Effect of ferric carboxymaltose on functional capacity in patients - - PowerPoint PPT Presentation

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Effect of ferric carboxymaltose on functional capacity in patients - - PowerPoint PPT Presentation

Jan 05, 2024 432 likes •664 views

Effect of ferric carboxymaltose on functional capacity in patients with heart failure and iron deficiency (CONFIRM-HF) Piotr Ponikowski , Dirk J. van Veldhuisen, Josep Comin-Colet Georg Ertl, Michel Komajda, Viacheslav Mareev Theresa McDonagh,

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SLIDE 1

Effect of ferric carboxymaltose

  • n functional capacity in patients

with heart failure and iron deficiency (CONFIRM-HF)

Piotr Ponikowski, Dirk J. van Veldhuisen, Josep Comin-Colet Georg Ertl, Michel Komajda, Viacheslav Mareev Theresa McDonagh, Alexander Parkhomenko, Luigi Tavazzi Victoria Levesque, Claudio Mori, Bernard Roubert Gerasimos Filippatos, Frank Ruschitzka, Stefan D. Anker for the CONFIRM-HF Investigators. Sponsor: Vifor Pharma Ltd.

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SLIDE 2

Presenter Conflict of Interest Disclosures

  • Honoraria from Vifor Pharma Ltd as member of the

CONFIRM-HF Steering Committee

  • Consultancy and speakers bureau from Vifor Pharma Ltd

and Amgen Inc

  • Research grant from Vifor Pharma Ltd
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SLIDE 3

Treatment of iron deficiency: Attractive therapeutic target in heart failure?

  • Iron deficiency (ID) – frequent co-morbidity in stable HF

and in patients admitted to hospital due to HF worsening

  • HF complicated with ID – associated with impaired

functional capacity, poor quality of life and increased mortality

  • Deleterious consequences of ID in HF syndrome are

irrespective of anaemia

  • Correction of ID itself as an attractive therapeutic target

in HF – hypothesis recently being tested in clinical studies

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SLIDE 4
  • Longer-term sustainability of beneficial effects and

safety

  • Potential impact on the outcomes

Uncertainties on the appropriate use

  • f iron in heart failure

To address these questions we designed CONFIRM-HF study

(Ferric CarboxymaltOse evaluatioN on perFormance in patients with IRon deficiency in coMbination with chronic Heart Failure)

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SLIDE 5

CONFIRM-HF Study design

  • Design: Multicentre, randomised (1:1), double-blind, placebo-controlled
  • Main inclusion criteria:

ü NYHA class II / III, LVEF ≤45% ü BNP > 100 pg/mL or NT-proBNP > 400 pg/mL

ü Iron deficiency: serum ferritin <100 ng/mL or 100-300 ng/mL if TSAT <20%

ü Hb < 15 g/dL

  • Blinding:

ü Clinical staff: unblinded and blinded personnel ü Patients: usage of curtains and black syringes for injections FCM up to 2000mg (2 x 500-1000mg i.v.) FCM treatment continues if ID is not corrected (500mg i.v.)

Ponikowski P et al. ESC Heart Fail J 2014, in press

Correction phase Maintenance phase Placebo Screening D0

1° EP: 6MWT

W6 W12 W24 W36 W52 Ferric Carboxymaltose (FCM)

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SLIDE 6

Primary & key secondary endpoints

  • Primary:

– Change in 6-minute walking test (6MWT) distance from

baseline to Week 24

  • Key secondary:

– 6MWT distance at Week 6, 12, 36 and 52 – PGA score and NYHA class at Week 6, 12, 24, 36 and 52 – KCCQ, EQ-5D and Fatigue scores at Week 6, 12, 24, 36 and 52 – Outcome-related secondary endpoints:

  • hospitalisation rate (all hospitalisation, for any CV reason, due to worsening HF)
  • time to first hospitalisation (all hospitalisation, for any CV reason, due to worsening HF)
  • time to death (any death, death for any CV reason, due to worsening HF)
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SLIDE 7

Participating countries

304 randomized subjects 9 countries 41 sites

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SLIDE 8

151 received Placebo 128 completed 304 randomly allocated

152 allocated to FCM 152 received FCM

152 Safety Analysis Set

2 excluded from the Full Analysis Set

(lack of any post-baseline efficacy assessment)

150 Full Analysis Set

1 excluded from the Full Analysis Set

(lack of any post-baseline efficacy assessment)

151 Full Analysis Set

152 allocated to Placebo 152 received Placebo

152 Safety Analysis Set 150 received FCM 123 completed

3 Adverse Event 0 Lost to Follow-up 12 Death 1 Physician decision 2 Protocol violation 8 Withdrawal 3 Other

29 discontinued 24 discontinued

Patients disposition

589 screened

3 Adverse Event 2 Lost to Follow-up 14 Death 1 Physician decision 0 Protocol violation 3 Withdrawal 1 Other

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SLIDE 9

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)

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SLIDE 10

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)

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SLIDE 11

FCM improved 6MWT at week 24 FCM vs placebo: 33 ± 11 m (least squares mean ± SE)

P=0.002

Week 24

LSM change in 6MWT distance from baseline (m) FCM (N=150) Placebo (N=151) 30 20 10

  • 10
  • 20
  • 30

Primary endpoint: change in 6-minutes walking test distance at Week 24

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SLIDE 12

Self-reported Patient Global Assessment (PGA) score New York Heart Association Functional (NYHA) class

Odds ratio (95% CI)

FCM better Placebo better P=0.29 P=0.035 P=0.047 P=0.001 P=0.001 0.5 1 1.5 2 2.5 3 3.5 4 6 12 18 24 30 42 36 48 52

Weeks since randomization Odds ratio (95% CI)

FCM better Placebo better P=0.067 P=0.093 P=0.004 P<0.001 P<0.001 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

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SLIDE 13

Secondary endpoints: Changes in 6MWT distance and Fatigue score over time

14 (–5, 33) 16 (–3, 35) 33 (13, 53) 42 (21, 62) 36 (16, 57)

FCM Placebo 30 20

  • 10
  • 20

10

  • 30
  • 40

6MWT change from baseline LSM

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

Fatigue score change from baseline LSM 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 BL 6 18 30 36 42 48 52

FCM vs placebo LSM (95% CI)

6MWT 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)

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SLIDE 14

Secondary endpoints: Changes in Quality of Life over time

Weeks since randomisation Overall KCCQ score change from baseline LSM P=0.035 P=0.41 P=0.004 P=0.010

10

EQ-5D VAS score

EQ-5D VAS change from baseline LSM P=0.080 P=0.002 P=0.120

10 8 6 4 2

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

  • 2

BL 6 12 18 24 30 36 42 48 52

P=0.30 P=0.067

KCCQ

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SLIDE 15

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

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SLIDE 16

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):

Hazard Ratio (95% CI) – 0.30 (0.14-0.64), p=0.0019

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SLIDE 17

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

Hospitalization rate (per 100 subjects)

180 270 360 90

Time (days) Placebo FCM

Log–rank test P=0.009

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SLIDE 18

Primary endpoint: Subgroup analyses

P-value for interaction

Difference FCM-placebo in 6MWT distance in m LSM (95% CI) 150 100 50

  • 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

  • 50
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SLIDE 19

Safety end-point or adverse event (AE) FCM (N=152)

n (%) Events

Placebo (N=152)

n (%) Events

Subjects with at least one AE 121 (79.6) 555 115 (75.7) 547 Subjects with at least one severe AE 21 (13.8) 31 27 (17.8) 54 Subjects with at least one serious AE 43 (28.3) 68 53 (34.9) 106 Subjects with at least one AE leading to study drug withdrawal 14 (9.2) 14 19 (12.5) 19 Subjects with at least one severe AE leading to study drug withdrawal 0 (0.0) 0 0 (0.0) 0 Subjects with at least one serious AE leading to study drug withdrawal 0 (0.0) 0 0 (0.0) 0 Subjects with at least one drug-related AE leading to study drug withdrawal 1 (0.7) 1 0 (0.0) 0 Subjects with at least one drug related AE 14 (9.2) 24 5 (3.3) 7

Reported adverse events

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SLIDE 20

Conclusions

In symptomatic patients with chronic heart failure and iron deficiency treatment with i.v. ferric carboxymaltose over

  • ne year period results in:

sustainable improvement in functional capacity symptoms quality of life may reduce the risk of hospitalisations due to worsening heart failure

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SLIDE 21

Just online

eurheartj.oxfordjournals.org doi: 10.1093/eurheartj/ehu385