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

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