A Clinical Trial Assessing the Efficacy of Intravenous Iron for the Treatment of Anemia Following Cardiac Surgery

NCT04608539 | Completed Phase 4

• 1 other identifier: PICS-01
• Study Type: interventional
• Target: 110
• Locations: 1 country
• Sites: 1

Brief Summary

BACKGROUND Anemia and iron deficiency are highly prevalent in cardiac surgery patients. Both conditions may adversely affect postoperative rehabilitation. At hospital discharge, anemia is almost invariably present due to perioperative blood loss and frequent blood sampling. Two previous analyses demonstrated a prevalence of anemia early after coronary artery bypass grafting (CABG) of 94% and 98%, respectively. Almost half of CABG patients had persistent anemia two months after surgery. Postoperative anemia may result in debilitating symptoms, like dyspnoea, fatigue and poor exercise tolerance, and is associated with an increased likelihood of cardiovascular events and death after cardiac surgery. Mild to moderate anemia is commonly corrected with oral iron supplements. Oral iron is however poorly absorbed in patients with chronic diseases, and about 40% of patients suffer from debilitating gastrointestinal side-effects. As iron stores are frequently reduced or depleted after cardiac surgery, treatment with oral iron supplements may take several months. In patients with chronic heart failure (CHF), iron deficiency is associated with reduced exercise capacity, quality of life and survival even in the absence of anemia. Several large randomised trials demonstrated that treatment with intravenous iron improved clinical symptoms, exercise capacity and quality of life of CHF patients. RATIONALE It is desirable to replenish body iron stores rapidly after cardiac surgery with the aim to effectively correct anemia, optimize exercise tolerance and improve patient wellbeing. Modern intravenous iron formulations permit fast replenishment of body iron stores and have emerged as potential alternatives to oral iron. These formulations are well-tolerated and have become an established therapeutic option in anemic patients with reduced intestinal iron absorption. Several studies have demonstrated the efficacy of intravenous iron for the treatment of anemia following major non-cardiac surgery. Data regarding the efficacy of intravenous iron in cardiac surgery, however, are conflicting. HYPOTHESIS Single-dose intravenous iron therapy with ferric derisomaltose/iron isomaltoside is superior to oral iron supplementation for the correction of anemia following cardiac surgery. Moreover, single-dose intravenous iron therapy with ferric derisomaltose/iron isomaltoside results in a greater postoperative exercise capacity, an improved quality of life and less fatigue.

Conditions

Anemia Postoperative

Keywords

Anemia; Iron deficiency; Transfusion; Postoperative period; Rehabilitation

Outcome Measures

Primary Outcomes (1)

• The proportion of participants who are neither anemic nor have received allogeneic red blood cells since randomisation

  Unit: percentage; anemia according to WHO criteria defined as hemoglobin \< 12 g/dl in women and \< 13 g/dl in men.

  4-week follow-up

Secondary Outcomes (17)

• Mean change in hemoglobin level

  From baseline to 4-week follow-up

• Proportion of participants with a haemoglobin increase ≥ 1.3 mmol/l (≥ 2 g/dL)

  From baseline to 4-week follow-up

• Mean haemoglobin level

  4-week follow-up

• Mean reticulocyte count

  4-week follow-up

• Mean plasma iron

  4-week follow-up

Other Outcomes (4)

• Gastrointestinal symptoms

  4-week follow-up

• Treatment adherence to oral iron therapy

  4-week follow-up

• Cost-effectiveness analysis

  4-week follow-up

Study Arms (2)

Intravenous iron group

EXPERIMENTAL

Single-dose intravenous infusion of 20 mg/kg body weight ferric derisomaltose/iron isomaltoside 1000 (MonoFer®)

Drug: Ferric Derisomaltose

Oral iron group

ACTIVE COMPARATOR

Oral therapy with 100 mg oral ferrous sulfate twice daily

Drug: Ferrous sulfate; Drug: normal saline

Interventions

Ferric Derisomaltose DRUG

Single-dose intravenous infusion, 20 mg/kg body weight, postoperative day 1

Also known as: MonoFer, iron isomaltoside 1000

Intravenous iron group

Ferrous sulfate DRUG

Oral therapy, 100 mg twice daily, from postoperative day 4 until 4-week follow-up

Also known as: Ferro Duretter

Oral iron group

normal saline DRUG

Single-dose infusion (placebo), postoperative day 1

Also known as: 0.9% natriumchloride

Oral iron group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients 18 years of age or older undergoing first-time, non-emergent cardiac surgery with cardiopulmonary bypass. Eligible procedures are A: isolated CABG surgery (+/- arrhythmia surgery), B: isolated cardiac valve surgery (+/- arrhythmia surgery), C: a combination of CABG and cardiac valve surgery (+/- arrhythmia surgery)
• Moderate anaemia on the first postoperative day. According to World Health Organization-criteria defined as a haemoglobin concentration of equal to or greater than 5.0 mmol/l (8 g/dl) and less than 6.8 mmol/l (11 g/dl).

You may not qualify if:

• Known hypersensitivity to any iron formulation
• Multiple drug allergies or history of previous anaphylaxis
• Severe asthma, eczema or another atopic allergy
• Rheumatoid arthritis or systemic lupus erythematosus
• History of iron overload or disturbances in iron utilisation (e.g. haemochromatosis, hemosiderosis)
• History of liver disease (e.g. cirrhosis)
• Severe active infection or inflammation (e.g. endocarditis)
• Porphyria cutanea tarda
• Treatment with intravenous iron within 4 weeks prior to surgery.
• Untreated vitamin B12 or folate deficiency.
• Anticipated inability to perform a six-minute walk test.
• Women of childbearing potential, pregnant and nursing women.
• Anticipated postoperative length of stay in the intensive care unit (ICU) \> 48 hours.
• Patients incapable of giving consent personally.
• Significantly increased risk of non-adherence or loss to follow-up.

Sponsors & Collaborators

• Michael Kremke: lead
• Aarhus University Hospital: collaborator
• University of Aarhus: collaborator
• Pharmacosmos A/S: collaborator

Study Sites (1)

Aarhus University Hospital

Aarhus, 8200, Denmark

Location

Related Publications (18)

• Hogan M, Klein AA, Richards T. The impact of anaemia and intravenous iron replacement therapy on outcomes in cardiac surgery. Eur J Cardiothorac Surg. 2015 Feb;47(2):218-26. doi: 10.1093/ejcts/ezu200. Epub 2014 May 13.

  PMID: 24824650 BACKGROUND

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  PMID: 28117617 BACKGROUND

• Westenbrink BD, Kleijn L, de Boer RA, Tijssen JG, Warnica WJ, Baillot R, Rouleau JL, van Gilst WH; IMAGINE Investigators. Sustained postoperative anaemia is associated with an impaired outcome after coronary artery bypass graft surgery: insights from the IMAGINE trial. Heart. 2011 Oct;97(19):1590-6. doi: 10.1136/heartjnl-2011-300118. Epub 2011 Jul 13.

  PMID: 21757458 BACKGROUND

• Ranucci M, La Rovere MT, Castelvecchio S, Maestri R, Menicanti L, Frigiola A, D'Armini AM, Goggi C, Tramarin R, Febo O. Postoperative anemia and exercise tolerance after cardiac operations in patients without transfusion: what hemoglobin level is acceptable? Ann Thorac Surg. 2011 Jul;92(1):25-31. doi: 10.1016/j.athoracsur.2011.02.058. Epub 2011 May 18.

  PMID: 21592458 BACKGROUND

• Society of Thoracic Surgeons Blood Conservation Guideline Task Force; Ferraris VA, Brown JR, Despotis GJ, Hammon JW, Reece TB, Saha SP, Song HK, Clough ER; Society of Cardiovascular Anesthesiologists Special Task Force on Blood Transfusion; Shore-Lesserson LJ, Goodnough LT, Mazer CD, Shander A, Stafford-Smith M, Waters J; International Consortium for Evidence Based Perfusion; Baker RA, Dickinson TA, FitzGerald DJ, Likosky DS, Shann KG. 2011 update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines. Ann Thorac Surg. 2011 Mar;91(3):944-82. doi: 10.1016/j.athoracsur.2010.11.078.

  PMID: 21353044 BACKGROUND

• Task Force on Patient Blood Management for Adult Cardiac Surgery of the European Association for Cardio-Thoracic Surgery (EACTS) and the European Association of Cardiothoracic Anaesthesiology (EACTA); Boer C, Meesters MI, Milojevic M, Benedetto U, Bolliger D, von Heymann C, Jeppsson A, Koster A, Osnabrugge RL, Ranucci M, Ravn HB, Vonk ABA, Wahba A, Pagano D. 2017 EACTS/EACTA Guidelines on patient blood management for adult cardiac surgery. J Cardiothorac Vasc Anesth. 2018 Feb;32(1):88-120. doi: 10.1053/j.jvca.2017.06.026. Epub 2017 Sep 30. No abstract available.

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  PMID: 30146969 BACKGROUND

• Tolkien Z, Stecher L, Mander AP, Pereira DI, Powell JJ. Ferrous sulfate supplementation causes significant gastrointestinal side-effects in adults: a systematic review and meta-analysis. PLoS One. 2015 Feb 20;10(2):e0117383. doi: 10.1371/journal.pone.0117383. eCollection 2015.

  PMID: 25700159 BACKGROUND

• Piednoir P, Allou N, Driss F, Longrois D, Philip I, Beaumont C, Montravers P, Lasocki S. Preoperative iron deficiency increases transfusion requirements and fatigue in cardiac surgery patients: a prospective observational study. Eur J Anaesthesiol. 2011 Nov;28(11):796-801. doi: 10.1097/EJA.0b013e32834ad97b.

  PMID: 21885979 BACKGROUND

• Camaschella C. Iron-deficiency anemia. N Engl J Med. 2015 May 7;372(19):1832-43. doi: 10.1056/NEJMra1401038. No abstract available.

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• Jankowska EA, Malyszko J, Ardehali H, Koc-Zorawska E, Banasiak W, von Haehling S, Macdougall IC, Weiss G, McMurray JJ, Anker SD, Gheorghiade M, Ponikowski P. Iron status in patients with chronic heart failure. Eur Heart J. 2013 Mar;34(11):827-34. doi: 10.1093/eurheartj/ehs377. Epub 2012 Nov 23.

  PMID: 23178646 BACKGROUND

• von Haehling S, Ebner N, Evertz R, Ponikowski P, Anker SD. Iron Deficiency in Heart Failure: An Overview. JACC Heart Fail. 2019 Jan;7(1):36-46. doi: 10.1016/j.jchf.2018.07.015. Epub 2018 Dec 12.

  PMID: 30553903 BACKGROUND

• Enjuanes C, Klip IT, Bruguera J, Cladellas M, Ponikowski P, Banasiak W, van Veldhuisen DJ, van der Meer P, Jankowska EA, Comin-Colet J. Iron deficiency and health-related quality of life in chronic heart failure: results from a multicenter European study. Int J Cardiol. 2014 Jun 15;174(2):268-75. doi: 10.1016/j.ijcard.2014.03.169. Epub 2014 Apr 3.

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• Anker SD, Comin Colet J, Filippatos G, Willenheimer R, Dickstein K, Drexler H, Luscher TF, Bart B, Banasiak W, Niegowska J, Kirwan BA, Mori C, von Eisenhart Rothe B, Pocock SJ, Poole-Wilson PA, Ponikowski P; FAIR-HF Trial Investigators. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009 Dec 17;361(25):2436-48. doi: 10.1056/NEJMoa0908355. Epub 2009 Nov 17.

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• Ponikowski P, van Veldhuisen DJ, Comin-Colet J, Ertl G, Komajda M, Mareev V, McDonagh T, Parkhomenko A, Tavazzi L, Levesque V, Mori C, Roubert B, Filippatos G, Ruschitzka F, Anker SD; CONFIRM-HF Investigators. Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiencydagger. Eur Heart J. 2015 Mar 14;36(11):657-68. doi: 10.1093/eurheartj/ehu385. Epub 2014 Aug 31.

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• van Veldhuisen DJ, Ponikowski P, van der Meer P, Metra M, Bohm M, Doletsky A, Voors AA, Macdougall IC, Anker SD, Roubert B, Zakin L, Cohen-Solal A; EFFECT-HF Investigators. Effect of Ferric Carboxymaltose on Exercise Capacity in Patients With Chronic Heart Failure and Iron Deficiency. Circulation. 2017 Oct 10;136(15):1374-1383. doi: 10.1161/CIRCULATIONAHA.117.027497. Epub 2017 Jul 12.

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• Modrau IS, Kremke M. Post-operative iron in cardiac surgery trial - a protocol for a randomised controlled trial. Dan Med J. 2022 Jun 24;69(7):A12210952.

  PMID: 35781129 DERIVED

MeSH Terms

Conditions

Anemia; Iron Deficiencies

Interventions

ferric derisomaltose; iron isomaltoside 1000; ferrous sulfate; Saline Solution

Condition Hierarchy (Ancestors)

Hematologic Diseases; Hemic and Lymphatic Diseases; Iron Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Study Officials

• Michael Kremke, MD

  Aarhus University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: The study is primarily open label. It includes, however, a short period (from the 1. to the 4. postoperative day) of participant, care provider and investigator masking. The aim is to reduce differences in transfusion practices.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: September 17, 2020
• First Posted: October 29, 2020
• Study Start: May 21, 2021
• Primary Completion: June 27, 2023
• Study Completion: June 27, 2023
• Last Updated: June 28, 2023

Record last verified: 2023-06

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1)