficient and safer process.
Limitations
The small sample size in this study was a limitation. Retrospective data related to the management of infusion reactions and length of infusions were collected from nursing notes. The prospective use of a standardized evaluation tool for adverse drug reactions as well as bar code medication administration technology would improve the data available for this study. Additional studies also would be useful to validate the results.
Conclusions
The proactive measures that were used to implement the rapid infusion rituximab protocol improved HCP prescribing rates, nursing satisfaction, and the management of IRRs. Potential time savings with each infusion was significant. This study confirmed appropriateness of rapid administration of rituximab in this veteran population and has increased interest in implementing other rapid infusion protocols. Protocols, education, and order sets are being developed for daratumumab and infliximab.
1. Feugier P. A review of rituximab, the first anti-CD20 monoclonal antibody used in the treatment of B non-Hodgkin’s lymphomas. Future Oncol. 2015;11(9):1327-1342. doi:10.2217/fon.15.57
2. Rituxan [package insert]. South San Francisco, CA: Genentech; 2016.
3. Dakhil S, Hermann R, Schreeder MT, et al. Phase III safety study of rituximab administered as a 90-minute infusion in patients with previously untreated diffuse large B-cell and follicular lymphoma. Leuk Lymphoma. 2014;55(10):2335-2340. doi:10.3109/10428194.2013.877135
4. Dotson E, Crawford B, Phillips G, Jones J. Sixty-minute infusion rituximab protocol allows for safe and efficient workflow. Support Care Cancer. 2016;24(3):1125-1129. doi:10.1007/s00520-015-2869-4
5. Pritchard CH, Greenwald MW, Kremer JM, et al. Safety of infusing rituximab at a more rapid rate in patients with rheumatoid arthritis: results from the RATE-RA study. BMC Musculoskelet Disord. 2014;15:177. doi:10.1186/1471-2474-15-177
6. Hainsworth JD, Litchy S, Barton JH, et al. Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol. 2003;21(9):1746-1751. doi:10.1200/JCO.2003.09.027
7. Can M, Alibaz-Öner F, Yılmaz-Öner S, Atagündüz P, Înanç N, Direskeneli H. Accelerated infusion rates of rituximab are well tolerated and safe in rheumatology practice: a single-centre experience. Clin Rheumatol. 2013;32(1):87-90. doi:10.1007/s10067-012-2094-1
8. Sehn LH, Donaldson J, Filewich A, et al. Rapid infusion rituximab in combination with corticosteroid-containing chemotherapy or as maintenance therapy is well tolerated and can safely be delivered in the community setting. Blood. 2007;109(10):4171-4173. doi:10.1182/blood-2006-11-059469
9. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE). https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. Updated March 27 2020. Accessed June 15, 2020.
Rituximab is a genetically engineered chimeric immunoglobulin G1 monoclonal antibody. It functions by binding to the CD20 antigen on the surface of B-cell lymphocytes, leading to complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity.1 The US Food and Drug Administration approved this therapy to treat patients with B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia, along with other nonmalignant indications, including pemphigus vulgaris and rheumatoid arthritis (RA). Historically, a significant amount of time and labor on behalf of medical personnel has been required to administer rituximab according to the original manufacturer’s labeling due to the boxed warning associated with infusion-related reactions (IRRs).2
Originally, the elongated infusion times that were recommended for rituximab were largely due to the perceived risk of serious infusion-related adverse drug reactions. Slower infusion times should reduce the risk of a reaction and are considered to be a good option for those patients who are at a high risk of having a severe IRRs to rituximab. Examples of high-risk patients from previous studies include those with significant cardiovascular disease, a circulating lymphocyte count ≤ 5,000/µL at the start of infusion, and those who have previously had a reaction to rituximab.3-5 In appropriate patients, research has shown a decreasing incidence of all-grade IRRs for patients who are prescribed rituximab as they receive more doses of the drug.2,6 The ability to identify suitable patients for 90-minute infusions of rituximab and the prospect of better health system resource utilization has led investigators to study the effects of shortened infusion times.
The RATE trial addressed this subject with a phase 3 safety study on the effects of a 90-minute rituximab infusion for patients with previously untreated diffuse large B-cell and follicular lymphoma.3 The patients in this study received their first dose of rituximab using the traditional infusion approach. If it was well-tolerated, they received subsequent rituximab infusions using a 90-minute protocol. Only 1.1% of patients who had previously received a rituximab infusion developed a grade 3 or 4 IRR when receiving a faster infusion of the drug for the first time.3 This result led to the addition of instructions for a 90-minute infusion to the package insert.2
In contrast to the RATE trial, the RATE-RA trial evaluated the incidence of IRRs in patients who received rituximab for nonmalignant indications. This study assessed patients with RA receiving rituximab for > 120 minutes. The authors reported 0.6% of the patients in the study developed a grade 3 or 4 IRR associated with the first 120-minute infusion of the medication.5 The researchers concluded that rituximab can be administered at a faster rate during second and subsequent infusions in patients who have been shown to tolerate traditional infusions without increasing the risk or severity of IRRs.5
The US Department of Veterans Affairs (VA) Richard L. Roudebush VA Medical Center (RLRVAMC) in Indianapolis, Indiana, uses traditional directions for the infusion of rituximab due to perceived tolerability and safety concerns specifically in a veteran population—even while other VA medical centers have implemented shortened infusion protocols. This also is despite the fact that available research shows rapid infusions of the drug are well tolerated in a variety of community settings.7,8 Anticipated benefits of implementing a protocol include savings in chair time at the institution’s infusion clinic along with increased nursing and patient satisfaction. This project was conducted to prepare, implement, and assess the safety of a 90-minute rituximab protocol at the RLRVAMC.
Methods
Proactive measures were required before and during the implementation of the 90-minute protocol to ensure patient safety and staff satisfaction. Updates to the RLRVAMC policy for the management of medical emergencies within the infusion center were reviewed and approved by the acute care committee and nursing leadership. A protocol was developed to identify eligible patients, outline the hypersensitivity protocol, instruct pharmacy personnel on admixture preparation, and provide a titration schedule based on dose. Order sets also were created to assist health care providers (HCPs) with the prescribing of rituximab for nonantineoplastic indications. Educational materials were crafted to assist with order verification, product preparation, labeling, and programming of infusion pumps. Live education was provided for physicians, pharmacists, and nurses to ensure smooth implementation of the protocol and appropriate management of medical emergencies based on the updated policy.
Study Design
Nursing staff in the infusion clinic were surveyed once before a live education session and again after the conclusion of the study. The purpose of the survey was to assess the prior experience and current comfort level of the nursing staff with administering rituximab over 90 minutes. Nurses were asked the following questions: (1) Do you have prior experience administering rituximab via 90-minute infusion; and (2) do you feel comfortable administering rituximab via 90-minute infusion?
A weekly report of patients who received rituximab between November 1, 2018 through April 1, 2019 at the RLRVAMC was generated. HCPs were alerted to eligible patients based on protocol requirements. The HCPs then made the final determination and entered orders accordingly.
This study was a retrospective chart review of all who patients received a rapid infusion of rituximab. Patients who were included if they were aged ≥ 18 years, received rituximab infusions in the RLRVAMC infusion clinic, had an absolute lymphocyte count ≤ 5,000/mm3 at the time of their rapid infusions, had no significant baseline cardiovascular disease or respiratory compromise, and had no prior grade 3 or 4 rituximab IRRs as defined by Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.9 This study was a quality improvement initiative and considered exempt by the institutional review board. All data were deidentified and secured to ensure patient privacy.
The primary endpoint for this study was the incidence of grade 3 or 4 IRRs associated with the rapid infusion of rituximab. Secondary endpoints included the proportion of patients who experienced a grade 3 or 4 infusion reaction, who received proper treatment according to the institution’s hypersensitivity protocol, savings in infusion clinic chair time, and nursing satisfaction with education and implementation of the rapid infusion rituximab protocol.
The following data were collected for all included patients: demographics, lactic acid dehydrogenase level, white blood cell count, and absolute lymphocyte count prior to rituximab infusion, indication for treatment, dose of rituximab for 90-minute infusion, date of infusion, starting time, ending time, number of previous rituximab infusions within the past 3 months, symptoms of infusion reactions during rituximab infusion, and grade of any infusion reactions that occurred.
Estimated savings in infusion clinic chair time was calculated by taking the difference in time between each completed rapid infusion and the estimated amount of time it would have taken for each patient to receive a traditional infusion. The estimated amount of time for traditional infusion was determined by following the institution’s protocol for administering rituximab to patients who previously tolerated their first dose of the drug (eg, 100 mg/h starting rate and increasing by 100 mg/h every 30 minutes to a maximum infusion rate of 400 mg/h). All endpoints were analyzed using descriptive statistics.
Results
Between November 1, 2018 and April 1, 2019, 11 patients received a total of 24 rapid infusions of rituximab. The majority of patients included in the study were older males, and the most common indication for rapid infusion was follicular lymphoma (Table 1).
Primary Endpoint
All patients who received a rapid infusion of rituximab were reviewed in the analysis of the primary and secondary endpoints. Among the 24 rapid infusions of rituximab, 1 infusion was stopped due to the patient experiencing a grade 3 IRR according to criteria from CTCAE Version 5.0. The patient was found to have dysphagia at baseline and experienced severe symptoms in the days following the first infusion that put the patient at high risk for subsequent infusion related concerns. Eligibility criteria for the 90-minute protocol were updated based on these findings. No patient experienced a grade 4 or 5 IRR. The remaining 23 infusions were well tolerated by the patients with no clinically significant events.
Secondary Endpoints
The patient who experienced a grade 3 IRR to rituximab received proper treatment by infusion clinic nurses according to the RLRVAMC hypersensitivity protocol. Patients who received rapid infusions of rituximab had a mean length of infusion of 95.0 minutes. This was in contrast to the mean time of each patient’s previous nonrapid infusion of 134.3 minutes. The difference between the 2 values equated to a savings in infusion clinic chair mean time of 39.3 minutes per patient.
Nurses were asked whether they had prior experience administering rituximab via 90-minute infusion and whether they felt comfortable administering a 90-minute rituximab infusion. Before the live education session, none of the nurses surveyed had prior experience or felt comfortable administering rituximab over 90 minutes. When the nurses were surveyed poststudy, all reported that they were experienced administering rituximab and felt comfortable with the process (Table 2).
Discussion
The infusion of rituximab has been associated with significant challenges related to the time and labor required. Although a vast number of institutions across the country now infuse the medication over an abbreviated time, HCP concerns for patient safety and appropriate use of hypersensitivity protocol in a veteran population delayed implementation at RLRVAMC. The results from this quality improvement initiative highlight the positive impact of the proactive measures that were used to implement the rapid infusion protocol for rituximab on improving HCP prescribing rates, nursing satisfaction, and appropriate management of IRRs.
Rapid infusion saved on average 39.3 minutes per patient in infusion clinic chair time. Each successful rapid infusion of rituximab potentially opened additional time in clinic for ≥ 1 patients to receive an infusion therapy. The RLRVAMC usually operated at maximum capacity, so the ability to accommodate more patients helped decrease hospital admittances for time-sensitive infusions.
The initial criteria used to screen patients to determine whether a rapid infusion of rituximab would be appropriate was based on inclusion and exclusion criteria for past studies on the same subject.3-5 The incidence of hypersensitivity reactions associated with study participants who received rapid rituximab infusions also resembles past research done on the subject, which is important to note due to prior misconceptions of staff at the institution of a higher risk of reaction in this specific veteran population. One patient with RA experienced a grade 3 IRR in this study. Although this patient met the original inclusion criteria, the patient had baseline dysphagia, and following the first infusion, reported to the emergency department (ED) with symptoms of delayed anaphylaxis. In this case, the order for rapid infusion was placed in advance and the prescriber was unaware of the ED visit. Based on this event, eligibility criteria for 90-minute rituximab infusions were updated to include additional information specifying that candidates for a rapid infusion also may have no baseline airway compromise. This hypersensitivity reaction also highlighted the need for decision support technology to assist HCPs in patient selection as well as empowering nursing and pharmacy staff to identify concerns once they place orders.
Over the course of the study, investigators assisted the HCPs with preparation of orders for the rapid infusion of rituximab for antineoplastic indications. Due to feasibility issues with this practice moving forward, order sets containing rituximab were updated to include a 90-minute option. This created a more standardized process that allowed HCPs to screen potential patients on their own. The expectation is that HCPs will be more likely to order 90-minute infusions for eligible patients in the future with this efficient and safer process.
Limitations
The small sample size in this study was a limitation. Retrospective data related to the management of infusion reactions and length of infusions were collected from nursing notes. The prospective use of a standardized evaluation tool for adverse drug reactions as well as bar code medication administration technology would improve the data available for this study. Additional studies also would be useful to validate the results.
Conclusions
The proactive measures that were used to implement the rapid infusion rituximab protocol improved HCP prescribing rates, nursing satisfaction, and the management of IRRs. Potential time savings with each infusion was significant. This study confirmed appropriateness of rapid administration of rituximab in this veteran population and has increased interest in implementing other rapid infusion protocols. Protocols, education, and order sets are being developed for daratumumab and infliximab.
Rituximab is a genetically engineered chimeric immunoglobulin G1 monoclonal antibody. It functions by binding to the CD20 antigen on the surface of B-cell lymphocytes, leading to complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity.1 The US Food and Drug Administration approved this therapy to treat patients with B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia, along with other nonmalignant indications, including pemphigus vulgaris and rheumatoid arthritis (RA). Historically, a significant amount of time and labor on behalf of medical personnel has been required to administer rituximab according to the original manufacturer’s labeling due to the boxed warning associated with infusion-related reactions (IRRs).2
Originally, the elongated infusion times that were recommended for rituximab were largely due to the perceived risk of serious infusion-related adverse drug reactions. Slower infusion times should reduce the risk of a reaction and are considered to be a good option for those patients who are at a high risk of having a severe IRRs to rituximab. Examples of high-risk patients from previous studies include those with significant cardiovascular disease, a circulating lymphocyte count ≤ 5,000/µL at the start of infusion, and those who have previously had a reaction to rituximab.3-5 In appropriate patients, research has shown a decreasing incidence of all-grade IRRs for patients who are prescribed rituximab as they receive more doses of the drug.2,6 The ability to identify suitable patients for 90-minute infusions of rituximab and the prospect of better health system resource utilization has led investigators to study the effects of shortened infusion times.
The RATE trial addressed this subject with a phase 3 safety study on the effects of a 90-minute rituximab infusion for patients with previously untreated diffuse large B-cell and follicular lymphoma.3 The patients in this study received their first dose of rituximab using the traditional infusion approach. If it was well-tolerated, they received subsequent rituximab infusions using a 90-minute protocol. Only 1.1% of patients who had previously received a rituximab infusion developed a grade 3 or 4 IRR when receiving a faster infusion of the drug for the first time.3 This result led to the addition of instructions for a 90-minute infusion to the package insert.2
In contrast to the RATE trial, the RATE-RA trial evaluated the incidence of IRRs in patients who received rituximab for nonmalignant indications. This study assessed patients with RA receiving rituximab for > 120 minutes. The authors reported 0.6% of the patients in the study developed a grade 3 or 4 IRR associated with the first 120-minute infusion of the medication.5 The researchers concluded that rituximab can be administered at a faster rate during second and subsequent infusions in patients who have been shown to tolerate traditional infusions without increasing the risk or severity of IRRs.5
The US Department of Veterans Affairs (VA) Richard L. Roudebush VA Medical Center (RLRVAMC) in Indianapolis, Indiana, uses traditional directions for the infusion of rituximab due to perceived tolerability and safety concerns specifically in a veteran population—even while other VA medical centers have implemented shortened infusion protocols. This also is despite the fact that available research shows rapid infusions of the drug are well tolerated in a variety of community settings.7,8 Anticipated benefits of implementing a protocol include savings in chair time at the institution’s infusion clinic along with increased nursing and patient satisfaction. This project was conducted to prepare, implement, and assess the safety of a 90-minute rituximab protocol at the RLRVAMC.
Methods
Proactive measures were required before and during the implementation of the 90-minute protocol to ensure patient safety and staff satisfaction. Updates to the RLRVAMC policy for the management of medical emergencies within the infusion center were reviewed and approved by the acute care committee and nursing leadership. A protocol was developed to identify eligible patients, outline the hypersensitivity protocol, instruct pharmacy personnel on admixture preparation, and provide a titration schedule based on dose. Order sets also were created to assist health care providers (HCPs) with the prescribing of rituximab for nonantineoplastic indications. Educational materials were crafted to assist with order verification, product preparation, labeling, and programming of infusion pumps. Live education was provided for physicians, pharmacists, and nurses to ensure smooth implementation of the protocol and appropriate management of medical emergencies based on the updated policy.
Study Design
Nursing staff in the infusion clinic were surveyed once before a live education session and again after the conclusion of the study. The purpose of the survey was to assess the prior experience and current comfort level of the nursing staff with administering rituximab over 90 minutes. Nurses were asked the following questions: (1) Do you have prior experience administering rituximab via 90-minute infusion; and (2) do you feel comfortable administering rituximab via 90-minute infusion?
A weekly report of patients who received rituximab between November 1, 2018 through April 1, 2019 at the RLRVAMC was generated. HCPs were alerted to eligible patients based on protocol requirements. The HCPs then made the final determination and entered orders accordingly.
This study was a retrospective chart review of all who patients received a rapid infusion of rituximab. Patients who were included if they were aged ≥ 18 years, received rituximab infusions in the RLRVAMC infusion clinic, had an absolute lymphocyte count ≤ 5,000/mm3 at the time of their rapid infusions, had no significant baseline cardiovascular disease or respiratory compromise, and had no prior grade 3 or 4 rituximab IRRs as defined by Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.9 This study was a quality improvement initiative and considered exempt by the institutional review board. All data were deidentified and secured to ensure patient privacy.
The primary endpoint for this study was the incidence of grade 3 or 4 IRRs associated with the rapid infusion of rituximab. Secondary endpoints included the proportion of patients who experienced a grade 3 or 4 infusion reaction, who received proper treatment according to the institution’s hypersensitivity protocol, savings in infusion clinic chair time, and nursing satisfaction with education and implementation of the rapid infusion rituximab protocol.
The following data were collected for all included patients: demographics, lactic acid dehydrogenase level, white blood cell count, and absolute lymphocyte count prior to rituximab infusion, indication for treatment, dose of rituximab for 90-minute infusion, date of infusion, starting time, ending time, number of previous rituximab infusions within the past 3 months, symptoms of infusion reactions during rituximab infusion, and grade of any infusion reactions that occurred.
Estimated savings in infusion clinic chair time was calculated by taking the difference in time between each completed rapid infusion and the estimated amount of time it would have taken for each patient to receive a traditional infusion. The estimated amount of time for traditional infusion was determined by following the institution’s protocol for administering rituximab to patients who previously tolerated their first dose of the drug (eg, 100 mg/h starting rate and increasing by 100 mg/h every 30 minutes to a maximum infusion rate of 400 mg/h). All endpoints were analyzed using descriptive statistics.
Results
Between November 1, 2018 and April 1, 2019, 11 patients received a total of 24 rapid infusions of rituximab. The majority of patients included in the study were older males, and the most common indication for rapid infusion was follicular lymphoma (Table 1).
Primary Endpoint
All patients who received a rapid infusion of rituximab were reviewed in the analysis of the primary and secondary endpoints. Among the 24 rapid infusions of rituximab, 1 infusion was stopped due to the patient experiencing a grade 3 IRR according to criteria from CTCAE Version 5.0. The patient was found to have dysphagia at baseline and experienced severe symptoms in the days following the first infusion that put the patient at high risk for subsequent infusion related concerns. Eligibility criteria for the 90-minute protocol were updated based on these findings. No patient experienced a grade 4 or 5 IRR. The remaining 23 infusions were well tolerated by the patients with no clinically significant events.
Secondary Endpoints
The patient who experienced a grade 3 IRR to rituximab received proper treatment by infusion clinic nurses according to the RLRVAMC hypersensitivity protocol. Patients who received rapid infusions of rituximab had a mean length of infusion of 95.0 minutes. This was in contrast to the mean time of each patient’s previous nonrapid infusion of 134.3 minutes. The difference between the 2 values equated to a savings in infusion clinic chair mean time of 39.3 minutes per patient.
Nurses were asked whether they had prior experience administering rituximab via 90-minute infusion and whether they felt comfortable administering a 90-minute rituximab infusion. Before the live education session, none of the nurses surveyed had prior experience or felt comfortable administering rituximab over 90 minutes. When the nurses were surveyed poststudy, all reported that they were experienced administering rituximab and felt comfortable with the process (Table 2).
Discussion
The infusion of rituximab has been associated with significant challenges related to the time and labor required. Although a vast number of institutions across the country now infuse the medication over an abbreviated time, HCP concerns for patient safety and appropriate use of hypersensitivity protocol in a veteran population delayed implementation at RLRVAMC. The results from this quality improvement initiative highlight the positive impact of the proactive measures that were used to implement the rapid infusion protocol for rituximab on improving HCP prescribing rates, nursing satisfaction, and appropriate management of IRRs.
Rapid infusion saved on average 39.3 minutes per patient in infusion clinic chair time. Each successful rapid infusion of rituximab potentially opened additional time in clinic for ≥ 1 patients to receive an infusion therapy. The RLRVAMC usually operated at maximum capacity, so the ability to accommodate more patients helped decrease hospital admittances for time-sensitive infusions.
The initial criteria used to screen patients to determine whether a rapid infusion of rituximab would be appropriate was based on inclusion and exclusion criteria for past studies on the same subject.3-5 The incidence of hypersensitivity reactions associated with study participants who received rapid rituximab infusions also resembles past research done on the subject, which is important to note due to prior misconceptions of staff at the institution of a higher risk of reaction in this specific veteran population. One patient with RA experienced a grade 3 IRR in this study. Although this patient met the original inclusion criteria, the patient had baseline dysphagia, and following the first infusion, reported to the emergency department (ED) with symptoms of delayed anaphylaxis. In this case, the order for rapid infusion was placed in advance and the prescriber was unaware of the ED visit. Based on this event, eligibility criteria for 90-minute rituximab infusions were updated to include additional information specifying that candidates for a rapid infusion also may have no baseline airway compromise. This hypersensitivity reaction also highlighted the need for decision support technology to assist HCPs in patient selection as well as empowering nursing and pharmacy staff to identify concerns once they place orders.
Over the course of the study, investigators assisted the HCPs with preparation of orders for the rapid infusion of rituximab for antineoplastic indications. Due to feasibility issues with this practice moving forward, order sets containing rituximab were updated to include a 90-minute option. This created a more standardized process that allowed HCPs to screen potential patients on their own. The expectation is that HCPs will be more likely to order 90-minute infusions for eligible patients in the future with this efficient and safer process.
Limitations
The small sample size in this study was a limitation. Retrospective data related to the management of infusion reactions and length of infusions were collected from nursing notes. The prospective use of a standardized evaluation tool for adverse drug reactions as well as bar code medication administration technology would improve the data available for this study. Additional studies also would be useful to validate the results.
Conclusions
The proactive measures that were used to implement the rapid infusion rituximab protocol improved HCP prescribing rates, nursing satisfaction, and the management of IRRs. Potential time savings with each infusion was significant. This study confirmed appropriateness of rapid administration of rituximab in this veteran population and has increased interest in implementing other rapid infusion protocols. Protocols, education, and order sets are being developed for daratumumab and infliximab.
1. Feugier P. A review of rituximab, the first anti-CD20 monoclonal antibody used in the treatment of B non-Hodgkin’s lymphomas. Future Oncol. 2015;11(9):1327-1342. doi:10.2217/fon.15.57
2. Rituxan [package insert]. South San Francisco, CA: Genentech; 2016.
3. Dakhil S, Hermann R, Schreeder MT, et al. Phase III safety study of rituximab administered as a 90-minute infusion in patients with previously untreated diffuse large B-cell and follicular lymphoma. Leuk Lymphoma. 2014;55(10):2335-2340. doi:10.3109/10428194.2013.877135
4. Dotson E, Crawford B, Phillips G, Jones J. Sixty-minute infusion rituximab protocol allows for safe and efficient workflow. Support Care Cancer. 2016;24(3):1125-1129. doi:10.1007/s00520-015-2869-4
5. Pritchard CH, Greenwald MW, Kremer JM, et al. Safety of infusing rituximab at a more rapid rate in patients with rheumatoid arthritis: results from the RATE-RA study. BMC Musculoskelet Disord. 2014;15:177. doi:10.1186/1471-2474-15-177
6. Hainsworth JD, Litchy S, Barton JH, et al. Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol. 2003;21(9):1746-1751. doi:10.1200/JCO.2003.09.027
7. Can M, Alibaz-Öner F, Yılmaz-Öner S, Atagündüz P, Înanç N, Direskeneli H. Accelerated infusion rates of rituximab are well tolerated and safe in rheumatology practice: a single-centre experience. Clin Rheumatol. 2013;32(1):87-90. doi:10.1007/s10067-012-2094-1
8. Sehn LH, Donaldson J, Filewich A, et al. Rapid infusion rituximab in combination with corticosteroid-containing chemotherapy or as maintenance therapy is well tolerated and can safely be delivered in the community setting. Blood. 2007;109(10):4171-4173. doi:10.1182/blood-2006-11-059469
9. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE). https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. Updated March 27 2020. Accessed June 15, 2020.
1. Feugier P. A review of rituximab, the first anti-CD20 monoclonal antibody used in the treatment of B non-Hodgkin’s lymphomas. Future Oncol. 2015;11(9):1327-1342. doi:10.2217/fon.15.57
2. Rituxan [package insert]. South San Francisco, CA: Genentech; 2016.
3. Dakhil S, Hermann R, Schreeder MT, et al. Phase III safety study of rituximab administered as a 90-minute infusion in patients with previously untreated diffuse large B-cell and follicular lymphoma. Leuk Lymphoma. 2014;55(10):2335-2340. doi:10.3109/10428194.2013.877135
4. Dotson E, Crawford B, Phillips G, Jones J. Sixty-minute infusion rituximab protocol allows for safe and efficient workflow. Support Care Cancer. 2016;24(3):1125-1129. doi:10.1007/s00520-015-2869-4
5. Pritchard CH, Greenwald MW, Kremer JM, et al. Safety of infusing rituximab at a more rapid rate in patients with rheumatoid arthritis: results from the RATE-RA study. BMC Musculoskelet Disord. 2014;15:177. doi:10.1186/1471-2474-15-177
6. Hainsworth JD, Litchy S, Barton JH, et al. Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol. 2003;21(9):1746-1751. doi:10.1200/JCO.2003.09.027
7. Can M, Alibaz-Öner F, Yılmaz-Öner S, Atagündüz P, Înanç N, Direskeneli H. Accelerated infusion rates of rituximab are well tolerated and safe in rheumatology practice: a single-centre experience. Clin Rheumatol. 2013;32(1):87-90. doi:10.1007/s10067-012-2094-1
8. Sehn LH, Donaldson J, Filewich A, et al. Rapid infusion rituximab in combination with corticosteroid-containing chemotherapy or as maintenance therapy is well tolerated and can safely be delivered in the community setting. Blood. 2007;109(10):4171-4173. doi:10.1182/blood-2006-11-059469
9. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE). https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. Updated March 27 2020. Accessed June 15, 2020.