Clinical Consequences of Withdrawing Guideline-Directed Medical Therapy in Heart Failure with Improved Ejection Fraction: A Systematic Review and Meta-Analysis.

Heart failure with reduced ejection fraction (HFrEF) and heart failure with improved ejection fraction (HFimpEF) represent dynamic states modifiable by pharmacologic therapy. Guideline Directed Medical Therapy (GDMT) reduces morbidity and mortality in HFrEF, but the necessity and safety of continued GDMT after recovery in HFimpEF remains uncertain and the safety of stopping therapy in these patients is unclear. We conducted a systematic review and meta-analysis of randomized controlled trials and observational studies comparing GDMT withdrawal with continuation in HFimpEF. Five studies involving 4,773 patients were included. Withdrawal of comprehensive GDMT, defined as discontinuing two or more than two drug classes of GDMT, significantly increased the risk of relapse of adverse cardiac remodelling (RR = 9.35, p = 0.02). Critically, stopping renin-angiotensin-aldosterone system inhibitors (RAASi) was associated with a higher risk of all-cause mortality (RR=1.50, 95%CI=1.09_2.07; p=0.01). In contrast, withdrawal of beta-blockers alone showed no significant effect on mortality. These findings highlight that the recovery of HFimpEF is often contingent on continued GDMT. Withdrawal, particularly of multiple agents or RAASi carries substantial risk of relapse and death. Our findings mandate a paradigm of continued, lifelong GDMT for vast majority of HFimpEF patients as they remain vulnerable despite apparent recovery, and continuation of GDMT is essential to prevent relapse and improve survival. Selective withdrawal may only be considered in highly selected patients under strict monitoring until reliable predictors of durable recovery are established.