Effect of ferric carboxymaltose on functional capacity in patients with heart failure and iron deficiency (CONFIRM-HF)

Transcription

1 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, 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.

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

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

4 Uncertainties on the appropriate use of iron in heart failure Longer-term sustainability of beneficial effects and safety Potential impact on the outcomes 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)

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 ng/ml if TSAT <20% ü Hb < 15 g/dl Blinding: ü ü Clinical staff: unblinded and blinded personnel Patients: usage of curtains and black syringes for injections Correction phase FCM up to 2000mg (2 x mg i.v.) Maintenance phase FCM treatment continues if ID is not corrected (500mg i.v.) Screening Ferric Carboxymaltose (FCM) 1 EP: 6MWT D0 W6 W12 W24 W36 W52 Ponikowski P et al. ESC Heart Fail J 2014, in press

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)

7 Participating countries 304 randomized subjects 9 countries 41 sites

8 Patients disposition 589 screened 304 randomly allocated 152 allocated to FCM 152 received FCM 152 Safety Analysis Set 152 allocated to 152 received 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 3 Adverse Event 0 Lost to Follow-up 12 Death 1 Physician decision 2 Protocol violation 8 Withdrawal 3 Other 29 discontinued 24 discontinued 3 Adverse Event 2 Lost to Follow-up 14 Death 1 Physician decision 0 Protocol violation 3 Withdrawal 1 Other 150 received FCM 123 completed 151 received 128 completed

9 Baseline characteristics (1/2) FCM (N=150) (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)

10 Baseline characteristics (2/2) Concomitant medications FCM (N=150) (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)

11 Primary endpoint: change in 6-minutes walking test 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 (N=150) (N=151) -30 Week 24

12 Secondary endpoints: Changes in PGA & NYHA class over time Self-reported Patient Global Assessment (PGA) score Odds ratio (95% CI) FCM better better No. of patients FCM 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) 12 P<0.001 class Odds ratio (95% CI) FCM better better 10 No. of patients FCM P=0.093 P= P=0.004 P< Weeks since randomization Weeks since randomisation

13 Secondary endpoints: Changes in 6MWT distance and Fatigue score over time 6MWT change from baseline LSM FCM vs placebo LSM (95% CI) P=0.16 BL ( 5, 33) P= ( 3, 35) 6MWT P= (13, 53) P< (21, 62) P< (16, 57) Weeks since randomisation FCM Fatigue score change from baseline LSM FCM vs placebo LSM (95% CI) Fatigue score P= P=0.40 P=0.002 P< P= 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) Weeks since randomisation

14 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 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

15 Secondary endpoints: Outcome events FCM (N=150) (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 ( ) 0.009

16 Secondary endpoints: Outcome events FCM (N=150) (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): Hazard Ratio (95% CI) 0.30 ( ), p=0.0019

17 Secondary endpoint: First hospitalization due to worsening HF 30 FCM Log rank test P=0.009 Hospitalization rate (per 100 subjects) Time (days) No. of subjects at risk FCM

18 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

19 Reported adverse events Safety end-point or adverse event (AE) FCM (N=152) n (%) Events (N=152) n (%) Events Subjects with at least one AE 121 (79.6) (75.7) 547 Subjects with at least one severe AE 21 (13.8) (17.8) 54 Subjects with at least one serious AE 43 (28.3) (34.9) 106 Subjects with at least one AE leading to study drug withdrawal 14 (9.2) (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

20 Conclusions In symptomatic patients with chronic heart failure and iron deficiency treatment with i.v. ferric carboxymaltose over one year period results in: sustainable improvement in functional capacity symptoms quality of life may reduce the risk of hospitalisations due to worsening heart failure

21 Just online doi: /eurheartj/ehu385 eurheartj.oxfordjournals.org