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Drug therapy in HF &m anaging co-morbiditiesin HF: focus on iron deficiency
-- Delhi, 07. February 2015 --
Stefan D. Anker, MD PhD Dept. für Innovative Clinical Trials
Universitätsmedizin Göttingen (UMG)
Relevant co-morbidities in CHF that require medical attention
• CAD / ischemia
• Hypertension
• Diabetes mellitus
• Depression / other neurological disease
• Renal dysfunction and kidney injury
• Anemia and iron deficiency
• COPD
• Liver & bowel dysfunction
• Cachexia & muscle wasting
Relevant co-morbidities in CHF that require medical attention
• CAD / ischemia
• Hypertension
• Diabetes mellitus
• Depression / other neurological disease
• Renal dysfunction and kidney injury
• Anemia and iron deficiency
• COPD
• Liver & bowel dysfunction
• Cachexia & muscle wasting
Ageing, CHF, T2DM, COPD, CKD, Liver Failure,
Stroke & Cancer
Bigger lives longer
7
6
5
4
3
2
1
<22 22-25 25-30 30-35 ≥35 BMI (kg/m2)
Placebo group: Obesity is not a risk factor for
increased mortality
33 156 900 921 452 N
* p<0.05
HR for All-cause mortality
* *
PROactive: Baseline BMI vs all-cause mortality
Doehner et al. Int J Cardiol 2012
PROactive: BMI vs all-cause mortality
HR 95%CI P
Weight gain (1%) 1.02 0.95-1.08 0.61 Weight loss (1%) 1.15 1.11-1.18 0.0001
Placebo group
Excluding all episodes with oedema
HR 95%CI P
Weight gain (1%) 0.96 0.95-0.99 0.037 Weight loss (1%) 1.12 1.09-1.15 <0.0001
Pioglitazone group
BMI & outcome after stroke
Doehner W et al, EHJ 2013
MUSCLE = Fitness / QoL
BUT
MUSCLE & FAT = Survival
Similar results now are found in chronic renal failure, cancer and ageing.
Immune Activation / Inflammation Neuroendocrine Activation
Hormone Resistance Lack of Anabolism
Genetic Factors
Catabolic / Anabolic Imbalance
Common Pathophysiology of Cachexia
Cachexia and plasma angiotensin II
normal range 20 - 40 pg/mL
Controls nc-CHF c-AIDS c-CHF c-Liverfailure Starvation c-C ancer ideopathic
pg/mL similar results for norepinephrine
and aldosterone
Anker & Coats, unpublished
200
150
100
50
0
normal value < 40 pg/mL
CHF cachexia treatment development – the general approache –
Clinical Landscape in Cancer Cachexia – by Stage of Development Drug Development in Cancer Cachexia
12
Program Preclinical Phase 1 Phase 2 Phase 3 Company
Enobosarm (SARM) GTx
Anamorelin (oral GH secretagogue)
Helsinn
Xilonix (anti- IL-1α MAb) Xbiotech
MT-102 (dual action cat/anab transf agent)
PsiOxus
OHR/AVR118 (pept NAA, cytoprotectant, immunomodulator)
Ohr Pharm
Bimagrumab/BYM338 (Anti-Activin receptor-IIb MAb)
Novartis
LY2495655 (anti-myostatin MAb)
Lilly
Macimorelin (oral GH secretagogue)
Aeterna Zentaris
Clazakizumab /ALD-518 (anti-IL-6 MAb)
Alder Biosciences
APD-209 (proges(n/β2 agonist) Acacia Pharma
CK-2127107 (oral, sele, fast skel musc troponin activator)
Cytokinetics/ Astellas
IP-1510 (oral, IL-1 receptor antagonist)
Itis Pharma.
STM 434 (sol recep fused to part MAb blocking Activin-A)
ATARA
NINA 842 (myostatin MAb) ATARA
Treatment & preven(on of muscle was(ng in 1L NSCLC
NSCLC & CRC; 1˚weight gain
Adv cancers; 1˚ fxnal symptoms, PROs
NSCLC; 1˚ Hgb, LBM
Adv cancers; 1˚ ∆ quad size/strength
Cachexia in 1L NSCLC
Treatment of refractory CRC w/cachexia
NSCLC & Pancrea(c ca; 1˚aLBM
Pancrea(c ca, combo w/gem; 1˚OS
Adv cancers; 1˚
Dz assoc w/muscle weakness
Cancer cachexia
Ca cachexia
Ovarian Ca (not specific to cachexia)
Endpoints for Cachexia / Muscle Wasting Trials What are the options – my discussion slide
mortality / hospitalisation
QoL / symptoms / PGA
muscle performance
exercise capacity (pVO2, 6MWT)
weight / lean tissue gain (PoC)
appetite, food intake, QoL scores
SAFETY !! (mortality, PFS)
hand grip strength (Helsinn) stair climbing power (GTx)
SPPBT, gait speed
Relevant co-morbidities in CHF that require medical attention
• CAD / ischemia
• Hypertension
• Diabetes mellitus
• Depression / other neurological disease
• Renal dysfunction and kidney injury
• Anemia and iron deficiency
• COPD
• Liver & bowel dysfunction
• Cachexia & muscle wasting
Mechanisms of Anemia in Chronic Heart Failure & Chronic Kidney Failure
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 ↑
Haemodilution Plasma Volume ↑
Forward failure Bone marrow dysfunction
Iron deficiency Fe++ uptake ↓ inflammation induced malabsorption chron. bleeding (aspirin)
Iron Metabolism
p = 0.001
Iron stores: 35-45 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)
Iron loss: 1-2 mg / 24 h (every day !)
Iron uptake: 1-2 mg / 24 h (critical !)
Andrews NC, NEJM 1999
Inflammation, Hepcidin, Ferroportin & the regulation of iron metabolism
Hentze MW et al. Cell 2004;117:285–297
Macrophages (including in liver)
Intestine cells (Enterocytes)
Macrophages
Produced
Chyme Erythrocytes
↓O2 saturation
↑ Iron need
Iron status ↑ Inflammation
Bone Marrow
Liver
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
Absolute & functional iron deficiency – definitions
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 30–99 µg/L or serum ferritin 100–299 µg/L and TSAT<20%
1. Wish JB. Clin J Am Soc Nephrol 2006;1:S4–8. 2. Muñoz M, et al. World J Gastroenterol 2009;15:4617–26.
Anemia (Hb <12 g/dL)
ID-Anemia
Iron Deficiency (without anemia)
Functional Iron Deficiency = poor Prognosis definition: serum ferritin <100 µg/L or <300 µg/L, if TSAT <20%
0 100 200 300 400 500 600 700
Endpoint: Death & HF hospitalisation
Follow-up (days)
ID (n=64)
Non-ID (n=103)
HR 2.9 (95%CI: 1.6-5.1) P<0.001
0
20
40
60
80
100 Prevalence of ID in CHF patients
20
40
60
79 / 182 (43%)
22 / 36 (61%)
% of CHF pts
Non-anaemics Anaemics (Hb ≤ 12 g /dL)
Jankowska et al., EHJ 2010 Grzeslo A et al. (abstract at HFA 2006)
ID in Asian CHF patients & Controls (Singapore)
Yeo TJ et al. & Lam CS. Eur J Heart Fail. 2014;16:1125-32.
N= 751 HF patients & 601 community-based controls
Iron deficiency = a special issue
in India
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 2000 7;5,:1147-60 2 – Zijp IM et al. Crit Rev Food Sci Nutr 2000;40:371-98
3 – Nelson M et al. J Hum Nutr Diet 2004;7:43–54
Iron in food (in Asia)
From: The American Dietetic Association’s COMPLETE FOOD & NUTRITION GUIDE, 2nd ed. 2002. USDA National Nutrient Database
Iron in food (in Asia)
From: The American Dietetic Association’s COMPLETE FOOD & NUTRITION GUIDE, 2nd ed. 2002. USDA National Nutrient Database
Top 7 vegetarian foods for Asia by iron content - Fortified cereals - Pumkin seeds - Soybean nuts - Spinach - Red kidney beans - Tofu - Enriched rice
Polynuclear iron– oxyhydroxide core
The structure of intravenous iron
• 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.
Carbohydrate shell – Gluconate – Dextran – Sucrose (Phase 2) – Carboxymaltose (Phase 3)
Filippatos G, et al. Eur J Heart Fail 2013;1:1267-76.
Overall Patients with anaemia (Hb ≤120 g/L)
Patients without anaemia (Hb >120 g/L)
Correction phase
Maintenance phase
Correction phase
Maintenance phase
Number of patients 300 154 139 146 136
Mean ±SD dose (mg iron) 1850±433 1105±291 840±199 985±216 915±114
Median dose (mg iron) 2000 1100 800 1000 1000
Dose range (mg iron) 200–2400 200–1900 200–1000 200–1600 400–1000
Dosing
NYHA, PGA, QoL, 6min-Walking-Test -- Week 4, 12 & 24 --
Patient Global Assessment NYHA functional class
6-minute walk test KCCQ overall score EQ-5D VAS score
Anker et al, NEJM 2009;361:2436-2448
Co-Primary Endpoints
50% vs 27% much/moderate better
P<0.0001
47% vs 30% In NYHA I / II
P<0.0001
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±1 0.21
*Mean treatment effect, adjusted for the baseline value
Anker et al, NEJM 2009;361:2436-2448
Anemia & iron deficiency & organ performance
Haas JD & Brownlie T. J Nutr 2001;131(2 suppl 2):676S–690S; Dallman PR. J Intern Med 1989;226:367–372; Willis WT & Dallman PR. Am J Physiol 1989;257:C1080–1085;
Figure adapted from: Anker et al. EJHF 2009
organ performance
ATP O2
Hb
Iron deficiency
Mitochondrion Oxidative phosphorylation
Aerobic enzymes
O2 utilization O2 delivery
(i.e. anemia)
Effect of iv-iron on kidney function
* LSM mean ± SE
Treatment effect (mL/min/1.73m2):* 2.8 ± 1.5 3.0 ± 1.5 4.0 ± 1.7
P=0.054 P=0.049 P=0.017
weeks after randomization
Change in eGFR from baseline
(mL/min.1.73m2)
Ponikowski et al. 2015 (in press)
Clinicaltrials.gov identifier: NCT01453608.
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
• 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
Placebo
n=300 Screening
R
D0
1° EP: 6MWT
W6 W12 W24 W36 W52
Safety EP
FCM up to 2000mg (2x1000mg)
Treatment continues if ID is not corrected
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)
Baseline characteristics (1/2)
*mean (SD)
FCM (N=150)
Placebo (N=151)
Concomitant medications 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/1.73m2 * 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)
Baseline characteristics (2/2)
*mean (SD)
FCM improved 6MWT at week 24 FCM vs placebo: 33 ± 11 m (least squares mean ± SE)
P=0.002
Week 24
LSM
cha
nge
in 6
MW
T di
stan
ce
from
bas
elin
e (m
)
FCM Placebo
30
20
10
0
-10
-20
-30
Primary endpoint: change in 6-minutes walking distance at Week 24
A PubMed search for “6 minute walk test & heart failure & mortality”
results in 142 hits (05.02.2015, 8pm)
The Clinical Meaning of the 6-minute Walking Test Distance
6-minute walking test distance has been used to approve therapies
Primary endpoint: Subgroup analyses
P-value for interaction
Difference FCM-placebo in 6MWT distance in m
LSM (95% CI)
150 100 50 0 -50
0.933
0.960
0.710
0.510
0.086
P-value for interaction
Difference FCM-placebo in 6MWT distance in m
LSM (95% CI)
Subgroup No. of patients FCM/placebo
Median age *
Age high (≥71 years) 65/55
Age low (<71 years) 65/76
Median BNP
BNP high (≥425 pg/mL) 66/61
BNP low (<425 pg/mL) 64/70
NYHA function class
Class III 60/52
Class II 70/79
Heart failure aetiology
Non-ischaemic 20/21
Ischaemic 110/110
Median LVEF (%)
LVEF high (≥40) 75/64
LVEF (<40) 54/67
Subgroup No. of patients FCM/placebo
Estimated GFR
eGFR ≥60 mL/min/1.732 85/72
eGFR <60 mL/min/1.732 45/59
Gender
Male 73/64
Female 57/67
Median ferritin *
Ferritin high (≥46 ng/mL) 65/63
Ferritin low (<46 ng/mL) 65/68
Diabetes
No 98/96
Yes 32/35
Haemoglobin
Haemoglobin ≥12 g/dL 86/83
Haemoglobin <12 g/dL 44/48
0.042
0.680
0.900
0.040
0.150
* Defined post-hoc
150 100 50 0 -50
Self-reported Patient Global Assessment (PGA) score
New York Heart Association Functional (NYHA) class
Odd
s ra
tio (9
5% C
I)
FCM
bet
ter
Pla
cebo
be
tter
P=0.29
P=0.035 P=0.047
P=0.001 P=0.001
0
0.5
1
1.5
2
2.5
3
3.5
4
6 12 18 24 30 42 36 48 52 Weeks since randomization
Odd
s ra
tio (9
5% C
I)
FCM
bet
ter
Pla
cebo
be
tter
P=0.067 P=0.093
P=0.004
P<0.001 P<0.001
0
2
4
6
8
Weeks since randomization
12
10
Secondary endpoints: Changes in PGA & NYHA class over time
6 12 18 24 30 42 36 48 52
No. of patients FCM
Placebo
144 147
137 148
131 130
123 124
127 119
No. of patients FCM
Placebo
144 149
137 148
132 132
123 125
127 121
Weeks since randomisation
Weeks since randomisation
Secondary endpoints: Changes in 6MWT and Fatigue score over time
14
(–5, 33)
16 (–3, 35)
33 (13, 53)
42 (21, 62)
36 (16, 57)
FCM Placebo
30 20
0 -10 -20
10
-30 -40
6MW
T ch
ange
from
ba
selin
e LS
M
BL 6 12 18 24 30 36 42 48 52
P=0.16 P=0.10 P=0.001 P<0.001 P<0.001
40
Fatig
ue s
core
cha
nge
from
bas
elin
e LS
M
Weeks since randomisation
Weeks since randomisation -1.4
-0.6 -0.8 -1.0 -1.2
-0.4 -0.2
0.2 P=0.40 P=0.002
P=0.009 P=0.002 P<0.001
24 12
0
BL 6 18 30 36 42 48 52
FCM vs placebo LSM (95% CI)
6min-walking-test distance
Fatigue score
–0.2
(–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)
FCM vs placebo LSM (95% CI)
Secondary endpoints: Changes in Quality of Life over time
Weeks since randomisation O
vera
ll K
CC
Q s
core
cha
nge
from
bas
elin
e LS
M
P=0.035 P=0.41
P=0.004 P=0.010 10
EQ-5D VAS score
EQ
-5D
VA
S c
hang
e fro
m
base
line
LSM
P=0.080 P=0.002 P=0.120 10
8
6
4
2
0 Weeks since randomization
FCM Placebo
FCM vs placebo LSM (95% CI)
1.8 (–1.2, 4.8)
3.3 (0.2, 6.4)
1.3 (–1.9, 4.6)
5.0 (1.6, 8.3)
4.5 (1.1, 7.9)
FCM vs placebo LSM (95% CI)
1.5 (–1.4, 4.4)
2.8 (–0.2, 5.8)
2.8 (–0.3, 5.9)
5.2 (2.0, 8.5)
2.6 (–0.7, 5.9)
BL 6 12 18 24 30 36 42 48 52
P=0.25 8 6 4 2 0
-2
BL 6 12 18 24 30 36 42 48 52
P=0.30 P=0.067
KCCQ
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 12 12 (8.9) 14 14 (9.9) 0.89 (0.41 – 1.93) 0.77
Death for any CV reason 11 11 (8.1) 12 12 (8.5) 0.96 (0.42 – 2.16) 0.91
Hospitalisation 46 32 (26.3) 69 44 (37.0) 0.71 (0.45 – 1.12) 0.14
Hospitalisation for any CV reason 26 21 (16.6) 51 33 (26.3) 0.63
(0.37 – 1.09) 0.097
Hospitalisation due to worsening HF 10 10 (7.6) 32 25 (19.4) 0.39
(0.19 – 0.82) 0.009
FCM reduced the risk of recurrent hospitalisations due to worsening HF (post hoc): Incidence Rate Ratio (95% CI) – 0.30 (0.14-0.64), p=0.0019
Secondary endpoint: First hospitalization due to worsening HF
No. of subjects at risk
Placebo 151 138 127 117 78
FCM 150 140 131 126 77
10
20
30
Cumulative Hospitalization Rate (in %)
0 180 270 360 90 0
Time (days)
Placebo
FCM
Log–rank test P=0.009
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 2012:14:803–869
Iron Deficiency Treatment Recommendations
McMurray JJ, et al. Eur J Heart Fail 2012:14:803–869
CHF – Consolidating the Evidence
FAIR-HF CONFIRM-HF
EFFECT-HF iCHF 2
Meta-analysis II (syst CHF)
Meta-analysis III (all CHF) FAIR-HFpEF 1
Meta-analysis II (syst CHF) Meta-analysis III (CHF)
Sym
ptom
, QoL
, Fun
ctio
n M
orta
lity
syst
diast
Meta-analysis I (syst CHF/double-blind)
Meta-analysis I (syst CHF/double-blind)
FAIR-HF2 (M&M) 3
IRONMAN 4 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
Anker SD et al. N Eng J Med 2009;361:2436-4 Ponikowski P et al. Eur Heart J 2014 Epub ahead of print
Clinicaltrials.gov identifier: NCT01394562 & Ferinject® SmPC
Iron
Deficiency Treatment
FCM: 1000-2000mg
single or more doses of 500-1000mg to correct ID
check ferritin/TSAT within
next scheduled visit (preferable 1-3 months)
FCM: 500mg
to maintain ferritin/TSAT on target
check ferritin/TSAT if change
in clinical picture or Hb decrease or 1-2x/year
FCM: weekly 200mg single doses to correct ID according Ganzoni formula
check ferritin/TSAT within next scheduled visit
(preferable 1-3 months)
FCM: 4-weekly 200mg single doses for
maintenance
Evidence-based as used in CONFIRM-HF
Suggested treatment algorithm
Evidence-based as used in FAIR-HF
2015 Annual HFA Meeting focus on new therapies & the HF team
23-26 May 2015, Seville / Spain
www.escardio.org
Where will be more information ?
ESC Heart Failure Open Access
Launched in 2014 – in PubMed in 2015. Editor-in-Chief: SD Anker
Where you can publish on HF & everyone will see it !
www.escardio.org [email protected]
