Clinical Implications of Managing Iron Deficiency from AFFIRM-AHF

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Welcome to CME on ReachMD. This activity, entitled “Clinical Implications of Managing Iron Deficiency from AFFIRM-AHF" is provided by Medtelligence and is supported by an independent educational grant from Vifor Pharma. 

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Dr. Lewis:
As many as 70% of patients hospitalized with heart failure have evidence of iron deficiency.  We know that iron deficiency in patients with heart failure is associated with reduced functional capacity, reduced quality of life, and adverse outcomes.  We also know that the repletion of iron deficiency in patients that are ambulatory heart failure patients results in improvement in quality of life and improvement in functional capacity.  We now have emerging data from the AFFIRM-AHF trial in patients who are hospitalized with heart failure and undergo treatment with intravenous iron therapy. 

This is CME on ReachMD, and I’m joined today by Drs. Comin-Colet and Dr. Böhm to discuss the AFFIRM-AHF trial.

AFFIRM-AHF was a large trial.  It included 1,108 patients with heart failure and evidence of left ventricular ejection fraction less than 50% who were hospitalized for acute heart failure.  Patients were randomized to either intravenous ferric carboxymaltose or to placebo and were followed for a period of 52 weeks. 

Dr. Comin-Colet, what were the main findings from AFFIRM-AHF?

Dr. Comin-Colet:
Thanks for this important question.  The primary endpoint in this study was total heart failure hospitalizations or cardiovascular death.  And in this study, what we actually saw, there was a reduction in this primary endpoint, having a hazard ratio of 0.79 with a marginally – not significant P value of 0.059.  And we also saw in this study a reduction in the total number of cardiovascular hospitalizations alone or cardiovascular death, about 20%, and also what is actually more important in terms of the results, there was a significant reduction in the number of total heart failure hospitalization.  There was a 26% reduction to this endpoint.  Very importantly, a more conventional endpoint – so time to first heart failure hospitalization or cardiovascular death was significantly reduced in these patients receiving ferric carboxymaltose compared to patients with placebo.  It’s important to highlight that this study was pretty much affected by the COVID-19 pandemic in terms of follow-up of patients.  So before database log was undertaken, there was a prespecified sensitivity analysis in terms of COVID-19.  And this sensitivity analysis, where we actually – was confirmed that there was a significant 25% reduction in the primary endpoint, and then this reached statistical significance.  And also again, a reduction in total heart failure hospitalization was 30%, again significant.  So this is very important results. 

If you want more information on that, this interesting discussion from Dr. Piotr Ponikowski, who was actually the chair of this study, and you can actually have a look on the discussions in the American Heart Association 2020 Insights on Iron Deficiency in Heart Failure.  They’re actually available in the globalheartfailureacademy.org.

Dr. Lewis:
The data are very exciting.  How do these results affect the care of patients with acute heart failure? 

Dr. Comin-Colet:
We’ve seen from these results that treating iron deficiency in the acute phase with ferric carboxymaltose reduces the total volume of heart failure hospitalization in the vulnerable phase of patients.  So this is extremely important, since there are not many drugs that actually can have an impact in terms of heart failure hospitalization in this particular field of patients. 

The second very important aspect is that it really is going to raise the awareness of checking out about iron status in patients in the acute phase, right? So it is very important to check about ferritin and transferrin saturation in these patients, so this can be diagnosed in this acute phase.  On the other hand, it’s very important in terms of feasibility of the treatment.  So the treatment is giving intravenous iron before the start is simple.  It really simplifies the logistics of having this corrected.  And also very important – you can give it before discharge.  And most patients – 80% of patients will only need 1 or 2 injections of the drug to have their iron deficiency status corrected.

Dr. Lewis:
It is particularly attractive to have a benchmark to look at.  We know all of the patients enrolled had to meet a strict definition of iron deficiency, and we can follow the iron measures very easily to understand whether or not patients become iron replete.  And indeed, they did with the introduction of intravenous ferric carboxymaltose in this study.  That has not been the case with trying to give oral iron to patients with heart failure, as we learned when we conducted the IRONOUT Heart Failure trial a number of years ago and found that even with giving doses of oral iron that were 15 times in excess of daily recommended dose amounts of iron in the diet, we still found that patients with heart failure were relatively refractory to repletion of their iron stores when the iron is delivered orally, hence framing the need to give this medication intravenously. 

So, look forward to hearing from Dr. Böhm about his perspective and thoughts on the AFFIRM-AHF trial.

Dr. Böhm:
Thank you Dr. Lewis.  There are, I think, many very important clinical implications.  So what we have known before was this association of iron deficiency for symptomatic load of these patients.  With iron deficiency, we have seen that restoring iron reduces – or improves exercise tolerance and well-being, but the missing link was hospitalization.  And so AFFIRM-AHF now has convincingly shown that hospitalization is reduced.  And that is a typical and very critical endpoint in the heart failure population.  Their hospitalization is one of the urgencies – the urgent need to be improved, as it is predictive for deaths later on.  So now we have seen here a clear reduction of hospitalization rate.  The second important implication is that we enrolled patients in this trial who have a – very close to a decompensation.  So it is very important to see that the 30-days hospitalization rate already is reduced, so there is an early onset of this treatment efficacy, so there is no reason to defer the start of this treatment.  So that, I think, is the very second important implication.  And as we have now the clinical data and the hypothesis, iron deficiency turns into a modifiable risk factor.  And that is very important. Therefore, there is urgent need to screen every patient – in the hospital, outside the hospital – who is symptomatic for iron deficiency in order to allow to treat them appropriately.

Dr. Lewis:
Hey, thank you. So for those of you just tuning in I’m Greg Lewis, and we’re discussing on CME ReachMD the treatment of iron deficiency in patients hospitalized with heart failure, and I’m joined by Dr. Comin-Colet and Dr. Boehm here. And we’re discussing how we should be adjusting and thinking about adjusting the care of our patients who are hospitalized with heart failure and who have evidence of iron deficiency, and we’re learning that the treatment of iron deficiency in this setting of – in the hospitalization, when it’s simple to infuse intravenous iron is translating to certainly a strong trend towards reduction in endpoints following that hospital admission. So, Dr. Böhm, can you tell us a little bit more about how we should think about changing our management of patients with heart failure and iron deficiency going forward?

Dr. Böhm:
So iron deficiency now, I think, has turned to a marker of disease outcome, and furthermore, into a treatment target.  So I think there is urgent need to screen for iron deficiency in every patient with chronic heart failure who is symptomatic.  And I’m very sure that we will get and have this in the guidelines with a very strong recommendation. 

So how to do it? I think transferrin saturation has been shown to be the most sensitive marker by a very recent and in-depth analysis of Piotr Ponikowski, who was the principal investigator of these iron studies and, therefore, this is the first step.  And the other thing is, of course, ferritin.  This should be incorporated into the regular workup of patients with chronic heart failure.  There is also, if you are more interested, there is a download here by this program where you have a very simple scheme, how to look for iron deficiency.  And I think this should be on the desk of every heart failure physicians, not to forget that. 

And then, if iron deficiency is diagnosed, and as it has now been shown that replacement reduces hospitalization, it has turned into a modifiable risk factor, and therefore it has a fixed place in the treatment of these patients.  And in addition to the FAIR-HF study and CONFIRM-HF and meta-analysis, now iron deficiency should be evaluated as we have in the AFFIRM-AHF now.  Indeed, evidence that the heart failure-related endpoint is significantly reduced, in particular, in a population very close to a decompensation and very close to discharge or even the hospital.  And that is very important as these beneficial effects occur very early, and already, 30-days hospitalization rate is significantly reduced.

Dr. Lewis:
Great.  Thank you.  So we’re really seeing a growing body of evidence here, starting with the ambulatory heart failure patient with iron deficiency, in which there were consistent signals across FAIR-HF and CONFIRM-HF for improvement in exercise capacity, improvement in quality of life metrics.  Now we’re hearing about the extension of that benefit to the hospitalized heart failure patients in terms of recurrent hospitalizations. 

And as we look ahead, there’s more evidence that’s going to be forthcoming, and I’d like to hear from Dr. Comin-Colet about additional ongoing studies in iron-deficient heart failure patients that we can look forward to hearing more about.

Dr. Comin-Colet:
This is a very exciting moment in terms of research around iron deficiency and treatment, and of course, there are many other studies coming along.  I think it’s a good aspect to know that not just for acute patients that we may have this benefit on treating iron deficiency using ferric carboxymaltose.  But also, other studies will explore in different moments of trajectories of the patient, which are going to be the benefits from this treatment.  For instance, IRONMAN, which is a study that is already conducted in patients looking to specific, let’s say, hard endpoint, and that’s hospitalization and events.  And other studies are coming along, too.  And they’re going to be testing, again, ferric carboxymaltose against placebo for use in FAIR-HF2, which is more or less the same design as FAIR-HF.  There’s always going to be stable patients in laboratory-based test, agreed to evaluate and treat iron deficiency.  Again, looking to hard endpoints.  But also have exciting studies we can look to in the US, such as the Heart-FID.  They’re going to be checking out also combinations in terms of endpoints and other biomarkers.  And again, there are another – other type of patient that we sometimes wonder as a heart failure specialist whether we should extend the benefit when seeing and treating patients with HFrEF [heart failure with reduced ejection fraction] and iron deficiency.  And these are patients with HFpEF [heart failure with preserved ejection fraction].  So fortunately, we are going to have studies that are going on now.  They’re going be evaluating the effect in patients with HFpEF of treating iron deficiency in terms of symptoms and functional capacity.  So there’s a very interesting, exciting landscape of studies that are coming along, and it’s going be interesting to see what happens about results.

Dr. Lewis:
Great.  Thank you for your insights.  And perhaps we can just hear a take-home message from both of you in this regard, starting with Dr. Böhm.

Dr. Böhm:
Yes, I think there is one for me, one crucial take-home message.  So the problem in heart failure is that these people need a lot of interventions.  They need a lot of drugs, and the first is to implement the detection of iron deficiency in the workup of the heart failure patients with symptoms.  So transferrin saturation and ferritin is one of the crucial lab tests, in addition to the evaluation of symptoms and anything else.  So that is my take-home message.  Recognize iron deficiency and then treat it.

Dr. Comin-Colet:
My take-home message will be also think about – in the acute phase, patients with heart failure and iron deficiency may get benefit from correcting iron deficiency.  And this is a very important benefit because you’re going to be reducing the burden of heart failure hospitalization in these patients.  So make sure in these acute patients, you evaluate that and make sure that you’re going to bring these patients a chance to reduce the risk of being readmitted.

Dr. Lewis:
Thank you.  I would certainly agree and would add to that that the most effective way to go about replenishing iron stores is to give intravenous iron.  We still see a lot of oral iron being tried in our heart failure population. 

So that’s all time that we have today.  I’d like to thank our audience for attending, and I’d like to thank our panelists for their expert views on the important AFFIRM-AHF trial.  Thank you very much.

Dr. Böhm:
Thank you very much for the invitation.  Thank you for having me here. 

Dr. Comin-Colet:
It’s been a great pleasure to share these moments with you. 

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You have been listening to CME on ReachMD.  This activity is provided by Medtelligence and is supported by an independent educational grant from Vifor Pharma.

To receive your free CME credit, or to download this activity, go to ReachMD.com/heartfailure Thank you for listening.