FAIR-HF

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Anker SD, et al. "Ferric Carboxymaltose in Patients with Heart Failure and Iron Deficiency". The New England Journal of Medicine. 2009. 361(25):2436-48.
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Clinical Question

In patients with heart failure with reduced ejection fraction (LVEF ≤ 45% and NYHA II-III symptoms) and concomitant iron deficiency, does IV iron improve heart failure symptoms compared to placebo?

Bottom Line

Among patients with heart failure with reduced ejection fraction (LVEF ≤ 45% and NYHA II-III symptoms) and concomitant iron deficiency, IV iron replacement resulted in significant improvements in NYHA functional class, 6-minute walk distance, and several quality-of-life assessments.

Major Points

Despite recent improvements in the medical management of heart failure with reduced ejection fraction (HFrEF), morbidity related to reduced exercise tolerance and functional capacity remains a significant problem. Although the cause of reduced functional status in this condition is multifactorial, impaired oxygen delivery is thought to be a major contributor. Iron deficiency with or without anemia has been showed to impair aerobic performance, and incidence of iron deficiency is increased among patients with HFrEF. Furthermore a small study in patients with chronic heart failure suggested the possibility of symptomatic benefit of IV iron replacement in this population even in patients without anemia.[1]

The 2009 Ferinject Assessment in Patients with Iron Deficiency and Chronic Heart Failure (FAIR-HF) trial assessed whether the administration of IV ferric carboxymaltose versus placebo in 459 patients with symptomatic HFrEF (defined as LVEF ≤ 40% with NYHA II-III symptoms or LVEF ≤ 45% with NYHA III symptoms) and concomitant iron deficiency (ferritin < 100 ug/L or ferritin 100-299 ug/L with iron saturation < 20%) with mild or no anemia (hemoglobin 9.5-13.5 g/dL) resulted in symptomatic improvement or gains in functional status. FAIR-HF demonstrated that the use of IV iron repletion in these patients resulted in a 20% absolute increase over placebo in the number of patients reporting at least moderate improvement in heart failure symptoms. IV iron also resulted in a 17% absolute increase over placebo in the number of patients with improvement to NHYA class I or II by the end of the study period. IV iron also resulted in a mean 35 meter increase in 6-minute walk distance at 24 weeks. Finally, there was a trend towards a lower rate of first cardiac hospitalization among those in the IV iron group. Importantly, there was no difference in adverse event rate between the IV iron and placebo groups.

The results of FAIR-HF identified IV iron repletion as a low-risk intervention that results in respectable symptomatic benefit in a relatively broad population of HFrEF patients (i.e., those with iron deficiency with mild or no anemia. Based on the findings of FAIR-HF, assessment and treatment for iron deficiency even in the absence of anemia is now routinely practiced in patients with heart failure, particularly patients with chronic heart failure and worsening symptomatology.

Guidelines

No guidelines have been updated based on the results of FAIR-HF.

Design

  • Multicenter, randomized, double-blind, placebo-controlled controlled trial
  • N=459
    • IV iron (ferric carboxymaltose) (n=344)
    • Placebo (n=155)
  • Setting: 75 sites in 11 countries
  • Enrollment: June 25, 2007 to December 31, 2008
  • Follow-up: 24 weeks
  • Analysis: Intention-to-treat
  • Primary outcomes: Self-reported Patient Global Aassessment and NYHA Class at week 24

Population

Inclusion Criteria

  • LVEF ≤ 45% with NYHA Class II-III symptoms
  • LVEF ≤ 40% with NYHA Class II symptoms
  • Baseline hemoglobin 9.5 to 13.5 g/dL
  • Iron deficiency, defined as either of
    • ferritin < 100 ug/L
    • ferritin 100-299 ug/L and transferrin saturation < 20%

Exclusion Criteria

  • Uncontrolled HTN
  • Additional clinically significant heart disease
  • Clinically significant inflammation
  • Clinically significantly mpaired liver or renal function

Baseline Characteristics

From the placebo group.

  • Demographics: Age 67 years, 55% female, 100% white race
  • Comorbidities: BMI 28.1, HTN 83%, HLD 45%, DM 24%, AF 28%
  • Heart failure characteristics: NYHA II 19%, NYHA III 81%, LVEF 33%, 6-minute walk distance 269m, ischemic CM 79%
  • CVD History: MI 58%, angina 57%, CVA 5.8%, revascularization 20%
  • Labs: Hgb 11.9 g/dL, ferritin 60 ug/L, transferritin saturation 16.7%, CRP 9.1, Cr 1.2
  • Medications: Diuretic 90%, ACE/ARB 91%, beta blocker 83%, antiplatelet 63%, anti-lipid 46.5%, anticoagulant 14%

Interventions

  • Randomized 2:1 ratio:
    • IV iron - IV ferric carboxymaltose
    • Placebo
  • Baseline clinical history, physical examination, 6-minute walk test, 12-lead ECG, and quality-of-life assessments performed at first assessment
  • Total iron dose for repletion calculated using Ganzoni's formula
  • IV iron or saline dosed weekly until repletion achieved then every 4 weeks during the maintenance phase (weeks 8-24 or 12-24 depending on iron-repletion dose)
  • Study personnel involved in preparation and administration of study drug not blinded but excluded in all study assessments
  • If ferritin exceeded 800 ug/L or ferritin 500-800 ug/L with transferrin saturation > 50% or hgb > 16.0 g/dL, IV iron was switched to placebo
    • IV iron could be restarted after all of above criteria met: ferritin < 400 ug/L, transferrin saturation < 45%, hgb < 16.0 g/dL
  • If severe anemia developed (hgb < 9.0 g/dL), treatment permanently discontinued
  • In addition to dosing visits, planned reassessments occurred at weeks 4, 12, 24, and 26

Outcomes

Comparisons are IV iron vs. placebo.

Primary Outcomes

Improvement in Patient Global Assessment at week 24 (much or moderately improved)
50% vs. 28% (odds ratio for improvement 2.51; 95% CI 1.75-3.61; p<0.001)
Improvement in NYHA Class at week 24 (NYHA Class I or II)
47% vs. 30% (odds ratio for improvement by one class 2.40; 95% CI 1.55-3.71; p<0.001)

Secondary Outcomes

6-minute walk distance
313m vs. 277m (mean effect 35m; p<0.001)
Kansas City Cardiomyopathy Questionnaire
66 vs. 59 (mean effect 7; p<0.001)
EQ-5D Visual Assessment Scale
63 vs. 57 (mean effect 7; p<0.001)
First hospitalization for cardiovascular reasons
HR 0.53; 95% CI 0.25-1.09; p=0.08)

Safety Outcomes

Side effects leading to premature discontinuation
16 (5.3%) vs. 14 (9.0%)
Kansas City Cardiomyopathy Questionnaire
66 vs. 59 (mean effect 7; p<0.001)
EQ-5D Visual Assessment Scale
63 vs. 57 (mean effect 7; p<0.001)

Subgroup Analyses

  • A consistent benefit regarding the two primary endpoints was observed in all prespecified subgroups
  • Treatment effect was similar in patients with anemia and in those without anemia
  • Mean difference in hemoglobin with IV iron vs. placebo at week 24 significantly higher in patients with anemia at baseline vs. those without anemia (0.91 g/dL vs. 0.24 g/dL; interaction p<0.001)

Criticisms

  • Study findings limited to symptomatic improvement using self-reported assessments and NYHA class. Demonstration of a benefit in terms of objective cardiovascular events would require much larger sample size and longer duration of follow up.
  • Study findings only applicable to patients with presenting hemoglobin in the 9.5-13.5 g/dL range. As a result, it is unclear if symptomatic improvement could be expected in patients with more severe anemia or more robust hemoglobin values.
  • Although clearly demonstrated in FAIR-HF, the physiological mechanism underlying the benefit of IV iron replacement in patients with normal hemoglobin at baseline is not well-understood.

Funding

  • Sponsored by Vifor Pharma who had representatives on the study's Executive Committee
  • Authors with multiple ties to industry including Vifor Pharma

Further Reading

  1. Effect of intravenous iron sucrose on exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart failure and iron deficiency FERRIC-HF: a randomized, controlled, observer-blinded trial. J Am Coll Cardiol 2008; 51(2):103-12