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Superiority of "triple" drug therapy in heart failure: insights from the PROVED and RADIANCE trials

James B. Young, MD, FACC^*, Mihai Gheorghiade, MD, FACC, Barry F. Uretsky, MD, FACC, J. Herbert Patterson, PharmD and Kirkwood F. Adams, Jr., MD, FACC^||

^* Department of Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio, USA
Department of Medicine, Northwestern University Medical School, Evanston, Illinois, USA
Department of Medicine, University of Texas Medical Branch, Galveston, Texas, USA
^|| Departments of Medicine and Radiology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

View larger version (24K): [in a new window]   Figure 1 Study schema of the PROVED and RADIANCE studies. Following a period of single-blind stabilization, patients were randomized to continue or discontinue digoxin while maintaining background therapy as indicated. Treatment failure was determined by a committee blinded to drug assignment. ACEI = angiotensin-converting enzyme inhibitor, Chg Dig = investigator change in digoxin dose, CXR = chest x-ray, Echo = echocardiogram, ER = emergency room, ETT = maximal treadmill exercise test, HF = heart failure, Hx = history, LVEF = left ventricular ejection fraction, NYHA = New York Heart Association functional class, PE = physical examination, SDC = serum digoxin concentration, Wk = week, 6 MinWalk = 6 min walk test.

View larger version (24K): [in a new window]   Figure 2 The frequency of treatment failure is shown for the four therapeutic groups. Patients randomized to triple therapy were significantly less likely to fail compared to any of the other three groups. Treatment failure did not differ significantly between double therapy arms. ACEI + Diur = ACEI and diuretic, Dig + Diur = digoxin and diuretic, Diur = diuretic, triple = digoxin, diuretic and ACEI. *p < 0.01 compared to all other groups.

View larger version (16K): [in a new window]   Figure 3 Likelihood of deterioration in heart failure (HF) status in the four treatment groups as previously defined. Patients receiving triple therapy were less likely to experience treatment failure compared to any of the other three groups (all p < 0.01).

View larger version (15K): [in a new window]   Figure 4 Changes in maximal exercise duration after 12 weeks. Patients on triple therapy had significantly better exercise capacity than patients on diuretic alone (p < 0.001) or on ACEI and diuretic (p < 0.001), but not compared to patients on digoxin and diuretic (p = 0.134).

View larger version (17K): [in a new window]   Figure 5 Changes in left ventricular ejection fraction (LVEF) from randomization to final study measurement in the four treatment groups. Left ventricular ejection fraction declined significantly in both regimens of digoxin withdrawal compared to either regimen of digoxin continuation.