Articles
Science Matters: Research Summary of the Carvedilol as Single Therapy for Heart Failure with Improve Ejection Fraction: A Randomized Clinical Trial (CATHEDRAL-HF)
About the Author: Michael Katsnelson MD, PhD, FACC is currently a research fellow at Washington University in St. Louis School of Medicine. He specializes in advanced heart failure/transplant cardiology, and his main research interest lies in studying the role of the innate immune system in the progression of ischemic cardiomyopathy.
Background: Heart failure with improved ejection fraction (HFimpEF) has been defined as an improvement in the LVEF of a patient with HFrEF to ≥40% either as a result of the resolution of the initial disease process or as a consequence of pharmacotherapy. Evidence from prior studies suggests that patients with HFimpEF remain at increased risk for recurrence of left ventricular dysfunction and clinical heart failure. However, the benefit of indefinitely continuing GDMT in HF patients who have achieved full remission of their disease is currently unclear. Remission of HF is generally defined as an absence of clinical heart failure signs or symptoms, recovery of LVEF to a value ≥50%, normalization of NT-pro-BNP levels, and absence of genetic mutations associated with cardiomyopathy. Guideline directed medical therapy for heart failure brings with it the risk of adverse events including hypotension, bradycardia and renal dysfunction. The current standard of care for HFrEF patients is a combination of medications from four different classes: ACEi/ARB/ARNi, beta blocker, MRA and SGLT2i. An emerging area of interest within the field has been to investigate the safety of de-escalation of pharmacotherapy in HFrEF patients who achieve full remission. The CATHEDRAL-HF clinical trial investigated the effects of maintaining patients with HFimpEF on beta blocker therapy while discontinuing other classes of GDMT.
Study Design: CATHEDRAL-HF was a single center randomized clinical trial comparing the effects of single agent therapy with beta blocker vs conventional medical therapy in patients with HFimpEF. The study included 30 patients in the investigational arm and 30 patients in the standard therapy control arm. Patients were included if they had a previous LVEF≤40, current LVEF ≥50%, no symptoms of heart failure, and normal serum NT-pro-BNP level. All patients were periodically evaluated with clinical exam, NT-pro-BNP level, TTE, 6-minute walk test, and the Minnesota Living With Heart Failure Questionnaire. The primary endpoint of the study was a recurrence of LV dysfunction at 24 weeks as evidenced by a reduction in LVEF to a value <50%, increase in LVEDVi to greater than the normal range, increase in NT-pro-BNP to >400 pg/ml, or the development of clinically evident heart failure.
Results: Three patients in the treatment arm and one patient in the control group experienced the primary outcome (rise in NT-pro-BNP or increase in LVEDVi) after a follow- up period of 24 weeks. Treatment with multi-agent GDMT was reinitiated in the three patients of the treatment arm who exhibited the primary outcome with a resulting decrease in the NT-pro-BNP level and LVEDVi to normal baseline values. After a follow-up period of 52 weeks, a decline in LVEF occurred in four patients of the treatment arm and four patients of the control group. The LVEF, LVEDVi and NT-pro-BNP level were not significantly different when comparing the treatment and control groups after 52 weeks of follow-up. There were also no episodes of death, hospitalization, or sustained ventricular arrhythmia reported over the 52-week follow-up period of the trial.
Discussion: The results of the study suggest that treatment of HFimpEF patients with single agent carvedilol therapy is not associated with a significantly increased risk of heart failure relapse when compared to multi-agent GDMT. The findings of the study differ from those of the recent TRED-HF trial, which observed a substantial increase in the risk of asymptomatic decline in LVEF following withdrawal of GDMT in a cohort of patients with dilated cardiomyopathy. These seemingly discordant findings suggest that the risk of HF relapse associated with GDMT withdrawal may differ depending on the etiology of HF and the presence of associated risk factors. A recent predictive model called the ESC EORP PPCM Recovery Score was developed to predict the risk of relapse in patients with peripartum cardiomyopathy. This model incorporates factors such as LVEF, LVEDD, duration of HF symptoms, QRS duration, history of pre-eclampsia, and human development index of the country where the patient resides. The development of similar risk scores to evaluate a patient’s probability of recovery in other types of cardiomyopathy (e.g. Takotsubo, complicated acute myocarditis or chemotherapy-induced cardiomyopathy) may help to differentiate between those patients who would benefit from indefinite continuation of multi-drug GDMT vs those in whom the risk of relapse is sufficiently low to warrant treatment with single agent beta blocker therapy or discontinuation of pharmacologic therapy altogether.
