Deprescribing Calcium-Based Phosphorus Binders in Dialysis Patients Presented by Aaron Schmitz, Michael Russell, Kelsey Coffman Project Advisor: Michelle Fravel

Outline Background Objectives Methods Results Conclusion Future Directions

Background Chronic kidney disease complications Bone and mineral disorder- Imbalance between phosphorus, calcium, parathyroid, and vitamin D Hyperphosphatemia has been linked to A reduction in alpha-1-hydroxylase activity causing decreased active vitamin D levels An increase in parathyroid hormone These effects cause increased CV mortality, morbidity, and all cause mortality Hyperphosphatemia occurs in CKD because the kidneys are not able to excrete phosphorus efficiently leading to elevated serum levels of phosphorus Vitamin D is activated in the kidneys by alpha-1-hydroxase and this function is impaired in CKD. When phosphorus goes up and vitamin D goes down, the body makes PTH and this causes calcium to move from your bones into the blood. This leads to weakened bones and can lead to worsened cardiovascular outcomes

Background Maintaining phosphorus levels is a priority Current treatments are dietary restriction, dialysis, and medication therapy Medication therapy options Calcium carbonate and Calcium acetate Sevelamer HCl (Renagel) and Sevelamer carbonate (Renvela) Lanthanum (Fosrenol) 2 new iron-based: Auryxia and Velphoro Calcium-based binders are more common due to affordability, ease of use, and good patient tolerability Serious adverse events with calcium-based binders Large doses of all of these agents have to be taken with meals (2-3 large tablets with meals). Main side effects are GI disturbances Sevelamer and Lanthanum became generic October 2017 Serious adverse events such as calcifications of arteries, cardiovascular arrhythmias, and increased risk of cardiovascular-related mortality have been associated with administration of high doses of calcium in patients with chronic kidney disease

Background Kidney Disease: Improving Global Outcomes (KDIGO Guidelines) were updated in 2017 for bone and mineral disorders Current Recommendation (2017): Restricting the dose of calcium-based phosphorus binders in all adult patients with CKD G3a-G5D (2B) Driven by 3 RCT (Block 2012, Di Lorio 2012, Di Lorio 2013) Previous Recommendation (2009): Restrict only in adults with hypercalcemia with CKD G3a-G5D (1B) Data from RCT: Suggested increased harm with calcium-based phosphate binder utilization G3a is Crcl 45-59 CKD-Mineral and Bone Disorder (CKD-MBD).” KDIGO, 21 June 2017

Di Lorio 2013 466 dialysis patients randomly assigned to sevelamer or calcium carbonate for 24 months, follow up until 36 months Sevelamer arm resulted in lower phosphorus levels Sevelamer treated patients experienced lower CV mortality due Cardiac arrhythmias (HR 0.06; 95% CI 0.01-0.25, P < 0.001) All cause CV death (HR 0.09; 95% CI 0.05-0.19; P < 0.001) Limitations: Open-label, higher baseline coronary artery calcification scores in calcium carbonate group Trial with the largest effect was the dialysis population patients were either treated with a non-calcium-containing phosphate binder (sevelamer) or a calcium-based phosphate binder. The results of the trial showed that patients on non-calcium-containing therapy had a greater than 10-fold risk reduction (hazard ratios of 0.06 and 0.09, respectively) Di Lorio, Biagio. Sevelamer Versus Calcium Carbonate in Incident Hemodialysis Patients: Results of an Open-Label 24-month Randomized Clinical Trial Pubmed, AJKD, 20 May 2013

Objectives Describe the current prescribing patterns of calcium-based phosphate binders in patients receiving dialysis at the UIHC Center Dialysis Unit Explore the opportunity to minimize the exposure to calcium-based phosphorus binders Work with physicians to deprescribe calcium-based phosphorus binders The University of Iowa Hospitals and Clinics has no standardized protocol for managing hyperphosphatemia

Methods Chart Review We reviewed the charts of 46 patients receiving dialysis at University of Iowa Hospitals and Clinics who were currently taking a phosphate binder. Patient demographics, phosphate binding therapy, and lab values were collected. Targeted one dialysis site at UIHC and patients that were taking phosphate binder

Methods Patients were categorized based on their phosphate binding therapy into one of three treatment categories: Calcium-based binding therapy Sevelamer binding therapy Sevelamer + Calcium-based binding therapy (dual therapy) Add slide after this that includes: demographics and reasons for switching

Methods We analyzed each phosphate binder therapy category for patterns related the patient demographics including age and gender. If patients had been on alternative phosphate binder therapy previously we examined factors related to the switch including: What the reason for the switch was (adverse events, changes in lab values, etc.) If the switch occurred before or after the KDIGO guideline update

Methods Lab values related to phosphate binder therapy were then examined for each treatment category. We used the average of their three most recent results to categorize their levels as: low, normal, high and fluctuating. Calcium Phosphate Low < 8.5 mg/dl Medium 8.5-10.5 mg/dl High > 10.5 mg/dl Fluctuating Variable Low < 2.5 mg/dl Medium 2.5-4.5 mg/dl High > 4.5 mg/dl Fluctuating Variable

Results Total patients = 46 Calcium - 22/46 Sevelamer - 19/46 Combo - 5/46 If we have X number of patients at UIHC, this many people would be on calcium, sevelamer, etc.

Results If we got rid of all the low levels, how many patients could benefit from intervention? Add another graph

Results If we got rid of all the low levels, how many patients could benefit from intervention? Add another graph Green box = possible intervention group; 14 patients

Results 14 / 46 overall patients

Results Star = intervention group

Results Fluctuator = had low, medium, and high levels for past 3 readings Another potential intervention = low phosphorus on calcium based binder; should back off; percent of patients

Results Fluctuator = had low, medium, and high levels for past 3 readings Another potential intervention = low phosphorus on calcium based binder; should back off; percent of patients Potential intervention on an additional 3 patients

Conclusion Non-calcium-based phosphorus binders are preferred in chronic kidney disease Possible intervention groups for patients currently on calcium-based binders include patients with Normal or high calcium levels Low phosphorus levels Of the 46, how many could we make a recommendation on based on calcium/phosphorus levels? 17 / 46 total 17 / 22 on calcium therapies

Future Direction Work with physicians to deprescribe calcium-based phosphorus binders where appropriate Evaluate the effect of deprescribing efforts on Maintenance of calcium-based binder dose de-escalation/discontinuation On clinical endpoints

Questions? Deprescribing Calcium-Based Phosphorus Binders in Dialysis Patients at UIHC Aaron Schmitz, Kelsey Coffman, Michael Russell Project Advisor: Michelle Fravel, PharmD, BCPS