Thread by @AnandJag1

My team recently asked WHY we give Fe to pts with HFrEF+anemia.

First answer: b/c someone told me so
Better answer: let me get back to you on that

Let’s explore and try to understand, #medtwitter #medstudenttwitter 0/14

1/First off, it helps to review a general schema for anemia.

Blood loss, decreased production, increased destruction

So, why are patients with HFrEF anemic?

2/Controlling for other co-morbids or meds that can lead to blood loss and destruction, it turns out that ↓RBC production drives anemia in HFrEF.

Why?

3/Turns out all these factors play a role! Some brief specifics:

Inflamm -> ↑hepcidin -> ↑sequestration ↓gut absorp
Dilution (acute exacerbation)
↓Fe (hepcidin)
CKD (EPO stimulation from ↓renal pO2 blocked by inflamm)

Graphic (bit.ly/2A5BA41)

4/The ACE-i bit confused me. Rabbit hole summary:

ACE nlly ↑RBCs through several pathways
ACE-i gets in the way by ↑goralatide, ↓IGF-1, and ↓IL-12 -> ↓RBCs

Clinically significant? Maybe, but still debated. I need a kidney doc.

@kidneyboy @NephJC help!

5/Phew, ok let’s uncross our eyes and do a quick recap:

So far we know that HFrEF -> multifactorial anemia. Inflammation probably leading the charge of ↓production.

Inflammation -> ↑hepcidin -> ↓available Fe ->↓Hb

6/This isn’t your everyday Fe-def anemia though.

Hepcidin is sequestering Fe in the liver and macrophages so we actually HAVE Fe, we just can’t use it -> FUNCTIONAL Fe deficiency.

Cool, so it’ll show up on Fe studies, right?

Sorta…

7/The studies are a little tricky.

Normal Fe-def -> ↓Fe, ferritin, %sat; ↑TIBC
Fe-def in HFrEF -> ferritin <100 OR ferritin 100-299 + Tsat <20%

This criteria tries to account for ↑ferritin in inflammation (and used by all the Fe def+HF trials)

8/K, so we know Fe-def in HFrEF is functional and we can detect it. Why do we treat it?

These pts have ↓NYHA/exercise, QoL, and ↑mortality (bit.ly/2A5BA41)

Here’s the kicker: pts don’t have to be anemic! The Fe-def alone does it

9/Yikes! How do we treat it this? First thought was correct the anemia with ESAs. A little history:

In 2000, 142 pts in Tel Aviv w/anemia+HFrEF were given darbopoietin+Fe ->↑NYHA fxnl class.

Darbo was made king and tons of ESA trials followed.

10/The RED-HF trial was the biggest study of darbo v placebo in pts w/ HFrEF+anemia (2278 pts, rndmizd, dbl-blnd).

Sadly, death and hospitalization didn’t improve, AND there were ↑strokes and thromboembolic events.

Darbo was done.

11/But, a small study of 16 pts w/HFrEF+anemia that gave IV Fe alone was published just before RED-HF.

-> ↑NYHA class, Hb, and QoL! bit.ly/3gtqxSW

Great! We may be able to answer the, “why” of Fe rx in HFrEF.

12/Oral vs IV?

IRON-OUT (oral Fe v placebo): no ∆ in VO2max, 6MWD, ntBNP

Most studies are IV Fe b/c presumed poor PO absorp from ↑hepcidin. Findings: ↑QoL, 6MWD, NYHA

Meta-analyses (IV Fe) -> ↓hospitalizations+CV mortality+ntBNP+↑QoL

IV Fe wins.

13/Quick note on HFpEF

The jury is still out as to whether Fe replacement helps. The FAIR-HF-HFpEF study is currently recruiting pts to try to answer this question (clinicaltrials.gov/ct2/show/NCT03…)

14/Summary

💥HFrEF is an inflammatory state -> fxnl Fe-deficiency via hepcidin
💥↓Fe worsens outcomes in HFrEF
💥ESAs don’t help, make things worse
💥IV Fe helps! Give it!

15/Big thanks to @noahrosenberg1 and @DoctorVig’s recent #tweetorial convo for nudging me to make this.

I learned a ton and realized there’s a ton left to learn. @cardionerds @myanamandala @SalKumarMD @ceciliaberard10, #cardiotwitter, teach us more!

Fin/

Further reading:
bit.ly/2Xpypfs
bit.ly/2zuM8cK
bit.ly/2A5BA41
bit.ly/3glmYy7
bit.ly/3gtqxSW
bit.ly/3d3Ip4E
bit.ly/2AbPkdC