Iron Deficiency and Heart FailureEfficacy of IV Iron Sucrose or Ferric Carboxymaltose Investigated...
Transcript of Iron Deficiency and Heart FailureEfficacy of IV Iron Sucrose or Ferric Carboxymaltose Investigated...
Inder S. Anand, MD, FRCP, D Phil, (Oxon.)
Professor of Medicine, Cardiovascular Division
University of Minnesota Medical School
Director of Heart Failure Clinic
VA Medical Center
Minneapolis and San Diego
Iron Deficiency and Heart Failure:
Iron supplements as a Treatment for Heart Failure
• Anemia and Iron deficiency (ID) are common comorbidities in HF
& often coexist. Together or independently they are associated
with worse symptoms and outcomes.
• Whether anemia or ID are just a marker of severe HF or
mediators of adverse outcomes, that need to be targeted has
been debated for long.
• Treating anemia in HF with erythropoiesis-stimulating agent does
not improve outcomes, may be deleterious and is not
recommended.
• Increasing data suggests that treating ID with IV iron improves
symptoms and exercise capacity, but long-term outcomes and
safety data are not yet available.
Heart Failure, Anemia and Iron Deficiency
Absolute or Relative Iron Deficiency is
Common in Heart Failure
Absolute Iron Deficiency:
• When total body iron is decreased
Functional Iron Deficiency:
• When total body iron is normal or increased but
inadequate to meet the needs of target tissues
because of sequestration in the storage pool
In patients with HF, ferritin <100 μg/L or 100 to 300 μg/L if
transferrin saturation (TSAT) is <20%
include patients with both absolute and functional ID.
Iron Deficiency is Common in Heart Filure
• 546 patients, stable HF; 55+11 y, 88% males, LVEF 26+7%, Iron def: ferritin <100 mg/L, or 100–300 mg/L with T-Sat <20%.
Jankowska et al. Eur Heart J. 2010:31;1872–1880
Iron Deficiency is Common in Heart Filure
• 751 HF patients SHOP Study; age 62±12 y, 76% men, 65% Chinese, 24% Malay, 10% Indian and 601 controls; age 60±10 y, 50% men, 71% Chinese, 22% Malay, 7% Indian). ID: 100 mg/L, or 100–300 mg/L with T-Sat <20%.
Yeo et al. Eur J Heart Failure 2014 16, 1125–1132; doi:10.1002/ejhf.161
SHOP (Singapore HF Outcomes and Phenotypes study) in a
Multi-ethnic community-based Southeast Asian controls and heart
failure population.
Jankowska et al Eur Heart J (2010) 31, 1872–1880
Absolute or Relative ID in Heart Failure is
Associated with Worse Outcomes
546 patients with stable HF; LVEF 26 ± 7%. Overall, absolute or relative ID was
present in 37% patients; 57% in those with anemia, 33% in those without anemia.
Absolute or Relative ID was present
in 37% all CHF patients (199/546)
20
40
60
% o
f C
HF
Patients
33%
Non
anemics
57%
Anemic
(Hb 12 g /dL)
ID was associated with death or Heart Tx independent
of anemia (HR 1.58, 95% CI 1.14-2.17)
Jankowska EA, et al. Eur Heart J 2010;31:1872–80.
In HF Iron Deficiency May be a More Important Prognostic Marker Anemia
Klip et al. Am Heart J 2013;165:575-582.e3.
International pooled cohort, 1,506 HF patients with and without ID and
anemia
Iron deficiency but not anemia remained an independent
predictor of mortality (HR] 1.42, 95% CI 1.14-1.77, p = .002)
Does Iron Replacement Therapy Help?
• Oral iron supplementation is standard therapy
for ID in non-HF patients; readily available,
inexpensive & effectively raises serum iron.
• In HF, iron is not absorbed well because of
elevated hepcidin, which inhibits iron absorption
• Oral iron is also associated with adverse GI
effects and not well tolerated.
• Few studies have investigated the effects of oral
iron in patients with ID and HF.
IRONOUT-HF (Iron Repletion Effects on Oxygen Uptake in Heart Failure)
• Phase 2 RCT, 225 patients with NYHA class II to IV HF
• Median LVEF, 25%
• Hb; 9 - 15 g/dL (men) or 9 - 13.5 g/dL (women) and ID
• Randomized: oral iron polysaccharide 150 mg BD/
placebo.
Primary Endpoint: • Change in peak VO2 from baseline at 16 weeks
Secondary Endpoints: • 6MWD, NT-proBNP levels and KCCQ QoL score
Lewis, GD et al.JAMA. 2017;317(19):1958-1966. doi:10.1001/jama.2017.5427
IRONOUT-HF (Iron Repletion Effects on Oxygen Uptake in Heart Failure)
Lewis, GD et al.JAMA. 2017;317(19):1958-1966. doi:10.1001/jama.2017.5427
Studies with Intravenous Iron in Heart Failure Efficacy of IV Iron Sucrose or Ferric Carboxymaltose Investigated in 5 RCT
• ↑ Exercise capacity (6MWT; Peak Vo2)
• Improved QoL scores
• Improved NYHA class • ↓ NT-proBNP level
Anand and Gupta Circulation. 2018;138:80–98
• Because of small size - outcomes could not be
assessed
CV Deaths and CV Hospitalization Recurrent Event Analysis - 42% ↓
Meta-analysis of 4 RCT Comparing IV Ferric Carboxymaltose and Placebo HFrEF
Individual patient data from 4 RCTs comparing FCM with placebo in 839
patients with HFrEF and ID, 504 randomized to FCM and 335 to placebo.
Anker et al. Eur J Heart Fail. 2017; doi:10.1002/ejhf.823
Meta-analysis of 4 RCT using Similar Protocol as FAIR-HF of IV FCM in HFrEF
Individual patient data from 839 patients with HFrEF and ID
504 randomized to Ferric Carboxymaltose, 335 to placebo.
Anker et al. Eur J Heart Fail. 2017; doi:10.1002/ejhf.823
Recurrent Cardiovascular Outcomes
Anker et al. Eur J Heart Fail. 2017; doi:10.1002/ejhf.823
All Cause Mortality and Recurrent CV Hospitalization
Meta-analysis of 4 RCT using Similar Protocol of IV FCM in HFrEF
Individual patient data from 839 patients with HFrEF and ID
504 randomized to Ferric Carboxymaltose, 335 to placebo.
Deleterious Effects of Iron on the Body
Anand and Gupta Circulation. 2018;138:80–98
• Human body is unable to excrete iron
• Under normal conditions, iron absorption is
reduced in the duodenum to prevent overload
• This protective mechanism is bypassed when
iron is given intravenously
• At higher TSAT, Reactive Oxygen Species are
formed - can mediate cell death in most organs
• Hence iron toxicity could be a major concern of
IV iron therapy
Guidelines for the Treatment of Iron Deficiency in Patients with Heart Failure
“In patients with NYHA class II and III HF and ID
(ferritin <100 μg/L or 100–300 μg/L, TSAT <20%),
intravenous iron replacement might be reasonable
to improve functional status and QoL.”
2017 - AHA/ACC Guidelines
Class IIb, Level of evidence BR recommendation:
2016 - ESC Guidelines
Class IIa, Level of Evidence A recommendation:
Yancy CW, et al. 2017 Circ. 2017;136:e137–e161.
Ponikowski, P et al. Eur Heart J. 2016;37:2129–2200.
Conclusions
• Increasing hemoglobin in anemic patients with HF does
not appear to be a therapeutic target
• Use of IV iron in the management of absolute or
functional ID in HF patients with or without anemia,
appears promising, and could become a therapeutic
target.
• Long-term clinical studies are required to confirm that
treatment of ID improves outcomes. A number of large
RCT in patients with Acute and Chronic HFrEF and
HFpEF are underway to address these issues.
Personalized Algorithm for Management of Patients with HF and ID
Anand and Gupta 2020. Blood: /doi.org/10.1182/blood.2019004004
HFrEF (with Hb ≤15 g/dL,
LVEF ≤45% and NYHA II-IV)
HFpEF
No data yet for IV
iron. Enroll in ongoing
trials, if possible
Optimize heart failure management.
Chronic anemia*
Ferritin <100 mg/L or ferritin 100-300 mg/L with TSAT <20%
Yes No
Consider IV iron infusion**
Monitor cardiac status, Hb and iron indices – repeat
IV iron if necessary
Continue monitoring
clinical status, Hb and iron indices
No anemia
Check iron indices We recommend considering
judicious packed red cell transfusion with IV furosemide
to prevent fluid overload if Hb <7-8
g/dL. However, there are no
prospective data for red cell transfusion
*Hb <13 g/dL (men) Hb <12 g/dL (women)
**Dose based on Ganzoni formula
Identify and treat correctable as well as co-existing causes of anemia
Heart Failure
Acute anemia
Judicious packed red
cell transfusion
Hemodynamic instability or tissue hypoxia
or ongoing bleeding or Hb <7-8 g/dL
Yes No
Continue monitoring
clinical status and labs
Consider possibility of ID from bleeding, identify cause, treat
accordingly