Dr Sarah Cuddy:

My name is Sarah Cuddy, I'm a cardiologist at the Brigham and Women's Hospital in Boston and I'm the co-director of the amyloidosis program there.

Can you provide an overview of the current landscape of HFpEF therapies and latest evidence from landmark trials?

So, in cardiac amyloidosis, both in TTR amyloidosis and in the more rare AL amyloidosis, we've seen a huge improvement with therapies in the last decade or even less, where now we have disease-modifying therapies. So we're able to address the precursor proteins that cause the cardiac amyloidosis, either TTR or light chain. So we're able to really stabilise the disease, slow progression of the amyloid buildup itself. So now we really have the opportunity to look after these patients more holistically and address their heart failure needs better.

What does the available evidence tell us about the efficacy and safety of SGLT2 inhibitors in patients with cardiac amyloidosis and heart failure?

For years treating heart failure and cardiac amyloidosis, we just solely relied on diuretics, mainly loop diuretics. And that was because these patients really poorly tolerated other guideline-directed medical therapy for heart failure, such as beta-blockers, ACE inhibitors, ARBs, because these patients are very preload dependent and intolerant of afterload reduction.

So what we see in these patients is that they became quite hypotensive when we tried to introduce other GDMT. However, I think all of us in the amyloid field got quite excited when we saw the evidence behind SGLT2 inhibitors in HFpEF and heart failure with preserved ejection fraction and thought, could this mechanism work for amyloid patients?

So I know a lot of us who look after patients with cardiac amyloidosis were keen to start using these medications, even though they didn't have an indication specifically for cardiac amyloidosis. But we thought since this phenotype is more a HFpEF phenotype, hopefully the patients will respond. And I think clinically that's what I saw.

And then a lot of groups have been able to translate their clinical observations into observational studies and produce quite compelling retrospective data that shows improved, relative, amelioration in NT-proBNP, EGFR, and also trends towards survival, reduced hospitalization, particularly reduced CV hospitalisation, with the use of SGLT2 inhibitors.

So we think this kind of retrospective, observational data has even driven us further to use these medications in patients with heart failure and cardiac amyloidosis.

How should clinicians approach the use of mineralocorticoid receptor antagonists in the cardiac amyloidosis population?

So in cardiac amyloidosis, like I mentioned, loop diuretics for years were the mainstay. So a lot of the time I think we saw an MRA, as something that might kind of augment diuresis. And again, translating clinical trial data from more generalised heart failure with reduced ejection fraction and preserved ejection fraction, we thought there could be a role.

Again, observational data was somewhat positive, and it was really a study from the National Amyloidosis Centre in the UK that showed, in retrospective data, that there was a survival benefit in the patients who were on MRA and a propensity score matched analysis.

So again, I think this kind of matched what we were doing clinically. So, it kind of led us to say yeah, I think we should use these medications, MRAs, when tolerated in patients with heart failure and cardiac amyloidosis.

What is the emerging role of GLP-1 receptor agonists in managing patients with cardiac amyloidosis and heart failure?

So GLP-1 receptor agonists have gotten so much attention for their weight loss value, but also then for the associated cardiac value in giving these medications. However, I think there's really no data in cardiac amyloidosis. And as a clinician I've been quite reluctant to use this medication in my patients with cardiac amyloidosis because, especially in transthyretin amyloidosis, this is a disease of ageing.

Patients are often frail. One of their main complaints to me is loss of muscle mass. And we know that there's some kind of degree or concern over degree of loss of muscle mass with the use of the GLP-1 receptor agonists. So, I think there's been a reluctance to use these, especially because it would be completely off-label. So, really the only data out there that we have is TriNetX database, which is hard to really bury down into the details of.

Can you discuss the potential role of implantable hemodynamic monitors in this patient population and how this technology might fit into clinical care pathways?

So again, implantable hemodynamic monitors, a lot of us think of the CardioMEMS device, like the GLP-1s, really a data-free zone. When I was looking into this to see what the evidence base behind it was, really I could only find abstracts or case reports detailing the use of these devices and cardiac amyloidosis. But I think intuitively it makes a lot of sense to get these invasive hemodynamic measures, especially when you have a challenging patient to look after.

And I have definitely in my clinical practice gained huge benefit in using this in patients who've had recurrent admissions, whose fluid balance is very difficult to manage, and they've done really well with the use of an invasive hemodynamic monitoring. So I think probably there's a lot of us out there using these clinically and really we need the data to catch up with that.

What are your key take-home messages for clinicians managing heart failure in patients with cardiac amyloidosis today?

Luckily, it doesn't have to be my key take-home message because there's been two excellent documents published only in the last month. One is still in press, one from the American College of Cardiology and another from the European Society of Cardiology Heart Failure Association.

And they've put together these expert consensus statements or documents on how to manage various components of ATTR amyloidosis particularly, and they've looked at use of GDMT. And I think their guidance has strongly encouraged the use of the SGLT2 inhibitors, the use of MRAs when tolerated, and then potentially the use of beta-blockers with low ejection fraction, and then a lot more uncertainty when it comes to ACE inhibitors, ARBs, and RNAs.