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.
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
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
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 C arboxymalt O se evaluatio N on per F ormance in patients with IR on deficiency in co M bination with chronic H eart F ailure)
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 Correction phase Maintenance phase FCM treatment continues FCM up to 2000mg if ID is not corrected (2 x 500-1000mg i.v.) (500mg i.v.) Ferric Carboxymaltose (FCM) Screening 1° EP: 6MWT Placebo W6 W12 W24 W52 D0 W36 Ponikowski P et al. ESC Heart Fail J 2014, in press
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) -
Participating countries 304 randomized subjects 9 countries 41 sites
Patients disposition 589 screened 304 randomly allocated 152 allocated to FCM 152 allocated to Placebo 152 received FCM 152 received Placebo 152 Safety Analysis Set 152 Safety Analysis Set 2 excluded from the Full Analysis Set 1 excluded from the Full Analysis Set (lack of any post-baseline efficacy (lack of any post-baseline efficacy assessment) assessment) 150 Full Analysis Set 151 Full Analysis Set 3 Adverse Event 3 Adverse Event 0 Lost to Follow-up 2 Lost to Follow-up 29 discontinued 12 Death 24 discontinued 14 Death 1 Physician decision 1 Physician decision 2 Protocol violation 0 Protocol violation 8 Withdrawal 3 Withdrawal 3 Other 1 Other 150 received FCM 151 received Placebo 123 completed 128 completed
Baseline characteristics (1/2) FCM Placebo (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)
Baseline characteristics (2/2) FCM Placebo (N=150) (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/1.73m 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)
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 ) 30 FCM (N=150) P=0.002 Placebo (N=151) 20 LSM change in 6MWT distance 10 from baseline (m) 0 -10 -20 -30 Week 24
Secondary endpoints: Changes in PGA & NYHA class over time Self-reported Patient Global Assessment (PGA) score 4 P=0.001 P=0.001 3.5 FCM better Odds ratio (95% CI) 3 P=0.047 P=0.035 2.5 P=0.29 2 1.5 1 Placebo better 0.5 Weeks since 0 randomisation 6 12 18 24 30 36 42 48 52 Weeks since randomization No. of patients FCM 144 137 131 123 127 Placebo 147 148 130 124 119 New York Heart Association Functional (NYHA) class 12 P<0.001 P<0.001 10 Odds ratio (95% CI) FCM better 8 P=0.004 6 4 P=0.093 P=0.067 2 Placebo better Weeks since 0 randomisation 6 12 18 24 30 36 42 48 52 Weeks since randomization No. of patients FCM 144 137 132 123 127 Placebo 149 148 132 125 121
Secondary endpoints: Changes in 6MWT distance and Fatigue score over time 6MWT FCM Placebo 40 P=0.001 P<0.001 P=0.16 P=0.10 P<0.001 30 6MWT change from 20 10 baseline LSM 0 -10 -20 -30 Weeks since randomisation -40 BL 6 12 18 24 30 36 42 48 52 14 16 33 42 36 FCM vs placebo (–5, 33) (–3, 35) (13, 53) (21, 62) (16, 57) LSM (95% CI) Fatigue score P=0.002 P=0.40 P=0.002 0.2 P<0.001 Fatigue score change P=0.009 0 from baseline LSM -0.2 -0.4 -0.6 -0.8 -1.0 -1.2 Weeks since - 1.4 randomisation BL 6 12 18 24 30 36 42 48 52 –0.2 –0.5 –0.6 –0.8 0.7 FCM vs placebo (–0.5, 0.2) (–0.9, –0.1) (–1.0, –0.2) (–1.2, –0.4) (–1.1, –0.2) LSM (95% CI)
Secondary endpoints: Changes in Quality of Life over time KCCQ FCM Placebo Overall KCCQ score change P=0.004 P=0.035 P=0.010 10 P=0.41 from baseline LSM 8 P=0.25 6 4 2 0 Weeks since -2 randomisation BL 6 12 18 24 30 36 42 48 52 1.8 3.3 1.3 5.0 4.5 FCM vs placebo (–1.2, 4.8) (0.2, 6.4) (–1.9, 4.6) (1.6, 8.3) (1.1, 7.9) LSM (95% CI) EQ-5D VAS score EQ-5D VAS change from P=0.002 P=0.120 10 P=0.080 P=0.30 P=0.067 baseline LSM 8 6 4 2 Weeks since 0 randomization BL 6 12 18 24 30 36 42 48 52 FCM vs placebo 1.5 2.8 2.8 5.2 2.6 (–1.4, 4.4) (–0.2, 5.8) (–0.3, 5.9) (2.0, 8.5) (–0.7, 5.9) LSM (95% CI)
Secondary endpoints: Outcome events FCM Placebo (N=150) (N=151) Incidence/ Time to first Total Incidence/ Total (100 event P- End-point or event events (100 patient events patient Hazard ratio value (n) risk-year) (n) risk-year 95% CI 0.89 Death 12 12 (8.9) 14 14 (9.9) 0.77 (0.41 – 1.93) 0.96 Death for any CV reason 11 11 (8.1) 12 12 (8.5) 0.91 (0.42 – 2.16) 0.71 Hospitalisation 46 32 (26.3) 69 44 (37.0) 0.14 (0.45 – 1.12) Hospitalisation for any CV 0.63 26 21 (16.6) 51 33 (26.3) 0.097 reason (0.37 – 1.09) Hospitalisation due to 0.39 10 10 (7.6) 32 25 (19.4) 0.009 worsening HF (0.19 – 0.82)
Secondary endpoints: Outcome events FCM Placebo (N=150) (N=151) Incidence/ Time to first Total Incidence/ Total (100 event P- End-point or event events (100 patient events patient Hazard ratio value (n) risk-year) (n) risk-year 95% CI 0.89 Death 12 12 (8.9) 14 14 (9.9) 0.77 (0.41 – 1.93) 0.96 Death for any CV reason 11 11 (8.1) 12 12 (8.5) 0.91 (0.42 – 2.16) 0.71 Hospitalisation 46 32 (26.3) 69 44 (37.0) 0.14 (0.45 – 1.12) Hospitalisation for any CV 0.63 26 21 (16.6) 51 33 (26.3) 0.097 reason (0.37 – 1.09) Hospitalisation due to 0.39 10 10 (7.6) 32 25 (19.4) 0.009 worsening HF (0.19 – 0.82) 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
Secondary endpoint: First hospitalization due to worsening HF Placebo 30 FCM Log–rank test P=0.009 Hospitalization rate (per 100 subjects) 20 10 0 0 90 180 270 360 Time (days) No. of subjects at risk Placebo 151 138 127 117 78 FCM 150 140 131 126 77
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