Presentation on theme: "Anemia and Cardiovascular Disease: The Good, The Bad, The Ugly"— Presentation transcript:
1Anemia and Cardiovascular Disease: The Good, The Bad, The Ugly Scott D. Solomon, MDDirector, Noninvasive CardiologyBrigham and Women’s HospitalAssociate Professor of MedicineHarvard Medical School
2DisclosuresDr. Solomon receives research grant support from Amgen, Alteon, Novartis, Genzyme, Genentech, Guidant, Medtronic, Kai, National Cancer Institute, National Institute for Diabetes, Digestive and Kidney Diseases, National Heart Lung and Blood Institute
3eGFR (mL/min/1.73m2) < 45 n = 1644 45–59.9 n = 3218
4CV Death, MI, HF, RSD, or Stroke by Renal Function ³ 75 (95.0 ± 33.4)45–59.9 (53.3 ± 4.3)60–74.9 (67.5 ± 4.3)< 45 (37.3 ± 5.8)eGFR (mL/min/1.73m2):0.61.7 ± 0.4 (154.5)0.50.41.3 ± 0.2 (118.2)Probability of Event0.31.1 ± 0.1 (100.0)0.9 ± 0.1(81.8)0.2Twenty hypertensive (BP between 140/90 and 180/110 mmHg), non-obese patients (BMI>30 kg/m2) and 20 normotensive healthy subjects matched for age, gender, and BMI were enrolled.1 All patients in the study group received valsartan 80 mg qd for 3 months.SBP and DBP were significantly reduced after valsartan treatment; BMI and FSG did not change significantly. Before valsartan treatment, plasma fasting insulin and HOMA-IR scores in hypertensive patients were higher than in subjects from the reference group (19.6 +/–7.1 vs /–1.9, P<0.001; and 4.4 +/–1.7 vs 1.9 +/–0.5, P<0.001, respectively).1Plasma fasting insulin levels and HOMA-IR were reduced after valsartan treatment (19.6 +/–7.1 vs 9.8 +/–4.5, P<0.001; and 4.4 +/–1.7 vs 2.2 +/–1.1, P<0.001, respectively).1Reference:1. Top C, Cingozbay BY, Terekeci H, et al. The effects of valsartan on insulin sensitivity in patients with primary hypertension. J Int Med Res. 2002;30:15–20.0.1Months61218243036£45–60–³
5Cardiovascular Events eGFR (mL/min/1.73m2):>75<45Similar to my recommended version, but uses the logo on the left.CV Death Reinfarction CHF Stroke RSD Composite
6Spectrum of Risk (CV events) 1412108Adjusted (70) Hazard Ratio642p <153045607590105120135eGFR (mL/min/1.73m2)Anavekar NS et al NEJM 2004; 351:1285
7% of patients with eGFR < 60: 33% VALIANT CKDMean eGFR in VALIANT:67% of patients with eGFR < 60:33%Total # of patients going on to ESRD: 14/14,703 = < 0.1%
9World Health Organization (WHO) Anemia Definition1 Women:<12 g/dLMen:<13 g/dLFemale 13.3 0.9 g/dLMale 15.2 0.9 g/dL50010001500200025003000FrequencyKey Point: Superimposing the World Health Organization (WHO) anemia definition over graphs of the distribution of Hb levels by gender is revealing: anemia under this definition comprises Hb levels that are significantly lower than mean Hb levels in the population.References:1. Dallman PR, Looker AC, Johnson CL, Carroll M. Influence of age on laboratory criteria for the diagnosis of iron deficiency anaemia and iron deficiency in infants and children. In: Hallberg L, Nils-Georg A, ed. Iron Nutrition in Health and Disease. London, UK: John Libbey & Company; 1996:65-74.2. World Health Organization. Iron deficiency anaemia assessment, prevention and control: a guide for programme managers. Geneva: World Health Organization; 2001.1010.51111.51212.51313.51414.51515.51616.51717.518Hemoglobin (g/dL)1. World Health Organization. Geneva, Switzerland; Dallman et al. In: Iron Nutrition in Health and Disease. London, UK: John Libbey & Co; 1996:65-74.
10Based on WHO Definition, 9% of Adults Have Anemia: ARIC Study* ARIC Study1 Population: Ages 45 to 64; N = 15,792AnemicAll9%WomenMen91%95%87%Key Point: Approximately 9% of the population is anemic based on the WHO definition of anemia.The Atherosclerosis Risk in Communities (ARIC) study is a prospective cohort study of atherosclerosis and its risk factors in four US communities. A total of 15,792 subjects aged 45 to 64 years at recruitment were enrolled from 1986 to This analysis of the ARIC public-use database showed that 13% of adult females, 5% of adult males, and 9% of all individuals studied had anemia.5%13%Anemia definition:2 Men = Hgb <13 g/dL Women = Hgb <12 g/dLReferences:1. Sarnak MJ, Tighiouart H, Manjunath G, et al. Anemia as a risk factor for cardiovascular disease in The Atherosclerosis Risk in Communities (ARIC) study. J Am Coll Cardiol. 2002;40(1):27-33.2. World Health Organization. Iron deficiency anaemia assessment, prevention and control: a guide for programme managers. Geneva: World Health Organization; 2001.*The Atherosclerosis Risk in Communities (ARIC) study enrolled subjects in 4 US communities: Forsyth County, NC; Jackson, Miss; Minneapolis, Minn; and Washington County, Md.1. Sarnak et al. J Am Coll Cardiol. 2002;40: World Health Organization. Geneva, Switzerland; 2001.
11Causes of Anemia in CVDNormally, bone marrow generates ~ 200 billion new cells per day to match the cells lost or removed from circulation.The expected compensatory response to anemia is a heightened rate of erythropoiesis.Failure to demonstrate a compensatory response signifies slowed or defective erythropoiesis.Most common cause of defective erythropoiesis in CAD population is chronic kidney disease (even mild CKD).
12Anemia and Increased Cardiovascular Disease ARIC Study Women (P=.04) (Hgb <12 g/dL)1.00.980.960.940.92Proportion of Patients Free of Cardiovascular Disease0.900.88Nonanemic WomenMen (P=.04) (Hgb <13 g/dL)0.86Anemic WomenN=14,410* Fully adjusted N=13,8830.84Nonanemic Men0.82Anemic Men0.8050010001500200025003000Time From Baseline (days)*Patients with hemoglobin levels. Sarnak et al. J Am Coll Cardiol. 2002;40:27-33.
13Anemia and CV Death in ACS > ( ) ( ) 0.007( ) ( ) 0.637( ) ( )reference reference( ) ( ) 0.175( ) ( ) 0.009( ) ( ) 0.003( ) ( ) 0.004< ( ) ( ) 0.0012.05.01.00.5OR & 95% CI for CV Death by 30 dUnadjusted Adjusted for Baseline CharacteristicsHgb (g/dl) n OR (95% CI) OR (95% CI) P valueSabatine et al. Circulation 2005
14Acute MI: Higher Hematocrit is Associated with Lower Risk of Death 3.16Odds Ratio% Mortality at 1 year1.941.351.0HematocritLangston, Kid Int 2003, 64:Retrospective cohort of 709 Medicare patients admitted to community hospitals for acute MIOdds Ratio Adjusted for age, sex, race, kidney function and cardiovascular co-morbidities4% decrease in one year risk of death per 1% increase in hematocrit
15ESRD - USRDS: Higher Hematocrit is Associated with Fewer Hospital Days N4,30811,55822,19210,2652,256Li & Collins, Kid Int 2004, 65:50,579 incident HD patients in the US between Jan 98 – Dec 1999Follow-up 2.5 yrs (hospitalization) and 3.0 yrs (mortality)Unadjusted data
16Anemia, Diabetes and CKD Have Similar Impact on Mortality CKD onlyAnemia onlyDM onlyNoneDM/CHF only3.71.52.01.00.03.04.05.0Relative RiskDM/CKD/Anemia only3.6Finally, we all know that DM is a potent RF for CVD and mortality, but in fact, anemia appears to have an equivalent impact on risk of mortalityKey Point:Patients with the diagnosis of CKD and anemia have the same relative risk of death as patients diagnosed with diabetes or CHF.Collins, AJ. Adv Stud in Med. 2003;3(3C):S14-S17.
17Anemia and CKD are Risk Factors for Mortality Unit ChangeRR (95% CI)Hematocrit1% decrease1.06 (1.04–1.08)GFR10 mL/min decrease1.06 (1.03–1.10)Retrospective analysis of 6,635 patients – SOLVD databaseWe discussed earlier w/ Shulman's data that worsening kidney function was associated with increase risk of mortality. These data give some sense of how anemia compares to progression of CKD as a risk factor for mortality.Key point:Declining kidney function and declining Hct were independent risk factors for mortality in patients with heart failure. The presence of both had a synergistic effect on increasing mortality risk in this study.Al-Ahmad A, et al. J Am Coll Cardiol. 2001;38(4):
18Hazard Ratio for 3-yr Mortality eGFR (ml/min/1.78 m²)Hematocrit (%)Gurm et al. Am J Cardiol 2004;94:30-4.
19Dual Antiplatelet Agents Increase Risk of GI Bleeding in Cardiac Patients Risk ratioStudy(95% CI)% WeightMATCH2.92 (1.96,4.36)40.5CURE1.78 (1.25,2.54)59.5Overall (95% CI)2.24 (1.72,2.92)In VALIANT, dual antiplatelet agent use was associated with an 85% increased adjusted risk of GI bleeding (each 10 points of reduced eGFR increased GI bleeding risk by 20%)1
21Anemia In Patients With Heart Failure Hb = hemoglobinHct = hematocritHF = heart failureMcClellan WM, Flanders WD, Langston RD, et al. Anemia and renal insufficiency are independent risk factors for death among patients with congestive heart failure admitted to community hospitals: a population-based study. J Am Soc Nephrol. 2002;13:Androne AS, Katz SD, Lund L, et al. Hemodilution is common in patients with advanced heart failure. Circulation. 2003;107:Silverberg DS, Wexler D, Blum M, et al. The use of subcutaneous erythropoietin and intravenous iron for the treatment of the anemia of severe, resistant congestive heart failure improves cardiac and renal function and functional cardiac class, and markedly reduces hospitalizations. J Am Coll Cardiol. 2000;35:Wexler D, Silverberg DS, Sheps D, et al. Prevalence of anemia in patients admitted to hospital with a primary diagnosis of congestive heart failure. Int J Cardiol. 2004;96:79-87.Wisniacki N, Aimson P, Lye M. Is anemia a cause or a consequence of heart failure in the elderly? Heart. 2001;85(suppl 1):P1-P13.Felker GM, Gattis WA, Leimberger JD, et al. Usefulness of anemia as a predictor of death and rehospitalization in patients with decompensated heart failure. Am J Cardiol. 2003;92:Kosiborod M, Smith GL, Radford MJ, et al. The prognostic importance of anemia in patients with heart failure. Am J Med. 2003;114:James M, Kapadia S, O’Connor CM, et al. Anemia is common in patients with heart failure seen in specialty and community cardiology clinics: results from the STAMINA-HFP registry (study of anemia in a heart failure population). J Am Coll Cardiol. 2004;43(suppl A). AbstractHorwich TB, Fonarow GC, Hamilton MA, et al. Anemia is associated with worse symptoms, greater impairment in functional capacity and a significant increase in mortality in patients with advanced heart failure. J Am Coll Cardiol. 2002;39:Herzog CA, Li S, Collins AJ. The impact of congestive heart failure (CHF), chronic kidney disease (CKD) and anemia on survival in the medicare population. Circulation. 2002;106(suppl):2333A. Abstract.Cleland JG, Swedberg K, Follath F, et al. The EuroHeart Failure survey programme—a survey on the quality of care among patients with heart failure in Europe. Part 1: patient characteristics and diagnosis. Eur Heart J. 2003;24:Mozaffarian D, Nye R, Levy WC. Anemia predicts mortality in severe heart failure: the prospective randomized amlodipine survival evaluation (PRAISE). J Am Coll Cardiol. 2003;41:Anand I, McMurray JJV, Whitmore J, et al. Anemia and its relationship to clinical outcome in heart failure. Circulation. 2004;110:Anker SD, Coats AJS, Roecker EB, et al. Hemoglobin level is associated with mortality and hospitalization inpatients with severe chronic heart failure: results from the COPERNICUS study. J Am Coll Cardiol. 2004;43(suppl A). AbstractSharma R, Francis DP, Pitt B, et al. Haemoglobin predicts survival in patients with chronic heart failure: a substudy of the ELITE II trial. Eur Heart J. In pressSzachniewicz J, Petruk-Kowalczyk J, Majda J, et al. Anaemia is an independent predictor of poor outcome in patients with chronic heart failure. Int J Cardiol. 2003;90:Ezekowitz JA, McAlister FA, Armstrong PW. Anemia is common in heart failure and is associated with poor outcomes: insights from a cohort of 12,065 patients with new-onset heart failure. Circulation. 2003;107:Maggioni AP, Latini R, Anand I, et al. Prevalence and prognostic role of anemia in patients with heart failure in the IN-CHF registry and the Val-HeFT trial. Eur Heart J. 2002;4(suppl). Abstract 1480.Tanner H, Moschovitis G, Kuster GM, et al. The prevalence of anemia in chronic heart failure. Int J Cardiol. 2002;86:Cromie N, Lee C, Struthers AD, et al. Anaemia in chronic heart failure: what is its frequency in the UK and its underlying causes? Heart. 2002;87:The prevalence of anemia in heart failure patients is approximately:30% for Inpatients20% for Outpatients
22The Prevalence of Anemia and The Severity Of Heart Failure 70%60%60%56%52%50%44%40%40%Patients29%30%29%30%21%20%19%20%13%14%12%11%8%10%6%4%2%2%0%I (n=158)II (n=467)III (n=340)IV (n=25)NYHA ClassHb<10g/dL (n=32)Hb<=11g/dL (n=97)Hb<=11.5g/dL (n=165)Hb<=12.0g/dL (n=244)Hb<=12.5g/dL (n=337)Source: STAMINA Registry – 45 General Cardiologist sites, n=673, 12 Academic sites (incl. HF Specialists), n=337
23Heart Failure: Higher Hematocrit is Associated with Lower Risk of Death %1 Year MortalityOR> 40%30.3%31.3%1.0%22.9%33.8%1.0830 – 35%33.2%36.7%1.17< 30%13.6%50.0%1.60McClellan, JASN 2002, 13:Retrospective cohort of 655 Medicare patients admitted to community hospitals for heart failureAdjusted for age, sex, race, kidney function and cardiovascular co-morbidities2.4% decrease in one year risk of death per 1% increase in hematocrit
24The Etiology of Anemia in Heart Failure is Likely Multifactorial Anemia ofChronicDiseasePharmaco-therapyRenalDysfunctionMalnutritionDecreasedCardiacOutputInflammationBone marrow dysfunctionAbnormal iron homeostasis (uptake, release, utilization)Intravascular fluid imbalance (hemodilution)EPO deficiency or resistance
25Causes of Anemia in HF Cardiac Output Cytokines Iron Deficiency Impaired renal perfusion, leading to impaired renal function, decreased EPO production and anemia1Impaired bone marrow perfusion leading to impaired function and anemia1CytokinesTNF and other inflammatory cytokines may cause bone marrow suppression, interfere with the action of EPO and the cellular release and utilization of iron2Iron DeficiencyEdematous GI may diminish absorption of ironChronic aspirin therapy may lead to blood lossACE inhibitorsDown-regulation of EPO by angiotensin-converting enzyme (ACE) inhibitors3DilutionalPlasma volume expansion41Chatterjee et al. Eur J Heart Fail. 2000;2: Silverberg et al. J Am Coll Cardiol. 2000;35(7) Volpe et al. Am J Cardiol. 1994;74: Androne et al. Circulation. 2003;107:
27Patients with Anemia Have Worse Heart Failure: Val-HeFT Database Baseline VariablesNo AnemiaAnemiaP-value(n = 3857)(n = 1145)Age ≥65 yrs %62±1166 ±11<0.001NYHA III-IV %3645<0.001History of PND %811<0.001SBP (mmHg, mean±SD)124.2±18122.6±18<0.001Edema (%)2338<0.001GFR (ml/min/1.73m2)60±1552 ±17<0.001MLHFQ score (mean±SD)31±2335±24<0.001Background therapy, %Key Point: Anemia appears to be more common in HF patients than in the general population, ranging in prevalence from 16% to 48% in the HF population.Diuretics8491<0.001Digoxin66700.02Serum Albumin (g/L, mean±SD)References:1. Herzog CA, Guo H, Collins AJ. The prevalence of CHF, chronic kidney disease, anemia, and multiple comorbid conditions in the Medicare population [abstract 228; S63]. 6th Annual Scientific Meeting of the Heart Failure Society of America: September 22-25, 2002; Boca Raton, Fla.2. Ezekowitz JA, McAlister FA, Armstrong PW. Anemia is common in heart failure and is associated with poor outcomes: insights from a cohort of patients with new-onset heart failure. Circulation. 2003;107:3. Kosiborod M, Smith GL, Radford MJ, Foody JM, Krumholz HM. The prognostic importance of anemia in patients with heart failure. Am J Med. 2003;114:4. Tang WHW, Miller H, Partin M, Harris CM, Young JB. Anemia in heart failure: a single-center experience [presentation]. 52nd Annual Scientific Session of the American College of Cardiology: March 30 to April 2, 2003; Chicago, Ill.5. Horwich TB, Fonarow GC, Hamilton MA, MacLellan WR, Borenstein J. Anemia is associated with worse symptoms, greater impairment in functional capacity and a significant increase in mortality in patients with advanced heart failure. J Am Coll Cardiol. 2002;39:6. Anker SD, Sharma R, Francis D, et al. Patients with chronic heart failure (CHF) in the ELITE II trial [abstract 2335]. Circulation. 2002;106(suppl): #19 I-II-I 992.4.2±0.34.0±0.4<0.001CRP (pg/mL, mean±SD)5.7±8.98.9±12.9<0.001BNP (pg/mL, mean±SD)162±210242±276<0.001LVEF % (mean±SD)27±726±70.21LVIDd/BSA cm/m2 (mean±SD)3.6±0.53.7±0.50.09Anand et al 2005, Circulation ;112:
28Anemia Risk Assessment Anemia is Associated with Increased Risk for Hospitalization in Heart Failure PatientsStudyDesignNAnemia Risk AssessmentLimitationsAlexander1Retrospective cohort study of a population based HF database90,316Anemia was an independent risk factor of 1-year rehospitalization (RR 1.162; 95% CI: to 1.191)no confirmation of the HF diagnosis; undercounts of minorities and biased results.Polanczyk2Prospective, single center, observational study205Anemia was an independent predictor of 3-month rehospitalization (p=0.002)Too small of a population to resolve a small difference in readmission rates; role of confounding variables due to lack of controlOPTIME-CHF3Retrospective chart review906Anemia was an independent predictor of 60-day death or rehospitalization (odds ratio of 0.89 per 1 g/dL increase in hemoglobin; 95% CI: 0.82 to 0.97)Anemia may have been caused by hemodilution in hospitalized patientsKosiborod4Retrospective chartreview2,281Patients had 2% higher risk of 1-year rehospitalization for every 1% lower hematocrit (95% CI: 1.01 to 1.03; p=0.0002)Lack of data on transfusions or other treatments for anemia; study generalizability to non-study populationCOPERNICUS5Randomized,double blind,placebo controlledtrial2,286Anemia was an independent risk factor for 1-year morbidity (HF hospitalization) and mortality outcomes-1Alexander M, et al. Am Heart J. 1999;137:2Polanczyk CA, et al. J Card Failure. 2001;7:3Felker GM, et al. Am J Cardiol. 2003;92:4Kosiborod M, et al. Am J Med. 2003;114:5Anker SD, et al. J Am Coll Cardiol. 2004;43(suppl A):Abstract 842-2
30Anemia and Mortality In Heart Failure Patients: RENAISSANCE RENAISSANCE Study1Kaplan-Meier Survival Curve by Baseline Hb ConcentrationNYHA Class II to IVLVEF<30%N=912P=0.0172**Log-rank test; 1-year mortality was 28% in anemic subjects (Hb<12 g/dL) vs. 16% in non-anemic subjects1Anand et. al., Circulation. 2004;110:
31Anemia and Mortality In Heart Failure Patients: PRAISE 1.7PRAISE Study1NYHA Class IIIb or IVLVEF<30%N=1,1301.61.521.5For patients in the lowest quintile of Hct (<37.6%), each 1% decrease in Hct was associated with an 11% higher risk of death (P<0.01)1.4Adjusted* Hazard Ratio for Death18.104.22.168.101.121.1n=2251.01.0n=229n=224n=229n=2230.9<37.6>46.0Hematocrit (%)*Adjusted for age, gender, diabetes, smoking, heart failure etiology, EF, NYHA Class, systolic BP, WBC count & serum creatinine1Mozaffarian et al. J Am Coll Cardiol. 2003;41:
321-Year Death or HF Hospitalization Kaplan-Meier Event Rates (%) Severity Of Anemia and the Risk For Death Or Heart Failure HospitalizationCOPERNICUS Study1Hemoglobin (g/dL)1-Year Death or HF Hospitalization Kaplan-Meier Event Rates (%)N<1146.611511 to <12.536.131512.5 to <13.530.543213.5 to <1531.983415 to 16.526.5463>16.525.5127N=2,286; LVEF<25%; severe HF with dyspnea or fatigue at rest or on minimal exertion1Anker SD, et al. J Am Coll Cardiol. 2004;43(suppl A):Abstract 842-2
33Worsening of Hb from Baseline to 12 Months was Associated with Increased Mortality in Val-HeFT 510152025P = 0.024P = 0.31P = 0.3213.2Percent Mortality22.214.171.124Q1Q2Q3Q4Quartile change in Hgb, g/dL< - 0.8> to < -0.1> to < + 0.5≥ + 0.5Mean change in Hgb, g/dL- 1.66- 0.47+ 0.15+ 1.11Mean BL Hgb, g/dL14.2413.9213.7113.30Mean 12 month Hgb, g/dL12.5813.4413.8614.40Number of patients9509919371028Anand et al 2005, Circulation ;112:
34CHARM Programme 3 component trials comparing candesartan to placebo in patients with symptomatic heart failureCHARM AlternativeCHARM AddedCHARM Preservedn=2028LVEF £40% ACE inhibitor intolerantn=2548LVEF £40% ACE inhibitor treatedn=3025LVEF >40% ACE inhibitor treated/not treatedPrimary outcome for each trial: CV death or CHF hospitalisationPrimary outcome for Overall Programme: All-cause death
35Relevant exclusions Serum creatinine ≥ 265 µmol/l (3 mg/dl) Known bilateral RASHaemoglobin/anaemia NOT specifically mentioned
36Baseline characteristics Alternative Added Preserved Overall n=2028 n=2548 n=3023 n=7599Mean age (years)Women (%)NYHA class (%) II III IV Mean LVEFMedical history (%) myocardial infarction diabetes hypertension atrial fibrillation
37Median eGFR and Haemoglobin quintiles Hgb 14.4Hgb 15.7Hgb 13.6Hgb 12.8(ml/min/1.73m2)Median eGFRHgb 11.3O’Meara et al. CHARM Investigators. Circulation 2006
38CHARM anemia independent of GFR O’Meara et al. CHARM Investigators. Circulation 2006
39Relationship between haemoglobin and ECG LVH CHARM-Overall O’Meara et al. CHARM Investigators. Circulation 2006
40Relationship between haemoglobin and radiological cardiomegaly CHARM-Overall O’Meara et al. CHARM Investigators. Circulation 2006
41Hemoglobin and Mortality Hgb 11.3Hgb 12.8Hgb 13.6Hgb 15.7Hgb 14.4O’Meara et al. CHARM Investigators. Circulation 2006
43Potential Benefits of Treating Anemia in CVD Improved oxygen deliveryImproved exercise toleranceAttenuate adverse remodelingImproved QoLAntiapoptotic?Decrease in hosp./death?Adapted from Felker and O’Connor J Am Coll Cardiol. 2004;44:
44Erythropoietin Receptors are Present on Adult Cardiac Myocytes Immunocytochemistry using EPOR Pab against N-terminal region.Other figs in the paper also show figs using EPOR Mab and Pab against C-terminal region. Also do blocking experiments.50 m50 mEPOR protein in adult rat heartsections using immuno- histochemistryEPOR protein in isolated adult rat cardiac myocytes visualized by fluorescence microscopyWright et al FASEB.
45EPO Administered at time of LAD Ligation Reduces Myocyte Apoptosis TUNEL Positive Nuclei as % Total35302010ShamMI25155MI + EPO*Tramontano et al. Biochem Biophys Res Commun. 2003;308:
46N-terminal ANP plasma levels (pmol/L) Effect of EPO on Cardiac Function in Rats Post-MIN-terminal ANP plasma levels (pmol/L)LVEDP (mmHg)*p <0.05 vs MI; **p <0.01 vs MI; #p <0.01 vs shamVan der Meer P, et al. JACC 2005
47Clinical Trials of Anemia Correction with Erythropoeitin
48Studies Evaluating The Effect Of Treatment Of Anemia With Recombinant Human Erythropoietin (rHuEPO) In Heart Failure PatientsStudyNMean changes in selected endpointsP ValueSilverberg et alNo control groupNot blinded26NYHA class (3.66 2.66)LVEF (27.7% 35.4%)Number of hospitalizations/patient (2.72 0.22)<0.05<0.001Silverberg et alRandomized control groupNot blinded, no placebo32NYHA class (3.8 2.2; 3.5 3.9 for control)LVEF (30.8% 36.3%; 28.4% 23.0% for control)Hospital days (13.8 2.9; 9.9 15.6 for control)<0.0001<0.013<0.03Silverberg et al179NYHA class (3.90 2.54)LVEF (34.9% 38.7%)Number of hospitalizations/patient (2.90 0.12)Fatigue, shortness of breath VAS (8.76 2.75)Mancini et alRandomized, placebo controlledSingle blinded23Hb ( g/dL; g/dL for controlPeak VO2 ( ml/kg/min; ml/kg/min for control)Exercise Duration ( sec; sec for control)6-min walk ( ft; ft for control)MLHFQ (9 point decrease for EPO; 10 point increase for control)<0.004<0.04Silverberg et al78NYHA class (3.7 2.5)LVEF (33.3% 36.9%)Number of hospitalizations/patient (2.7 0.7)<0.011J Am Coll Cardiol. 2000;35(7):2J Am Coll Cardiol. 2001;37(7):3Nephrol Dial Transplant. 2003;18:4Circulation. 2003;107:5Kidney Blood Press Res. 2005;28:41-47
49126 Anemic Patients With Resistant CHF Congestive Heart Failure (CHF) and CKD: Clinical Benefit of Anemia Correction126 Anemic Patients With Resistant CHFBeforeAfterHemoglobin (g/dL)*10.313.1*Serum creatinine (mg/dL)2.42.3GFR (mL/min/month)*-0.950.27*NYHA class (0–4)*3.82.7*Fatigue/SOB index (0–10)*8.9Hospitalizations*3.70.2*Systolic BP (mmHg)132131Diastolic BP (mmHg)7576Key Point:This study suggests that the correction of even mild anemia in CHF may be an important addition to the treatment of patients with the combination of CHF and CRFStatistical difference following anemia correction p < 0.05NYHA = New York Heart AssociationSilverberg DS, et al. Peritoneal Dial Int. 2001;21(suppl 3):S236-S240.
50Effect of Treatment Of Anemia With rHuEPO On Exercise Duration And 6-Minute Walk… Mean Change in Exercise DurationMean Change in 6-Minute Walk DistanceExercise Duration (seconds)6-Minute Walk Distance (feet)Eligible patient population consisted of NYHA class III-IV with Hct < 35%, serum creatinine < 2.5, and endogenous rHuEPO level < 100 mU/mL. Study design was randomized (2:1 randomization of patients to rHuEPO or placebo), placebo-controlled, single-blind. Study duration was 3 months. Patients randomized to rHuEPO also received ferrous gluconate 325 mg qd and folate 1 mg qd.Results for the rHuEPO and placebo groups were as follows:1. Increase in Hb for rHuEPO group (11.0 0.6 to 14.3 1.2 g/dL, p<0.0001); no change in Hb for placebo group (10.9 1.1 to 11.5 1.3 g/dL, p=NS)2. Peak VO2 increased significantly for rHuEPO group (11 0.8 to 12.7 2.8 ml/kg/min, p<0.05); peak VO2 declined for placebo group (10.0 1.9 to 9.5 1.6 ml/kg/min, p=NS)3. Exercise duration increased significantly for rHuEPO group (590 107 to 657 119 sec, p<0.004); exercise duration declined for placebo group (542 115 to 459 172 sec, p=NS)4. 6-min walk increased significantly for rHuEPO group (1187 279 to 1328 254 ft, p<0.05); 6-min walk also increased for placebo group (929 356 to 1052 403 ft, p=NS)5. MLHFQ score decreased significantly for rHuEPO group (9 points, p<0.04); MLHFQ score increased for placebo group (10 points, p not available)P=NSP<0.004P<0.05Randomized, placebo-controlled, single-blinded study; N=23 (n=8 for placebo group, n=15 for EPO group)Mancini et al. Circulation. 2003;107:
51…As Well As Peak VO2 And Quality Of Life In Heart Failure Patients Mean Change in Peak VO2Mean Change in MLHFQ ScorePeak VO2 (mL/kg/min)MLHFQ (points)MLHFQ: Minnesota Living With Heart Failure Questionnaire score.Lower MLHFQ scores indicate higher quality of life.Results for the rHuEPO and placebo groups were as follows:1. Increase in Hb for EPO group (11.0 0.6 to 14.3 1.2 g/dL, p<0.0001); no change in Hb for placebo group (10.9 1.1 to 11.5 1.3 g/dL, p=NS)2. Peak VO2 increased significantly for rHuEPO group (11 0.8 to 12.7 2.8 ml/kg/min, p<0.05); peak VO2 declined for placebo group (10.0 1.9 to 9.5 1.6 ml/kg/min, p=NS)3. Exercise duration increased significantly for rHuEPO group (590 107 to 657 119 sec, p<0.004); exercise duration declined for placebo group (542 115 to 459 172 sec, p=NS)4. 6-min walk increased significantly for rHuEPO group (1187 279 to 1328 254 ft, p<0.05); 6-min walk also increased for placebo group (929 356 to 1052 403 ft, p=NS)5. MLHFQ score decreased significantly for rHuEPO group (9 points, p<0.04); MLHFQ score increased for placebo group (10 points, p was not provided)Placebo GrouprHuEPO GroupPlacebo GrouprHuEPO GroupP=NSP<0.05(P not available)P<0.04Randomized, placebo-controlled, single-blinded study; N=23 (n=8 for placebo group, n=15 for EPO group)Mancini et al. Circulation. 2003;107:
52Pooled Analysis of HF Anemia Trials Placebo n=209Darbepoetin alfa n=266Outcomes hazard ratio (95% CI)p valueComposite endpoint0.67 (0.44, 1.03)0.064HF-related hospitalization0.66 (0.40, 1.07)0.091All-cause mortality0.76 (0.39, 1.48)0.418Abraham W. ESC 2006
53Pooled Analysis of HF Anemia Trials Placebo n=209Darbepoetin alfa n=266Outcomes hazard ratio (95% CI)p valueComposite endpoint0.67 (0.44, 1.03)0.064HF-related hospitalization0.66 (0.40, 1.07)0.091All-cause mortality0.76 (0.39, 1.48)0.418Abraham W. ESC 2006
54Potential Benefits and Risks of Treating Anemia in HF Improved oxygen deliveryImproved exercise toleranceAttenuate adverse remodelingImproved QoLAntiapoptotic?Decrease in hosp./death?Potential RisksIncreased thrombosisPlatelet activationHypertensionEndothelial activationAdapted from Felker and O’Connor J Am Coll Cardiol. 2004;44:
55Recent Oncology Publications Raised Concern Regarding VTE Risk in EPO-Treated Patients The Lancet Oncology 2003;4:
56Treatment of Anemia with Erythropoietin Stimulating Agents (ESAs): What We Know Dialysis CKDImprovementsHbReduces Transfusion /-Quality of Life /-CV Outcomes no3 RCTs
57Normal Hematocrit Dialysis Trial ~Hb 13N=618~Hb 10N=615Besarab et al,New Engl J Med 1998
58Besarab et al,New Engl J Med 1998 Normal Hematocrit Dialysis TrialN=618No benefit higher Hct (Hb)More vascular access problemsDeath or MIN=615RR 1.3 (95 CI 0.9 to 1.9)Besarab et al,New Engl J Med 1998
59Current NKF/ KDOQI Guidelines for Anemia Correction In patients with CKD, Hb should be 11.0 g/dL or greater (MODERATELY STRONG RECOMMENDATION)Observational data that patients with lower Hb do worseAssocation between anemia and LVHImprovement in QOL with anemia correction to g/dLIn the opinion of the Work Group, there is insufficient evidence to recommend routinely maintaining Hb levels at 13.0 g/dL or greater in ESA-treated patients.
603 RCTs Designed to Address Whether Anemia Correction in CKD May Improve CV Morbidity and Mortality CREATE (Cardiovascular risk Reduction by Early Anemia Treatment with Epoetin beta) - CompletedDetermine the impact of early vs late anemia correction on mortality and cardiovascular morbidity in patients with CKDCHOIR (Correction of Hemoglobin and Outcomes In Renal insufficiency) – Terminated EarlyDetermine the impact of degree of anemia correction on mortality and cardiovascular morbidity in patients with CKDTREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy) - EnrollingDetermine the impact of anemia therapy (yes/no) on mortality and cardiovascular morbidity in patients with CKD and type 2 diabetes
61Hemoglobin Concentrations (Mean SE) Over Time* Pooled Efficacy Results: Hemoglobin Response in Studies 170 and 171Hemoglobin Concentrations (Mean SE) Over Time*Darbepoetin alfaPlacebo*For subjects in study 170 who stayed on study longer than 27 weeks, the Hb concentration remained stable throughout the study
62General Design Differences CREATECHOIRTREATDesignRandomized, open-labelRandomized, double-blind, controlledSponsor / AgentRoche / Neorecormon(epoetin beta)J&J / Procrit(epoetin alfa)Amgen / Aranesp(darbepoetin alfa)Dosing2,000 QWInitiate 10,000 QW When stable go to Q2W0.75mcg/kg/Q2W Double dose when stable and go to QMDosing FrequencyDe novo to QWDe novo to QW to Q2WDe novo to Q2W to QMHb Target(s),g/LArm 1135130Arm 2*113Rescue for Hb <90Regions/CountriesEU, Mexico, China, Taiwan, ThailandUSUS, EU, CAN, AU, LA, RUS# CentersUnknown~700Censor at RRTNo* Treatment starts when Hb <10.5 g/dL
63Key Inclusion Criteria and Baseline Characteristics CREATE(N = 472)a, c, dCHOIR(N = )a, bTREAT(N = )aInclusionHb (g/L)110 – 125<110110eGFR/CrCl*15-3515-5020-60DiabetesNo (~20%)No (48.5%)Yes (100%)Baseline Characteristics116101-24.527.0a Study population sample w/ available datab Abstracts, 2004 ASN, St. Louis, MOc MacDougall et al. NDT 2003;18[suppl 2]:ii13-ii16d* TREAT, CHOIR: mL/min/1.73m2* CREATE: mL/min
64European Best Practice Guideline 4: Comments Regarding Initiation of rHuEPO "There is widespread agreement that symptoms usually begin when the Hb is <11 g/dL.""There is abundant evidence, including data from randomized studies, that quality of life, CV morbidity, exercise capacity, endocrine, immune and sexual function, and hospitalization rates, are all improved in pre-dialysis patients if the Hb is increased from lower levels to >10-11 g/dL.""Prospective data suggesting mortality can be diminished by increasing the Hb concentration are, as yet, lacking."Nephrol Dial Transpl 1999;14(Suppl 5):11-13.
65Study Endpoints CREATE CHOIR TREAT Primary Endpoint 1. Change in LVMI: baseline to 1 year2. Time to:Sudden deathMI (fatal, non-fatal)Stroke (fatal, non-fatal)Heart failure (acute)Angina (hosp >24 hrs)Arrhythmias (hosp >24 hrs)PVD (necrosis, amputation)Time to all-cause mortality or CV morbidity:- MI- StrokeHeart failure HospitalizationUnplanned hospitalization for heart failure [No coincident initiation of RRT] with administration of IV inotrope, diuretic, vasodilator- Heart failure- Hosp for acute myocardialischemiaSecondary Endpoints- All-cause mortality- CV mortality- CHF (change in NYHA class)- CV interventions- Hospitalization- LV growth and systolic fxn- Progression of CKD- Nutritional status- QOL-All Cause Mortality-CHF Hospitalization-MI-CVA-RRT-CV Hospitalization-Incident CHF-All cause Hospitalization-Change from baseline for Hct/Hb, eGFR, Fe stores-HRQOLTime to each of:- ESRD or all-cause mortality- ESRD- Components of 1o endpointChange in pt-reported fatigue: baseline to wk 25Change in eGFRDate study stopped.
66600 patients from >20 countries Standard target Hb (10.5–11.5 g/dl) CREATE: Study designPrimary study objectives: To investigate the effects of early epoetin beta treatment to normal target haemoglobin (Hb) values compared to partial anaemia correction on cardiovascular (CV) events600 patients from >20 countriesHgeGFR 15-35RandomisationHigh target Hb (13–15 g/dl)Standard target Hb (10.5–11.5 g/dl)Group 1Group 2
67Primary endpoint Time to first CV events (105 events) Events: 58 vs 47HR=1.22 (0.83–1.79)Log rank test p=0.20
68Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin beta (CREATE) CREATEaReason for StoppingLast subject followed 2 yearsDuration Enrollment (months)UnknownTotal Study Duration (months)48Median Follow-up (years)2.5Hb Achieved (g/L)Arm 1135Arm 2Unknown ('stable')Composite Primary Event Rate (% per year)5.8# Composite Primary Events Observed5847HR (95% CI) Composite Primary Endpoint1.22 (0.83, 1.79) - estimated# ESRD Events Observed127111HR (p value) Time to ESRD1.32 (p = 0.034)Secondary EndpointsImproved QOL (p = 0.003) in higher Hb arm, but clinical significance uncertain;no difference in other 2ndarysUntil Recently, CREATE was the only RCT trial we had results to guida
69Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) 1432 Patients Randomized715 Group A (Hb 135 g/L)717 Group B (Hb 113 g/L)279 Early Withdrawal without experiencing primary endpoint271 Early Withdrawal without experiencing primary endpointDSMB Stopped Study May 2005 for Futility (not a stopping rule)Results Released April 2006 at NKF meetingSingh A et al. NEJM 2006
70Kaplan-Meier Plot of the Time to the Primary Composite Event between Randomization and Termination: ITT PopulationPrimary Composite Endpoint:Death, MI, CHF hosp (no RRT) and/or strokeRandomized TreatmentHemoglobin Target 13.5 g/dLHemoglobin Target 11.3 g/dLKaplan-Meier Failure Estimate (%)0%5%10%15%20%25%30%Months from Randomization61218243036Hazard ratio (1.025, 1.743)P=Hazard ratio (1.025, 1.743)P=71571758759410110745749927029355443At riskSingh A et al. NEJM 2006
71Components of the Primary Endpoint DeathCHF Hospitalization (where RRT did not occur)p =p =Hazard ratio (0.969, 2.268)Hazard ratio (0.967, 2.054)Myocardial InfarctionStrokep =p =Hazard ratio (0.454, 2.249)Hazard ratio (0.484, 1.729)Singh A et al. NEJM 2006
72CHOIR Outcomes: Mortality and CV Morbidity Endpoint# EventsHR (95% CI)p-valueHb 135Hb 113Composite Primary125971.337 (1.025, 1.743)*0.0312SecondaryAll-cause death52361.483 (0.969, 2.268)0.0674CV death2622?MI18200.915 (0.484, 1.720)0.78Stroke121.010 (0.454, 2.249)0.9803Heart Failure64471.409 (0.967, 2.054)0.0727Time to ESRD1.186 (0.941, 1.495)Cardiovascular hospitalization1.225 (1.0131, 1.448)Composite primary event rate17.5%13.5%KM – 3yr event rate29.5%24.9%* Time for KM curves to separate: ~ 6-8 monthsSingh A et al. NEJM 2006
73CHOIR Results Primary Composite Endpoint Death CHF Hospitalization Myocardial InfarctionStroke135 g/L targetbetter113 g/L targetbetterSingh A et al. NEJM 2006
74Cause of Death in CHOIR Deaths Hb 135 g/L Hb 113 g/L 52 36 Causes Cardiovascular2622Thrombotic2ESRDSepsis5Other1912Key Point:Patients with diabetes and no prior MI had as high a risk of MI as patients with a history of MI without diabetes. Patients who had both diabetes and a history of MI had the highest risk of repeat MI.
77TREAT: Trial to Reduce Cardiovascular Events with Aranesp (Darbepoetin alfa) Therapy Hypothesis:Treatment of anemia with darbopoetin alfa reduces the risk of mortality and nonfatal cardiovascular events in patients with CKD and type 2 diabetesN = 2000Darbopoetin alfa Group (Target Hemoglobin 13 g/dL)Study PopulationHemoglobin 11 g/dLGFR mL/minType 2 DMDesign – randomized (1:1), double blind, controlledTREAT is a randomized, double blind, controlled trial designed to test the hypothesis that anemia therapy reduces the risk of mortality and nonfatal cardiovascular events in patients with CKD and type 2 diabetes mellitus.TREAT will provide pivotal data that can advance the management of cardiovascular risk in patients with CKD, and inform the next generation of guidelines for anemia management in patients with CKD.N = 2000Control GroupEvent-driven: 1200 patientsEvent-driven
78TREAT almost 2x greater overall exposure to study drug than CHOIR CHOIR vs. TREAT: Subject ExposureStudyNMedian(Pt-months)Total(Pt-years)EventsTREAT*3225133346.6362CHOIR143216~1900**222TREAT almost 2x greater overall exposure to study drug than CHOIR* Based on 01-Mar-2007 Oracle Clinical Database** Crude estimate: 1432 patients x (16 months / 12 months/year) = 1900 patient-years
82Anemia is a readily identifiable surrogate associated with …high rates of adverse clinical outcomes. Because ESP can raise hematocrit, it is imperative to definitively determine the risk: benefit ratios of these available therapies…. To accept a benefit based on the existing data may be exposing patients to an expensive therapy that is either ineffective or may even contribute to adverse outcome. On the other hand, to accept harm based on existing data may deny patients the ability to improve their prognosis as well as quality of life.Rev Cardiovasc Med 2005
83RED-HF Trial: Hypothesis and Study Design Treatment of anemia with darbepoetin alfa in subjects with symptomatic left ventricular systolic dysfunction and anemia decreases the risk of all-cause mortality or hospital admission for worsening HFDarbepoetin alfa group (target Hb 13.0, not to exceed 14.5 g/dL)N = 1700Study PopulationHb 9 to 12 g/dLLVEF < 35%NYHA Class II to IV1:1 randomizationPlacebo groupN = 1700Young JB, et al J Cardiac Failure 2006;(Suppl 1):6:S77.
84Randomized Controlled Trials Play A Critical Role in Advancing Patient Care Through Guidelines Clinical TrialsDrug DiscoveryGuidelinesPatientOutcomesQualityIndicatorsRCTs drive medical practice principally through guidelines, which can be used to evaluate caregiver performance and impact on patient outcomes, which point to the need for additional therapies and clinical trialsGuidelines depend on RCTs to support their highest-level recommendations, i.e., those recommendations that practitioners should consider most seriously.Ideally, guidelines are based on RCTs. Unfortunately, RCTs are not always available, requiring that guidelines be supported by data of lesser quality.While the development, promotion and adherence to US and European anemia management guidelines for patients with CKD have been a critical first step in improving anemia management in patients with CKD, and adherence to these guidelines in clinical practice is appropriate, these guidelines are based on limited data comprising several small, poorly controlled HRQOL trials of short duration, observational data demonstrating an association between anemia and CVD, and opinion.Strong recommendations to follow the anemia management guidelines can not be made until the limited data supporting them are validated with well designed and analyzed RCTs examining hard clinical outcomes.This validation process underscores the fundamentally dynamic nature of guidelines, whereby guidelines point out gaps in our knowledge, informing clinical investigation, and evolving as new and better data to support them become available.CaregiverPerformanceCaliff, R et al JACC 2002;40(11):
85Monthly Hemoglobin (Hb) of US Dialysis Patients ~15%Hb 12.0-<13.0Hb10.0-<11.0Hb 9.0-<10.0Hb 11.0-<12.0~43%~22%Hb <9.0Hb level 11 g/dL a CMS Performance MeasureSteinbrook, Lancet 2006;368:2191.
86Randomized Controlled Trials Have Driven the Evolution of Guidelines in Cardiology ACC/AHA Guidelines for Management of Acute MI: Beta Blockade1990 – Beta blockers are first recommend for targeted patients (reflex tachycardia, systolic hypertension, persistent angina, no signs of heart failure)11996 – Guidelines include 'non ST MI' patients in the highest level recommendation21999 – Patients with 'moderate LV failure' are moved from the class III (potentially harmful) to the class IIb (potentially useful) level recommendation32001 – Beta blockers are a highest-level recommendation for all post-MI patients4The dynamic nature of guidelines is exemplified by the US guidelines for management of myocardial infarction developed by the American College of Cardiology and American Heart Association.Beta blockers were first indicated in the guidelines for a very targeted population of patientsFollowing multiple RCTs, their recommended use gradually evolved to become a highest-level recommendation for all patients following MI.1 Gunnar RM, et al. Circulation 1990;82(2):2 Ryan TJ, et al. Circulation 1996;94(9):3 Ryan TJ, et al. Circulation 1999;100(9):4 Smith CC, et al. Circulation 2001;104(13):1577-9ACC = American College of CardiologyAHA = American Heart AssociationMI = myocardial infarctionLV = left ventricular
87Negative Results From Randomized Controlled Trials Evolve The Practice of Medicine Secondary prevention of cardiovascular disease with estrogens1Prophylaxis against ventricular dysrhythmia in the peri-myocardial infarction setting with lidocaine2Prophylaxis against pre-eclampsia with calcium supplementation3RCTs are the gold standard for testing therapeutic interventions like the treatment of anemia.The value of RCTs lies in their ability to minimize bias, which can influence the interpretation of results of less robust investigative strategies.The importance of this point is illustrated by medical practices that evolved in the absence of RCTs, and then were reconsidered when RCTs were eventually conducted.1 Hulley S, et al. JAMA 1998;280(7):2 Sadowski ZP, et al. American Heart Journal 1999;137(5):3 Levine RJ, et al. NEJM 1997;337(2):69-76.
88Patients who are deficient in X do not necessarily benefit from repleting X Hormone Replacement TherapyReduced Estrogen associated with increased risk ofHeart DiseaseBone LossObservational Suggested Benefits of HRTRandomized Trials suggested harm with HRTThyroid ReplacementJust enough – goodToo much - bad
89Beneficial Impact on HRQOL Does Not Always Extrapolate to Other Health Outcomes Improvement in: Exercise duration Heart failure symptoms1RR p<0.05Studies in patients with heart failure demonstrate the importance of validating findings with respect to HRQOL, with studies assessing harder outcomes such as cardiovascular morbidity and deathDecreased survival2HRQOL =health-related quality of life1 Packer M, et al. JACC 1993; 22(1):65-72.2 Packer M, et al. (abstract) Circulation 1993;88(Suppl):I-301.2 Van Veldhuisen DJ, et al. International Journal of Cardiology 2001;80(1):19-27.
90Anemia Management Guidelines State that Additional Data Are Needed National Kidney Foundation1:"Additional studies are needed to clarify the relationship between Hgb/Hct and outcomes in CKD patients, particularly those with heart disease."European Best Practice Guidelines:"Prospective data suggesting mortality can be diminished by increasing the Hb concentration are, as yet, lacking."2"…no prospective data have yet shown an improvement in survival in any single group of patients treated with erythropoiesis-stimulating agents."3The guidelines for anemia management in patients with CKD clearly state that data regarding the impact of anemia therapy on hard clinical outcomes like mortality and CV morbidity remain unavailable.1 Am J Kid Dis 2001;1(Suppl 1):S182-S238.2 Nephrol Dial Transpl 1999;14(Suppl 5):11-13.3 Nephrol Dial Transplant 2004;19(Suppl 2):ii6-ii15.
91ConclusionsAnemia is a risk factor for adverse outcome in patients with CKD and CVDCorrection of anemia with ESPs may offer benefits to some patients in some clinical circumstances, although degree of correction is hotly debatedNevertheless, the potential for harm has been demonstrated with anemia correction in the CKD populationWe should be cautious until we have results from ongoing major clinical trials in anemia correction to reduce CV risk
92The definition of equipoise I was hoping I’d be in the active therapy group?Well, I was hoping I’d be in the placebo group?The definition of equipoise
93Trials of Anemia Targets in CKD CHOIR study1432 subjects recruited, diabetic and nondiabetic CKD patientsEpoetin-alfa130 centers, US onlyHb 13.5 g/dL vs 11.3 g/dLStudy stopped by Data and Safety and Monitoring BoardCREATE studyApproximately 603 subjectsEpoetin-beta100 centers. 22 countriesStudy reported data at European Renal Association/European Dialysis and Transplant Association conferenceTREAT study4000 subjects with CKD and type 2 diabetesDarbepoietin700 centers, 26 countriesPlacebo-controlled with rescue arm: Hb 9.0 g/dL vs 13.0 g/dLEnrollment under wayCHOIR = American Correction of Hemoglobin and Outcomes in Renal Insufficiency; CREATE = Cardiovascular Risk Reduction by Early Anemia Treatment With Epoetin-beta; TREAT = Trial to Reduce Cardiovascular Events with Aranesp® Therapy.
94CHOIR Study Design Open label, Randomized Controlled Trial 130 sites randomized 1432 subjects in US3 years durationMedian f/u 16 monthsStudy populationHb < 11 g/dlAge 18Steady-state GFR 15 ml/min and 50 ml/minPrimary Endpoint: Composite eventDeathMyocardial infarctionStrokeCHF hospitalization (excluding RRT)In comparison to the general population, patients with diabetes mellitus, African-Americans, and hispanics will be appropriately over-represented.Singh et al In press
95Baseline Characteristics Group AHb 13.5 g/dLGroup BHb 11.3 g/dLAge6666.3Gender (male) %43.845.9Race (Black) %28.629.3Ethnicity (Hispanic) %12.513.5Smoking %47.544.6BMI30.4Hematocrit (%)31.4Transferrin Saturation (%)25.224.6Creatinine Clearance (mL/min)36.37.1Etiology of CKDDiabetes %46.850.8Hypertension %29.927.5Other %23.321.6Singh et al In press
96Hemoglobin and Epoetin alfa over Time Singh et al In press
97CHOIR: QOL 3 instruments Limitations LASA KDQ SF-36 Open label Subjective
98CHOIR QOL: LASA Longitudinal Analysis High vs. Low Difference P value Energy LevelAbility in DLOverall QOL
99Longitudinal Analysis CHOIR KDQ: FatigueWeekHigh Hb13.5 g/dLLow Hb12.3 g/dLDifference betw’n gpP valueN at risk(High,Low)663,656240.90.80.1456,44748364,389720.70.054,76960.50.262,791200.69,11144-0.7-.0.93,7Final0.664536,536Longitudinal AnalysisHigh Gp Low Gp Difference P valueEstimateSD
100Longitudinal Analysis CHOIR QOL: VitalityWeekHigh Hb!3.5 g/dLLow Hb12.3 g/dLDifference betw’n gpP valueN at risk(High,Low)684,6762414.912.12.8493,4814813.910.93.0395,416727.810.6-2.855,7896126.96.36.1991,831204.15.00.99,11144-13.313.126.43,7Final10.08.20.577579,577Longitudinal AnalysisHigh Gp Low Gp Difference P valueEstimateSD
101TREAT: Trial to Reduce Cardiovascular Events with Aranesp (Darbepoetin alfa) Therapy Hypothesis:Treatment of anemia with Aranesp reduces the risk of mortality and nonfatal cardiovascular events in patients with CKD and type 2 diabetesAranesp Group (Target Hemoglobin 13 g/dL)Control GroupStudy PopulationHemoglobin 11 g/dLGFR mL/minType 2 DMN = 2000Design – randomized (1:1), double blind, controlledTREAT is a randomized, double blind, controlled trial designed to test the hypothesis that anemia therapy reduces the risk of mortality and nonfatal cardiovascular events in patients with CKD and type 2 diabetes mellitus.TREAT will provide pivotal data that can advance the management of cardiovascular risk in patients with CKD, and inform the next generation of guidelines for anemia management in patients with CKD.Event-driven: 1200 patientsEvent-driven
102RED-HF Trial: Hypothesis and Study Design Treatment of anemia with darbepoetin alfa in subjects with symptomatic left ventricular systolic dysfunction and anemia decreases the risk of all-cause mortality or hospital admission for worsening HFDarbepoetin alfa group (target Hb 13.0, not to exceed 14.5 g/dL)N = 1700Study PopulationHb 9 to 12 g/dLLVEF < 35%NYHA Class II to IV1:1 randomizationPlacebo groupN = 1700Young JB, et al J Cardiac Failure 2006;(Suppl 1):6:S77.
103FDA Black Box Warning March 9 2007 WARNINGS: Erythropoiesis-Stimulating AgentsUse the lowest dose of ESA that will gradually increase the hemoglobin concentration to the lowest level sufficient to avoid the need for red blood cell transfusion (see DOSAGE AND ADMINISTRATION).ESAs increased the risk for death and for serious cardiovascular events when administered to target a hemoglobin of greater than 12 g/dL (see WARNINGS: Increased Mortality, Serious Cardiovascular and Thromboembolic Events).Cancer Patients: Use of ESAsShortened overall survival and increased deaths attributed to disease progression at 4 months in patients with metastatic breast cancer receiving chemotherapy when administered to target a hemoglobin of greater than 12 g/dL,Increased the risk of death when administered to target a hemoglobin of 12 g/dL in patients with active malignant disease receiving neither chemotherapy nor radiation therapy. ESAs are not indicated in this population.