Improving Transplant Medication Safety Through a Technology and Pharmacist Intervention (ISTEP): Protocol for a Cluster Randomized Controlled Trial.

BACKGROUND: Medication errors, adverse drug events, and nonadherence lead to increased health care utilization and increased risk of adverse clinical outcomes, including graft loss, in solid organ transplant recipients. Veterans living with organ transplants represent a population that is at substantial risk for medication safety events and fragmented care coordination issues. To improve medication safety and long-term clinical outcomes in veteran transplant patients, interventions should address interorganizational system failures and provider-level and patient-level factors. OBJECTIVE: This study aims to measure the clinical and economic effectiveness of a pharmacist-led, technology-enabled intervention, compared with usual care, in veteran organ transplant recipients. METHODS: This is a 24-month prospective, parallel-arm, cluster-randomized, controlled multicenter study. The pharmacist-led intervention uses an innovative dashboard system to improve medication safety and health outcomes, compared with usual posttransplant care. Pharmacists at 10 study sites will be consented into this study before undergoing randomization, and 5 sites will then be randomized to each study arm. Approximately, 1600 veteran transplant patients will be included in the assessment of the primary outcome across the 10 sites. RESULTS: This study is ongoing. Institutional review board approval was received in October 2018 and the study opened in March 2019. To date there are no findings from this study, as the delivery of the intervention is scheduled to occur over a 24-month period. The first results are expected to be submitted for publication in August 2021. CONCLUSIONS: With this report, we describe the study design, methods, and outcome measures that will be used in this ongoing clinical trial. Successful completion of the Improving Transplant Medication Safety through a Technology and Pharmacist Intervention study will provide empirical evidence of the effectiveness of a feasible and scalable technology-enabled intervention on improving medication safety and costs. CLINICAL TRIAL: ClinicalTrials.gov NCT03860818; https://clinicaltrials.gov/ct2/show/NCT03860818. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/13821.

Impact of selective serotonin reuptake inhibitors in the veteran population: 10-year risk outcomes.

AIM: To evaluate the comparative risk of hip fracture or osteoporosis among US Veterans based on selective serotonin reuptake inhibitor (SSRI) exposure. PATIENTS & METHODS: A retrospective cohort study of eligible US Veterans Health Administration patients enrolled in 2003-2004 was performed to examine SSRIs' 2-, 5- and 10-year impact on bone health using multiple logistic regression. RESULTS: Veterans on SSRIs were found to be 56.7% more likely over a 10-year period to suffer a hip fracture (risk ratio: 1.567; 95% CI: 1.464-1.676) and 34.6% more likely to develop osteoporosis (risk ratio: 1.346; 95% CI: 1.319-1.374) when compared with those who were SSRI naive. CONCLUSION: SSRI usage was associated with greater risk of hip fracture and osteoporosis over a 10-year period in the veteran population, with similar effect sizes to smaller studies.

Long-term Assessment of NSAID Prescriptions and Potential Nephrotoxicity Risk in Adult Kidney Transplant Recipients.

BACKGROUND: Nonsteroidal anti-inflammatory drug (NSAID) use is recommended to be avoided in kidney transplantation, with a paucity of studies assessing their safety within this population. This study aims to use a large cohort of Veterans Affairs (VA) kidney transplantation recipients to assess the risk of acute kidney injury (AKI) with NSAID use. METHODS: This is a 10-year longitudinal cohort study of adult kidney transplant recipients retrospectively followed in the VA system from 2001 to 2010 that assessed for risk of AKI with NSAID prescriptions. NSAID prescriptions, patient characteristics, and estimated glomerular filtration rates were abstracted from the VA comprehensive electronic health record. NSAID exposure was assessed by duration, dosage, and type. AKI events were defined by ≥50% decrease in estimated glomerular filtration rate. Risk was estimated using longitudinal multivariable generalized logistic regression model. RESULTS: About 5100 patients were included with a total of 29 980 years of follow-up; 671 NSAID prescriptions in 273 (5.4%) patients (2.24 per 100 patient-y) with 472 (70%) high dose were identified. High-dose NSAID prescriptions were associated with 2.83 (95% confidence interval [CI], 1.55-5.19; P < 0.001) higher odds of AKI events within a given year; low dose was not associated with AKI (odds ratio, 1.93; 95 % CI, 0.95-6.02; P = 0.256). One 7-day NSAID course was associated with 5% higher odds of increasing AKI events, whereas chronic use (≥180 d) was associated with 3.25 (95% CI, 1.78-5.97; P < 0.001) higher odds of AKI. CONCLUSIONS: Prescriptions for NSAIDs were uncommon in this cohort but were associated with a significant increase in the risk of AKI, which was impacted by higher NSAID dose and longer NSAID durations.

Characterization of Potentially Unsafe Ambulatory Antibiotic Use and Associated Outcomes in an Adult Kidney Transplant Population.

BACKGROUND: Antibiotics are frequently prescribed to kidney transplant (KTX) recipients in the outpatient setting, but there are limited data assessing the safety and outcomes associated with this practice. OBJECTIVE: The primary objective of this study was to describe ambulatory antibiotic prescribing in a large cohort of adult KTX recipients. The secondary objective was to assess the outcomes associated with potentially unsafe antibiotic use in this population. METHODS: National Veterans Health Administration data compiled between 2001 and 2010 were used to conduct a pharmacovigilance assessment of antibiotic prescribing, excluding intravenous agents, antifungals, antivirals, and prophylactic regimens. Multivariable Cox proportional hazard regression was used to determine the impact of safe and potentially unsafe antibiotic use on time to event for graft loss. RESULTS: Among 5130 KTX recipients and 30 127 patient-years of follow-up, 14 259 antibiotic courses were prescribed at a rate of 0.47 courses per patient-year. Transplant or nephrology providers prescribed 24.8% of courses. Overall, 608 courses (4.3%) in 311 patients (6.1%) were considered potentially unsafe for dosages in disagreement with recommended adjustments for renal function, interaction with immunosuppressive regimens, and other pertinent safety concerns. After adjusting for baseline characteristics, unsafe antibiotic use was associated with a 40% higher risk of graft loss (adjusted hazard ratio = 1.40; 95% CI = 1.03-1.89; P = 0.030) compared with safe use. CONCLUSIONS AND RELEVANCE: Although unsafe antibiotic prescribing was uncommon, it was associated with increased risk of graft loss. Prospective research is needed to elucidate whether the driver of poor outcomes is the safety of the antibiotic prescription or fragmented care.

Improvement in immunosuppression therapy monitoring in organ transplant recipients.

PURPOSE: The results of a study to determine whether a technology-enabled pharmacist intervention improved immunosuppression monitoring in organ transplant recipients are presented. METHODS: This was a retrospective, longitudinal cohort study. Eligible patients included veteran solid organ transplant recipients receiving immunosuppression therapy from a Veterans Affairs Medical Center (VAMC) between July 1, 2013, and July 1, 2015. A clinical pharmacist used an electronic surveillance system to determine need for laboratory monitoring and engaged the recipients to obtain regular laboratory monitoring at the VAMC or an outside facility. The primary aim was to determine whether the intervention improved immunosuppression monitoring using an interrupted time series inquiry with segmented regression analysis. The secondary aim was to assess care coordination using descriptive statistics. RESULTS: A total of 110 veteran transplant recipients were included; 96% were male, 50% received kidney transplants, 36% received liver transplants, and 14% received thoracic transplants. During the 6-month initial intervention period, the rate of patients meeting minimum immunosuppression monitoring criteria increased by 4.7% per month (p < 0.001). The monthly rate of patients meeting immunosuppressant monitoring for tacrolimus, cyclosporine, and antimetabolites increased by 4.1% (p = 0.0013), 9.5% (p = 0.0442), and 1.5% (p = 0.0077), respectively. The clinical pharmacist performed 126 medication reconciliations, documented 259 outside laboratory values, and referred 9 patients to other providers. CONCLUSION: Clinical pharmacist intervention resulted in an increased number of patients with solid organ transplant meeting minimum immunosuppressant monitoring recommendations.

The Impact of Health Care Appointment Non-Adherence on Graft Outcomes in Kidney Transplantation.

BACKGROUND: Non-adherence to medication is a well-studied and known cause of late allograft loss, but it is difficult to measure and prospectively monitor. The aim of this study was to assess if appointment non-adherence was correlated with medication non-adherence and a predictor of graft outcomes. METHODS: This was a longitudinal cohort study that used the National United States Renal Data System and veterans affairs health records data with time-to-event analyses conducted to assess the impact on graft and patient survival. RESULTS: The number of transplants that were included in the analysis was 4,646 (3,656 with complete records); 14.6% of patients had an appointment no show rate of ≥12% (non-adherence). Appointment and medication non-adherence were highly correlated and both were significant independent predictors of outcomes. Those with appointment non-adherence had 1.5 times the risk of acute rejection (22.0 vs. 14.7%, p < 0.0001) and a 65% higher risk of graft loss (adjusted hazards ratio (aHR) 1.65, 95% CI 1.38-1.97, p < 0.0001). There was a significant interaction between appointment and medication non-adherence; those with appointment and medication non-adherence were at very high risk of graft loss (aHR 4.18, 95% CI 3.39-5.15, p < 0.0001), compared to those with only appointment non-adherence (aHR 1.39, 95% CI 0.97-2.01, p = 0.0766) or only medication non-adherence (aHR 2.44, 95% CI 2.11-2.81, p < 0.0001). CONCLUSION: These results demonstrate that non-adherence to health care appointments is a significant and independent risk factor for graft loss.

Impact of Cardiovascular Risk Factors on Graft Outcome Disparities in Black Kidney Transplant Recipients.

Although outcome inequalities for non-Hispanic black (NHB) kidney transplant recipients are well documented, there is paucity in data assessing the impact of cardiovascular disease (CVD) risk factors on this disparity in kidney transplantation. This was a longitudinal study of a national cohort of veteran kidney recipients transplanted between January 2001 and December 2007. Data included baseline characteristics acquired through the United States Renal Data System linked to detailed clinical follow-up information acquired through the Veterans Affairs electronic health records. Analyses were conducted using sequential multivariable modeling (Cox regression), incorporating blocks of variables into iterative nested models; 3139 patients were included (2095 non-Hispanic whites [66.7%] and 1044 NHBs [33.3%]). NHBs had a higher prevalence of hypertension (100% versus 99%; P<0.01) and post-transplant diabetes mellitus (59% versus 53%; P<0.01) with reduced control of hypertension (blood pressure <140/90 60% versus 69%; P<0.01), diabetes mellitus (A1c <7%, 35% versus 47%; P<0.01), and low-density lipoprotein (<100 mg/dL, 55% versus 61%; P<0.01). Adherence to medications used to manage CVD risk was significantly lower in NHBs. In the fully adjusted models, the independent risk of graft loss in NHBs was substantially reduced (unadjusted hazard ratio, 2.00 versus adjusted hazard ratio, 1.49). CVD risk factors and control reduced the influence of NHB race by 9% to 18%. Similar trends were noted for mortality, and estimates were robust across in sensitivity analyses. These results demonstrate that NHB kidney transplant recipients have significantly higher rates of CVD risk factors and reduced CVD risk control. These issues are likely partly related to medication nonadherence and meaningfully contribute to racial disparities for graft outcomes.

Association between caffeine citrate exposure and necrotizing enterocolitis in preterm infants.

PURPOSE: The results of a case-control study of the potential role of caffeine citrate therapy in the development of necrotizing enterocolitis (NEC) are presented. METHODS: Patient records for a 10-year period were reviewed to collect sufficient data to test the hypothesis that newborns treated in a hospital's perinatal intensive care unit for NEC might have had a higher cumulative exposure to caffeine citrate relative to that of neonates of similar postconceptional and postnatal age who did not develop NEC. Ninety-five cases of NEC were identified; each case was matched to a control case by gestational age and birth weight. To enable comparative analyses, each control was assigned an index date according to the number of days from birth to NEC diagnosis in the paired case. Data collected for analysis included patient demographics, information on caffeine citrate and concomitant medication use, and potential confounding factors. RESULTS: Analysis of aggregated data for the entire seven-day NEC event timeframe indicated no significant differences between cases and controls with regard to average caffeine citrate loading doses (p = 0.5), cumulative exposure (p = 0.2), and trough serum concentrations (p = 0.5); mean cumulative exposure values differed significantly at one time point (four days prior to NEC diagnosis (p = 0.04). CONCLUSION: Cumulative exposure to caffeine citrate among infants who developed NEC and infants who did not develop NEC differed significantly at only one of six evaluated time points during the seven days before NEC development or the index date. There was no significant difference between groups in the proportions of patients who received caffeine citrate or in mean serum caffeine concentrations.

Daptomycin experience in critical care patients: results from a registry.

BACKGROUND: Vancomycin is often the drug of choice in critically ill patients with gram-positive infections, although circumstances often prevent its use. In these situations, clinicians are frequently left with limited data regarding alternative agents. OBJECTIVE: To describe patients with reported sepsis receiving daptomycin in a critical care unit. METHODS: This multicenter, noncomparative, noninterventional study identified patients in critical care units, using the Cubicin Outcomes Registry and Experience (CORE) 2005-2009 registry. A descriptive account of patient characteristics, infectious etiology, outcomes at the end of daptomycin therapy, and 30-day mortality is reported. Nonevaluable patients were excluded from the efficacy analysis but included in the safety analysis. RESULTS: We identified 128 patients, 98 (77%) of whom were evaluable for efficacy. Patient characteristics for the efficacy population were 55 (56%) males, 30 (31%) aged 66 years or older, 38 (39%) had creatinine clearance less than 30 mL/min, and 27 (28%) were on dialysis. Common underlying diseases included acute or chronic renal failure 44 (45%), hypertension 40 (41%), and diabetes 27 (28%). Seventy-two (73%) patients were bacteremic. The most common pathogens found were methicillin-resistant Staphylococcus aureus (32%), vancomycin-resistant Enterococcus faecium (21%), and coagulase-negative staphylococci (20%). Prior to daptomycin, antibiotics were used in 84 (86%) patients, most commonly vancomycin (65/84; 77%). The median (range) initial daptomycin dose was 6 mg/kg (3-10) and duration of 10 days (1-58). Overall success rate was 70% (31% cured; 39% improved). Twelve adverse events possibly related to daptomycin were reported in 9 of 128 (7%) patients in the safety population; 4 of these in 4 (3%) patients were serious. The mortality rate within 30 days of completing daptomycin was 42 of 128 (33%) patients. CONCLUSIONS: These data provide preliminary results on the use of daptomycin in critically ill patients with complicated conditions. Controlled studies are needed to best evaluate daptomycin use in these patients.

Projecting future drug expenditures: 2011.

PURPOSE. Drug expenditure trends in 2009 and 2010, projected drug expenditures for 2011, and factors likely to influence drug expenditures are discussed. SUMMARY. Various factors are likely to influence drug expenditures in 2011, including drugs in development, the diffusion of new drugs, generic drugs, health care reform, and biosimilars. Two distinct patterns of drug expenditures continue to exist. The dominant trend over the past several years is substantial moderation in expenditure growth for widely used drugs, primarily due to the ongoing introduction of generic medications for high-cost, frequently used medications and the influence of the economic downturn. The second pattern is substantial increases in expenditures for specialized medications, particularly in the outpatient setting. The influence of health care reform, the economy, and the emergence of biosimilars will be important trends to follow over the next several years, but they are unlikely to have substantial impact on drug expenditures in 2011. From 2008 to 2009, total U.S. drug expenditures increased by 5.2%, with total spending rising from $284.8 billion to $299.5 billion. Growth in drug expenditures in clinics grew by 5.1% from 2008 to 2009. Hospital drug expenditures increased at the moderate rate of 2.8% from 2008 to 2009; through the first nine months of 2010, hospital drug expenditures increased by only 0.8% compared with the same period in 2009. CONCLUSION. For 2011, we project a 3-5% increase in drug expenditures in outpatient settings, a 4-6% increase in expenditures for clinic-administered drugs, and a 1-3% increase in hospital drug expenditures.