a Hamilton Health Sciences, Hamilton, Ontario, Canada
b Toronto General Hospital, Toronto, Ontario, Canada
c Montreal Heart Institute, Montreal, Quebec, Canada
d The Cleveland Clinic Foundation, Cleveland, Ohio, USA
e Instituto di Recerche Farmacologiche, Milano, Italy
f AstraZeneca, AB, Mölndal, Sweden
* Correspondence to: Dr R. S. McKelvie, Hamilton Health Sciences, General Division, 237 Barton Street East, Hamilton, Ontario, Canada L8L 2X2. Tel: (905) 572-7155; fax: (905) 577-1480
E-mail address: mckelrob{at}hhsc.ca
Received 29 April 2003; revised 15 July 2003; accepted 31 July 2003
Abstract
Aims RESOLVD study patients were randomized to candesartan (C), enalapril (E), or C+E. Patients were later randomized to metoprolol CR (M) or placebo. Examine impact of C or E (C/E), C+E, C+M/E+M, C+E+M on ventricular remodelling in heart failure (HF) over 43 weeks.
Methods and results Four hundred and twenty-six of 768 patients receiving C, E, or C+E were randomized to either M or placebo. Patients were New York Heart Association class IIIV, ejection fraction (EF) <0.40 and 6-min walk distance <500m. Ejection fraction (EF), cardiac volumes, blood pressures, heart rates, and neurohormones were measured. End diastolic volumes changed +29.4±6.4ml for C/E, +16.6±10.4ml for C+E, +19.7±6.5ml for C+M/E+M, and 6.4±7.5ml for C+E+M (P0.01). End systolic volumes changed +22.9±5.8ml for C/E, +11.9±9.1ml for C+E, +6.0±5.7ml for C+E/E+M, and 16.5±7.0ml for C+E+M (P
0.001). Ejection fraction changed +0.01±0.01 for C/E, +0.01±0.01 for C+E, +0.03±0.01 for C+M/E+M, and +0.05±0.01 for C+E+M (P
0.0001). No significant differences for blood pressure or neurohormones; heart rate for C+M/E+M and C+E+M decreased (P
0.01) vs C/E or C+E.
Conclusion C+E+M had a modest but beneficial effect on cardiac function compared to the other groups. Combination of C+E+M has potential for providing HF patients with further benefit.
Key Words: Heart failure Drugs Cardiac volume Blood pressure
1. Introduction
Angiotensin converting enzyme inhibitors (ACE-I) and beta-blockers reduce mortality and morbidity in heart failure patients.13They also beneficially affect left ventricular dilatation.48Angiotensin II receptor blockers (ARB) have been compared to ACE-I in heart failure patients. No clear differences in mortality, morbidity or impact on left ventricular dilatation have been demonstrated.9,10The addition of an ARB appears to add to the benefits of an ACE-I.1013Since each of the above three drugs have complementary pharmacologic actions, it is possible that combinations of these drugs may be superior to any of these agents alone. The question is especially important in light of the recently published Val-HeFT trial which showed the addition of valsartan to ACE inhibitor therapy may not provide clinical benefits in patients already receiving a beta-blocker.13The Randomized Evaluation of Strategies for Left Ventricular Dysfunction Pilot Study (RESOLVD) provides a unique opportunity to address this question in part.6,10
As part of the RESOLVD study patients were randomized to receive an ACE-I (enalapril), an ARB (candesartan), or an ARB plus ACE-I. Eligible patients from each of the above three groups were randomized to a beta-blocker (Metoprolol CR) or placebo.6The aim of this work was to evaluate the impact of candesartan or enalapril (C/E) versus candesartan plus Metoprolol CR or enalapril plus Metoprolol CR (C+M/E+M) versus candesartan plus enalapril (C+E) versus candesartan plus enalapril plus Metoprolol CR (C+E+M) on left ventricular remodelling in symptomatic heart failure patients.
2. Methods
RESOLVD was a previously described6,10international, double-blind, randomized, placebo controlled trial at 60 centres. Patients (n=768) were initially randomized to receive candesartan up to 16mg daily, or candesartan up to 8mg daily in combination with enalapril 20mg daily, or enalapril 20mg daily. After 19 weeks of therapy, patients eligible for beta-blocker treatment (n=426) were further randomized to metoprolol CR up to 200mg daily or placebo while continuing on their original treatments. Only patients eligible for beta-blocker therapy were included in this analysis. Patients were followed for 43 weeks with the final 24 weeks including beta-blocker or placebo.
The design of RESOLVD allowed categorising patients as to whether they were randomized to C/E, vs C+E, versus C+M/E+M, versus C+E+M (Fig. 1). Single drug therapy consisted of either candesartan or enalapril. By design, no patient was on metoprolol alone as ACE-I were considered of proven value and ARB was considered to have the potential to be as effective as an ACE-I. Moreover at the time we conducted the study, the value of a beta-blocker was still unproven.
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The endpoints in this analysis were EF, cardiac volumes, blood pressure, heart rate, and plasma neurohormonalconcentrations. Measurements were at baseline and after 43 weeks of follow up. End diastolic volume (EDV), end systolic volume (ESV), and EF were measured by radionuclide angiography utilizing standardized protocols and a central core laboratory.14Norepinephrine was measured with HPLC; endothelin I, angiotensin II, and aldosterone were measured with radioimmunoassay;15,16brain natriuretic peptide (BNP) and pro-atrial natriuretic factor (pro-ANF) were measured with previously reported techniques.17,18Neurohormone measurements were made using standardised protocols and a central core laboratory.6,10
Analysis of variance (ANOVA) was conducted using change from baseline as a response across the four different groups of therapy exploring differences among the groups.19When a significant difference was found using an F-test then specific differences were examined adjusting by a post hoc TukeyKramer procedure. Clinical event rates were estimated using survival analysis technique and log-rank testing was used for statistical significance. Statistical significance was claimed at P<0.05. Results are reported as the mean±standard error unless otherwise specified.
3. Results
The 426 patients randomized to metoprolol CR or placebo while continuing their originally assigned therapy of candesartan, enalapril, or candesartan plus enalapril were included in the analysis to evaluate the effects of C/E, C+E, C+M/E+M, or C+E+M therapy (Fig. 1). There were 126 patients randomized to C/E, 86 patients to C+E, 125 patients to C+M/E+M, and 89 patients to C+E+M. The unequal randomization reflects the original design of the study. The mean age, aetiology of heart failure, EF, NYHA-FC, 6MWD, and percentage of patients taking ACE-I, digoxin and diuretic were similar at baseline among the groups (Table 1).
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The baseline EF for C/E was 0.27±0.01, 0.29±0.01 for C+E, 0.28±0.01 for C+M/E+M, and 0.26±0.01 for C+E+M. Over 43 weeks EF increased by 0.01±0.01 for C/E, 0.01±0.01 for C+E, 0.03±0.01 for C+M/E+M, and 0.05±0.01 for C+E+M (P0.0001). There was a significant difference between C+E+M compared to either C+E (P
0.01), or C/E (P
0.001) therapy (Fig. 2).
3.2. Changes in systolic blood pressure, diastolic blood pressure, and heart rate
At baseline no significant differences were observed among the four groups for systolic (C/E 122±2mmHg, C+E 121±2mmHg, C+M/E+M 123±2mmHg, C+E+M 121±2mmHg) or diastolic (C/E 76±1mmHg, C+E 73±1mmHg, C+M/E+M 74±1mmHg, C+E+M 74±1mmHg) blood pressures. After 43 weeks of follow up there were no significant differences found among the four groups for changes in systolic and diastolic blood pressures (Fig. 3). At baseline there were no significant differences observed among the four groups for heart rate (C/E 78±1bpm, C+E 77±1bpm, C+M/E+M 77±1bpm, C+E+M 78±1bpm). After 43 weeks of therapy there was a significant (P0.01) decrease of 9±1bpm for C+M/E+M compared to 3±1bpm for C/E or 2±1bpm for C+E (Fig. 3). There was also a significant (P
0.01) decrease after 43 weeks for C+E+M of 10±1bpm compared to C/E or C+E (Fig. 3).
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4. Discussion
The central role of the renin-angiotensin-aldosterone system in promoting the development and progression of heart failure has been well established.20,21ACE-I therapy has been repeatedly demonstrated to be efficacious in the treatment of heart failure.1,21However, mortality and morbidity remain unacceptably highdespite the use of ACE-I therapy. This may be related to the numerous abnormalities in patients with heart failure. For example, neurohormonal activation is multiple and could include pathways other than angiotensin converting enzyme responsible for the production of angiotensin II.22,23Previous studies have demonstrated re-elevation of angiotensin II levels (escape phenomenon) in patients treated chronically with ACE-I.24Activation of the sympathetic nervous system has also been observed in heart failure patients.2527In fact activation of the sympathetic nervous system would appear to develop even before activation of the renin-angiotensin-aldosterone system28and it can contribute to worsening heart failure independent of the renin- angiotensin-aldosterone system. Furthermore, angiotensin II can cause further activation of the sympathetic nervous system.2931Therefore, the use of only one class of drug would not be expected to address the various abnormalities found in heart failure patients.
In the present study patients were randomized to receive an ACE-I, an ARB, a beta-blocker, or various combinations of these agents. Thus the renin-angiotensin-aldosterone and sympathetic nervous systems were inhibited to varying degrees and at different levels. Although a group without the use of ACE-I or with metoprolol alone would have been scientifically interesting, this was not considered to be ethical at the time we conducted the study.
The present study has demonstrated that treatment with C+E+M has a more beneficial effect on cardiac volumes and EF than treatment with either C/E or C+E, however the effect was modest. Although not statistically significant, the effects of C+E+M tended to have a more beneficial effect on cardiac volumes and EF than C+M/E+M. This finding was not related to a reduction in blood pressure as there were no significant differences observed among groups for changes in blood pressure. The reduction in heart rates were greatest in the C+E+M and the C+M/E+M groups because all patients were taking metoprolol CR with no differences observed between these two groups. The data from the present study found the incidence of hyperkalaemia or increases in creatinine concentrations were similar among the four groups.Furthermore, in no cases did the plasma potassium concentration exceed 6.7mmol/l or did the plasma creatinine concentration exceed 292µmol/l. These results suggest C+E+M was tolerated as well as the other combinations of therapy. Nevertheless, when combining these drug therapies it would be advisable to monitor the plasma potassium and creatinine concentrations. The observation of a slightly higher discontinuation rate in C+M/E+M and C+E+M is not unexpected because with multiple therapies there is a greater likelihood of discontinuing one of the drugs. The observation that heart failure hospitalization rates are different among the groups is consistent with the findings of the main RESOLVD study which demonstrated a greater rate of heart failure hospitalizations in patients randomized to receive metoprolol CR.6The reason for the more common heart failure hospitalizations may be related to the vigorous metoprolol CR titration regimen used in RESOLVD.
The concept of combination therapy for heart failure patients has been previously considered but not using a combination of therapies which would completely antagonize the renin-angiotensin-aldosterone and sympathetic nervous systems. In the present study approximately 83% of patients were taking diuretics and approximately 68% were on digoxin. Young et al examined the effect of therapy with digoxin, ACE-I, and diuretics compared to other combinations of these drugs using data from two previous studies (PROVED and RADIANCE) of digoxin efficacy.32The findings of the study demonstrated therapy with three agents resulted in a significantly lower rate of worsening heart failure and better exercise time than either therapy with two drugs or diuretics alone. The findings of the DIG trial33were also consistent with combination therapy being better than monotherapy. The group of patients taking digoxin, who were also taking ACE-I and diuretic, experienced fewer episodes of heart failure than those not taking digoxin.
A retrospective analysis of the SAVE data base in post myocardial infarction patients with left ventricular dysfunction found the beneficial effects of beta-blocker therapy were additive to those of captopril.34In a retrospective analysis of the SOLVD data base evidence was found that a combination of a beta-blocker and enalapril was associated with a synergistic reduction in the risk of death.35The recently published systematic overview of data from individual patients with heart failure in long-term ACE-I1trials as well as the CIBIS II3andMERIT-HF2trials have demonstrated the potential benefits of combination therapy with ACE-I plus beta-blocker. Even patients with severe heart failure, as demonstrated by the COPERNICUS study, benefit from combination therapy with ACE-I and beta-blocker.36Whether or not beta-blocker would cause similar benefits without ACE-I is however unknown as similar data in large trials have not been reported. However, the CARMEN trial comparing carvedilol, carvedilol plus enalapril, or enalapril alone should help in answering this question.
Hamroff et al.11have recently compared the effects of combining the ARB losartan with an ACE-I to placebo. In that study, improvements in exercise capacity and symptoms were found for those patients taking the combination of losartan and an ACE-I. A study by Baruch et al.12compared the effects of adding valsartan with an ACE-I to placebo. After four weeks of therapy net reductions in pulmonary capillary wedge pressure, pulmonary artery diastolic pressure, and systolic blood pressure were observed in the group taking valsartan compared to placebo. The recently published Val-HeFT study has demonstrated that the addition of valsartan to background ACE-I therapy resulted in a significant reduction of the combined outcome of all-cause mortality and hospitalizations.13Therefore the present study is consistent with others in the literature suggesting there are benefits associated with combination medical therapy in heart failure patients. Furthermore, the present study extends previous findings as the results demonstrate patients tolerate the combination of ACE-I, ARB, and beta-blocker. In the Val-HeFT study an echocardiographic assessment of cardiac dimensions and EF was performed.37Overall the group receiving valsartan had an increase in EF of 4.5±8.9% compared to the 3.2±8.6% observed in the placebo group. Thus there was a further approximately 1.3% increase in the EF for the valsartan group compared to placebo which is consistent with the findings of the present study which found approximately a 1% increase in EF. However, in Val-HeFT for the patients taking ACE-I plus beta-blocker there was no difference in change of EF between the valsartan and placebo groups. This is not consistent with the present study which demonstrated a significant increase in EF for those patients receiving ARB, ACE-I, and beta-blocker. It is difficult to explain the differences between the two studies; however, in the present study the dose of ARB, ACE-I, and beta-blocker were all determined by study protocol whereas for Val-HeFT only valsartan was determined by study protocol. Based on the data from other studies demonstrating survival is better in patients with smaller cardiac volumes4,5,38the results of the present study would suggest survival should be improved in patients taking the combination of an ACE-I, ARB, and beta-blocker. The size of the present study was too small to confidently evaluate whether the changes in cardiac volumes translate into an improvement in clinical events. Results of the CHARM39and VALIANT studies will serve to shed more light on this issue.
There are some limitations to this study. One of these is the sample size was too small to confidently evaluate the effects of the different combinations of therapy on clinical outcomes. Another limitation was the fact patients were randomized to the various combinations in a sequential fashion. The candesartan and enalapril were used over the full 43 weeks of the study while the metoprolol CR was used during the final 24 weeks of the study. The analysis examined changes over 43 weeks because an analysis of changes occurring between 19 weeks and end of study would have biased the findings against the groups not receiving metoprolol CR therapy. Although RESOLVD patients were randomized to the various drug therapies this was a post-hoc analysis of the study. Thus disabled patients may have been excluded from the analysis, however comparison of baseline data of patients included versus those excluded found no differences between the groups.
This is the only study, to our knowledge, that has examined in a completely randomized fashion, the issue of single (C/E) versus double (C+E, C+M/E+M) versus triple (C+E+M) drug therapy and it is unlikely that such a study could be conducted in the future because both ACE-I and beta-blockers are proven treatment. The present study has demonstrated that therapy with ACE-I, ARB, and beta-blocker is well tolerated in patients with heart failure. These results indicate the combination of an ARB, ACE-I, and beta-blocker has the potential for providing further benefit to the heart failure patient. This hypothesis of clinical benefit will be explored in larger trials such as CHARM.39
Acknowledgments
This study was partially funded by AstraZeneca, Mölndal, Sweden. We would also like to thank Ms Mirela Lukac for her assistance in preparing the manuscript forpublication.
References
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