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

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

Background

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

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

Anaemia and Outcomes in Heart Failure

Prevalence of Iron Deficiency and/or Anaemia in Heart Failure

Iron Deficiency and/or Anaemia and Outcomes in Heart Failure

Mechanisms of Iron Deficiency in Heart Failure

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

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

Heart Failure Trials with Darbepoetin

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

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

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

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

Heart Failure Trials with IV Iron

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 100-299 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

Changes to Iron Markers

Improvement in functional status with IV iron (patient scored)

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

Sub-Group Analysis

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

Treatment Schedule Randomised 1:1 ferric carboxymaltose to placebo 10 or 20 mL of ferric carboxymaltose at a time (equivalent to 500 or 1000 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

Improvement in functional status and fatigue sustained over a year

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

IV Iron & HF: Meta-analysis of RCTs

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

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?

Summary

SIGN 147- Management of Chronic HF (March 2016)

Case Study

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

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

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

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

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%

Mr AH (4) Ponikowski P et al. Eur Heart J. 2016 Jul 14;37(27):2129-200 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

Mr AH (4) Ponikowski P et al. Eur Heart J. 2016 Jul 14;37(27):2129-200 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

Thank You! Questions?