Stefan D. Anker, MD PhD

Transcription

1 Drug therapy in HF &m anaging co-morbidities in HF: focus on iron deficiency -- Delhi, 07. February Stefan D. Anker, MD PhD Dept. für Innovative Clinical Trials Universitätsmedizin Göttingen (UMG)

2 CAD / ischemia Hypertension Diabetes mellitus Relevant co-morbidities in CHF that require medical attention Depression / other neurological disease Renal dysfunction and kidney injury Anemia and iron deficiency COPD Liver & bowel dysfunction Cachexia & muscle wasting

3 CAD / ischemia Hypertension Diabetes mellitus Relevant co-morbidities in CHF that require medical attention Depression / other neurological disease Renal dysfunction and kidney injury Anemia and iron deficiency COPD Liver & bowel dysfunction Cachexia & muscle wasting

4 Bigger lives longer Ageing, CHF, T2DM, COPD, CKD, Liver Failure, Stroke & Cancer

5 PROactive: Baseline BMI vs all-cause mortality HR for All-cause mortality Placebo group: Obesity is not a risk factor for increased mortality * * * p< N < BMI (kg/m 2 ) Doehner et al. Int J Cardiol 2012

6 PROactive: BMI vs all-cause mortality Excluding all episodes with oedema Placebo group HR 95%CI P Weight gain (1%) Weight loss (1%) Pioglitazone group HR 95%CI P Weight gain (1%) Weight loss (1%) <0.0001

7 BMI & outcome after stroke Doehner W et al, EHJ 2013

8 MUSCLE = Fitness / QoL BUT MUSCLE & FAT = Survival Similar results now are found in chronic renal failure, cancer and ageing.

9 Common Pathophysiology of Cachexia Catabolic / Anabolic Imbalance Immune Activation / Inflammation Neuroendocrine Activation Hormone Resistance Lack of Anabolism Genetic Factors

10 Cachexia and plasma angiotensin II 200 pg/ml similar results for norepinephrine and aldosterone normal value < 40 pg/ml normal range pg/ml Controls nc-chf c-aids c-chf c-liverfailure Starvation c-c ancer ideopathic Anker & Coats, unpublished

11 CHF cachexia treatment development the general approache

12 Clinical Landscape in Cancer Cachexia by Stage of Drug Development in Cancer Cachexia Development Program Preclinical Phase 1 Phase 2 Phase 3 Company Enobosarm (SARM) Anamorelin (oral GH secretagogue) Xilonix (anti- IL-1 α MAb) MT-102 (dual action cat/ anab transf agent) OHR/AVR118 (pept NAA, cytoprotectant, immunomodulator) Bimagrumab/BYM338 (Anti- Activin receptor-iib MAb) LY (anti-myostatin MAb) Macimorelin (oral GH secretagogue) Clazakizumab /ALD-518 (anti-il-6 MAb) APD-209 (proges(n/β 2 agonist) CK (oral, sele, fast skel musc troponin activator) IP-1510 (oral, IL-1 receptor antagonist) STM 434 (sol recep fused to part MAb blocking Activin-A) NINA 842 (myostatin MAb) Treatment & preven(on of muscle was(ng in 1L NSCLC Cachexia in 1L NSCLC Treatment of refractory CRC w/cachexia NSCLC & CRC; 1 weight gain Adv cancers; 1 fxnal symptoms, PROs NSCLC & Pancrea(c ca; 1 albm Pancrea(c ca, combo w/gem; 1 OS Adv cancers; 1 NSCLC; 1 Hgb, LBM Adv cancers; 1 quad size/strength Dz assoc w/muscle weakness Cancer cachexia Ovarian Ca (not specific to cachexia) Ca cachexia 12 GTx Helsinn Xbiotech PsiOxus Ohr Pharm Novartis Lilly Aeterna Zentaris Alder Biosciences Acacia Pharma Cytokinetics/ Astellas Itis Pharma. ATARA ATARA

13 Endpoints for Cachexia / Muscle Wasting Trials What are the options my discussion slide mortality / hospitalisation QoL / symptoms / PGA muscle performance hand grip strength (Helsinn) stair climbing power (GTx) SPPBT, gait speed exercise capacity (pvo 2, 6MWT) weight / lean tissue gain (PoC) appetite, food intake, QoL scores SAFETY!! (mortality, PFS)

14 CAD / ischemia Hypertension Diabetes mellitus Relevant co-morbidities in CHF that require medical attention Depression / other neurological disease Renal dysfunction and kidney injury Anemia and iron deficiency COPD Liver & bowel dysfunction Cachexia & muscle wasting

15 Mechanisms of Anemia in Chronic Heart Failure & Chronic Kidney Failure Haemodilution Plasma Volume Forward failure Bone marrow dysfunction Iron deficiency Fe ++ uptake inflammation induced malabsorption chron. bleeding (aspirin) Chronic immune activation TNF alpha - production of Epo - Epo activity in BM Drugs ACE-I: Epo synthesis Epo activity in BM Chronic kidney failure Production of Epo Loss in urine

16 Iron Metabolism Iron stores: mg/kg BW Iron distribution: Blood Transferrin (3 mg) Hemoglobin (bone marrow & erythrocyts, 1800 mg) Storage: mainly liver (1000 mg) & RES (600 mg) Muscle Myoglobin (300 mg) p = Iron loss: 1-2 mg / 24 h (every day!) Iron uptake: 1-2 mg / 24 h (critical!) Andrews NC, NEJM 1999

17 Inflammation, Hepcidin, Ferroportin & the regulation of iron metabolism O 2 saturation Iron need Bone Marrow Liver Produced Iron status Inflammation Erythrocytes Chyme Macrophages Macrophages (including in liver) Intestine cells (Enterocytes) Hentze MW et al. Cell 2004;117:

18 Iron deficiency is an underestimated cause of anaemia in CHF Patients with anaemia and advanced CHF n=37 NYHA: IV LVEF: 22% Ferritin: 113 ng/ml Bone-marrow biopsy confirmed ID in 73% (27/37) of patients MCV, MCH and serum ferritin concentration significantly lower in patients with ID compared with patients without ID Nanas JN et al.; JACC 2006

19 Absolute & functional iron deficiency definitions Anemia (Hb <12 g/dl) ID-Anemia Iron Deficiency (without anemia) 1. Absolute iron deficiency (Reduction in iron stores) Causes: chronic blood loss (aspirin), malnutrition, malabsorption Diagnosis: low serum ferritin level <30 µg/l 2. Functional iron deficiency (Disturbed iron metabolism in bone marrow; iron stores =/ ) Causes: chronic inflammation & kidney dysfunction Diagnosis: serum ferritin µg/l or serum ferritin µg/l and TSAT<20% 1. Wish JB. Clin J Am Soc Nephrol 2006;1:S Muñoz M, et al. World J Gastroenterol 2009;15:

20 Functional Iron Deficiency = poor Prognosis definition: serum ferritin <100 µg/l or <300 µg/l, if TSAT <20% Prevalence of ID in CHF patients % of CHF pts Endpoint: Death & HF hospitalisation Non-ID (n=103) / 182 (43%) 22 / 36 (61%) ID (n=64) HR 2.9 (95%CI: ) P< Non-anaemics Anaemics (Hb 12 g /dl) Follow-up (days) Jankowska et al., EHJ 2010 Grzeslo A et al. (abstract at HFA 2006)

21 ID in Asian CHF patients & Controls (Singapore) N= 751 HF patients & 601 community-based controls Yeo TJ et al. & Lam CS. Eur J Heart Fail. 2014;16:

22 Iron deficiency = a special issue in India

23 Food intake, tea & iron 150 ml black tea within 1 hour of a meal will reduce absorption by 75 80% 1 Note: Black tea is ~2x as inhibiting as green tea or peppermint tea and >3x as inhibiting as herbal tea Factor associated with tea drinking and other inhibiting dietary factors (phytate, coffee and calcium in the meal) 2 Prevalence of microcytic anemia amongst tea drinkers was much greater (32.6%) than amongst non tea drinkers (3.5%) 3 What to do? Have 1hr between meal and tea drinking. 1 Hallberg ll et al. Am. J Clin Nutr ;5,: Zijp IM et al. Crit Rev Food Sci Nutr 2000;40: Nelson M et al. J Hum Nutr Diet 2004;7:43 54

24 Iron in food (in Asia) From: The American Dietetic Association s COMPLETE FOOD & NUTRITION GUIDE, 2nd ed USDA National Nutrient Database

25 Iron in food (in Asia) Top 7 vegetarian foods for Asia by iron content - Fortified cereals - Pumkin seeds - Soybean nuts - Spinach - Red kidney beans - Tofu - Enriched rice From: The American Dietetic Association s COMPLETE FOOD & NUTRITION GUIDE, 2nd ed USDA National Nutrient Database

26 The structure of intravenous iron Polynuclear iron oxyhydroxide core Carbohydrate shell Gluconate Dextran Sucrose (Phase 2) Carboxymaltose (Phase 3) Dextran can cause anaphylactic reactions Larger/heavier iron carbohydrate complexes are more stable than smaller/lighter complexes Macdougall IC. J Ren Care 2009;35 Suppl 2:8 13.

27 Dosing Overall Patients with anaemia (Hb 120 g/l) Correction phase Maintenance phase Patients without anaemia (Hb >120 g/l) Correction phase Maintenance phase Number of patients Mean ±SD dose (mg iron) 1850± ± ± ± ±114 Median dose (mg iron) Dose range (mg iron) Filippatos G, et al. Eur J Heart Fail 2013;1:

28 NYHA, PGA, QoL, 6min-Walking-Test -- Week 4, 12 & Patient Global Assessment 50% vs 27% much/moderate better P< NYHA functional class 47% vs 30% In NYHA I / II P< Co-Primary Endpoints 6-minute walk test KCCQ overall score EQ-5D VAS score Anker et al, NEJM 2009;361:

29 iv-fcm improves PGA & NYHA class in CHF patients with and without anemia week 24 results FCM Placebo p value* Patients with anaemia (at BL) Serum ferritin (μg/l) 275±18 68±11 <0.001 TSAT (%) 29±1 17±1 <0.001 Haemoglobin (g/l) 127±1 118±2 <0.001 Patients without anaemia (at BL) Serum ferritin (μg/l) 349±19 80±11 <0.001 TSAT (%) 30±1 22±1 <0.001 Haemoglobin (g/l) 133±1 132± *Mean treatment effect, adjusted for the baseline value Anker et al, NEJM 2009;361:

30 Anemia & iron deficiency & organ performance Iron deficiency (i.e. anemia) Hb Aerobic enzymes Mitochondrion O 2 delivery O 2 ATP O 2 utilization Oxidative phosphorylation organ performance Haas JD & Brownlie T. J Nutr 2001;131(2 suppl 2):676S 690S; Dallman PR. J Intern Med 1989;226: ; Willis WT & Dallman PR. Am J Physiol 1989;257:C ; Figure adapted from: Anker et al. EJHF 2009

31 Effect of iv-iron on kidney function Change in egfr from baseline (ml/min.1.73m 2 ) P=0.054 P=0.049 P=0.017 Treatment effect (ml/min/1.73m 2 ):* 2.8 ± ± ± 1.7 weeks after randomization * LSM mean ± SE Ponikowski et al (in press)

32 CONFIRM-HF Design Design: Multicentre, randomized (1:1), double-blind, placebo-controlled Main inclusion criteria: NYHA class II / III, LVEF 45% BNP > 100 pg/ml or NT-proBNP > 400 pg/ml Iron deficiency: serum ferritin <100 µg/l or <300 µg/l, if TSAT <20% Hb 15 g/dl FCM up to 2000mg (2x1000mg) Treatment continues if ID is not corrected Screening R n=300 Placebo 1 EP: 6MWT Safety EP D0 W6 W12 W24 W36 W52 Primary endpoint ü Exercise capacity: change in 6MWT distance from baseline at week 24 Secondary endpoints ü Change in biomarkers for iron deficiency, cardiac biomarkers, NYHA functional class, PGA and QoL ü Overall safety over the treatment period Clinicaltrials.gov identifier: NCT

33 Baseline characteristics (1/2) FCM (N=150) Placebo (N=151) Age yrs * 68.8 (9.5) 69.5 (9.3) Female n (%) 67 (45) 74 (49) NYHA class II n (%) 80 (53) 91 (60) NYHA class III n (%) 70 (47) 60 (40) LVEF % * 37.1 (7.5) 36.5 (7.3) Ischemic aetiology n (%) 125 (83) 126 (83) 6MWT m * 288 (98) 309 (97) Medical history Hypertension n (%) 130 (87) 130 (86) Atrial fibrillation n (%) 66 (44) 73 (48) Diabetes mellitus n (%) 38 (25) 45 (30) Myocardial infarction n (%) 90 (60) 90 (60) *mean (SD)

34 Baseline characteristics (2/2) Concomitant medications FCM (N=150) Placebo (N=151) Diuretics n (%) 132 (88) 139 (92) ACEi/ARB n (%) 143 (95) 143 (95) Beta-Blocker n (%) 133 (89) 139 (92) Aldosterone inhibitors n (%) 90 (60) 88 (58) Laboratory parameters BNP pg/ml * 772 (995) 770 (955) NT-proBNP pg/ml * 2511 (5006) 2600 (4555) Estimated GFR ml/min/1.73m 2 * 55.1 (10.6) 53.5 (11.2) Hb g/dl * 12.4 (1.4) 12.4 (1.3) Ferritin ng/ml * 57.0 (48.4) 57.1 (41.6) <100 ng/ml n (%) 136 (91) 133 (88) TSAT % * 20.2 (17.6) 18.2 (8.1) *mean (SD)

35 Primary endpoint: change in 6-minutes walking distance at Week 24 FCM improved 6MWT at week 24 FCM vs placebo: 33 ± 11 m (least squares mean ± SE) LSM change in 6MWT distance from baseline (m) P=0.002 FCM Placebo -30 Week 24

36 The Clinical Meaning of the 6-minute Walking Test Distance A PubMed search for 6 minute walk test & heart failure & mortality results in 142 hits ( , 8pm) 6-minute walking test distance has been used to approve therapies

37 Primary endpoint: Subgroup analyses Subgroup No. of patients FCM/placebo P-value for interaction Subgroup No. of patients FCM/placebo P-value for interaction Median age * Estimated GFR Age high ( 71 years) 65/55 Age low (<71 years) 65/ egfr 60 ml/min/ /72 egfr <60 ml/min/ / Median BNP Gender BNP high ( 425 pg/ml) 66/ Male 73/ BNP low (<425 pg/ml) 64/70 Female 57/67 NYHA function class Median ferritin * Class III 60/ Ferritin high ( 46 ng/ml) 65/ Class II 70/79 Ferritin low (<46 ng/ml) 65/68 Heart failure aetiology Diabetes Non-ischaemic 20/21 Ischaemic 110/ No 98/96 Yes 32/ Median LVEF (%) Haemoglobin LVEF high ( 40) 75/64 LVEF (<40) 54/ Haemoglobin 12 g/dl 86/83 Haemoglobin <12 g/dl 44/ Difference FCM-placebo in 6MWT distance in m LSM (95% CI) Difference FCM-placebo in 6MWT distance in m LSM (95% CI) * Defined post-hoc

38 Secondary endpoints: Changes in PGA & NYHA class over time Self-reported Patient Global Assessment (PGA) score Odds ratio (95% CI) FCM better Placebo better No. of patients FCM Placebo P=0.29 P=0.035 P=0.047 P=0.001 P= Weeks since randomization Weeks since randomisation New York Heart Association Functional (NYHA) class Odds ratio (95% CI) FCM better Placebo better No. of patients FCM Placebo P=0.093 P=0.067 P=0.004 P<0.001 P< Weeks since randomization Weeks since randomisation

39 Secondary endpoints: Changes in 6MWT and Fatigue score over time 6MWT change from baseline LSM FCM vs placebo LSM (95% CI) P=0.16 BL ( 5, 33) 6min-walking-test distance P= ( 3, 35) P= (13, 53) P< (21, 62) P< (16, 57) Weeks since randomisation FCM Placebo Fatigue score change from baseline LSM FCM vs placebo LSM (95% CI) Fatigue score P= P=0.40 P=0.002 P< P= Weeks since -1.4 randomisation BL ( 0.5, 0.2) 0.5 ( 0.9, 0.1) 0.6 ( 1.0, 0.2) 0.8 ( 1.2, 0.4) 0.7 ( 1.1, 0.2)

40 Secondary endpoints: Changes in Quality of Life over time Overall KCCQ score change from baseline LSM FCM vs placebo LSM (95% CI) P= ( 1.2, 4.8) P= (0.2, 6.4) KCCQ P=0.41 P=0.004 P=0.010 BL ( 1.9, 4.6) 5.0 (1.6, 8.3) 4.5 (1.1, 7.9) Weeks since randomisation FCM Placebo EQ-5D VAS score EQ-5D VAS change from baseline LSM FCM vs placebo LSM (95% CI) P= ( 1.4, 4.4) P= ( 0.2, 5.8) P= ( 0.3, 5.9) P= (2.0, 8.5) P=0.120 BL ( 0.7, 5.9) Weeks since randomization

41 Secondary endpoints: Outcome events FCM (N=150) Placebo (N=151) End-point or event Total events (n) Incidence/ (100 patient risk-year) Total events (n) Incidence/ (100 patient risk-year Time to first event Hazard ratio 95% CI P- value Death (8.9) (9.9) Death for any CV reason (8.1) (8.5) Hospitalisation (26.3) (37.0) 0.89 ( ) 0.96 ( ) 0.71 ( ) Hospitalisation for any CV reason (16.6) (26.3) 0.63 ( ) Hospitalisation due to worsening HF (7.6) (19.4) 0.39 ( ) FCM reduced the risk of recurrent hospitalisations due to worsening HF (post hoc): Incidence Rate Ratio (95% CI) 0.30 ( ), p=0.0019

42 Secondary endpoint: First hospitalization due to worsening HF Cumulative Hospitalization Rate (in %) 30 Placebo FCM Log rank test P= Time (days) No. of subjects at risk Placebo FCM

43 ESC Guidelines on HF 2012 Measurement of iron parameters are newly recommended (1C) as standard for the diagnosis in ambulatory patients suspected of having HF: In addition to standard biochemical [sodium, potassium, creatinine/ estimated glomerular filtration rate (egfr)] and haematological tests (haemoglobin, haematocrit, ferritin, leucocytes, and platelets), TSAT= Serum iron/tibcx100 TIBC = Total Iron-Binding Capacity McMurray JJ, et al. Eur J Heart Fail 2012:14:

44 Iron Deficiency Treatment Recommendations McMurray JJ, et al. Eur J Heart Fail 2012:14:

45 CHF Consolidating the Evidence syst diast Meta-analysis III (all CHF) FAIR-HFpEF 1 Meta-analysis II (syst CHF) ichf 2 EFFECT-HF Meta-analysis I (syst CHF/double-blind) CONFIRM-HF FAIR-HF Symptom, QoL, Function 1 IIT, fundet by grant from Vifor 2 IIT, fundet by grant from Vifor 3 IIT, fundet by grant from German CV Research Center 4 IIT, fundet by grant from UK NHS Meta-analysis I (syst CHF/double-blind) Meta-analysis II (syst CHF) Meta-analysis III (CHF) FAIR-HF2 (M&M) 3 IRONMAN 4 Mortality

46 Suggested treatment algorithm Evidence-based as used in FAIR-HF Iron Deficiency Treatment Evidence-based as used in CONFIRM-HF FCM: weekly 200mg single doses to correct ID according Ganzoni formula check ferritin/tsat within next scheduled visit (preferable 1-3 months) FCM: mg single or more doses of mg to correct ID check ferritin/tsat within next scheduled visit (preferable 1-3 months) FCM: 4-weekly 200mg single doses for maintenance FCM: 500mg to maintain ferritin/tsat on target check ferritin/tsat if change in clinical picture or Hb decrease or 1-2x/year Anker SD et al. N Eng J Med 2009;361: Ponikowski P et al. Eur Heart J 2014 Epub ahead of print Clinicaltrials.gov identifier: NCT & Ferinject SmPC

47 Where will be more information? 2015 Annual HFA Meeting focus on new therapies & the HF team May 2015, Seville / Spain

48 Where you can publish on HF & everyone will see it! ESC Heart Failure Open Access Launched in 2014 in PubMed in Editor-in-Chief: SD Anker