Erythropoiesis Stimulation and Heart Failure: Current Status

Transcription

1 Erythropoiesis Stimulation and Heart Failure: Current Status Marc A. Pfeffer, MD, PhD Dzau Professor of Medicine, Harvard Medical School Cardiovascular Division, Brigham & Women s Hospital Boston, Massachusetts Disclosures: Dr. Pfeffer receives research grants, or serves as a consultant for Amgen, Astra Zeneca, Baxter, Biogen, Boehringer, Boston Scientific, Bristol-Myers Squibb, Celladon, Centocor, CVRx, Genentech, Genzyme, Medtronic, Novartis, Roche, Sanofi Aventis, Via and Zensun. Dr. Pfeffer is a co-inventor of a patent awarded to BWH regarding the use of inhibitors of the renin-angiotensin system in selected survivors of MI. A licensing agreement with Boehringer Ingelheim and Novartis is not linked to sales.

2 Possible etiologies of anemia in heart failure Bone marrow - Insensitivity to EPO - Cytokines (TNF ) Malnutrition - Low iron - Vitamine B11,B12 Renal failure - EPO production Anemia Chronic blood loss - Use of Anticoagulation Medication - Use of ACE-inhibitors Hemodilution Van der Meer et al, Eur Heart J. 2004

3 CHARM CV death or HF hospitalization and Anemia O'Meara, E. et al. Circulation 2006;113:

4 O'Meara, E. et al. Circulation 2006;113: CHARM All cause mortality per Haemoglobin Quintiles % 35 Hgb Hgb 12.8 Hgb 13.6 Hgb Hgb I II III IV V Haemoglobin quintiles

5 Kaplan-Meier survival curve by Hb strata (all-cause mortality) COMET-study Komajda, Poole-Wilson, et al. Eur Heart J :

6 Anemia and Mortality in Heart Failure Patients A Systematic Review and Meta-Analysis Hessel F. Groenveld, MD,* James L. Januzzi, MD, FACC, Kevin Damman, MD,* Jan van Wijngaarden, MD, PHD, Hans L. Hillege, MD, PHD,* Dirk J. van Veldhuisen, MD, PHD, FACC,* Peter van der Meer, MD, PHD J Am Coll Cardiol 2008;52: Risk of All-Cause Mortality of Anemic Versus Nonanemic CHF Patients: n = Conclusions: Anemia is associated with an increased risk of mortality in both systolic and diastolic CHF. Anemia should, therefore, be considered as a useful prognosticator, and therapeutic strategies aimed to increase hemoglobin levels in CHF should be investigated.

7 Use of Erythropoietin in Heart Failure First data in 26 patients, treated for 7.2 months Silverberg et al. JACC 2000

8 Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) 1432 Patients Randomized 715 Group A (Hb 13.5 g/dl) 717 Group B (Hb 11.3 g/dl) 279 Early Withdrawal without experiencing primary endpoint 271 Early Withdrawal without experiencing primary endpoint DSMB Stopped Study May 2005 for Futility (not a stopping rule) Results Released April 2006 at NKF meeting Singh A et al. NEJM 2006

9 Achieved 12.6 g/dl Achieved 11.3 g/dl 17.5% vs. 13.5%; HR 1.34; 95% CI ; P = 0.03 NEJM 2006;355:

10 Kaplan-Meier Failure Estimate (%) Kaplan-Meier Failure Estimate (%) CHOIR Components of 1 Endpoint 20% 15% 10% p = Death Hazard ratio (0.969, 2.268) CHF 20% Hospitalization (where RRT did not occur) 15% 10% p = Hazard ratio (0.967, 2.054) 5% H = 52 L = 36 0% % H = 64 L = 47 0% % 15% 10% 5% Stroke 20% 15% p = p = Hazard ratio (0.454, 2.249) H = 12 L = 12 10% 5% Myocardial Infarction Hazard ratio (0.484, 1.729) H = 18 L = 20 0% Months from Randomization 0% Months from Randomization Randomized Treatment Hemoglobin Target 13.5 g/dl Hemoglobin Target 11.3 g/dl Singh A et al. NEJM 2006

11 Singh A et al. NEJM 2006

12 Hemoglobin (g/dl) Pooled Efficacy Results Hemoglobin Response Hemoglobin Concentrations (Mean SE) Over Time* N=209 N=263 N=201 N=254 N=199 N=256 N=198 N=257 N=201 N=255 N=195 N=252 N=194 N=253 N=187 N=238 N=184 N=240 N=179 N=237 N=179 N=245 N=178 N=236 N=176 N=231 N=175 N=229 N=127 N=140 BL Visit Week Darbepoetin alfa *For subjects in study 170 who stayed on study longer than 27 weeks, the Hb concentration remained stable throughout the study Placebo

13 Pooled Safety Results Summary Placebo n = 209 Darbepoetin alfa n = 264 Any adverse events, n (%) 184 (88) 231 (88) Serious adverse events, n (%) 94 (45) 101 (38) Deaths, n (%) 18 (9) 17 (6) Study 170 deaths* 18 (11) 11 (7) Study 171 deaths* 0 (0) 6 (6) Number of subjects with adverse events of special interest**, n (%) 67 (32) 69 (26) Hypertension 12 (6) 15 (6) Deep vein thrombosis 2 (1) 0 (0) Pulmonary emboli 1 (<1) 0 (0) Heart failure 53 (25) 50 (19) Cerebrovascular disorder 4 (2) 9 (3) Myocardial infarction 5 (2) 6 (2) Seizure 2 (1) 1 (<1) *n for placebo vs. darbepoetin alfa in studies 170 and 171 were 157 and 162, and 55 and 108, respectively **No anti-erythropoietic protein neutralizing antibodies were detected

14 Erythropoietin Treatment in HF: meta-analysis P Van der Meer et al. Heart 2009; 95:

15 Erythropoietin Treatment in HF: meta-analysis Effect on all-cause mortality P Van der Meer et al. Heart 2009; 95:

16 Erythropoietin Treatment in HF: meta-analysis Effect on HF Hospitalizations P Van der Meer et al. Heart 2009; 95:

17 HF and Anemia studies as of 08/25/ Anemia AND HF 22 studies Therapeutic intervention 15 Observational, Case-control 7 Iron Supplementation 7 PRBC post MI M/M endpoint 92 patients Erythropoietin Stimulating Agents 7 6 RCTs, 1 open label VO 2, ΔHgb, QOL 3165 patients Non M/M ΔHgb, VO2, QOL, remodeling 580 patients (largest 300) Mortality/Morbidity 1 RCT 2600 patients

18 European Journal of Heart Failure (2009) 11,

19 RED-HF Trial 2600 patients planned primary endpoint: morbidity and mortality target: 620 sites, 32 countries first patients in: July 2006 August 2010: ~ 2/3 of target enrolled

20 Trial to Reduce Cardiovascular Events with Aranesp Therapy Marc A. Pfeffer, Emmanuel A. Burdmann, Chao-Yin Chen, Mark E. Cooper, Dick de Zeeuw, Kai-Uwe Eckardt, Jan M. Feyzi, Peter Ivanovich, Reshma Kewalramani, Andrew S. Levey, Eldrin F. Lewis, Janet B. McGill, John J.V. McMurray, Patrick Parfrey, Hans-Henrik Parving, Giuseppe Remuzzi, Ajay K. Singh, Scott D. Solomon, Robert Toto for the TREAT investigators* Disclosures: This study was sponsored by Amgen. All investigators received research funding and some received consulting fees from the sponsor. A full list of disclosures is publicly released.

21 Survival Probability (All-Cause Mortality) Incremental Risk of CKD and Anaemia on Mortality in Subjects With Diabetes 1.0 ARIC, Cardiovascular Health Study, Framingham Heart Studies. n = 3015 subjects with DM DM DM, Anaemia DM, CKD Hypothesis Anemia+, CKD+, (71) HR: 2.84 (2.05 to 3.91) Anemia+, CKD-, (174) HR: 1.21 (0.89 to 1.65) Anemia-, CKD+, (344) HR: 1.51 (1.25 to 1.82) Anemia-, CKD-, (2426) HR: 1 In patients with type 2 diabetes, chronic kidney disease not requiring dialysis, and concomitant anaemia, raising haemoglobin with darbepoetin alfa would lower the rates of death and cardiovascular morbidity and/or death and end-stage renal disease Years Since Baseline Vlagopoulos PT et al. J Am Soc Nephrol 16: , 2005 DM, CKD, Anaemia

22 Design International (24) multi-center (623), doubleblind, placebo-controlled randomized trial Randomization in a 1:1 Active: darbepoetin alfa to attempt to achieve and maintain a hemoglobin (Hb) of 13 g/dl Control: placebo: with rescue therapy if Hb <9.0 g/dl with resumption of placebo once Hb 9.0 g/dl Blinding maintained during computer directed adjustments assigning pre-filled syringes

23 Endpoints 2 composite primary endpoints* Cardiovascular composite: death, MI, myocardial ischemia, CHF, stroke. alpha Renal composite: death or ESRD. alpha *All endpoints centrally adjudicated committee unaware of treatment assignment and with hemoglobin and hematocrit values masked from source documents

24 Baseline Characteristics Variable % Darbepoetin alfa N = 2012 Placebo N = 2026 P-value Age (years) Women CVD history CAD Heart failure Myocardial infarction Stroke PAD Systolic BP mmhg Diastolic BP mmhg egfr ml/min/1.73 m Urine protein to creatinine ratio g/g creatinine Baseline Hb g/dl LDL mg/dl

25 Mean Hemoglobin (g/dl) Hemoglobin Levels Darbepoetin alfa Placebo Hb Median: 12.5 IQR [ ] Median dose: 176 μg IQR [ ] Mean: 225 μg ± Hb Median: 10.6 IQR [ ] Median dose: 0 μg IQR [0 5] Mean: 5 μg ± Month No. of Patients Darbepoetin alfa Placebo

26 Primary Composite and Component Endpoints Endpoint Darbepoetin alfa N = 2012 Placebo N = 2026 HR (95% CI) P- value CV Composite 632 (31.4) 602 (29.7) 1.05 ( ) 0.41 Death 412 (20.5) 395 (19.5) 1.05 ( ) 0.48 Heart Failure 205 (10.2) 229 (11.3) 0.89 ( ) 0.24 MI 124 (6.2) 129 (6.4) 0.96 ( ) 0.73 Stroke 101 (5.0) 53 (2.6) 1.92 ( ) <0.001 Myocardial Ischaemia 41 (2.0) 49 (2.4) 0.84 ( ) 0.40 Renal Composite 652 (32.4) 618 (30.5) 1.06 ( ) 0.29 ESRD 338 (16.8) 330 (16.3) 1.02 ( ) 0.83

27 Conclusions In patients with Type 2 DM, CKD and anaemia a strategy to treat anaemia with darbepoetin alfa: 1 : Did not reduce either primary composite endpoint of: Death and CV events or Death and ESRD Reduced RBC transfusion FACT-Fatigue modestly improved Higher stroke rates were documented Supports data from cancer studies of higher mortality For many, these risks will outweigh the rather modest potential benefits NEJM 2009

28 TREAT Selected subgroup preliminary analyses History of HF LVEF

29 Heart Failure in TREAT. Preliminary subgroup analysis Hx of HF N = 1347 No Hx of HF N = 2691 Placebo Darb HR Placebo Darb HR /100 patient-years /100 patient-years CV primary Death Fatal & nonfatal HF Stroke * * Preliminary, unpublished data. ESC 2010

30 Heart Failure in TREAT. Patients with baseline LVEF (n = 667, Median EF 52%) All with Hx of HF EF <40% N = 170 EF>40% N = 497 Placebo Darb HR Placebo Darb HR /100 patient-years /100 patient-years CV primary Death Fatal & nonfatal HF Death or HF Stroke * * Preliminary, unpublished data. ESC 2010

31 ESA use in Anemic Heart Failure Patients: Impact on Overall Mortality 9 Randomized, Placebo-controlled Trials of ESA treatment in patients with HF and anemia (n=2039) Study Risk ratio (95% CI) % Weight Mancini (2003) 1.69 (0.08,37.26) 0.3 Cleland (2005) 0.12 (0.01,2.67) 1.0 Ponikowski (2007) 1.16 (0.08,17.28) 0.4 Van Veldhuisen (2007) 6.56 (0.38,114.34) 0.3 Ghali (2008) 0.59 (0.29,1.21) 8.0 Parissis (2008) 0.11 (0.01,2.09) 1.4 Palazzuoli (2009) 0.62 (0.11,3.45) 1.4 Parissis (2009) 0.20 (0.01,3.85) 1.1 TREAT (2009) 1.10 (0.93,1.29) 86.2 (CKD + DM) Overall (95% CI) 1.03 (0.89,1.21) P= Risk ratio χ 2 for Heterogeneity = 10.11, p=0.26 Desai AS, et al. Eur J Heart Fail 2010

32 RED-HF Trial 2600 patients planned primary endpoint: morbidity and mortality target: 620 sites, 32 countries first patients in: July 2006 August 2010: ~ 2/3 of target enrolled

33 Anemia 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

34 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 uncertainty

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