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3. Understanding the Recent Increase in Ferritin Levels in U.S. Dialysis Patients: Potential Impact of Changes in IV Iron and ESA Dosing Angelo Karaboyas, Jarcy Zee, Hal Morgenstern, Jacqueline G. Nolen, Raymond Hakim, Kamyar Kalantar-Zadeh, Philip Zager, Ronald L. Pisoni, Friedrich K. Port, Bruce M. Robinson Clinical Journal of the American Society of Nephrology 2015;10(10):1814-21

4. Introduction Substantial changes in anemia management occurred among US dialysis patients prompted by: –New CMS bundled payment system (January 2011) –ESA label change (June 2011) To gain an understanding of the coincident sustained rise in ferritin levels, we utilized this natural experiment to analyze the impact of policy-related changes in anemia management We studied relative contributions of higher IV iron doses and lower ESA doses on the observed increase in serum ferritin and hypothesized that IV iron dose was the primary driver Karaboyas et al. Clin J Am Soc Nephrol 2015;10(10):1814-21

5. International prospective cohort study of hemodialysis patients and HD unit practices Uniform international data collection Goal: Identify HD practice patterns associated with improved patient outcomes (adjusted for patient mix) Major outcomes: mortality, hospitalization, vascular access, quality of life Coordinated by Arbor Research Collaborative for Health (Ann Arbor, MI USA) DOPPS Background (1) Karaboyas et al. Clin J Am Soc Nephrol 2015;10(10):1814-21

6. Study PhaseYearsCountriesFacilitiesPatients DOPPS 11996-2001730817,034 DOPPS 22002-20041232212,839 DOPPS 32005-20081230011,170 DOPPS 42009-20111238015,528 DOPPS 52012-201521~505~18,500 DOPPS 1: France, Germany, Italy, Japan, Spain, UK, and US DOPPS 2-4: DOPPS 1 countries plus Australia/New Zealand, Belgium, Canada, Sweden DOPPS 5: DOPPS 4 countries plus China, GCC-6 (Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, and United Arab Emirates), Russia, Turkey DOPPS Background (2) Karaboyas et al. Clin J Am Soc Nephrol 2015;10(10):1814-21

7. Methods: Sample and crude trends Sample –9735 hemodialysis (HD) patients from 91 DOPPS facilities in two large dialysis organizations in the US –Prevalent patient data from July 1, 2009 (Q3 2009) to September 30, 2013 (Q3 2013) Reporting trends –Mean serum ferritin and hemoglobin (Hgb) within each patient-quarter –Mean IV iron and ESA doses administered calculated per quarter across all dialysis treatments; doses of 0 included –Non-anemia-related patient characteristics were abstracted from the DOPPS Practice Monitor (DPM) –Unadjusted since narrow time frame Karaboyas et al. Clin J Am Soc Nephrol 2015;10(10):1814-21

8. Methods: Defining facility groups Categorization of 91 HD facilities –3 groups based on the change in mean IV iron dose from 2010 to 2011 –N=34 facilities were not categorized due to lack of complete data across all study years Group A (N=16 facilities): mean IV iron dose increased by over 50 mg/month Group B (N=24 facilities): mean IV iron dose increased by less than 50 mg/month Group C (N=17 facilities): mean IV iron dose decreased Karaboyas et al. Clin J Am Soc Nephrol 2015;10(10):1814-21

9. Methods: Statistical analysis Model within-patient changes in ferritin over time to assess the degree adjustment for concurrent changes in IV iron and/or ESA dose attenuated the time effect –Unit of analysis: interval between 2 ferritin measurements Base model: mixed model with ferritin as the outcome –Covariates: time (linear spline with 2 knots), interval length, and previous ferritin value Stepwise adjustment –First, adjust for IV iron dose (per month) administered during the interval and dose*interval length interaction –Next, adjust for ESA dose (per week) administered during the interval Plot predicted values relative to reference point Karaboyas et al. Clin J Am Soc Nephrol 2015;10(10):1814-21

10. Trends in anemia variables (1) N=65,803 ferritin intervals, the time between two consecutive ferritin measurements, from 7,434 unique patients. Karaboyas et al. Clin J Am Soc Nephrol 2015;10(10):1814-21 ] 20092010201120122013 N unique patients18214009416544003427 N ferritin measurements373020692164491409010842 Interval since previous ferritin measurement 2-3 weeks4% 3%4% 4-5 weeks76%64%36%30%35% 6-11 weeks6%11%13%14%12% 12-14 weeks14%21%47%50%46% 15-17 weeks0%1% 2%4% Ferritin (ng/mL) 50-19911% 7%5%6% 200-49934%30%22%15%16% 500-79931%30%27%24%26% 800-119918%20%27%37%35% 1200-14995% 10%13%11% 1500-50002%4%7%8%6% Table 1

11. Trends in anemia variables (2) N=65,803 ferritin intervals, the time between two consecutive ferritin measurements, from 7,434 unique patients. IV iron dose summed across all treatments during the interval and divided by the interval length. A bolus dose of IV iron was defined as receiving ≥ 500 mg of IV iron during any 2 week period during an interval. TSAT at time of ferritin measurement was recorded. Karaboyas et al. Clin J Am Soc Nephrol 2015;10(10):1814-21 20092010201120122013 N unique patients18214009416544003427 N ferritin measurements373020692164491409010842 IV iron dose (mg/mo) No dose24%30%29%32% 1-12419%18%12%14%15% 125-24926%21%28%30%31% 250-39911% 9%8% 400+19%20%22%17%15% Received any bolus IV iron dose during interval % Yes 10%14%22%21%19% TSAT (%) < 2017%18%15%13%14% 20-2940%39%35%34%33% 30-4936% 39%43% ≥ 507%8%11%10% Table 1

12. Trends in anemia variables (3) Karaboyas et al. Clin J Am Soc Nephrol 2015;10(10):1814-21 20092010201120122013 N unique patients18214009416544003427 N ferritin measurements373020692164491409010842 Hemoglobin (g/dL) < 106%7%8%12%14% 10-1118%19%24%40%45% 11-1242%44%50%37%30% ≥ 1234%30%18%11% ESA dose (units/week) No dose2%4%8%10%13% 1-4,99919%20%24%31%34% 5,000-9,99919%20%22%24%23% 10,000-24,99934%32%30%25%22% 25,000+26%24%17%10%9% N=65,803 ferritin intervals, the time between two consecutive ferritin measurements, from 7,434 unique patients. ESA dose summed across all treatments during the interval and divided by the interval length. Hemoglobin was calculated as the mean of all Hgb measurements during the interval. Table 1

13. Trends in patient characteristics in US dialysis patients Patient characteristic August 2010 August 2011 August 2012 August 2013 Age (years)63 (52, 73) 63 (53, 73) Vintage (years)2.7 (1.1, 5.1)2.8 (1.2, 5.5)2.9 (1.3, 5.7) Vintage < 90 days (%)5.2%4.1%4.8%4.9% Male (%)56%55%56% Black race (%)32%33%37%34% BMI (kg/m 2 )27.0 (22.9, 32.2)27.3 (23.3, 32.1)27.5 (23.4, 32.3)27.2 (23.5, 32.4) Diabetes (%)64%63%61%62% Systolic BP (mmHg)148 (131, 163)147 (131, 163)148 (132, 165)146 (130, 163) Treatment time (min)212 (195, 240) 215 (196, 240)215 (199, 241) Single pool Kt/V1.56 (1.41, 1.72)1.58 (1.43, 1.75)1.62 (1.47, 1.78)1.60 (1.44, 1.77) s. Phosphorus (mg/dL)4.9 (4.1, 6.0)4.9 (4.1, 5.9)4.8 (3.9, 5.8)4.8 (4.0, 5.8) s. PTH (pg/mL)247 (163, 379)307 (192, 488)311 (196, 501)322 (198, 496) s. Albumin (g/dL)3.84 (3.57, 4.06)3.85 (3.59, 4.07)3.89 (3.61, 4.10)3.90 (3.69, 4.17) Transfusions* (%)2.5%3.1%3.3%-- Catheter use (%)18%19%16% Median (IQR), or proportion of patients shown. Source: US-DOPPS Practice Monitor, December 2014; http://www.dopps.org/DPM. *Source: Center for Medicare and Medicaid Services Claims, 2010-2012. Karaboyas et al. Clin J Am Soc Nephrol 2015;10(10):1814-21 Table 2

14. US Trends in Hgb and ESA dose 20092010 201120122013 BUNDLE LABEL CHANGE Mean ESA dose (units/week) Mean hemoglobin (g/dL) ESA dose Hgb Karaboyas et al. Clin J Am Soc Nephrol 2015;10(10):1814-21 Figure 1

15. US Trends in ferritin and IV iron dose Mean IV iron dose (mg/month) Mean ferritin (ng/mL) IV Iron dose Ferritin 20092010 201120122013 BUNDLE LABEL CHANGE Karaboyas et al. Clin J Am Soc Nephrol 2015;10(10):1814-21 Figure 1

16. + ESA dose Base model Rise in ferritin unaccounted for + IV iron dose (Ref) Difference in ferritin (ng/mL) BUNDLE LABEL CHANGE Modeling trends in within-patient ferritin Figure 1 20092010 201120122013 Karaboyas et al. Clin J Am Soc Nephrol 2015;10(10):1814-21

17. Trends in anemia variables: Group A Figure 1.A Karaboyas et al. Clin J Am Soc Nephrol 2015;10(10):1814-21 Group A: Facilities where mean IV iron dose increased > 50 mg/month from 2010 to 2011  Mean ferritin increased very dramatically

18. Trends in anemia variables: Group B Figure 1.B Karaboyas et al. Clin J Am Soc Nephrol 2015;10(10):1814-21 Group B: Facilities where mean IV iron dose increased < 50 mg/month from 2010 to 2011  Mean ferritin increased dramatically

19. Trends in anemia variables: Group C Figure 1.C Karaboyas et al. Clin J Am Soc Nephrol 2015;10(10):1814-21 Group C: Facilities where mean IV iron dose decreased from 2010 to 2011  Mean ferritin still increased moderately

20. Crude trends in mean TSAT and IV iron dose Supplementary Figure 1 Karaboyas et al. Clin J Am Soc Nephrol 2015;10(10):1814-21

21. Timing of IV iron dosing A bolus dose of IV iron was defined as ≥500 mg during any 2 week period during an interval –Sensitivity analysis adjusting for bolus dose did not further attenuate the trend in ferritin –Despite a presumed high initial peak in ferritin, patients did not exhibit larger increases in ferritin, as measured at interval end, than patients given maintenance IV iron Trends in ferritin could not be attributed to bias due to proximity of IV iron dosing to ferritin measurement –Proportion of patients administered IV iron during the dialysis treatment prior to ferritin measurement was constant over the study period: 17% in 2010, 19% in 2011, and 17% in 2012 Karaboyas et al. Clin J Am Soc Nephrol 2015;10(10):1814-21

22. Facility reported ferritin and TSAT targets Upper ferritin target limit rose from 2010 to 2011 –In 2010, 50% of US study sites had a ferritin upper target of 800 ng/mL and 35% had a target ≥1000 ng/mL –In 2011, only 27% had a target of 800 ng/mL and 65% had a target ≥1000 ng/mL Lower TSAT target limit also rose from 2010 to 2011 –In 2010, 75% of US study sites had a lower TSAT limit of 20% and 21% had a target of 25-30% –In 2011, only 55% had a target of 20%, and 41% had a target of 25-30% Karaboyas et al. Clin J Am Soc Nephrol 2015;10(10):1814-21

23. Additional factors? Models showed that changes in IV iron dose and ESA dose combined to explain about 50% of the increase in ferritin over the study period –Adjusting for ESA resistance rather than ESA dose yielded similar results Cumulative iron exposure may help explain why high ferritin levels initiated by high IV iron doses did not decline following subsequent decreases in IV iron dosing –However, this would not explain the sustained rise in ferritin observed among the facilities that lowered their IV iron doses Karaboyas et al. Clin J Am Soc Nephrol 2015;10(10):1814-21

24. Conclusions Mean IV iron dose peaked in 2011 before returning to near prior levels, while mean ferritin remained high through study end (Q3 2013) The sustained high ferritin levels after 2011 policy changes appeared partly due to ESA dosing reductions and not solely IV iron dosing practices, perhaps due to decreased need for iron due to reduced erythropoiesis and lower Hgb levels The potential impact on health outcomes requires further investigation Karaboyas et al. Clin J Am Soc Nephrol 2015;10(10):1814-21

25. Acknowledgements, 2015 The DOPPS Program would not be possible without the support for independent scientific research to improve patient care from the following organizations: Principal Funders: Amgen Baxter Healthcare Kyowa Hakko Kirin Country/Project-Specific Support: ERA-EDTA, Keryx, Amgen, Hexal, AbbVie, Sanofi Renal, Shire, WiNe Institute, Japanese Society for PD, Societies of Nephrology in Germany, Italy & Spain Public Funding of Projects/Ancillary Studies In: Australia, Canada, France, United Kingdom, United States All support for the DOPPS program is provided without restrictions on publications