Rethinking recovery in heart failure: Beyond improvement in left ventricular ejection fraction

MYOCARDIAL REMISSION VS RECOVERY IN HFimpEF

The first question is whether there exists a subset of patients with HFimpEF who are at sufficiently low risk of relapse and adverse events such that GDMT could be safely de-escalated. Among patients with HFimpEF, there are likely 2 distinct clinical trajectories:

• Remission with residual myocardial disease that requires indefinite GDMT to prevent relapse

• Complete myocardial recovery with full resolution of both myocardial pathology and the underlying etiology that could allow for safe de-escalation of GDMT.

Currently, however, there are no robust clinical features or biomarkers for predicting the clinical trajectory of any given patient with HFimpEF. One salient distinction among patients with HFimpEF could be the degree of LVEF improvement. In particular, patients who achieve merely partial improvement of LVEF (41%–49%) might be more likely to be in remission and, in turn, benefit from continued GDMT, compared with patients who achieve complete LVEF recovery (≥ 50%).⁷

Yet perhaps more importantly, there has been growing recognition that LVEF alone does not sufficiently encapsulate the heterogenous and complex pathophysiology of heart failure, warranting consideration of other clinical features and metrics in addition to LVEF.^2,8 We recently proposed that the following constellation of clinical features could potentially identify patients with HFimpEF who are at low risk of relapse and adverse events²:

• Complete and sustained recovery of LVEF (≥ 50%)

• Normalization of all imaging features assessed by cardiac magnetic resonance

• Full resolution of clinical signs and symptoms

• Normalization of natriuretic peptide levels and other cardiac biomarker levels

• Absence of pathogenic genetic variants

• Absence of electrocardiogram abnormalities and rhythm disorders

• Absence of relevant comorbidities (eg, renal dysfunction)

• An underlying etiology of heart failure that is resolvable following treatment.

Granted, this rigorous definition has yet to be clinically validated, and it is likely that only a small subset of patients with HFimpEF would fulfill all these criteria. Nevertheless, assuming this definition is valid, one can argue that the inclusion criteria in the TRED-HF (Therapy Withdrawal in Recovered Dilated Cardiomyopathy—Heart Failure) trial³ might not have been sufficiently stringent, which could partially account for the observed relatively high incidence of relapse upon total withdrawal of GDMT in patients with HFimpEF with complete LVEF recovery.

PARTIAL DE-ESCALATION OF GDMT IN HFimpEF

The second question is whether partial de-escalation of GDMT could be a safer and more feasible alternative to complete de-escalation and, if so, which medications should be withdrawn. Clinical trials are currently investigating whether partial de-escalation of GDMT could be feasible in patients with HFimpEF who have complete LVEF recovery, are asymptomatic, and have relatively low natriuretic peptide levels.² There remains debate, however, about which specific medications should be withdrawn.

A recent randomized controlled pilot trial found that stepwise withdrawal of renin-angiotensin-aldosterone system inhibitors and mineralocorticoid receptor antagonists (MRA) while maintaining beta-blocker therapy (specifically carvedilol) in 60 patients with HFimpEF with complete LVEF recovery did not increase the risk of relapse at up to 1 year of follow-up.⁹ Limitations of this trial included the small sample size and relatively short follow-up duration. In contrast, a retrospective cohort study of 8,728 patients with HFimpEF found that withdrawal of renin-angiotensin-aldosterone system inhibitors or MRA was associated with increased morbidity and mortality at 1 year of follow-up, whereas this was not the case for beta-blockers.¹⁰

Several ongoing trials are further investigating partial de-escalation of GDMT in patients with HFimpEF with complete LVEF recovery, including selective withdrawal of beta-blockers (NCT06518694) and selective withdrawal of MRA and sodium-glucose cotransporter 2 inhibitors (NCT06091475).

ESCALATION OF GDMT IN HFimpEF

The third question is whether patients with HFimpEF benefit from escalation and up-titration of GDMT. Evidence suggests that patients with HFimpEF who have persistent clinical signs and symptoms along with elevated natriuretic peptide levels (typically > 300 pg/mL) may benefit from the addition of sodium-glucose cotransporter 2 inhibitors such as dapagliflozin¹¹ and MRA such as finerenone.¹² Whether this is also true for other GDMT medication classes remains to be seen.

NEXT STEPS IN RESEARCH AND PRACTICE

In summary, we agree with Tesoro and Bandaru⁶ that, at present, all patients with HFimpEF should remain on GDMT indefinitely, in alignment with current guideline recommendations.¹ As the field evolves, there is a critical need for further research to identify clinical phenotypes and biomarkers that can distinguish between patients who are merely in remission and those who have achieved complete myocardial recovery, as this could allow for a more tailored approach to GDMT in patients with HFimpEF. Additionally, ongoing and future trials will hopefully determine whether partial de-escalation of GDMT is a safer and more feasible alternative to complete de-escalation. Moreover, given the accumulating evidence for continued benefit of GDMT in patients with HFimpEF who are symptomatic and have elevated natriuretic peptide levels, clinical trials investigating natriuretic peptide–guided intensification of GDMT may be warranted. Most importantly, and perhaps long overdue, we need to adopt a more comprehensive framework for assessing clinical status and optimizing therapy in heart failure with reduced ejection fraction, one that looks beyond LVEF alone.

DISCLOSURES

Dr. Tang has disclosed consulting for Alexion, Alleviant Medical, BioCardia, Boston Scientific, Bristol-Myers-Squibb, CardiaTec Biosciences, Cardiol Therapeutics, Genomics PLC, Intellia, Kiniksa Pharmaceuticals, Salubris Biotherapeutics, Sequana Medical, WhiteSwell, Zehna Therapeutics, and other activities from which remuneration is received or expected, including Board exam writing/approval committee for American Board of Internal Medicine, Editorship/Authorship for Belvoir Media Group, and Editorship/Authorship for Springer Nature. Nandan Kodur reports no relevant financial relationships which, in the context of their contributions, could be perceived as a potential conflict of interest.