Thread by @dr_benoy_n_shah

So...after time to read things through, a 🧵 on #IRONMAN

Better late then never! 😆

This was a useful exercise personally as iron deficiency (ID) in HF wasn't an area of great knowledge for me, but I've done my homework now!

Here's what I learnt

#cardiotwitter

Iron deficiency (ID) is common in HF. It isn't always associated with anaemia. Its aetiology is considered multifactorial:

⬇️ dietary iron intake
⬇️ dietary iron absorption
⬆️ GI tract iron loss
Impaired iron handling / redistribution

Previous studies of oral iron replacement were very small & did not find significant benefit

It is cheap & widely available but a very slow method of correcting ID, taking many months to produce noticeable changes

Previous RCTs have assessed role of IV iron replacement in HF

These include FAIR-HF, CONFIRM HF & AFFIRM HF

1 tweet per trial coming up

FAIR-HF

459pts with chronic HF, EF <40% & ID randomised to IV iron (ferric carboxymaltose - FCM) or placebo

PEP - Self-reported Patient Global Assessment & NYHA Class at 6m

PRO - signif improvement in PGA, NYHA Class & 6MWT distance

CON - small N, short F/U, no hard outcomes

CONFIRM-HF

304pts chronic HF, EF <45%, ID randomised to IV FCM or placebo for 1 year

PEP - 6MWT distance at 6m

PRO - Signif improvement in 6MWT, +18m vs -16m, p 0.002 & ⬇️ HF hospitalizations

CON - Small sample size

AFFIRM-HF

1110 pts, acute HF episode, EF <50% with ID, randomized to IV FCM or placebo

PEP: HF hospitalizations & CV death up to 1yr

Just failed to meet statistical significance - RR 0.79, p 0.059 - but strong trend towards benefit with IV iron

So...IRONMAN. Prospective open-label RCT at 70 NHS hospitals across 🇬🇧

Used ferric derisomaltose, not ferric carboxymaltose

Recruited Aug '16 - Oct '21, so was affected by COVID-19 pandemic (more on that later)

1869 pts screened, 1137 randomized: 569 IV iron, 568 usual care

Incl / Excl Criteria

>18yrs age
New / known HF with EF <45% in past 2yrs
NYHA II - IV
Confirmed ID

PLUS either current HF hospitalization (or within past 6m) OR elevated biomarkers (NTproBNP > 250 or > 1000 for SR & AF, respectively

Hb <9g/dL or >14g/dL excluded

Mean age 73yrs
75% male
91% Caucasian
>50% ischaemic CM
58% NYHA II, 40% NYHA III
Mean EF 32-35%

44-50% AF
55% HTN
~50% T2DM
Mean eGFR ~50

2/3 recruited due to ⬆️⬆️ BNP
1/3 recruited after HF hospitalization

~90% on BBs
>85% on ACEi / ARB / ARNI
>50% on MRA
>80% loop diuretic

Treatment

IV Iron Group

38% received 1 infusion
40% received 2 infusions
14% received 3 infusions
6% received 4 or more infusions
10 patients didn't receive IV iron

Usual Care Group

17% received IV iron!
12% had 1 infusion
4% had 2 infusions
1% had 3 or more infusions

Median F/U 2.7yrs

2% withdrew consent for F/U
1% lost to follow-up

These are extremely low percentages especially given the pandemic, so big credit to researchers for this 👍🏽

COVID-19 & national lockdowns across 🇬🇧 affected trial, as many couldn't attend in person for IV iron

Endpoint

PEP - composite of CV death & all HF hospitalizations

Multiple secondary endpoints...

Authors explain that due to impact of the COVID-19 pandemic, they had an additional sensitivity analysis incorporated into the trial design, censoring patients 6 months after the 1st national lockdown in the UK (i.e. censored at 30/09/2020)

PEP occurred in 336 IV iron cohort vs 411 usual care cohort - 95% CI 0.66 - 1.02, p 0.07

Better QoL score at 4 months but no difference at 20 months - was this due to inadequate topping up of Fe levels due to pandemic??

EQ-5D scores & exercise capacity unchanged between groups

Conclusion

Authors conclude IV iron is good and should be used more widely in HF patients than presently done

Here's the AHA summary slide

My thoughts

Well run trial
Pragmatic design
Can't rule out placebo effect on that 4 month QoL score given open label design
⬇️ attendance for F/U visits over time may have been partly due to usual care group having less motivation to attend as know they're not getting treatment?

Financial CoIs

Present in 13/21 authors, combination of speaker fees, consulting fees, research grants & Board member

Fairly standard for modern RCTs, I would suggest

I suspect that a MA of IRONMAN, CONFIRM-HF & AFFIRM-HF may have enough power to show IV iron improves how people feel & may ⬇️ HF hospitalizations also

I really don't think it's a big deal if IV iron doesn't improve prognosis. If it makes you feel better, great!

I do think the paper's conclusion is a little strange, given strictly speaking the trial didn't meet its primary EP

If blaming COVID and thus wishing to emphasize the COVID-19 sensitivity analysis, why not state that unequivocally?

The 4 month QoL benefit was not apparent at 20 months
No improvement in exercise capacity
No improvement in EQ-5D score

Yet HF hospitalizations seem ⬇️. So maybe it helps your internal physiology without massive impact on symptoms? Though CONFIRM HF found symptom benefit ++?

There are on going trials in this field - it may require a meta analysis to prove definitively that routine screening of HF patients for ID with IV replacement is the right thing to do

I'm not a HF expert, so views / comments welcome! 😁

Finally, if you want to read a proper medical journalist write-up of IRONMAN, check this link out by @ShelleyWood2 for @TCTMD!

tctmd.com/news/ironman-m…