Heart failure module 5: special cases in heart failure

Released1 November 2017     Expires: 01 November 2019      Programme:

Haematinic deficiencies

Iron deficiency is a common cause of anaemia in heart failure. Of patients with heart failure and anaemia, 58% were iron deficient whereas only 5% were vitamin B12 deficient and 4% folate deficient.70 While the true cause is unclear, it is likely that iron deficiency in patients with heart failure stems from a combination of reduced iron stores, poor absorption and sub-acute blood loss (due to oral antiplatelets and anticoagulants).71,72

Not all patients that are iron deficient are also anaemic; anaemia may be the end point of iron depletion. In one study of approximately 4,500 patients with heart failure, approximately 12% of patients with a haemoglobin ≥14 g/dL had transferrin saturations <15%, a further 23% of patients with a haemoglobin 13–14 g/dL had transferrin saturations <15%.56

Patients with heart failure and iron deficiency without anaemia (ferritin <100 μg/L and haemoglobin ≥13 g/dL for men, ≥12 g/dL for women) have lower six- minute walk test (6MWT) distances and peak exercise oxygen consumption than patients with normal iron stores.73 Furthermore, iron deficiency is associated with an increased risk of mortality independent of low haemoglobin levels.56

Treating anaemia in patients with heart failure

Anaemia in patients with heart failure is a result of various mechanisms with two central pathways: iron depletion and reduced EPO levels. Both have been therapeutic targets in clinical trials with varying degrees of success.

Early studies suggested that treatment with erythropoiesis-stimulating agents,74 intravenous iron,75 or both,76 may improve functional capacity in patients with heart failure and anaemia; large scale randomised controlled trials (RCT) followed.

Erythropoesis-stimulating agents (ESA)

The RED-HF (Reduction of Events by Darbepoetin Alfa in Heart Failure) trial investigated the effect of darbepoetin on patients with heart failure and anaemia not due to iron deficiency (median age 72 years, median LVEF 31%, median Hb 11.15 g/dL, median transferrin saturations 24%).77

1,278 patients were randomised to two-weekly subcutaneous injections of either darbepoetin (dose adjusted to baseline haemoglobin) or placebo until they reached normal haemoglobin levels (≥13 g/dL), injections were monthly thereafter to maintain haemoglobin in the normal range. The primary end point was a composite of all-cause mortality and hospitalisation with heart failure, quality of life (QoL) measures were secondary outcomes.

After a median 28 months of follow up, the study was terminated with no difference in primary outcome between treatment and placebo groups. Darbepoetin caused a rapid and sustained improvement in haemoglobin, which was associated with a small but significant (P=0.01) improvement in QoL measures after six months compared to placebo.

Mortality and hospitalisation rates, however, were unaffected. Furthermore, there was a significantly higher rate of embolic and thrombotic events with darbepoetin arm compared to placebo (13.5% vs. 10%, p = 0.009).

Similar neutral results for cardiovascular outcomes and increased risk of thrombotic events have been observed with ESAs in other patient populations.78 Consequently, ESAs are not used to treat anaemia in patients with heart failure. However, they continue to be used to treat anaemia in patients with CKD and the co-diagnosis of heart failure is not a contraindication.79


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