CLINICAL STUDIES
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
Manuscript received October 21, 1997;
revised manuscript received April 7, 1998,
accepted May 14, 1998.
Address for correspondence: Dr. Kirkwood F. Adams, Jr., Division of Cardiology, University of North Carolina at Chapel Hill, CB# 7075, Burnett-Womack Building, Chapel Hill, North Carolina 27599-7075
kfa{at}med.unc.edu
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Abstract
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Objectives. We sought to study the efficacy of "triple" therapy with digoxin, diuretic and angiotensin-converting enzyme inhibitor (ACEI) compared to other combinations of these drugs in patients with symptomatic left ventricular systolic dysfunction.
Background. Controversy continues concerning the role of combining digoxin with diuretic and ACEI in the initial management of patients with heart failure.
Methods. The study utilized data from two studies of digoxin efficacy: Prospective Randomized Study of Ventricular Function and Efficacy of Digoxin (PROVED) and Randomized Assessment of Digoxin and Inhibitors of Angiotensin-Converting Enzyme (RADIANCE). Worsening heart failure defined as augmentation of heart failure therapy or an emergency room visit or hospitalization for increased heart failure was the main outcome measure.
Results. A total of 266 patients comprising the four treatment groups of the combined PROVED (diuretic alone or digoxin and diuretic) and RADIANCE (ACEI and diuretic, or digoxin, diuretic and ACEI) trials were analyzed. Worsening heart failure occurred in only 4 of the 85 patients who continued digoxin, diuretic and ACEI therapy (4.7%) compared to 18 of the 42 patients (19%) on digoxin and diuretic therapy (p = 0.009), to 23 of the 93 patients (25%) on ACEI and diuretic therapy (p = 0.001) and to 18 of the 46 patients (39%) on diuretic alone (p < 0.001). Life table and multivariate analysis also demonstrated that worsening heart failure was least likely in patients treated with triple therapy (p < 0.01 vs. all other groups).
Conclusion. Pending definitive, prospective clinical trials, our results argue for triple therapy as the initial management of patients with symptomatic heart failure due to systolic dysfunction.
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Abbreviations and Acronyms
| | ACEI | = angiotensin-converting enzyme inhibitor | | DIG | = Digoxin Investigators Group | | PROVED | = Prospective Randomized Study of Ventricular Function and Efficacy of Digoxin | | RADIANCE | = Randomized Assessment of Digoxin and Inhibitors of Angiotensin-Converting Enzyme |
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A number of well-designed and conducted clinical trials have demonstrated the benefits of individual pharmacologic agents in the treatment of heart failure (1). In the setting of systolic dysfunction, administration of enalapril reduced morbidity and mortality in symptomatic patients and attenuated the risk of developing heart failure in patients with few or no symptoms (2,3). As a consequence of these favorable results, clinical guidelines have advocated a stepped-care approach to pharmacotherapy of patients with heart failure due to left ventricular systolic dysfunction (4). Recommendations favor commencing therapy with an angiotensin-converting enzyme inhibitor (ACEI) and, if necessary, adding diuretic rather than "triple" therapy treatment with digoxin, ACEI and diuretic (5).
Other interpretations of the available clinical data are possible. Dissimilar and potentially complementary mechanisms of action argue for combination therapy with digoxin and ACEI (6–15). Heart failure trials of ACEI, including the treatment arm of the Studies of Left Ventricular Dysfunction, utilized digoxin and diuretic as background therapy in many patients. Prospective Randomized Study of Ventricular Function and Efficacy of Digoxin (PROVED) (16) and Randomized Assessment of Digoxin and Inhibitors of Angiotensin-Converting Enzyme (RADIANCE) (17), two placebo-controlled withdrawal trials, provided evidence of digitalis efficacy, with or without ACEI, in patients with heart failure due to systolic dysfunction. The favorable effect of digoxin administration on the risk of cardiovascular hospitalization observed in the Digoxin Investigators Group (DIG) study supports the concept of triple therapy (18) since the majority of patients in this trial were taking ACEI and diuretic as background therapy. The public health importance of this issue is highlighted by surveys demonstrating the huge cost of treating decompensated heart failure and community practice patterns which continue to indicate that many heart failure patients are treated with diuretic alone while triple therapy is the exception (19–21).
Although prior studies provide some information concerning the relative merits of triple therapy, data from patients randomized to this therapy vs. other combinations of digoxin, ACEI and diuretic are currently unavailable and not likely to be forthcoming. Lacking such randomized data, we have turned to two trials of digoxin efficacy, PROVED and RADIANCE. These two studies had, by design, the same inclusion and exclusion criteria, methodology and end points but they differed in the treatments utilized. PROVED compared patients treated with digoxin and diuretic vs. diuretic alone, while RADIANCE compared patients treated with diuretic and ACEI to those given digoxin, diuretic and ACEI. In addition, these trials gathered data concerning the short-term effect of different therapeutic combinations not only on worsening heart failure but also on exercise capacity and left ventricular function. Thus, the aim of this work was to examine the combined PROVED and RADIANCE results for potential differences between triple therapy and other combinations of ACEI, digoxin and diuretic on a variety of clinical end points in patients with heart failure due to systolic dysfunction.
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Methods
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Design of protocols.
The PROVED (16) and RADIANCE (17) trials shared a similar design (Fig. 1). Both studies were multicenter, double-blind, randomized, placebo-controlled, parallel group protocols. Each study began with an 8-week single-blind stabilization phase that patients had to successfully complete to be eligible for randomization. During this run-in period, the patients’ background therapy for heart failure, consisting of digoxin and diuretic in the PROVED trial and digoxin, diuretic and ACEI in the RADIANCE study, was optimized. Patients completing this baseline phase were randomized to continue digoxin or to receive placebo instead of digoxin while trial-specific background therapy was kept constant for as long as possible during follow-up. After randomization, patients were reassessed in detail regarding clinical status, exercise capacity and ventricular function. Patients were withdrawn from either study for adverse reactions during follow-up or if their heart failure worsened sufficiently to require one of the following therapeutic interventions: augmentation in therapy for heart failure, visit to an emergency room for increasing heart failure or hospitalization for heart failure.
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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.
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Analysis of end points.
Data from the PROVED and RADIANCE trials were combined for purposes of this analysis. The primary objectives of both PROVED and RADIANCE were to compare patients randomized to continue or discontinue digoxin with respect to the following end points: 1) rates of withdrawal due to worsening heart failure, 2) time to withdrawal and 3) changes in exercise capacity as assessed by treadmill testing or the 6-min walk test. In the present analysis, end points 1 and 2 were evaluated and analysis of exercise capacity was restricted to treadmill data. In addition, we compared the change in left ventricular ejection fraction from randomization to the last measured value in the study patients.
Treatment groups.
A total of 88 patients in PROVED and 178 patients in RADIANCE completed the single-blind stabilization period and were randomized to continue or discontinue digoxin. For the purposes of this study, the two trial populations were pooled and reanalyzed according to treatment allocation after baseline characterization and randomization. The four patient groups that resulted were 1) those on the triple therapy of digoxin, diuretic and ACEI (n = 85), 2) those on ACEI and diuretic (n = 93), 3) those on digoxin and diuretic (n = 42) and 4) the remainder on diuretic alone (n = 46).
Statistical methods.
Differences between baseline characteristics in the treatment groups were determined according to the chi-Square test for categorical data and analysis of variance or Student’s t test for continuous variables. Differences in the frequency of worsening heart failure in the treatment groups were assessed by the chi-square test. The Kaplan–Meier life table technique and the Cox proportional-hazards method were used to compare time to treatment failure among the therapeutic groups (22,23). Differences in maximal treadmill exercise testing and change in left ventricular ejection fraction during follow-up were compared by nonparametric methods and Student’s t test, respectively. In the exercise analysis, treatment failures were assigned the lowest rank and carried forward while patients who dropped out for other reasons had their last test result carried forward.
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Results
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Patient characteristics.
Patient characteristics in each of the four treatment groups were generally similar (Table 1). Patients in the groups treated with an ACEI covered a greater distance during the 6-min walk test than groups not on ACEI. Although this difference reached nominal statistical significance (p = 0.035), duration on maximum exercise testing was similar in the treatment groups (p = 0.764). The differences noted in Table 1 did not appear to affect the comparability of the treatment groups and must be regarded with caution given their magnitude and the number of comparisons made.
Treatment failure.
Figure 2 depicts the frequency of worsening heart failure in the four treatment groups. The frequency of treatment failure was greater in diuretic alone compared to digoxin plus diuretic (p = 0.039), and there was a strong trend for treatment failure to be lower in patients with ACEI and diuretic vs. diuretic alone (p = 0.080).
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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.
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Figure 3 plots time to treatment failure in the four therapeutic groups. Cox proportional-hazards analysis of the follow-up data demonstrated that the risk of treatment failure was significantly greater on diuretic alone (p < 0.001), ACEI and diuretic (p = 0.001) or digoxin and diuretic (p = 0.011) compared to patients treated with a combination of digoxin, diuretic and ACEI (Table 2). Further multivariate analysis demonstrated increased risk of worsening heart failure in other treatment groups vs. triple therapy after adjustment for left ventricular ejection fraction, cardiothoracic ratio and heart failure score determined at randomization (all p < 0.01). A final multivariate analysis which added to the previous model gender, supine heart rate and distance walked in 6 min at baseline, also demonstrated increased risk of worsening heart failure in other treatment groups vs. triple therapy (all p < 0.01).
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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).
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Double therapy was also compared with diuretic alone. The relative risk of treatment failure was significantly less for digoxin and diuretic compared to diuretic alone (relative risk 0.41 with a 95% confidence interval of 0.18 to 0.95, p = 0.035), and a strong trend was present for less risk of treatment failure on ACEI and diuretic compared to diuretic alone (relative risk 0.58 with a 95% confidence interval of 0.31 to 1.07, p = 0.077). The relative risk of treatment failure did not differ between patients treated with digoxin and diuretic vs. ACEI and diuretic (p = 0.410). The risk of treatment failure was significantly less for the combined group of double therapy patients (ACEI and diuretic + digoxin and diuretic) vs. diuretic alone (relative risk 0.52 with a 95% confidence interval of 0.29 to 0.93, p = 0.027).
Exercise testing.
Median changes in maximal treadmill exercise time during follow-up in the various treatment groups are shown in Figure 4. After 12 weeks, patients on triple therapy had a significantly greater change (median +16 s) in exercise time compared to patients on ACEI and diuretic (median –27 s, p < 0.001) or diuretic alone (median –96 s, p < 0.001) but not digoxin and diuretic (median +2 s, p = 0.134). Exercise capacity was significantly better in the triple therapy group compared to the combined group of double therapy patients (ACEI and diuretic + digoxin and diuretic, p = 0.001). The difference in change in exercise time between ACEI and diuretic vs. digoxin and diuretic was not significant after 12 weeks of treatment (p = 0.221).
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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).
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Change in ejection fraction.
The change in left ventricular ejection fraction from randomization to the last measured value for each of the four treatment groups is shown in Figure 5. The change in ejection fraction was higher among patients who continued digoxin and diuretic than in those patients treated with triple therapy. Left ventricular ejection fraction declined significantly in patients withdrawn from digoxin compared to patients who continued digoxin whether ACEI were included in their regimen.
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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.
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Discussion
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Extensive studies have established the role of ACEI in reducing morbidity and mortality associated with heart failure, and the primacy of these agents has been appropriately emphasized in clinical guidelines for heart failure (4,5). However, previous findings from the PROVED and RADIANCE studies combined with recent results from the DIG trial suggest that the therapeutic role of digoxin in heart failure should be reassessed (16–18). Our pooled analysis of PROVED and RADIANCE results support the concept that triple therapy with digoxin, diuretic and ACEI may be the most effective treatment strategy in symptomatic heart failure due to systolic dysfunction. Patients treated with triple therapy had the lowest risk of worsening heart failure of any of the four therapeutic groups in these combined trials. Exercise capacity was significantly better maintained in patients on triple therapy compared to diuretic alone or ACEI and diuretic and a trend toward superiority was found compared to digoxin and diuretic. The change in exercise capacity was significantly greater in triple therapy compared to the combined groups of double therapy (ACEI and diuretic and digoxin and diuretic). Administration of triple therapy resulted in better maintenance of left ventricular ejection fraction compared to regimens that lacked digoxin. The appearance of improved ventricular function with digoxin and diuretic therapy relative to triple treatment was unexpected and seems most likely a chance observation. Additional data concerning the possibility that ACEI treatment might lessen the positive inotropic effects of digoxin during chronic therapy would help resolve this issue. The work of Gheorghiade et al. (24) did not demonstrate such an effect during immediate treatment. These investigators found that stroke work index was increased following the acute administration of the combination of digoxin and captopril.
Our data point particularly to the inadequacy of diuretic alone compared to triple therapy. Patients receiving just diuretic had a high incidence of treatment failure, experienced a substantial decrease in exercise capacity and had a significant decline in ejection fraction over 12 weeks of follow-up relative to triple therapy. Diuretic alone also appeared to be inferior to either combination of double therapy.
Previous work.
To our knowledge, there are no studies that permit randomized, placebo controlled, double-blind comparison of the efficacy of triple therapy vs. other combinations of digoxin, diuretic and ACEI. Data from the DIG trial add more nonrandomized support for triple therapy (18). In this study, a very high percentage of patients randomized to digoxin or placebo were taking ACEI (94% to 95%) and most diuretics (81% to 82%) at baseline. Given this therapeutic background, patients in the DIG trial were frequently taking either triple therapy or ACEI and diuretic. Thus, the reduced morbidity in the DIG trial in patients treated with digoxin is consistent with our findings on the beneficial effects of triple therapy. Several randomized studies have investigated the relative, short-term effectiveness of double therapy with ACEI and diuretic vs. digoxin and diuretic (25–29). Overall, these studies are consistent with our results and appear to support similar short-term efficacy of digoxin compared to ACEI therapy. In citing these studies, we wish to emphasize evidence of the therapeutic efficacy of digoxin. The important and substantial benefits of ACE inhibition on morbidity and mortality in heart failure strongly support the routine use of these agents in patients with symptomatic and symptomatic left ventricular dysfunction and the use of alternative therapy to block the renin-angiotensin system in cases of ACEI intolerance.
Mechanism of action.
Disparate mechanisms of action suggest a rationale for combining ACEI and digoxin to improve the clinical status of patients with heart failure as ACEI do not exert positive inotropic effects. To the extent that digoxin’s efficacy depends on its inotropic action, additive salutary effects could be expected when both drugs are administered. Angiotensin II has complex autonomic effects which appear to include augmentation of central sympathetic outflow, presynaptic and postsynaptic potentiation of peripheral sympathetic nerve activity and diminution of parasympathetic tone (8,9). Clinical studies have associated administration of ACEI with reduction in sympathetic activity and augmentation of parasympathetic tone (10,11). Recent evidence substantiates a significant sympathoinhibitory effect of digitalis that may occur at modest serum digoxin concentrations and could be related to drug efficacy (12–15). Although the neurohormonal inhibitory actions of ACEI and digoxin might be reduced by simultaneous administration (16), major sympatholytic effects of digoxin appear indirect and related to changes in baroreceptor function (17). Another rationale for combining digoxin and ACEI is the tendency for these latter agents to increase serum potassium which could limit digoxin toxicity.
Limitations.
It is not our intention to argue that the PROVED and RADIANCE trials provide definitive evidence concerning the efficacy of triple therapy with digoxin, diuretic and ACEI in patients with heart failure due to systolic dysfunction. Investigation of the relative benefits of triple therapy was not prespecified as part of the PROVED and RADIANCE study analyses. The patients were randomized separately into the two trials so that differences in the study populations may exist. A number of considerations do, however, lessen the impact of these concerns. The two trials shared the same design which supports the pooling of data across the studies. The various treatment groups were similar at baseline for the characteristics evaluated. Multivariate analysis, the classical statistical technique to adjust for baseline characteristics that might have influenced the likelihood of treatment failure, confirmed the results obtained by unadjusted lifetable analysis. Finally, the findings in these two trials related to the two double therapy groups are consistent with previous studies.
Utilization of results from the PROVED and RADIANCE trials to study aspects of the efficacy of digoxin has been challenged by some investigators because of their withdrawal design. Interestingly, results from the DIG trial (18) support the validity of findings from PROVED and RADIANCE (16,17). In the DIG study, patients withdrawn from digoxin experienced clinical deterioration while clinical benefit was evident when randomization resulted in the addition of digoxin to background therapy.
Conclusion.
In patients with severe systolic dysfunction, triple therapy with digoxin, diuretic and ACEI significantly reduced the risk of worsening heart failure and improved exercise tolerance during short-term follow-up compared to double therapy with diuretic plus ACEI or digoxin or monotherapy with diuretic alone. Pending definitive, prospective clinical trials, our results suggest consideration of triple therapy as the initial management of patients with symptomatic heart failure due to severe systolic dysfunction.
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Acknowledgments
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The authors gratefully acknowledge the efforts in manuscript preparation provided by Tyler Joscelyn.
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Footnotes
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The PROVED and RADIANCE studies were supported by a grant from Glaxo-Wellcome, Inc., Research Triangle Park, North Carolina. Work related to the present publication was supported in part by the PHS Research MO1 RR00046 from the General Clinical Research Centers branch of the Division of Research Resources and by an unrestricted grant from Glaxo-Wellcome, Inc., Research Triangle Park, North Carolina.
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Abstract
Methods