Transcript Is Correction of Iron Deficiency a New Addition to the

Is Correction of Iron
Deficiency a New Addition
to the Treatment of Heart
Failure?
Silverberg DS, Wexler D,
Schwartz D.
Department of Nephrology and
Cardiology, Tel Aviv Medical
Center, Tel Aviv, Israel.
How common is anemia in
heart failure?
• Anemia (Hb <13g% in men
and <12g% in women) is
present in about 50% of
Heart Failure (HF) patients.
How do you define iron
deficiency in heart failure?
• Iron deficiency (ID), is defined
as either a serum ferritin of
<100ug/l or a serum ferritin of
100-300 ug/l along with %
Transferrin Saturation of <20%,
How common is iron deficiency
in anemic heart failure patients?
• Iron deficiency is present in
about 50% of the HF patients
How common is iron deficiency
in heart failure patients with a
normal Hb ?
• Iron deficiency is found in
about 50% of patients without
anemia
So how common is iron
deficiency in heart failure?
Thus ID is present in about
half the patients with HF both in
those who are anemic and those
who are not.
Therefore every patient who has
heart failure should be checked for
iron deficiency anemia whether
they are anemic or not!!!!!
What are the arguments that
support the importance of iron
deficiency in heart failure?
• The ID in HF is associated with reduced
iron stores in the bone marrow and the
heart.
• ID is an independent risk factor for
severity and worsening of the HF
• Correction of ID with intravenous (IV)
iron corrects both the anemia and the
ID.
Structure of Mitochondria
How oxygen gets converted into
ATP
What iron deficiency does to the
cell
• 1. Reduces Hb causing reduced supply of
oxygen to the cell
• 2. It reduces myoglobin concentration in the
cell reducing the storage of oxygen
• 3. Reduces oxygen utilization- the
conversion of oxygen to ATP
• All these make the heart and skeletal
muscles weak and interfere with all cell
functions in the body
Animal Studies
• In animal studies
• If you give iron to iron deficient
anemic rats but keep the Hb level
unchanged they improve greatly
• SO THAT IT IS NOT JUST THE Hb
THAT IS IMPROVING THE PATIENT
WHO IS TREATED FOR IRON
DEFICIENCY BUT THE IRON AS
WELL
• Iron deficiency in animal studies has
shown to cause the development of
• left ventricular hypertrophy and
dilatation,
• cardiac fibrosis and dysfunction
leading to heart failure,
• mitochondrial swelling,
• disruption of sarcomeres
• and release of reactive oxygen species
that can cause cell damage
What improvements are seen with
the use of IV iron in HF
• Improved NYHA functional status,
• Improved Exercise capacity as
judged by oxygen utilization in
exercise and 6 min walk distance,
• Decreased C Reactive Protein, BNP,
RDW (Red Cell Disribution Width)
• Improved Quality of life
What improvements are seen with
the use of IV iron in HF
• IV iron correction of ID in HF is
associated with improvement in
• rate of hospitalization for HF (falls
about 72%),
• cardiac dilation and hypertrophy,
• cardiac function including systolic and
diastolic function, and
• renal function
The Quality of Life as judged by standard
questionnaires was improved
• What does this mean?
• Improvement in
• activities of daily living,
• appetite,
• mobility,
• dressing themselves,
• hobbies,
• general interest
• depression improved
Meta-analysis of IV iron in HF
• 5 trials- 509 IV iron and 342 controls
• Combined end point of risk of all-cause
death or cardiovascular
hospitalizations reduced by 56%
• Combined endpoint of risk of CV death
or hospitalization for worsening heart
failure reduced by 61%
• Hospitalization for HF reduced by 72%
• NYHA class reduced by 0.54
• 6 Minute Walking Distance increased by
31 m
• Increased Quality of Life increased by 4
different scales .
• In Summary
• Improved outcomes death and
hospitalization
• Increased exercise capacity
• Improved Quality of Life
• Alleviation of Heart Failure Symptoms
Is IV iron treatment costeffective?
• The cost-effectiveness of the treatment
in terms of quality of life is about
equivalent to the use of beta blockers,
ACE inhibitors and ARBs
Is this improvement due to the
improvement in the anemia or
the improvement in iron
deficiency?
• The improvement seem to be related
more to the correction of the iron
deficiency than to correction of the
anemia.
Which IV iron products have
been used in HF and are they
safe?
• The large placebo- controlled
studies have only been done
with Ferric carboxymaltose and
Ferric sucrose and the
incidence of adverse effects of
these agents is similar to
placebo.
In the 5 placebo-controlled studies and
3 non-placebo studies patients in
patients with HF, IV iron was given over
a few weeks either as
Ferric saccharate – (Venofer) total 1000
mg) 200 mg once a week for 5 weeks
Or
Ferric Carboxymaltose (Ferinject) 1000
mg given as 1000 mg once or 500 mg
twice over a week or 200 mg per week
for 5 weeks
The drawbacks of the studieswhat data is lacking?
Large long-term adequatelycontrolled mortality-driven
intervention studies are still
needed to clarify the effect of IV
iron in HF.
What are the current policies
of international heart
associations about detection and
treatment of IV iron in heart ?
• Several Heart Associations, including
the European,
• French
• Australian and New Zealand
• Heart Associations, suggest that ID
should now be routinely sought for in
all HF patients and corrected if present.
What is the role of oral iron in
iron deficiency in heart failure?
• There is currently insufficient data on
this subject. Some experts say that if
the patient is stable, oral iron can be
tried for a few weeks but if it fails to
correct the iron deficiency IV iron
should be used.
• Others would not wait and would treat
the iron deficiency with IV iron right
away
When should Erythropoietin
(EPO) be added?
• A large placebo- controlled multicenter
study, the RED-HF study, has been
done in anemic HF patients which
failed to show any advantage of EPO
over placebo. In addition the EPO was
associated with increased
cardiovascular complications. These
findings are confirmed by metaanalysis. But QOL is improved as is
dyspnea
• In metaanalysis the effects of short and
long acting EPO are similar.
• EPO should be added only when the Hb
remains less than 10-11g% and only
given in the lowest doses needed to get
to a Hb of around 11g%
What has caused the iron
deficiency?
• Reduced intake- anorexia or low
protein diets
• Reduced iron absorption from the
intestines caused by Hepcidininduced reduction in iron
absorption from the gut
• Hepcidin- induced lack of release
of iron from iron stores in the liver
cells and macrophages
What has caused the iron
deficiency?
• Gastritis –due Helicobacter pylori or
not
• Intestinal edema from Heart Failure
• Bleeding gastric or duodenal ulcers
• Carcinoma of the stomach or colon
• Warfarin-like agents, NSAIDs, ASA,
Clopidogril etc
• Medications such as calcium
• The use of Erythropoietin
How does hepcidin reduce
iron absorption?
• CHF is an inflammatory condition
like renal failure, cancer,
rheumatoid arthritis etc
• In all inflammatory conditions the
body produces a cytokine called
interleukin 6 which goes into the
liver and causes the production of
hepcidin
• This hepcidin is released into the blood and
reduces ferroportin activity in the gut and
the liver and RES
• This prevents the absorption of iron from
the gut and prevents the release of iron from
iron stores in the liver and RES
• For these 2 reasons not enough iron gets
into the blood and therefore not enough iron
is delivered to the tissues including the
bone marrow and heart
How does IV iron alone compare
to IV iron and EPO in Cardio
Renal Syndrome?
• We recently compared the 2 approaches in
81 cases of CRS and we found that
• 74% of the IV iron alone group could reach a
Hb of 11g/dl and
• 85% of the combination could reach a Hb of
11g/dl
• So the great majority can reach a satisfactory
Hb with IV iron alone
•
Ben –Assa and Silverberg Cardiorenal Med 2015;5:248-53
Conclusions
• 50% of the patients with heart failure have
iron deficiency whether or not they are
anemic
• Intravenous iron reduces hospitalization for
heart failure by about 72% without causing
serious side effects in iron deficient CHF
patients
• IV iron has a great effect on improving
Quality of Life, exercise capacity, and
probably renal and cardiac function in CHF
• Most IV iron preparations are safe and
effective but iron carboxymaltose probably
has the most advantages
• The role of oral iron is uncertain and
has not been studied sufficiently
References
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Silverberg DS et al Is Correction of Iron Deficiency
a New Addition to the Treatment of the Heart Failure?
Int J Mol Sci. 2015 Jun 18;16(6):14056-74.
Qian C, et al. The Efficacy and Safety of Iron
Supplementation in Patients With Heart Failure and
Iron Deficiency: A Systematic Review and Metaanalysis. Can J Cardiol 2015 Jun 21. [Epub ahead of
print]
Wong CC, et al . Iron Deficiency in Heart Failure:
Looking Beyond Anaemia. Heart Lung Circ. 2015 Jul
15 [Epub ahead of print]
McDonagh T, Macdougall IC Iron therapy for the
treatment of iron deficiency in chronic heart failure:
intravenous or oral? Eur J Heart Fail. 2015
Mar;17(3):248-62
Jankowska EA et al Effects of IV iron therapy in irondeficient patients with systolic heart failure. Eur J
Heart Failure 2016 Jan 28 (ahead of print)
.