Heart Failure with Improved Ejection Fraction: The Evidence Against Stopping Therapy That Appears to Have Worked
DOI:
https://doi.org/10.5281/zenodo.22497139Keywords:
Heart failure with improved ejection fraction, Guideline-directed medical therapy, Treatment withdrawal, Dilated cardiomyopathy, RelapseAbstract
When left ventricular ejection fraction recovers from below 40% to 40% or higher on guideline-directed medical therapy,
patients and clinicians alike are often tempted to see this as cure rather than remission and to ask whether treatment can be
safely withdrawn. The randomized evidence says otherwise. In TRED-HF, a pilot trial that phased out heart failure medication
in 25 patients with recovered dilated cardiomyopathy while 26 continued therapy, 11 (44%) of the withdrawal group relapsed
within 6 months versus none of the continuation group (p=0.0001). Long-term follow-up at a median of 6 years found that 33
of the original 51 patients (65%) had relapsed overall, with a 5-year relapse rate of 61% measured from enrollment and 39%
measured from the trial's end -- risk that keeps accruing well beyond the original 6-month endpoint. A Swedish national
registry of 8,728 patients with improved ejection fraction confirmed the signal outside a trial setting: withdrawing
renin-angiotensin-system inhibitors or neprilysin inhibitors was associated with a 38% higher hazard of cardiovascular death
or heart failure hospitalization at 1 year (hazard ratio 1.38, 95% CI 1.08-1.77), and withdrawing a mineralocorticoid receptor
antagonist with a 36% higher hazard (1.36, 95% CI 1.07-1.73), though beta-blocker withdrawal showed no such signal
overall. A separate small trial, CATHEDRAL-HF, found that withdrawing every drug except a beta-blocker produced a far
lower recurrence rate (14.8% at 52 weeks) than TRED-HF's full withdrawal, suggesting the withdrawal strategy itself, not just
the underlying disease, shapes the risk. Candidate predictors of relapse -- older age, higher NT-proBNP, more baseline
medications, no mineralocorticoid receptor antagonist use, and reduced peak radial strain -- remain hypotheses from a single
small trial, not a validated way to select patients for safe withdrawal. This review sets the real trial and registry evidence
against the understandable clinical impulse to de-prescribe once a patient looks recovered.
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