Recovery after dilated cardiomyopathy often means remission rather than cure
AHA 2018 – Chicago, IL, USA
Withdrawal of Pharmacological Heart Failure Therapy in Recovered Dilated Cardiomyopathy - A Randomised Controlled Trial (TRED-HF)
Presented at the AHA congress 2018 by: Brian P Halliday (London, United Kingdom)
Introduction and methods
Dilated cardiomyopathy (DCM) is a prevalent problem, and the most common reason for cardiac implant. After therapy, recovery occurs. Does that mean cure or remission? The answer to that question has consequences for whether patients need to take medications forever. That can be important for patients in light of side effects, pregnancy or financial constraints.
To date, few data were available to guide discussions with patients on whether or not to continue to take therapy after recovery. The TRED-HF therefore set out to examine the safety and feasibility of phased therapy withdrawal, in an open-label pilot randomized trial. Recruitment was done in a network of hospitals, but enrolment took place in a single center. Patients >16 years old with a prior diagnosis of DCM and LVEF <40% at diagnosis were included. Subsequent recovery was defined by: LVEF >50% and normal LVEDVi, NT-proBNP <250 ng/L and NYHA class I. Patients with arrhythmia requiring beta-blocker, uncontrolled hypertension, valvular disease, eGFR<30 ml/min, pregnancy or angina were excluded. After a screening visit, 51 patients were randomized to the therapy withdrawal protocol with clinic review every 4 weeks and interim telephone reviews (n=25) or continued therapy with clinic visit at 8 weeks (N=26). All patients had a follow-up visit at 16 weeks, and after 6 months. After completing follow-up, control patients crossed over to therapy withdrawal using the same protocol, to increase numbers.
The primary endpoint was relapse of DCM defined by any 1 of: 1: Reduction in LVEF by >10% and to below 50%, 2: increase in LVEDV by >10% and to above normal range, 3: two-fold rise in NT-pro-BNP and to >400ng/L, 4: clinical evidence of heart failure. These endpoints led to immediate re-introduction of therapy. Safety of patients was ensured by the possibility of 24-hour contact with a doctor, the regular physicians and GP’s were kept up-to-date, and all trial data were reviewed weekly, with AEs managed on an individual case basis. 1 Person in the withdrawal group withdrew from the study. 80% of patients in the withdrawal group and 58% in the control group had idiopathic etiology, and 28% and 15%, respectively, had a TTNtv mutation.
- During the randomized phase, 11 out of 25 patients (44%) in the withdrawal group had relapse, as compared to 0 of 26 control patients. In the single-arm cross-over phase, 9 out of 25 patients (36%) now on therapy withdrawal had relapse.
- In total, of 50 patients who began therapy withdrawal, 20 (40%) met the primary endpoint.
- 25 of 50 (50%) completed follow-up without re-initiation of treatment.
- 16 of 50 (32%) completed withdrawal without deterioration in LVEF (>3%).
- No deaths or unplanned HF hospitalizations or MACE occurred.
- In the withdrawal arm, 3 serious AEs occurred: hospitalizations for urinary sepsis, non-cardiac chest pain and an elective procedure. Three patients in the withdrawal arm developed atrial fibrillation.
- All patients who met the primary endpoint were asymptomatic at follow-up. 17 out of 20 patients had LVEF >50%, 2 had LVEF 45-50% and 1 had LVEF 43%.
These data show that withdrawal of pharmacological heart failure therapy from patients deemed to have recovered DCM resulted in relapse in about 40% of patients. This proportion is likely to be greater in the medium- and long-term. Withdrawal of therapy should not usually be attempted, until predictors of relapse are defined, and until we have better understanding of the importance of specific therapies and with monitoring in place. Thus, Halliday concluded that improvement in function represents remission rather than permanent recovery for many patients, and therapy should not be stopped until we understand who will relapse and who will not.
Jane Wilcox, as the discussant of this study, acknowledged the authors for addressing a provocative question; for acting expeditiously to resume medical therapies before overt clinical decompensation, and for a priori creating a process to adjudicate events and terminate the trial as needed. She noted the return of HF in 40% of patients within just 8 weeks.
The key commentary, however, is the scientific implication of these results. First, we are reminded that mechanisms of improvement after exposure to evidence based medical therapies, though well – informed, have not been fully resolved. We have no signal or barometer to suggest that a previously indicated therapy for reduced ejection fraction is no longer necessary and can be safely discontinued.
She also noted that recovery would necessarily suggest that intrinsic contractility and cardiac mechanics have been restored and protein expression and the neurohormonal milieu normalized. It has been demonstrated though, that many patients with restored EF still have underlying abnormal cardiac mechanics. These patients are at risk for clinical events and HF relapse, even with continued medical therapy. These observations may imply that true recovery of normal ventricular function is likely an infrequent process.
We are currently unable to identify true recovery. Patients with improved ventricular function as a response to therapy can be considered to be in remission, and should continue life-saving medical therapy without interruption. Wilcox thinks that these data may invigorate the field to dig deeper and to consider the genomics, proteomics and metabolomics of myocardial recovery. Assessment of the myocardial substrate is key, and the signals in cardiac mechanics are there, but require rigorous standardization.
During the discussion it was mentioned that intermediate therapeutic strategies in between complete withdrawal and continuation of optimal therapy may be good, for instance with lower doses. Such approaches are worthy of further investigation. All physicians in the panel acknowledged that many patients ask the question whether they should continue with medication, thus this type of research is important to inform that conversation.
- Our reporting is based on the information provided at the AHA Scientific Sessions -