Possible ways of building trial-level evidence for heart failure therapies in cardiac amyloidosis

Cardiac amyloidosis (CA) remains underdiagnosed despite growing awareness and better imaging pathways. Two major types dominate clinical practice: transthyretin amyloidosis (ATTR; both wild-type and variant) and immunoglobulin light-chain amyloidosis (AL). Both can produce a restrictive cardiomyopathy with diastolic dysfunction, low stroke volume, arrhythmias, and conduction disease,1 but they are biologically and clinically distinct entities, with different trajectories, co-morbidities, and competing risks, so that the balance of benefit and tolerability of standard HF therapies may not be the same in ATTR-CA and AL-CA. Most patients with CA present with heart failure (HF). Traditional HF therapies, i.e. beta-blockers, mineralocorticoid receptor antagonists (MRAs), renin-angiotensin system blockers, and sodium–glucose cotransporter-2 inhibitors (SGLT2i), could plausibly improve symptoms and outcomes by reducing congestion, moderating neurohormonal activation,2 and improving the renal–cardiac crosstalk.3 A recent consensus document endorsed the use of MRAs and SGLT2i as well as the cautious use of beta-blockers in patients with HF and reduced ejection fraction (HFrEF), while traditional renin-angiotensin blockade should be avoided.3 Empirically, many patients, especially those with ATTR and those with AL who achieve a haematologic and cardiac response, tolerate MRAs and SGLT2i well and, in selected cases, low-dose beta-blockers and renin-angiotensin blockers.4 These observational data are largely driven by ATTR-CA cohorts and by AL-CA patients with good haematologic and cardiac response, and clinicians recognize that neurohormonal antagonists are often less well tolerated in advanced AL-CA. This heterogeneity reinforces the need for subtype-specific estimates of safety and benefit, rather than treating CA as a single homogeneous condition. Evidence on efficacy and safety comes exclusively from retrospective cohorts, disease registries, propensity-matched studies, and small prospective series.3