The Neglected Issue of Cardiac Amyloidosis in Trials on Heart Failure with Preserved Ejection Fraction in the Elderly

Heart failure with preserved ejection fraction (HFpEF) is a major public health problem increasing mortality, morbidity and impaired quality of life. To date, none of the recommended treatments for heart failure (HF) with reduced ejection fraction (EF) has shown to reduce morbidity and mortality in patients with HFpEF.1 Indeed, as observed in previous studies with angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs), beta-blockers (BB) and mineralocorticoid receptor antagonist (MRA), also the recently published PARAGON-HF trial failed to show a significant benefit of sacubitril/valsartan in patients with HFpEF in terms of hospitalizations for HF and death from cardiovascular causes, with the only exceptions of patients with an EF ranging from 45% to 57% and women.2 Probably, the wide heterogeneity in the processes leading to HFpEF may account for the difficulty in identifying a ‘one size-fits all’ treatment for different conditions which are considered a homogeneous disease only on the basis of preserved EF. Historically, risk factors for HFpEF included age, female sex, hypertension, left ventricular hypertrophy, diabetes, obesity, renal dysfunction and physical inactivity.3 Recently, it has been demonstrated that an underdiagnosed cause of HFpEF, with a prevalence of 13% in HFpEF patients ≥60 years old, is wild-type transthyretin-related cardiac amyloidosis (CA).4 In CA, medications such as ACEi, ARBs, or angiotensin receptor–neprilysin inhibitor may not be well tolerated even at low-to-moderate doses because of hypotension, and BB may be poorly tolerated for the restrictive physiology.5, 6 Therefore, it is reasonable to postulate that in the PARAGON-HF trial, as well as in previous trials on HFpEF, enrolment of patients with undiagnosed CA may have contributed to poor treatment responsiveness. The failure to complete the recommended up-titration of sacubitril/valsartan due to reduced tolerability may have in part contributed to the missed goal in HFpEF patients. In support of this hypothesis, the analysis of patients who fulfilled inclusion criteria and entered run-in, but were not randomized due to adverse events (e.g. hypotension, renal dysfunction), showed that they were older, displayed higher New York Heart Association class, had lower blood pressure, were frequently hospitalized for HF, had higher N-terminal pro-B-type natriuretic peptide levels and had less use of ACEi, ARBs and BB.7 Furthermore, in PARAGON-HF among the pre-specified subgroups, men, patients ≥75 years old and patients with median EF >57% (frequent characteristics of patients with CA) were categories without a clear benefit from sacubitril/valsartan. Thus, to increase the likelihood of positive outcomes of HFpEF trials, patient selection should be addressed with specific attention to clinical and echocardiographic characterization of HFpEF. The underestimated prevalence of CA in HFpEF suggests a mandatory screening of this disease before patient enrolment in trials. However, screening costs are a major limitation and may not result affordable. It might be enough that all patients included in HFpEF trials at least undergo a purposed echocardiography and in presence of specific ‘red flags’,8 CA diagnosis should be investigated by second level examinations, such as bone scintigraphy. This approach could balance the costs of a more extensive evaluation with the benefit of obtaining a more homogeneous population in HFpEF trials, including a higher consideration of this potential confounder in ongoing trials.9