End stage renal disease patients require a large number of medications and are known to have high rates of nonadherence. It is estimated that >50% of ESRD patients do not take their phosphate binders as prescribed. The renal pharmacy FreseniusRx provides coordinated ESRD medication delivery and adherence support for enrolled patients.
We investigated whether coordinated pharmacy care of mineral and bone disorder (MBD) therapies is associated with improvements in laboratory outcomes. We used data from hemodialysis patients treated at Fresenius Medical Care North America (FMCNA) clinics from February 2014 to January 2015. We included patients who were residing in a state with ≥100 patients in the FMCNA network, not in a nursing home, and prescribed a phosphate binder and/or calcimimetic.
We found 15,287 pharmacy patients who met the study criteria. Concurrent control patients not in the pharmacy were matched to pharmacy patients on a monthly basis that was based off the first date of receipt of therapy from FreseniusRx using 1:1 nearest neighbor matching on the logit of the propensity score for an array of clinical and non-clinical parameters. Logistic regression was used to measure the association between pharmacy care and patients achieving their laboratory goals for phosphorus (PO4) and intact parathyroid hormone (iPTH), and combined goals for total calcium (Ca), PO4, and iPTH.
We analyzed data from 30,574 patients (15,287 pharmacy and control). In unadjusted and adjusted analyses, we consistently observed that pharmacy patients were more likely to achieve their MBD laboratory goals as compared to controls. In an adjusted analysis, we found pharmacy patients were more likely to achieve their MBD laboratory targets at 3, 6, 9, and 12 months for PO4 (11.1%, 10.5%, 11.8% and 12.7% respectively), iPTH (8.9%, 17.5%, 23.4% and 27.9% respectively) and combined goals for Ca, PO4, and iPTH (12.1%, 13.4%, 16.7% and 21.2% respectively) versus controls (p<0.01 for all comparisons).
These findings indicate that coordinated pharmaceutical care may be associated with improvements in patients achieving their MBD laboratory goals.
Patients with end-stage renal disease have a high burden of disease and require a large number of medications to manage their health state. On average, dialysis patients have been reported to be prescribed 10 to 12 routine medications, including phosphate binders, vitamin D analogs, calcimimetics, erythropoiesis stimulating agents, antihypertensives, antidiabetics, and others.1
The medication burden required for the management of dialysis patients has been found to be associated with high rates of medication nonadherence. In particular, phosphate binders are among the most reported classes of medications that patients have adherence issues with and the average nonadherence rates are estimated to exceed 50%. Medication nonadherence has been suggested to be associated to higher rates of mortality in the dialysis population and is potentially modifiable through enhanced management and support.2
Medication adherence has been found to be associated to patient health literacy, communication barriers, demographic parameters, comorbidities, dialysis vintage, and the number and frequency of medications regimens.1,3,4 Studies suggest that integration of coordinated care paradigms including pharmacists is associated with improvements in rates of hospitalizations and mortality in ESRD patients.5,6 Similarly, in the general population pharmacy medication management has been reported to be associated with decreased rates of hospitalizations.7
Coordinated care has the potential to improve dialysis patient outcomes through various enhanced medication care models, in particular for mineral and bone disorder (MBD) therapies. FreseniusRx is a specialty pharmacy that includes coordinated MBD medication delivery, MBD medication review, and adherence support for enrolled ESRD patients treated at Fresenius Medical Care North America (FMCNA) dialysis facilities (see Table 1).
In this analysis, we aimed to investigate whether FreseniusRx coordinated pharmacy care is associated with improvements in ESRD patients achieving their laboratory outcomes.
Study design and patients
This study was a 12-month, retrospective, observational analysis of data from chronic in-center hemodialysis patients treated at FMCNA clinics from February 1, 2014 to January 31, 2015. This study included data on adult patients who were 1) residing in a state with ≥100 in-center FMCNA hemodialysis patients, 2) not residing in a nursing home, 3) prescribed a phosphate binder and/or calcimimetic medication, 4) not enrolled in a Veterans Health Administration, or Indian Health Service, or Kaiser insurance plan, and 5) not participating in any clinical research trial with an investigational new drug.
Description of FreseniusRx coordinated care
FreseniusRx is a renal pharmacy that provides coordinated ESRD medication delivery, MBD medication review, and adherence support to enrolled patients through integration of specially-trained renal pharmacists with the care team (nephrologists, nurses, technicians, social workers, and dietitians) and laboratories at FMCNA. Patients can elect to be enrolled into the pharmacy to receive MBD medication delivery at the dialysis clinic or their home.
Patients are eligible for enrollment in FreseniusRx if they are able to have prescriptions delivered to the dialysis clinic, or are residing in a location where they can receive mail order prescriptions at home. For patients with economic hardships, the pharmacy provides assistance with review of available pharmaceutical manufacturer financial assistance programs.
Notably, patients who have Veterans Health Administration, Indian Health Service, and Kaiser insurance plans are not eligible for enrollment into the pharmacy. Overall, patients can enroll in the pharmacy if they are treated by a FMCNA facility and can receive medications at the dialysis clinic or by mail at home.
To limit medication adherence issues, the pharmacy provides rapid delivery of MBD prescriptions to the patient, proactive patient outreach when there is an anticipated need for a refill, and specialty pharmacists who review the patients’ MBD medications for contraindications. Ultimately, the specialty pharmacists assist the care team by comprehensively evaluating MBD drug regimens for appropriateness and provide advice if adjustments are needed to effectively support a patient’s treatment.
Adherence support is provided to pharmacy patients through outreach to those who are overdue, or have an anticipated need for a refill of their MBD medications. Additionally, FreseniusRx has a pharmacist who is available for patients and providers 24 hours per day, seven days per week. A description of the coordinated care services provided during the study period to patients enrolled in the pharmacy is detailed in Table 1.
Importantly for this investigation, the offering of FreseniusRx pharmacy services to ESRD patients was slowly expanded throughout FMCNA clinics during the study period. A beneficial aspect of the rollout of the offering of pharmacy services is that it inherently provides a robust control population to utilize for matching patients with similar parameters that may have the potential to influence the patients’ choice of selecting pharmacy services and/or outcomes.
Matching pharmacy patients to controls
There were 15,287 patients who met study inclusion criteria and were enrolled into the FreseniusRx pharmacy and prescribed a phosphate binder and/or calcimimetic therapy prior to enrollment. We matched control patients who were not enrolled into the pharmacy and met the same criteria to each pharmacy counterpart.
Matching was determined based on the date of each pharmacy patient’s receipt of their first shipment of a MBD therapy (i.e., phosphate binder and/or calcimimetic medication) from FreseniusRx. The first day of the follow up period for the pharmacy patients began on the first of the following month after the receipt of their first MBD therapy shipment from FreseniusRx. Control patients were matched based on respective month of the receipt of the first MBD prescription by their pharmacy counterparts.
Patients had a follow-up period of 12 months. Matching was performed on a monthly basis since pharmacy patients could have been enrolled anytime during the study period. Thereby, each pharmacy patient was matched to a control patient with a concurrent month for a matched start date of the follow up period. To avoid using the same control patient more than once, patients who were used as controls during the previous months of the study were not included again as candidates for matching to pharmacy patients who enrolled in the future months.
The matching of FreseniusRx pharmacy patients to controls was performed in a 1:1 ratio by the nearest neighbor on the logit of the propensity score without replacement using an array of baseline covariates; these included patient demographics, state of residence, insurance type, clinical characteristics, laboratory values, and other parameters denoted in Table 2.8
The facility UltraScore measure denoted in Table 2 is a quality indicator specific to FMCNA dialysis clinics; this metric is based on levels of albumin, hemoglobin, calcium (Ca), phosphorous (PO4), intact parathyroid hormone (iPTH), estimated Kt/V, rates of catheter use, and rates of mortality. For the covariate on economic status, we used concurrent data from the United States Internal Revenue Service to match patients by adjusted gross income by the ZIP code of the patient’s residence. Overall, this investigation analyzed the data from 15,287 pharmacy patients and 15,287 matched control patients.
Analysis cohorts and outcomes
This study included an Intention to Treat (ITT) analysis cohort and an As Treated (AT) analysis cohort, which considered two methods for analyzing the data for control patients who enrolled into the FreseniusRx pharmacy during the study period; these are defined below.
ITT cohort included an analysis whereby any data for control patients who were enrolled into the FreseniusRx pharmacy during the study period was included in the control group through the end of the follow up period.
AT cohort included an analysis whereby any data for control patients who were enrolled into the FreseniusRx pharmacy during the study period was censored from the control group 30 days after the first pharmacy MBD therapy shipment date.
With this design, ITT pharmacy patients were matched to control patients and data from both groups was captured throughout the follow up period (12 months), irrespective if the control patient was enrolled into the pharmacy during the follow up period. In the AT cohort, control patients who were enrolled into the pharmacy during follow up were censored from the cohort at the time point of 30 days after the first pharmacy MBD therapy shipment date; this date was chosen since we do not anticipate any immediate changes in laboratory outcomes. The analysis of an AT population was considered necessary to confirm the ITT analysis since there was notable crossover of control patients who were enrolled into the pharmacy during the follow up period.
The study outcome was the odds ratio of pharmacy patients versus matched controls meeting MBD laboratory goals for total PO4 and iPTH separately, as well as, for the total Ca, PO4 and iPTH measures combined together at 3, 6, 9, and 12 months after enrollment in the pharmacy. The target goal for the laboratory outcome measures were: Ca ≥8.5 to ≤10.0 mg/dL, PO4 ≥3.0 to ≤5.5 mg/dL, iPTH ≥150 to ≤600 pg/mL. Notably, FKC clinics have an option to utilize a standardized algorithm for management of active vitamin D administration. The mean values of all available laboratory results during each follow up period were calculated for determining the relevant outcomes.
Logistic regression was used to measure the associations between enrollment in FreseniusRx and the outcomes. Unadjusted and adjusted analyses were performed for the ITT and AT study cohorts. The adjusted analysis was computed for the models using the baseline covariates included in the matching process.
This study utilized data from 15,287 hemodialysis patients enrolled in the FreseniusRx coordinated care pharmacy who were matched to 15,287 control hemodialysis patients with similar demographic, socioeconomic, and clinical characteristics, but were not enrolled to have MBD therapies supplied from the pharmacy; the total study population included 30,574 patients. At baseline (pharmacy enrollment or concurrent date), the overall study population had a mean age of about 60 years old, was 57% male, and 22% of patients utilized a dialysis catheter.
As can be observed in Table 2, the matching process yielded a very balanced pharmacy and control cohorts as seen by the absolute standardized differences for every variable being < 2%.
Standard mean difference (std mean difference): standardized differences >10% indicate an imbalance between groups.
MBD laboratory outcomes
In the logistic regression analysis of the odds of MBD laboratory goals being within target range in pharmacy patients versus matched controls, we found that patients who received coordinated pharmaceutical care had significantly better short term and long term outcomes as compared to matched controls (see Table 3). These findings were consistent for the unadjusted and adjusted analysis of both the ITT and AT study cohorts.
Based on the adjusted analysis of the AT cohort, pharmacy patients were more likely to achieve their PO4 goals (range 10.5% to 12.7%) at 3, 6, 9, and 12 months after enrollment, as compared to matched controls (p<0.0001 for all comparisons); these improvements were relatively sustained throughout the follow-up period. With respect to iPTH, we observed progressive improvements in the proportion of patients achieving target goals with time receiving coordinated MBD pharmacy care.
In the adjusted analysis of the AT population, the pharmacy patients were 8.9%, 17.5%, 23.4%, and 27.9% more likely to meet their iPTH goals at 3, 6, 9, and 12 months after enrollment, respectively compared to the matched controls (p<0.01 for all comparisons). Similarly, in the adjusted analysis of the AT cohort we found that there was an association with progressively more patients achieving all three MBD laboratory goals with time being treated by the pharmacy.
These patients had a 12.1%, 13.4%, 16.7%, and 21.2% greater likelihood to meet their Ca, PO4, and iPTH goals at 3, 6, 9, and 12 months after enrollment compared to their matched control counterparts (p<0.0001 for all comparisons).
In this retrospective analysis considering an ITT and AT study cohort we observed that patients treated by FMCNA who were prescribed a phosphate binder and/or calcimimetic and received coordinated MBD medication delivery and adherence support from the FreseniusRx pharmacy were more likely to achieve their Ca, PO4, and iPTH goals throughout the first year after enrollment, as compared to matched control counterparts. The improvements in patients achieving PO4 goals associated with pharmacy care were observed 3 months after enrollment, and were sustained throughout the year of follow up.
For iPTH alone and all three goals combined, there were progressive improvements over time during the year of follow up for the pharmacy patients, as compared to controls. Although changes in the dosing of active vitamin D analogs have the potential to affect iPTH laboratory outcomes, FMCNA clinics utilize a standardized vitamin D algorithm. Overall, our results indicate that utilization of a renal pharmacy for enhanced delivery of ESRD medications combined with integration of a specialty pharmacist within the dialysis care team has the potential to improve MBD laboratory outcomes.
Similar to our results, a 24-month observational study has previously suggested that integration of coordinated full-service pharmacy services with pharmacist support was associated with improved outcomes in ESRD patients, as compared to matched controls.5 This study included 8,864 hemodialysis patients in a large dialysis system who received pharmacy services and 43,013 matched controls whose data was obtained from a national ESRD patient dataset. They performed an ITT and AT analysis and found that pharmacy patients were 2-7% less likely to experience a hospital admission (ITT HR=0.98, 95%CI 0.95-1.01; AT HR=0.93, 95%CI 0.90-0.96) and 8-21% less likely to die (ITT HR=0.92, 95%CI 0.86-0.97; AT HR=0.79, 95%CI 0.74-0.84) versus controls. This study, however, did not report any laboratory outcomes related to the coordinated pharmacy services.
Additionally, there have been some controlled trials performed that indicate that addition of a pharmacist in the ESRD care team can improve patient outcomes.
In a systematic review that assessed the impacts of pharmacist interventions in 37 controlled studies including hemodialysis patients (n=403), transplant patients (n= 47), and CKD patients not on dialysis (n= 294), it was indicated that integration of pharmacists in patient care was associated with a reduction in the rates of hospitalizations (1.3 less per patient year; p=0.02), improved blood pressure control (systolic blood pressure 145.3mmHg for patients with pharmacist intervention versus 175.8mmHg for controls; p=0.029), and improvements in serum PO4 levels (5.6 mg/dL for patients with pharmacist intervention versus 6.4 mg/dL for controls; p=0.03), in addition to other clinical benefits.9 This review only included one trial with the endpoint of PO4, and it was a controlled trial of 34 hemodialysis patients who were randomized to a PO4 management protocol with integrated renal dietitian and pharmacist care for four months versus standard of care.10
Although this trial was small, it was assessed in the systemic review to be of good quality9 and is consistent with our findings that included integration of a specialty pharmacist with the ESRD care team coupled with enhanced medication delivery.
In a recent review including 64 studies (n= 34,457), on pharmacist-led management of chronic disease care, four of which included both ESRD and CKD patients not on dialysis (n= 2,920), the authors identified that overall there is moderate evidence indicating that integration of pharmacists with independent prescribing privileges into chronic disease care teams improves outcomes and increases the likelihood of patients achieving their target goals as compared with typical care models.11
Within the analyses of renal disease patients, they found signals indicating that pharmacist-led management may lower overall medication use in ESRD patients, increase patients achieving anemia targets, and improve the quality of life in ESRD patients. Notably, this review did not find remarkable differences for the attainment of blood pressure goals or for all-cause mortality with pharmacist-led management.
Albeit studies in ESRD patients are limited, there is a consensus in observations indicating integration of pharmacists into the care team alone, or combined with enhanced medication delivery paradigms, has the potential to improve patient outcomes. However, it is noteworthy to mention that the specific impacts of the enhanced provision of medication delivery apart from the integration of pharmacists remains unknown.
Although this analysis was well-controlled and utilized a large pharmacy and matched control population with similar demographic, economic and clinical parameters, the study does have limitations inherent to observational analyses. These include a possible selection bias related to patient eligibility for enrollment into the pharmacy, including levels of health literacy and education. Albeit, we did control for exclusionary health insurance plans, matched patients on common health insurance plans, and matched patients on income status.
In this analysis we included pharmacy patients who received at least one MBD prescription from FreseniusRx; however, we did not consider patients who might have stopped utilizing the pharmacy during the follow up period. An additional limitation is that we did not adjust for markers of patient medication adherence throughout the study period, such as the medication possession ratio and refill history. Furthermore, these results should be interpreted within the context of the study population, which has differences in some characteristics compared to the overall dialysis population.
Our findings indicate that enrollment of ESRD patients into FreseniusRx coordinated pharmaceutical delivery and adherence support may lead to increases in the proportion of patients achieving their target goals for MBD laboratory goals, as compared to those not enrolled into the pharmacy. Ongoing analyses are needed to confirm that the delivery of coordinated pharmaceutical care continues to be associated with improvements in patient outcomes.
- Ghimire S, Castelino RL, Lioufas NM, Peterson GM, Zaidi ST. Nonadherence to Medication Therapy in Haemodialysis Patients: A Systematic Review. PLoS One. 2015;10(12):e0144119.
- Denhaerynck K, Manhaeve D, Dobbels F, Garzoni D, Nolte C, De Geest S. Prevalence and consequences of nonadherence to hemodialysis regimens. Am J Crit Care. 2007;16(3):222-235; quiz 236.
- St Peter WL, Wazny LD, Patel UD. New models of chronic kidney disease care including pharmacists: improving medication reconciliation and medication management. Curr Opin Nephrol Hypertens. 2013;22(6):656-662.
- Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005;353(5):487-497.
- Weinhandl ED, Arneson TJ, St Peter WL. Clinical outcomes associated with receipt of integrated pharmacy services by hemodialysis patients: a quality improvement report. Am J Kidney Dis. 2013;62(3):557-567.
- Pai AB, Boyd A, Depczynski J, Chavez IM, Khan N, Manley H. Reduced drug use and hospitalization rates in patients undergoing hemodialysis who received pharmaceutical care: a 2-year, randomized, controlled study. Pharmacotherapy. 2009;29(12):1433-1440.
- Romanelli RJ, Leahy A, Jukes T, Ishisaka DY. Pharmacist-led medication management program within a patient-centered medical home. Am J Health Syst Pharm. 2015;72(6):453-459.
- Rosenbaum PR RD. The central role of the propensity score in observational studies for causal effects. Biometrika. 1983;70:41-55.
- Salgado TM, Moles R, Benrimoj SI, Fernandez-Llimos F. Pharmacists’ interventions in the management of patients with chronic kidney disease: a systematic review. Nephrol Dial Transplant. 2012;27(1):276-292.
- Yokum D, Glass G, Cheung CF, Cunningham J, Fan S, Madden AM. Evaluation of a phosphate management protocol to achieve optimum serum phosphate levels in hemodialysis patients. J Ren Nutr. 2008;18(6):521-529.
- Greer N, Bolduc J, Geurkink E, et al. Pharmacist-led Chronic Disease Management: A Systematic Review of Effectiveness and Harms Compared With Usual Care. Ann Intern Med. 2016.