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Table 1 Studies evaluating role of blood transfusion, erythropoietin-stimulating agents and iron in heart failure

From: Anemia in heart failure: still an unsolved enigma

Trial/study Finding Recommendation/practice
Blood transfusion (BT)
Hebert PC et al. Retrospective and Prospective Cohort [32]
n = 4470 (critically ill patients)
Hb < 9.5gm/ dL associated with increased mortality in cardiac patients
BT in anemic patients with cardiac disease and APACHE II score > 20 associated with improved survival
Transfusion threshold
Hematocrit < 30% in cardiovascular disease
(Based on expert opinion) [11]
Transfusion for severe and symptomatic anemia in HF [17]
Hebert PC et al. Multicenter, Randomized Controlled Trial [33]
n = 838 critically ill euvolemic patients
Liberal BT strategy (Hb < 9 gm/dL) versus restrictive BT strategy (Hb < 7 gm/dL) strategy
Restrictive BT strategy as effective as liberal (perhaps superior) except in acute coronary syndrome patients  
Hebert PC et al. Randomized Controlled Trial [34]
n = 357 critically ill patients with cardiovascular disease
Liberal BT strategy (Hb < 10 gm/dL) [n = 197] versus restrictive BT strategy (Hb < 7 gm/dL) [n = 160]strategy
Restrictive BT strategy as effective as liberal (perhaps superior) except in acute coronary syndrome patients  
Garty et al. Prospective Cohort study ( Hospital based HF survey in Israel (HFSIS) [18]
n = 4,102 (CHF [ n = 1767] and ADHF [n = 2335]
After propensity score analysis, blood transfusion was associated with lower short term mortality; however, there is no difference in long term mortality  
Erythropoietin-stimulating agents
STAMINA HeFT trial. Randomized
Controlled Trial [35]
n = 319 patients (follow-up—53 weeks)
Inclusion criteria: LVEF ≤ 40%, Hb 9 -12.5 g/dl
Target Hb: 13 to 15 g/dl
Intervention: Darbepoetin Alfa [n = 162] versus placebo [n = 157]
No significant difference in exercise duration, NYHA class or QoL
Nonsignificant trend observed toward a lower risk of all-cause mortality or first HF hospitalization in darbepoetin alfa-treated group
Adverse events similar in both arms
Erythropoietin-stimulating agents are not recommended to be used for treatment of anemia in HF [17, 22,23,24]
RED-HF trial. Double blind Randomized Controlled Trial [20]
n = 2278 patients (follow-up—28 months)
Inclusion Criteria: LVEF ≤ 35%, Hb 9–12 g/dl
Target Hb: 13 to 14.5 g/dl
Intervention: Darbepoetin alfa [n = 1136] versus placebo [n = 1142]
No difference in primary outcome (all-cause death or first hospitalization for worsening HF
Significant increase in incidence of ischemic cerebrovascular accident and thromboembolic events with Darbepoetin alfa
 
Parenteral iron
FAIR-HF. Multicenter, Double blind Randomized Controlled trial [25]
n = 459 [follow-up—24 weeks]
Inclusion criteria: LVEF < 40% (NYHA class II) or < 45% (NYHA III) with ID (ferritin < 100 ng/mL or 100–300 ng/mL if TSAT < 20%) and anemia (Hb 9.5–12 gm/dl) or without anemia (Hb 12.0–13.5 gm/dl)
Intervention: Parenteral iron-FCM [n = 304] versus placebo [n = 155]
Significant improvement in NYHA class, 6MWT, QoL and patient global assessment ESC/ACC guidelines: Parenteral iron (preferable FCM or non-dextran iron) for symptomatic HF patients (NYHA II and III) with ID (ferritin < 100 ug/dl or ferritin between 100–299 ug/dL and TSAT < 20%) to improve symptoms and QoL [13,14,15,16,17]
CONFIRM-HF. Multicenter, Double blind Randomized Controlled trial [26]
n = 304 [follow-up—52 weeks]
Inclusion criteria: LVEF ≤ 45%, symptomatic HF with elevated natriuretic peptides and ID (ferritin < 100 ng/mL or 100–300 ng/mL
if TSAT < 20%)
Intervention: Parenteral iron—FCM [n = 152] versus placebo [n = 152]
Significant Improvement in NYHA class, 6MWT QoL and patient global assessment
Significant reduction in the risk of hospitalizations for worsening HF
 
EFFECT-HF. Randomized Controlled Trial [27]
n = 172 [follow-up—24 weeks]
Inclusion criteria: LVEF ≤ 45%, NYHA class II/III despite optimal medical therapy for HF ≥ 4 weeks
Intervention: Parenteral iron-FCM [n = 86] versus placebo [n = 86]
Significant increase in Peak oxygen consumption
Significant improvement in NYHA class and patient global assessment
Significant increase in iron stores
 
AFFIRM-AHF. Multicenter, Double blind Randomized Controlled trial [28]
n = 1132 [follow-up—52 weeks]
Inclusion criteria: LVEF < 50%, ADHF with concomitant ID (ferritin < 100 ng/mL or 100–300 ng/mL if
TSAT < 20%)
Intervention: Parenteral iron- FCM [n = 558] versus placebo [n = 550] [Intervention after stabilization, before discharge]
Significant decrease in HF related hospitalizations
No difference in cardiovascular deaths
Parenteral iron safe
 
Ongoing trials with parenteral iron in HF
FAIR-HF2. Multicenter, Double blind Randomized Controlled trial
[ClinicalTrials.gov Identifier: NCT03036462]
Estimated n = 1200 [Expected follow-up—52 weeks]
Inclusion criteria: Systolic HF with documented ID
Intervention: Parenteral iron- FCM versus placebo
Primary outcome: Combined rate of recurrent cardiovascular hospitalizations and of cardiovascular death
[ongoing]
 
HEART-FID. Multicenter, Double blind Randomized Controlled trial
[ClinicalTrials.gov Identifier: NCT03037931]
Estimated n = 3014 [Expected follow-up—52 weeks]
Inclusion criteria: LVEF ≤ 40%, NYHA II, III
with documented ID
Intervention: Parenteral iron- FCM versus placebo
Primary outcomes:
Incidence of death at 1 year
Incidence of hospitalization for HF at 1 year
Change in 6MWT distance at 6 months
[ongoing]
 
Oral iron
IRONOUT HF. Randomized Controlled trial [31]
n = 225 [follow-up—16 weeks]
Inclusion criteria: NYHA II-IV, LVEF ≤ 40% and ID (ferritin 15–100 ng/mL or between 100–299 ng/mL with a TSAT < 20%) and Hb: 9–15 g/dL (men) and 9–13.5 g/dL (women)
Intervention: oral iron polysaccharide (150 mg twice a day) [n = 111] versus placebo [n = 114]
No significant difference between peak oxygen consumption between two groups
No significant difference in exercise capacity, 6MWT, NT-pro-BNP and KCCQ Clinical Summary score
Oral iron: not enough evidence
  1. ACC, American College of Cardiology; ADHF, acute decompensated heart failure; APACHE, Acute Physiology and Chronic Health Evaluation; BT, blood transfusion; ESC, European Society of Cardiology; FCM, ferric carboxymaltose; Hb; hemoglobin; HF, heart failure; ID, iron deficiency; KCCQ, Kansas City Cardiomyopathy Questionnaire; LVEF, left ventricular ejection fraction; 6MWT; 6-min walk test; NT-pro BNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association; TSAT, transferrin saturation; QoL, quality of life