Dirk J. van Veldhuisen, MD 1; Piotr Ponikowski, MD2; Peter van der Meer, MD1; Marco Metra, MD3; Michael Böhm, MD4; Artem Doletsky, MD5; Adriaan A. Voors, MD1; Iain C. Macdougall, MD6; Stefan D. Anker, MD7; Bernard Roubert, PhD8; Lorraine Zakin, MD8; Alain Cohen-Solal, MD9; for the EFFECT-HF Investigators
1Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; 2Department of Heart Diseases, Medical University, Clinical Military Hospital, Wroclaw, Poland; 3Department of Cardiology, University Hospital Brescia, Italy; 4Universitätsklinikum des Saarlandes, Homburg/Saar, Germany; 5I.M. Sechenov First Moscow State Medical University, Moscow, Russia; 6King’s College Hospital, London, United Kingdom; 7Cachexia Research, University Medical Center Göttingen, Göttingen, Germany; 8Vifor Pharma, Glattbrugg, Switzerland; 9Hopital Lariboisiere, University Paris Diderot and UMR-S942, Paris, France
Abstract
Background
Iron deficiency is common in patients with heart failure (HF), and is associated with reduced exercise capacity and poor outcomes. Whether correction of iron deficiency with (intravenous) ferric carboxymaltose (FCM) affects peak oxygen consumption [peak VO2], an objective measure of exercise intolerance in HF, has not been examined.
Methods
We studied patients with systolic HF (left ventricular ejection fraction [LVEF] ”45%) and mild to moderate symptoms despite optimal HF medication, Patients were randomized 1:1 to treatment with FCM for 24 weeks or standard of care. The primary endpoint was the change in peak VO2 from baseline to 24 weeks. Secondary endpoints included effect hematinic and cardiac biomarkers, quality of life, and safety. For the primary analysis, patients who died had a value of zero imputed for 24-week peak VO2. Additional sensitivity analyses were performed to determine the impact of imputation of missing peak VO2 data.
Results
A total of 172 HF patients were studied are received FCM (n=86) or standard of care (control group, n=86). At baseline, the groups were well-matched; mean age was 64 years, 75% were male, LVEF was 32%, peak VO2 13.5 mL/min/kg. FCM significantly increased serum ferritin and transferrin saturation. At 24 weeks, peak VO2 had decreased in the control group (least square means -1.19±0.389 mL/min/kg), but was maintained on FCM (-0.16±0.387 mL/min/kg; p=0.020 between groups). In a sensitivity analysis, in which missing data were not imputed, peak VO2 at 24 weeks decreased by 0.63±0.375 mL/min/kg in the control group, and by 0.16±0.373 mL/min/kg in the FCM group; p=0.23 between groups). Patients’ global assessment and functional class as assessed by New York Heart Association improved on FCM vs. standard of care.
Conclusions
Treatment with intravenous FCM in patients with HF and iron deficiency improve iron stores. Although a favourable effect on peak VO2 was observed on FCM, compared to standard of care in the primary analysis, this effect was highly sensitive to the imputation strategy for peak VO2 among patients who died. Whether FCM is associated with an improved outcome in these high-risk patients needs further study.
Clinical Trial Registration: URL: https://clinicaltrials.gov Unique identifier: NCT01394562.
(Reference: http://circ.ahajournals.org/content/early/2017/07/11/CIRCULATIONAHA.117.027497.short )
European Heart Journal, Published 21 August 2014
Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency
Piotr Ponikowski1,2*, Dirk J. van Veldhuisen3, Josep Comin-Colet4, Georg Ertl5,6 ,Michel Komajda7 ,Viacheslav Mareev8, Theresa Mc Donagh9, Alexander Parkhomenko10, Luigi Tavazzi11, Victoria Levesque12, Claudio Mori12, Bernard Roubert12, Gerasimos Filippatos13, Frank Ruschitzka14, and Stefan D. Anker15, for the CONFIRM-HF Investigators
1Department of Heart Diseases, Medical University, Wroclaw, Poland; 2Department of Cardiology, Center for Heart Diseases, Clinical Military Hospital, Weigla553-114, Wroclaw, Poland; 3Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; 4Heart Diseases Biomedical Research Group, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain; 5Department of Internal MedicineI, University HospitalWu¨rzburg, Wu¨rzburg,Germany; 6Comprehensive Heart Failure Center, University of Wu¨rzburg, Wu¨rzburg, Germany; 7CHU Pitie-Salpetriere, Institut de Cardiologie, Paris, France;8Lomonosov Moscow State University, Moscow, Russia; 9Department of Cardiology, King’s College Hospital, Denmark Hill, London SE59RS, UK; 10Ukranian Strazhesko Institute of Cardiology, 5, Narodnoko Opolchenia St, Kiev 03151, Ukraine; 11Maria Cecilia Hospital, GVM Care & Research—E.S. Health Science Foundation, Cotignola, Italy; 12Vifor Pharma, Glattbrugg, Switzerland; 13Athens University Hospital Attikon, Athens, Greece; 14Department of Cardiology, University Hospital Zurich, Switzerland; and 15Department of Innovative Clinical Trials, University Medical Centre Gottingen, Gottingen, Germany
Abstract
Aim
The aim of this study was to evaluate the benefits and safety of long-term i.v. iron therapy in iron-deficient patients with heart failure (HF).
Methods and results
CONFIRM-HF was a multi-centre, double-blind, placebo-controlled trial that enrolled 304 ambulatory symptomatic HF patients with left ventricular ejection fraction ≤ 45%, elevated natriuretic peptides, and iron deficiency (ferritin ,100 ng/mL or 100–300 ng/mL if transferrin saturation , 20%). Patients were randomized 1:1 to treatment with i.v. iron, as ferric carboxymaltose (FCM, n=152) or placebo (saline, n=152) for 52 weeks. The primary end-point was the change in 6-min-walk-test (6MWT) distance frombaseline to Week 24. Secondary end-points included changes in New York Heart Association (NYHA) class, Patient Global Assessment (PGA), 6MWT distance, health-related quality of life (QoL), Fatigue Score at Weeks 6, 12, 24, 36, and 52 and the effect of FCM on the rate of hospitalization for worsening HF. Treatment with FCM significantly prolonged 6MWT distance at Week 24 (difference FCM vs. placebo: 33 ± 11 m, P = 0.002). The treatment effect of FCM was consistent in all subgroups and was sustained to Week 52 (difference FCM vs. placebo: 36 ± 11 m, P < 0.001). Throughout the study, an improvement in NYHA class, PGA, QoL, and Fatigue Score in patients treated with FCM was detected with statistical significance observed fromWeek 24 onwards. Treatment with FCM was associated with a significant reduction in the risk of hospitalizations for worsening HF [hazard ratio (95% confidence interval): 0.39 (0.19–0.82), P=0.009]. The number of deaths (FCM:12, placebo:14 deaths) and the incidence of adverse events were comparable between both groups.
Conclusion
Treatment of symptomatic, iron-deficient HF patients with FCM over a 1-year period resulted in sustainable improve-ment in functional capacity, symptoms, and QoLand may be associated with risk reduction of hospitalization for worsening HF (ClinicalTrials.gov number NCT01453608).
(Reference: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359359/pdf/ehu385.pdf )
N engl j med 361;25 nejm.org december 17, 2009
Ferric Carboxymaltose in Patients with Heart Failure and Iron Deficiency
Stefan D. Anker, M.D., Ph.D., Josep Comin Colet, M.D., Gerasimos Filippatos, M.D., Ronnie Willenheimer, M.D., Kenneth Dickstein, M.D., Ph.D., Helmut Drexler, M.D.,1Thomas F. Lüscher, M.D., Boris Bart, M.D., Waldemar Banasiak, M.D., Ph.D., Joanna Niegowska, M.D., Bridget-Anne Kirwan, Ph.D., Claudio Mori, M.D., Barbara von Eisenhart Rothe, M.D., Stuart J. Pocock, Ph.D., Philip A. Poole-Wilson, M.D.,1 and Piotr Ponikowski, M.D., Ph.D., for the FAIR-HF Trial Investigators2
From the Department of Cardiology, Campus Virchow-Klinikum, Charité Universitätsmedizin, Berlin, and the Center for Clinical and Basic Research, San Raffaele, Rome (S.D.A.); Hospital del Mar and Universitat Autonoma de Barcelona, Barcelona (J.C.C.); Athens University Hospital Attikon, Athens (G.F.); Heart Health Group and Lund University, Malmö, Sweden (R.W.); Stavanger University Hospital, Stavanger, and the University of Bergen, Bergen — both in Norway (K.D.); Medizinische Hochschule Hannover, Hannover, Germany (H.D.); University Hospital Zürich, Zurich (T.F.L.), SOCAR Research, Nyon (B.-A.K.), and Vifor Pharma, Glattbrugg (C.M., B.E.R.) — all in Switzerland; Russian State Medical University, Outpatient Diagnostic Consulting Center 1, Moscow (B.B.); Military Hospital, Wroclaw (W.B., P.P.); Centrum Medyczne, Telmont Centrum Medyczne, Sp. z O.O., Warsaw (J.N.), and Medical University, Wroclaw (P.P.) — all in Poland; and London School of Hygiene and Tropical Medicine (S.J.P.) and the National Heart and Lung Institute, Imperial College London (P.A.P.-W.) — both in London. Address reprint requests to Dr. Anker at Applied Cachexia Research, Department of Cardiology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum. Augustenburger Pl. 1,2Members of the Ferinject Assessment in Patients with Iron Deficiency and Chronic Heart Failure (FAIR-HF) study group are listed in the Appendix.
Abstract
Background
Iron deficiency may impair aerobic performance. This study aimed to determine whether treatment with intravenous iron (ferric carboxymaltose) would improve symptoms in patients who had heart failure, reduced left ventricular ejection fraction, and iron deficiency, either with or without anemia.
Methods
We enrolled 459 patients with chronic heart failure of New York Heart Association (NYHA) functional class II or III, a left ventricular ejection fraction of 40% or less (for patients with NYHA class II) or 45% or less (for NYHA class III), iron deficiency (ferritin level < 100 μg per liter or between 100 and 299 μg per liter, if the transferrin saturation was < 20%), and a hemoglobin level of 95 to 135 g per liter. Patients were randomly assigned, in a 2:1 ratio, to receive 200 mg of intravenous iron (ferric carboxymaltose) or saline (placebo). The primary end points were the self-reported Patient Global Assess-ment and NYHA functional class, both at week 24. Secondary end points included the distance walked in 6 minutes and the health-related quality of life.
Results
Among the patients receiving ferric carboxymaltose, 50% reported being much or moderately improved, as compared with 28% of patients receiving placebo, according to the Patient Global Assessment (odds ratio for improvement, 2.51; 95% confidence interval [CI], 1.75 to 3.61). Among the patients assigned to ferric carboxymaltose, 47% had an NYHA functional class I or II at week 24, as compared with 30% of pa-tients assigned to placebo (odds ratio for improvement by one class, 2.40; 95% CI, 1.55 to 3.71). Results were similar in patients with anemia and those without anemia. Significant improvements were seen with ferric carboxymaltose in the distance on the 6-minute walk test and quality-of-life assessments. The rates of death, adverse events, and serious adverse events were similar in the two study groups.
Conclusion
Treatment with intravenous ferric carboxymaltose in patients with chronic heart failure and iron deficiency, with or without anemia, improves symptoms, functional capacity, and quality of life; the side effect profile is acceptable. (ClinicalTrials.govnumber, NCT00520780.)
(Reference link : http://www.nejm.org/doi/full/10.1056/NEJMoa0908355#t=article )