Glad Your EF Is Better, But Stay on Your Meds

The TRED-HF Trial

Melissa Walton-Shirley, MD


November 12, 2018

Some of my patients with heart failure have teenage children now. I was there when they were frothing at the mouth, in florid pulmonary edema with dilated cardiomyopathies in labor or early postpartum. Others were never pregnant, or were male, some with family histories that predicted a grim future but were rescued by modern-day pharmacology from left ventricular assist devices, transplants, and certain death.  They share the very human desire to not only live well but also to be "normal." Their desire to be normal means that I have fended off frequent requests to curtail or stop medications over the past two and half decades. My reluctance, even insistence, is met with a range of emotion from acceptance to anger, but most have complied. TRED-HF extinguished any guilt I may have felt for continuing the pharmacologic therapy of dilated cardiomyopathy (DCM).

This was by any estimation a gutsy trial, facing head-on the fear of every practitioner: That if they curtailed the meds, the patient's left ventricular ejection fraction (LVEF) would again plummet and  pulmonary edema would ensue. Worse, the patients may present with tell-tale purplish crimson ears, low blood pressure,  cool skin, and wet lungs, languishing in need of circulatory support.   

TRED-HF was a small, open-label randomized trial of 51 patients with a prior diagnosis of DCM and an initial LVEF of less than 40% who were taking at least one heart failure medication. Patients with subsequent recovery (LVEF > 50% with a normal left ventricle size, N-terminal pro B-type natriuretic peptide (NT-pro-BNP) < 250 ng/L, and New York Heart Association classification I) were entered into the trial.  In a stepwise fashion, half of the patients had their  loop diuretics,  mineralocorticoid receptor antagonists, β-blockers, and then angiotensin-converting enzyme inhibitors or angiotensin receptor blockers reduced or stopped. They underwent clinical review every 4 weeks and had 24-hour access to a physician.

The primary endpoint was a reduction in ejection fraction by 10% and to below 50%, an increase in left ventricular end diastolic volume by more than 10% and to above normal range, a two-fold rise in NT-pro-BNP and to greater than 400 mg/L, and clinical evidence of heart failure. These adverse changes were seen in a concerning 44% of patients at just 8 weeks into the meds withdrawal.

In a conversation after the press conference, the presenter, Brian Halliday, MBChB, PhD (Imperial College, London, United Kingdom), conjectured, "Think what that percentage would have been at 6 months." He then added, "It will be difficult to perform this study again," hinting at a reluctance of both trial participants and trialists alike. 

Jane E. Wilcox, MD (Northwestern University, Chicago, Illinois), who served as the discussant, noted that this pilot study is not definitive and that the key implications lead to further questions. She suggested that "perhaps patients who still require loop diuretics might not really be recovered," despite the return of a normal LVEF on imaging studies. She emphasized that the search is ongoing for imaging signals that might point to risk or identify patients who can successfully sustain their left ventricular function off medications. She suggested the signal of higher global radial strain on cardiac MRI might help identify a subgroup that could tolerate discontinuation of meds  but cautioned  that "we still have no clinical markers that inform durability of recovery." This leads her to conclude that at this point in history, "these patients should continue their medications without interruption."

Although the TRED-HF trial was small,  the rapidity of the return of pathology off meds tempers any hope of acquiescing to the request of our patients with DCM to stop their heart failure meds after recovery.  Furthermore, the cost of monitoring after  discontinuation through NT-pro-BNP levels, echocardiography, and MRI, not withstanding office visits, would be staggering. 

Perhaps what we are left with after TRED-HF is a tremendous gratitude for the progress we've made since the era when furosemide and digitalis masqueraded as the only known "heart failure" therapies. For now, we stay the course with treatment and hope for meds that can effect a real cure. In the meanwhile, to our dear patients with heart failure:  Please, just stay on your meds.


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