Future Direction of Anemia Management in ESRD. Jay B. Wish, MD 2008 Nephrology Update March 20, 2008

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1 Future Direction of Anemia Management in ESRD Jay B. Wish, MD 2008 Nephrology Update March 20, 2008

2 The Evidence Normal Hct Study and CHOIR demonstrate adverse outcomes in ESA patients with target Hgb >13 vs g/dl CREATE study shows no outcomes benefit but better QOL with higher Hgb NKF KDOQI guidelines revised in 9/07 to target Hgb in ESA treated CKD patients (after 2006 revision target 11-13)

3 Benefit/Risk Considerations With Erythropoietic Therapy in CKD Meta-analysis of randomized, controlled trials: ALL-CAUSE MORTALITY Risk of all-cause mortality in the higher hemoglobin target group compared with the lower hemoglobin target group (fixed effects analysis) Phrommintikul A, et al. Lancet. 2007;369:

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7 The Politics 3/2007 FDA revised black box warning for ESAs based on CHOIR, CREATE, and cancer studies 4/2007 Kidney community meeting with FDA 5/2007 Oncology ESA guidelines revised 9/2007 FDA Cardio-renal Drug Advisory Committee (CRDAC) meeting

8 FDA ESA Label Change 3/9/07 (Black Box Warning)

9 FDA CRDAC Meeting on ESAs September 11, 2007 Rejects Proposals to Lower Target Hgb Ranges for ESRD or CKD Target Hgb should not exceed 11 g/dl in HD patients Rejected 14 to 5 Target Hgb should not exceed 11 g/dl in CKD patients Rejected 14 to 5 ESA dosages used to achieve Hgb levels in lower target groups in the Normal Hematocrit and CHOIR are sufficient to form the basis for ESA dosage recommendations Passed 14 to 3

10 November 2007: New FDA Labeling for ESAs Target hemoglobin is g/dl in CKD Statement that the minimum dose of ESA needed to avoid transfusion has been eliminated Statement that ESA should be discontinued when Hgb >12 g/dl has been eliminated Dose should be reduced by 25% if Hgb rises >1 g/dl in 2 weeks or if Hgb >12

11 Medicare Reimbursement for ESAs in ESRD Released July 20, 2007 (before FDA revision) Effective January 1, % reduction in payment for (last) Hgb >13 g/dl for 1 month; unless coded that dose reduced next month 50% reduction in payment for Hgb >13 g/dl for 3 consecutive months (no code for dose reduced) based on last Hgb of previous month Maximum monthly ESA dose 400,000 U; maximum monthly Aranesp dose 1200 mcg Medical justification required for Epogen dose >10,000 units per treatment in hemodialysis patients

12 (Actually Feb. 20, 2008)

13 Where does NKF-KDOQI stand on this? September 2007 Anemia Guidelines Hgb target range re-revised to g/dl (the same as in the 1997 and 2001 guidelines) from g/dl in the 2006 version No statement about withholding ESAs for Hb >12 g/dl (still recommend 25% decrease in dose) No statement about measuring Hb twice weekly for 2-6 weeks following ESA dose adjustment No revision of statement in 2006 version that IV iron is not useful in HD patients with serum ferritin >500 ng/dl despite DRIVE study

14 September 2007 KDOQI Guidelines

15 How are we doing? Data from 2006

16 Percent of Patients with HGB >= 13 by Network Source: Q Lab Data Collection Percent of Patients US Network

17 Mean Hb Values Distribution of Mean Hb Values for Adult In-Center Patients, October-December 2006 Compared to Previous Study Periods Percent of Patients 50 < Mean ± SD Hb, g/dl ± ± ± ± Hb, g/dl 2007 Annual Report, ESRD Clinical Performance Measure Project ± ± 1.2

18 Percentage of Patients With Mean Hb 11 g/dl Percent of Patients Adult In-Center HD Patients, Oct-Dec 2006 Compared to Previous Study Periods Annual Report, ESRD Clinical Performance Measures Project.

19 Mean Hb 11 g/dl by Patient Characteristic and Clinical Parameter Adult In-Center HD Patients, Oct-Dec Patients, % 20 0 Dialysis 0.5 y Dialysis <0.5 y Mean Serum Albumin <3.5/3.2 g/dl Mean Serum Albumin 3.5/3.2 g/dl Mean Kt/V<1.2 AVG Mean Kt/V 1.2 AVF Catheter White Black Female Al l Male 2006 Annual Report, ESRD Clinical Performance Measures Project.

20 Iron Trends: Adult In-Center HD Patients, Oct-Dec 2006 Compared to Previous Study Periods Percent of Patients Oct-Dec Oct-Dec 2005 Oct-Dec Patients TSAT 20% Serum Ferritin Serum Ferritin Prescribed 100 ng/ml >800 ng/ml IV Iron 2007 Annual Report, ESRD Clinical Performance Measures Project.

21 Future of ESRD CPMs CMS contracted with National Quality Forum (NQF) to evaluate and approve ESRD CPMs submitted by a number of developers Product was due November 30, 2007 CPMs will be used for public reporting and P4P Developers included CMS, RPA/PCPI, and KCQA NQF convened Steering Committee and TEPs to evaluate and approve submitted CPMs for facilities and physicians

22 NQF Action on Anemia CPMs Percent of patients with Hb <11 g/dl (CMS) Hb <10 g/dl irrespective of ESA use (CMS) Hb g/dl (CMS) Hb g/dl on ESAs (CMS) Hb >11 g/dl (CMS) Hct <33% (CMS) Hct 33%-36% (CMS) Hb >11 g/dl or plan of care if Hb <11 g/dl (KCQA and RPA / PCPI) Rejected Accepted Rejected Rejected Rejected Rejected Rejected Rejected

23 NQF Action on Anemia CPMs Percent of patients with Hb <11 g/dl or receiving ESA with Iron studies drawn Accepted in 3-month period (CMS) Serum ferritin >200 ng/ml and Rejected TSAT >20% or CHr >29 pg (CMS) Serum ferritin <200 ng/ml or Rejected TSAT <20% or CHr <29 pg who are prescribed IV iron (CMS)

24 What Happens Next Approved measures went to public comment, then were approved by NQF membership, except for the 2 resubmitted Hb measures (which are currently up for vote by the Steering Committee) Once approved by NQF, it is likely the measures will be adopted by CMS for public reporting (DFC Web site, state surveyors) and eventually P4P Other payers also likely to use NQF approved measures for provider profiling and P4P

25 What about iron? Current KDOQI Recommendations for IV Iron Use TSAT >20% Sufficient Iron During ESA Therapy CHr Serum ferritin >29 pg/cell >200 ng/ml for HD >100 ng/ml for CKD and PD When serum ferritin is >500 ng/ml, decisions about IV iron treatment should weigh clinical factors, such as the patient s clinical status, ESA dose and responsiveness, Hb level, and iron indices. KDOQI. Am J Kidney Dis. 2006;47(suppl 3):S11-S145.

26 Limited Evidence on Efficacy and Safety of IV Iron in Elevated Serum Ferritin Literature supports varying levels of efficacy of IV iron at serum ferritin ng/ml Little published data on serum ferritin targets >500 ng/ml Some evidence suggests tissue iron stores in patients with serum ferritin >500 ng/ml are normal to above normal KDOQI. Am J Kidney Dis. 2006;47(suppl 3):S11-S145.

27 Dialysis Patients Response to IV Iron at Elevated Ferritin (DRIVE): Objectives Examine efficacy of IV iron to improve anemia in HD patients with serum ferritin between 500 and 1200 ng/ml, TSAT 25%, and adequate EPO dose Analyze effect of sodium ferric gluconate on serum ferritin, TSAT, and CRP levels in these patients Coyne et al. JASN Express [serial online]. January 31, 2007;doi

28 Major Inclusion Criteria Hb 11 g/dl TSAT 25% Serum ferritin ng/ml EPO dose 225 IU/kg/wk or 22,500 IU/wk IV iron 125 mg/wk in the 4 weeks before prescreening No recent blood loss, active infection requiring antibiotics, or recent inpatient hospitalization Patient stratification by baseline ferritin ng/ml ng/ml Coyne et al. JASN Express [serial online]. January 31, 2007;doi

29 Study Design Patients were randomized to receive Ferric gluconate 125 mg 8 HD sessions for total of 1 g Control: no IV iron Both groups received a 25% increase in EPO dose at beginning of week 1 No change in EPO dose except for safety Coyne et al. JASN Express [serial online]. January 31, 2007;doi

30 DRIVE Results: Change in Hb Mean Hb, g/dl Baseline vs week 6, both groups: P= (n=64) Control (n=65) Ferric Gluconate 11.0 Ferric gluconate vs control: P= Start of DRIVE (Baseline) Week 6 (LOCF) Coyne et al. JASN Express [serial online]. January 31, 2007;doi

31 Responder Rate (% With 2 g/dl Increase in Hb) Percent of Responders P= Control (n=65) Ferric Gluconate (n=64) Response rates and superiority of IV iron similar for each ferritin stratum ( 800 ng/ml and >800 ng/ml): lower stratum: IV iron, 45.9%, and control, 29.7%; higher stratum: IV iron, 48.1%; control, 28.6% Coyne et al. JASN Express [serial online]. January 31, 2007;doi

32 Change in Mean Serum Ferritin Mean Serum Ferritin, ng/ml P<0.001* Start of DRIVE (Baseline) 929 Week 6 (LOCF) Control (n=65) Ferric Gluconate (n=64) *P value compares the 2 groups in change from baseline. Coyne et al. JASN Express [serial online]. January 31, 2007;doi

33 Adverse Events Control Ferric Gluconate No. of patients in safety population Adverse events Related adverse events Diarrhea, dyspepsia, dyspnea, dizziness, chest pain, back pain, and increased sweating Serious adverse events (all unrelated) Cardiac adverse events Cardiac arrest, CHF, cardio-respiratory arrest, endocarditis, MIs, and arrhythmias Blood disorders Anemia and coagulation disorders Vascular disorders Arterial stenosis, gangrene, hematoma, hot flashes, hypertension, hypotension, and TIA in 35 pts 69 in 32 pts 0 7 in 4 pts 14 in 9 pts 12 in 9 pts 4 in 4 pts 4 in 4 pts 6 in 4 pts 1 in 1 pt 21 in 13 pts 5 in 5 pts Infections Bronchitis, cellulitis, conjunctivitis, fungal infections, furuncles, C diff, line infections, pneumonia, nasopharyngitis, sepsis, skin infections, URIs, and UTIs Coyne et al. JASN Express [serial online]. January 31, 2007;doi in 10 pts 12 in 8 pts Categories by MedDRA coding

34 DRIVE-II Primary objective: to investigate the effect of ferric gluconate administration on weekly EPO doses IV iron and EPO dosing at discretion of anemia managers Secondary outcomes: changes in Hb, TSAT, and serum ferritin Kapoian et al. Presented at: ASN 2006; San Diego, Calif. Abstract and poster

35 Study Design 6-week follow-up observational study EPO doses at discretion of anemia managers No restrictions on iron administration Analysis duration: 12-week period from beginning of DRIVE study to end of DRIVE-II Kapoian et al. Presented at: ASN 2006; San Diego, Calif. Abstract and poster

36 Change in EPO Dose (Head-to-Head Comparison) Mean EPO Dose, IU/wk 50,000 45,000 40,000 35,000 30,000 IV ferric gluconate, DRIVE vs end of DRIVE-II: P= ,030 43,665 45,679 36,138 IV ferric gluconate vs no iron: P= Control (DRIVE n=65; DRIVE II n=56*) Ferric Gluconate (DRIVE n=64; DRIVE II n=56*) DRIVE Dose 1,2 End of DRIVE II Dose 2 *129 patients in DRIVE 1 ; 112 patients in DRIVE-II intent-to-treat population, based on having received dialysis for at least 1 complete week in DRIVE-II 2 Ferric gluconate group EPO dose decreased significantly from DRIVE dose to end of study (P=0.003) and compared with that of control group (8478 IU/wk; P=0.017) 1. Coyne et al. JASN Express [serial online]. January 31, 2007;doi Kapoian et al. Presented at: ASN 2006; San Diego, Calif. Abstract and poster

37 Overall DRIVE and DRIVE-II Conclusions 1 g ferric gluconate results in more efficient erythropoiesis in anemic HD patients with serum ferritin ng/ml and TSAT 25% Higher Hb vs no iron Safely decreases EPO requirements Adverse event profile similar to no iron Withholding IV iron from these patients results in a significant reduction in CHr levels 1 g ferric gluconate is not associated with increase in inflammation, as indicated by CRP Coyne et al. JASN Express [serial online]. January 31, 2007;doi Kapoian et al. Presented at: ASN 2006; San Diego, Calif. Abstract and poster

38 Recommendations The nephrology community needs more evidence to support the credibility of CPGs and CPMs regarding anemia management Target Hgb Use of IV iron Healthcare policy regarding ESRD anemia management is driven by both evidence and politics, but may become moot in the setting of a bundled payment system where it will be essential that the proper safeguards are in place to assure quality and minimize cherrypicking