1. IV Iron & Heart Failure Paul Forsyth (paul.forsyth@nhs.net)
Lead Pharmacist -Clinical Cardiology (Primary Care) / Heart Failure Specialist
NHS Greater Glasgow & Clyde
NES Pharmacy Training Evening Tuesday 4th October 2016

2. SIGN 147- Management of Chronic HF (March 2016)*

3. Background

4. Understanding the effects of iron in the body
Historically, clinicians have focused on the effect of inadequate iron supply on erythropoiesis and the resulting risk of anaemia.
Iron is however essential for proteins involved in:
cellular oxygen storage
generation of cellular energy in skeletal muscle and myocardiocytes
Myocardial tissue has been shown commonly to have reduced iron content in heart failure

5. Prevalence and Consequence of Anaemia and/or Iron Deficiency Heart Failure

6. Anaemia and Outcomes in Heart Failure

7. Prevalence of Iron Deficiency and/or Anaemia in Heart Failure

8. Iron Deficiency and/or Anaemia and Outcomes in Heart Failure

9. Mechanisms of Iron Deficiency in Heart Failure

10. Absolute Iron Deficiency in HF
Poor nutrition is common (resulting in low-iron consumption)
Gut oedema and reduced gastrointestinal blood flow (due to decreased cardiac output) may impair iron absorption
Heart failure often precipitates chronic renal disease
Heart failure patients are commonly prescribed antiplatelet or anticoagulation medications, with consequent blood loss

11. Functional Iron Deficiency and Heart Failure
Iron regulates hepcidin homeostasis
Increases in iron levels in the plasma and iron storage stimulate the production of hepcidin, which blocks iron absorption from the diet and its further storage
Inflammation through chronic disease increases hepcidin synthesis via interleukin-6 (IL-6) release

12. Heart Failure Trials with Darbepoetin

13. RED-HF Key Inclusion NYHA class II-IV LVEF ≤40% Hemoglobin 9 - 12g/dl
Treatment
Patients randomised 1:1 to Darbepoetin or placebo
Darbepoetin group received a starting dose of 0.75 μg per kg once every 2 weeks until a Hb level of 13.0 g/dl was reached on two consecutive visits. Thereafter, injections designed to maintain a Hb level of 13.0 g/dl

14. RED-HF: Changes in Hb (g/dl)

15. RED-HF: Effect on Mortality / Morbidity
No clinically significant change in Quality of Life between groups either (KCCQ)

16. Does ESA (without iron) exacerbate iron deficiency in chronic disease??
Erythropoesis-stimulating agents (ESA) stimultae red blood cell production
However, red blood cell production requires large amounts of iron, which is often trapped in cells in functional iron deficiency

17. Heart Failure Trials with
IV Iron

18. FAIR-HF
Key Inclusion
NYHA II and LVEF< 40% OR NYHA III and LVEF<45%
Hb between 95 and 135 g per liter
Serum ferritin level <100 μg per liter OR μg per liter AND transferrin saturation (TSAT) <20%
Treatment
Randomised 2:1 ferric carboxymaltose to placebo
4 ml ferric carboxymaltose (equivalent to 200 mg of iron) weekly until iron repletion was achieved (the correction phase) and then every 4 weeks during the maintenance phase

19. Changes to Iron Markers

20. Improvement in functional status with IV iron (patient scored)

21. Improvement in functional status with IV iron (physician scored or objective)

22. Sub-Group Analysis

23. CONFIRM-HF Key Inclusion NYHA II – III LVEF ≤45%, Longer duration
BNP >100 pg/mL and/or NT-pro-BNP>400 pg/mL
Ferritin level <100 ng/mL, or between 100 and 300 ng/mL if TSAT<20%
Hb<15 g/dL
Longer duration
Larger single doses

24. Treatment Schedule Randomised 1:1 ferric carboxymaltose to placebo
10 or 20 mL of ferric carboxymaltose at a time (equivalent to 500 or mg of iron)
Initial dosing and maintenance dosing based on subject weight and Hb value at screening
Initial total ferric carboxymaltose doses were between 500 and 2000 mg (but doses over 1000mg were given over two visits at baseline and Week 6)
Maintenance ferric carboxymaltose doses of 500 mg iron given at weeks 12, 24, and 36, if ID was still present

25. Improvement in functional status and fatigue sustained over a year

26. Trend towards reduced HF hospitalisation (although study not powered to prove this)

27. IV Iron & HF: Meta-analysis of RCTs

28. IV Iron vs. Oral Iron in HF
Lack of trials showing benefits of using oral iron
Oral iron causes gastrointestinal side effects (constipation, dyspepsia, nausea, diarrhoea, and heartburn) in up to 60% of patients
Food and some medications interact with iron absorption, such that iron uptake is best when taken on an empty stomach and this is difficult to adhere to
Non-adherence with iron salts is common for these reasons

29. IV Iron vs. Oral Iron in HF
Oral iron supplementation can take 6-7 months in heart failure patients to replenish iron stores
Will patients live that long?

30. Summary

31. SIGN 147- Management of Chronic HF (March 2016)

32. Case Study

33. Mr BMc (1) 61 yr old male with recent NSTEMI one month ago
Presents for outpatient review
NYHA 3 (i.e. SOB on a 50 yard walk)
Very tired
Bi-basal lung crackles
Occasional paroxysmal nocturnal dyspnoea
140/90mmHg.
Pulse 86bpm and SR

34. Mr BMc (2) Normal blood chemistry Current medications
Ramipril 5mg twice daily
Bisoprolol 2.5mg daily
Eplerenone 25mg daily
Furosemide 80mg morning and 40mg lunch
GTN 400mcg Spray when required
Simvastatin 40mg at night
Aspirin Disp 75mg daily
Ticagrelor 90mg twice daily
Normal blood chemistry

35. Mr BMc – Question 1
What changes should you consider making to his standard heart failure treatments at this first outpatient review?
Increase his Furosemide
Increase his Eplerenone
Increase his Bisoprolol
Stop his Bisoprolol
Start Sacubitril/Valsartan

36. Mr BMc – Question 1
What changes should you consider making to his standard heart failure treatments at this first outpatient review?
Increase his Furosemide
Increase his Eplerenone
Increase his Bisoprolol
Stop his Bisoprolol
Start Sacubitril/Valsartan

37. Mr BMc (3)
A few months later your patient again presents at clinic, having been optimised in the community by his HF nurse
NYHA 3
Pretty fatigued
Euvolaemic
BP 110/61mmHg
Pulse 56bpm and sinus rhythm
Full target doses of Ramipril, Bisoprolol & Eplerenone
Re-echo shows LV ejection fraction of 41%

38. Mr AH (4)
Ponikowski P et al. Eur Heart J Jul 14;37(27):
You follow the guidelines and decide also to test the patient for iron deficiency and his serum ferritin comes back at 43ug/l and his Hb 12.5g/dl. What should we do now?
Nothing
Consider oral iron
Consider Darbepoetin
Consider IV iron
Consider a bone marrow biopsy

39. Mr AH (4)
Ponikowski P et al. Eur Heart J Jul 14;37(27):
You follow the guidelines and decide also to test the patient for iron deficiency and his serum ferritin comes back at 43ug/l and his Hb 12.5g/dl. What should we do now?
Nothing
Consider oral iron
Consider Darbepoetin
Consider IV iron
Consider a bone marrow biopsy

40. Thank You!
Questions?