Anemia and Iron Deficiency: What Every Cardiologist Needs to Know

6th Saudi HF Group Symposium Riyadh - December 8-9, 2017 Anemia and Iron Deficiency: What Every Cardiologist Needs to Know Ammar Chaudhary MBChB, FRCPC Consultant Cardiologist Advanced Heart Failure Department of Cardiology King Faisal Specialist Hospital and Research Center Jeddah, Saudi Arabia

Outline Associations between HF, anemia, and iron deficiency Evidence for treating anemia and iron deficiency Guideline recommendations Ongoing studies

Extent of the Problem: Anemia in Ambulatory HF Patients Yi-Da Tang, et al. Heart Fail Rev (2008) 13:387 392

Anemia in Advanced HF Patients Yi-Da Tang, et al. Heart Fail Rev (2008) 13:387 392

Anemia Across RCTs of HFrEF Therapies Yi-Da Tang, et al. Heart Fail Rev (2008) 13:387 392

Anemia in Ambulatory HF Patients Yi-Da Tang, et al. Heart Fail Rev (2008) 13:387 392

Anemia in Advanced HF Patients Yi-Da Tang, et al. Heart Fail Rev (2008) 13:387 392

Anemia Across RCTs of HFrEF Therapies Yi-Da Tang, et al. Heart Fail Rev (2008) 13:387 392

Anemia in Ambulatory HF Patients Prevalence 15% - 55% ~ 31% Yi-Da Tang, et al. Heart Fail Rev (2008) 13:387 392

Anemia in Advanced HF Patients Prevalence 15% - 47% ~ 35% Yi-Da Tang, et al. Heart Fail Rev (2008) 13:387 392

Anemia Across RCTs of HFrEF Therapies Prevalence 4% - 49% ~ 11% Yi-Da Tang, et al. Heart Fail Rev (2008) 13:387 392

Extent of the Problem 50% of Medicare beneficiaries with HF > 65 yrs are anemic ^Bhatia RS, et al. N Engl J Med 2006;355:260-9

Extent of the Problem 50% of Medicare beneficiaries with HF > 65 yrs are anemic HB < 10 g/dl 9.9% HFrEF vs. 21.1% HFpEF, p < 0.001^ ^Bhatia RS, et al. N Engl J Med 2006;355:260-9

Extent of the Problem 50% of Medicare beneficiaries with HF > 65 yrs are anemic HB < 10 g/dl 9.9% HFrEF vs. 21.1% HFpEF, p < 0.001^ Factors: Age, heart failure stage, comorbidities (DM, CKD) ^Bhatia RS, et al. N Engl J Med 2006;355:260-9

Prognostic Implications of Anemia in HF HR 1.15-2.61 Pre-Tx HF Patients Yi-Da Tang, et al. Heart Fail Rev (2008) 13:387 392

Prognostic Implications of Anemia in HF HR 1.24-1.93 RCTs of ACEi, ARB, BB Yi-Da Tang, et al. Heart Fail Rev (2008) 13:387 392

Prognostic Implications of Anemia in HF www.seattleheartfailuremodel.org

Why Anemia Occurs in HF Dilutional anemia Anemia in HF

Why Anemia Occurs in HF Dilutional anemia RAASi Anemia in HF

Why Anemia Occurs in HF Dilutional anemia RAASi Anemia in HF CKD

Why Anemia Occurs in HF Dilutional anemia RAASi Anemia in HF Iron Deficiency CKD

Why Anemia Occurs in HF Dilutional anemia Hepcidin RAASi Anemia in HF Iron Deficiency CKD

Why Anemia Occurs in HF Inhibited iron absorption Dilutional anemia & iron release from RES Hepcidin RAASi Anemia in HF IL-6 Iron Deficiency CKD D Angelo, et al. Blood Res 2013;48:10-5

Summary of Erythropoetin Agents in HF Anand I, et al. J Am Coll Cardiol 2008;52:501 11

Darbopoetin-alpha for Anemia in HF N = 2278 Patients: LVEF 40%, NYHA II HB 9-12 g/dl, Intervention: darbapoetin alfa 0.75 mcg / kg weekly to HB > 13 then monthly Outcome: All-cause mortality or first HF hospitalization Swedberg K, et al. N Engl J Med 2013;368:1210-9

Erythropoiesis-Stimulating Agents in HF Guideline Recommendations COR, LOE ACC 2017 Update of ACC 2013 HF Guidelines Class III, LOE B In patients with HF and anemia, erythropoietin stimulating agents should not be used to improve morbidity and mortality COR, LOE Canadian Cardiovascular Guidelines 2017 Update Strong Recommendation; High-Quality We recommend erythropoiesis-stimulating agents (ESAs) not be routinely used to treat anemia in HF Evidence

Why Anemia Occurs in HF Inhibited iron absorption Dilutional anemia & iron release from RES Hepcidin RAASi Anemia in HF IL-6 Iron Deficiency CKD D Angelo, et al. Blood Res 2013;48:10-5

Lab Characteristics of Iron Def in HF Transferrin Sat Ferritin Hepcidin Iron Deficiency Low Low Low Anemia of Chronic Disease Low Normal/high High D Angelo, et al. Blood Res 2013;48:10-5

Lab Characteristics of Iron Def in HF Transferrin Sat Ferritin Hepcidin Iron Deficiency Low Low Low Anemia of Chronic Disease Anemia of Iron Low Normal/high High < 100 deficiency in Chronic Low or 100-299 + High Disease Tsat < 20% D Angelo, et al. Blood Res 2013;48:10-5

Iron deficiency as a Target in HF Iron is essential in hemoglobin synthesis, mitochondrial biogenesis and respiratory chain, oxidative phosphorylation, and citric acid cycle In animal models, iron deficieny can precipitate neurohormonal activation, LVH, LV dilatation, severe LV dysfunction, mitochondrial swelling Naito Y, et al. Am J Physiol Heart Circ Physiol 2009;296:H585 93 Melenovsky V, et al., Eur J Heart Fail. 2017 Apr;19(4):522-530

Iron deficiency as a Target in HF Iron is essential in hemoglobin synthesis, mitochondrial biogenesis and respiratory chain, oxidative phosphorylation, and citric acid cycle In animal models, iron deficieny can precipitate neurohormonal activation, LVH, LV dilatation, severe LV dysfunction, mitochondrial swelling Reduced expression of tranferrin receptor (Tfr) on cardiomyocites, low myocardial iron level (by 16-29%), impaired mitochondrial function, no corrleation with anemia Naito Y, et al. Am J Physiol Heart Circ Physiol 2009;296:H585 93 Melenovsky V, et al., Eur J Heart Fail. 2017 Apr;19(4):522-530

Iron deficiency as a Target in HF Jankowska E, et al. Eur Heart J (2013) 34, 827 834

IV Iron Replacement Elemental Iron Per Dose Properties Dose Calculation Number of Clinical Trials/Pts Ferric Carboxymaltose 100-1000 mg Rapid replenishment Weekly Ganzoni Formula 2 (n=763) Iron Sucrose 100-200 mg No test dose Ganzoni Forumla 200 mg weekly 7 (n=136) Iron Dextran 20 mg / kg over 4-6 hrs Test dose required Anaphylaxis risk max 100 mg daily Ganzoni Formula 1 Total Iron Deficit (Ganzoni s formula) = Weight x (Target Hb in g/dl - Actual Hb in g/dl) x 2.4 + Iron Stores Melenovsky V, et al., Eur J Heart Fail. 2017 Apr;19(4):522-530

Iron Deficiency and Anemia in HF FAIR-HF (NEJM 2009) CONFIRM-HF (EHJ 2015) N 459 (2:1) 304 (1:1) Patients NYHA II/III (80%), LVEF < 45, HB 9.5-13.5 (11.9), Ferritin <100 ng/ml or 100-299 (52) + Tsat <20% (avg 17) NYHA II/III (50%), LVEF < 45, BNP> 100 pg/ml (PBNP >400), Ferritin <100 ng/ml or 100-299 + Tsat <20%, HB <15 g/dl Intervention IV Ferric Carboxymaltose (correction + maintenance) IV Ferric Carboxymaltose (correction + maintenance) Outcome Primary: Week 24 NYHA class, PGA Secondary: KCCQ, 6 MWT Primary: 6MWT distance at 24 wks Sec: NYHA, PGA, KCCQ Anker SD, et al. N Engl J Med 2009;361:2436-48 Ponikowski P, et al. Eur Heart J. 2015 Mar 14;36(11):657-68

Iron Deficiency and Anemia in HF FAIR-HF (NEJM 2009) CONFIRM-HF (EHJ 2015) N 459 (2:1) 304 (1:1) Patients NYHA II/III (80%), LVEF < 45, HB 9.5-13.5 (11.9), Ferritin <100 ng/ml or 100-299 (52) + Tsat <20% (avg 17) NYHA II/III (50%), LVEF < 45, BNP> 100 pg/ml (PBNP >400), Ferritin <100 ng/ml or 100-299 + Tsat <20%, HB <15 g/dl Intervention Outcome IV Ferric Carboxymaltose (correction + maintenance) Primary: Week 24 NYHA class, PGA Secondary: KCCQ, 6 MWT IV Ferric Carboxymaltose (correction + maintenance) Median 1500 mg Primary: 6MWT distance at 24 wks Sec: NYHA, PGA, KCCQ Anker SD, et al. N Engl J Med 2009;361:2436-48 Ponikowski P, et al. Eur Heart J. 2015 Mar 14;36(11):657-68

FAIR-HF Anker SD, et al. N Engl J Med 2009;361:2436-48

Iron Deficiency and Anemia in HF FAIR-HF 47% NYHA I or II vs. 30% in the placebo group (OR of improvement by one class, 2.40; 95% CI, 1.55 to 3.71; P<0.001 Hospitalizations HR 0.53 95% CI, 0.25 to 1.09; P = 0.08 Anker SD, et al. N Engl J Med 2009;361:2436-48

Iron Deficiency and Anemia in HF CONFIRM HF HR for hospitalizations 0.39 (0.19 0.82), p=0.009 Ponikowski P, et al. Eur Heart J. 2015 Mar 14;36(11):657-68

van Veldhuisen D, et al. Circulation. 2017;136:1374 1383.

Anker S, et al. Eur J Heart Fail. 2017 Apr 24 van Veldhuisen D, et al. Circulation. 2017;136:1374 1383.

Meta-analysis Anker S, et al. Eur J Heart Fail. 2017 Apr 24

van Veldhuisen D, et al. Circulation. 2017;136:1374 1383. Anker S, et al. Eur J Heart Fail. 2017 Apr 24 Lewis G, et al. JAMA. 2017;317(19):1958-1966

Iron Deficiency and Anemia in HF: Guideline Recommendations COR, LOE ESC 2016 HF Guideilnes Intravenous FCM should be considered in symptomatic patients (serum ferritin <100 μg/l, or ferritin between 100 299 Class IIa, LOE A μg/l and transferrin saturation <20%) in order to alleviate HF symptoms, and improve exercise capacity and quality of life

Iron Deficiency and Anemia in HF: Guideline Recommendations COR, LOE Canadian Cardiovascular Guidelines 2017 Update Strong Recommendation; Moderate-Quality Evidence We recommend that I.V. iron therapy be considered for patients with HFrEF and ID, in view of improving exercise tolerance, quality of life, and reducing HF hospitalizations

Iron Deficiency and Anemia in HF: Guideline Recommendations COR, LOE ACC 2017 Update of ACC 2013 HF Guidelines In patients with NYHA class II and III HF and iron deficiency Class IIb, LOE B (ferritin <100 ng/ml or 100 to 300 ng/ml if transferrin saturation is <20%), intravenous iron replacement might be reasonable to improve functional status and QoL

Ongoing Trials FAIR-HF2 N = 1200 Primary end-point: Composite of HF hosp and CV mortality at 1 year Start & end dates: Feb 7, 2017 - October 2020 Source; VIFOR Pharma and clinicaltrials.gov

Ongoing Trials FAIR-HF2 N = 1200 Primary end-point: Composite of HF hosp and CV mortality at 1 year Start & end dates: Feb 7, 2017 - October 2020 Affirm-AHF Hospitalized patients with AHF after initial stabilization, EF < 50% Primary end-point: Composite of HF hosp and CV mortality at 1 year Start & end dates: April 3, 2017 - December 2019 HEART-FID N = 3014 Stable NYHA II-IV patients on OMT, LVEF < 35% Primary end-point: Time to all-cause death, HF hospitalization at 1 yr, change in 6 MWT at 6 months Start & end dates: March 15, 2017 - June 2022 Source; VIFOR Pharma and clinicaltrials.gov

Conclusions Anemia is common across HF patients, but is merely a marker of poor prognosis and not a legetimate therapeutic target in itself Iron deficiency is common across HF patients regardless of anemia, and is a predictor of poor survival. Pathophysiology and additional diagnostic markers are under investigation IV iron replacement, not oral iron, is associated with improved symptoms, quality of life, and likely reduced hospitalizations in symptomatic HFrEF A consensus for a strong recommendation for IV iron therapy will await ongoing clinical trials. Data is lacking for symptomatic iron-deficient HFpEF patients