Background β-Blocker therapy has been shown to increase ejection fraction in patients with heart failure of idiopathic etiology. However, in patients with heart failure of ischemic etiology, the effects of this treatment on left ventricular function remain uncertain, as do the effects on exercise performance and symptoms.
Methods and Results This study investigated the effects of carvedilol, a β-blocker with α1-blocking properties, on left ventricular size and function, maximal and submaximal exercise performance, and symptoms in 415 patients with stable heart failure of ischemic etiology (ejection fraction <45%). After a 2- to 3-week run-in phase on open-label low-dose carvedilol, patients were randomized to continued treatment with carvedilol (up to 25 mg BID) or to matching placebo. After 6 months, left ventricular ejection fraction measured by radionuclide ventriculography had increased by 5.2% (2P<.0001) in the carvedilol group compared with the placebo group, and left ventricular end-systolic and end-diastolic dimensions measured by two-dimensionally guided M-mode echocardiography had decreased by 2.6 mm (2P=.0005) and 1.3 mm (2P=.05), respectively. There were no significant changes in either treadmill exercise duration or 6-minute walk distance between carvedilol and placebo groups (both 2P>.1); in the carvedilol group, exercise performance was therefore maintained with a 23% lower rate-pressure product. Symptoms assessed by the New York Heart Association (NYHA) scale and the Specific Activity Scale (SAS) were unchanged in two thirds of patients in both groups, but there was a small excess of patients whose symptoms worsened and a deficit of patients whose symptoms improved among those assigned carvedilol (NYHA, 2P=.05; SAS, 2P=.02).
Conclusions In patients with heart failure of ischemic etiology, 6-month treatment with carvedilol improved left ventricular function and maintained exercise performance at a lower rate-pressure product, but symptoms assessed by functional class were slightly worsened. A larger-scale trial is now required to determine whether this treatment will reduce serious morbidity and mortality from heart failure.
The prognosis for many patients with congestive heart failure remains poor despite current drug therapy. Among patients with mild or moderate heart failure treated with an angiotensin-converting enzyme (ACE) inhibitor, the annual rate of hospital admission is about 15% to 20%, and the mortality rate is about 10%.1 Hence, there remains a need to identify new drugs that may further improve outcome. Any proposed new treatment must, however, be assessed not only for its effects on symptoms, exercise capacity, and left ventricular (LV) function but also for its effects on mortality, since the short-term effects of some drugs on outcomes such as exercise performance and LV hemodynamics have been shown to be dissociated from longer-term effects on survival.2 3
The degree of neurohormonal activation is of prognostic importance, and neurohormonal blockade offers the potential for both symptomatic and survival benefits in patients with heart failure. Activation of the renin-angiotensin system is associated with increased mortality,4 and blockade of this system with an ACE inhibitor improves symptoms, exercise capacity, and left ventricular function5 6 and reduces mortality.1 7 8 Activation of the sympathetic nervous system is also associated with increased mortality,9 10 and blockade of this system with β-blocker therapy may be of benefit in heart failure. In 16 previous randomized trials involving 906 patients with heart failure, mostly of idiopathic etiology, β-blocker therapy increased LV ejection fraction by an average of about 5%.11 There were no clearly discernible or consistent effects on symptoms or exercise performance, and even in combination these studies were too small to detect a plausible effect of treatment on mortality.
In Western populations, the major cause of heart failure is ischemic heart disease rather than idiopathic cardiomyopathy,12 and the effects of β-blocker therapy in patients with heart failure of ischemic etiology are not well established either for LV function or for exercise performance. Evidence from some trials of β-blockers after myocardial infarction suggests that such treatment reduced mortality in selected subgroups of patients with current or previous heart failure.13 14 At present, the clinical use of β-blockers in patients with heart failure and ischemic heart disease remains limited, reflecting uncertainty about the tolerability, safety, and efficacy of β-blockade in this large patient population.
The aim of the present study was to determine reliably the effects of β-blocker therapy on symptoms, exercise performance, and LV function in patients with heart failure and a history of ischemic heart disease. The drug chosen for study was carvedilol, a nonselective β-blocker without intrinsic sympathomimetic activity and with vasodilator action due to α1-receptor antagonism.15 This property may reduce the potential cardiodepressant effect of β-blockade and the consequent risk of decompensation after initiation of treatment. This study precedes a large-scale trial of the effects of carvedilol on mortality in patients with heart failure that is scheduled to begin later this year.
This randomized trial involved 415 patients with heart failure due to ischemic heart disease and was carried out in 20 hospitals in Australia and New Zealand by the Australia–New Zealand Heart Failure Research Collaborative Group (see “Appendix”). The protocol was approved by the ethics committee of each collaborating center, and all patients provided written informed consent to participate. The study was coordinated by the Clinical Trials Research Unit, Department of Medicine, University of Auckland, where all study materials were developed and all trial data were collated and analyzed. An independent data monitoring committee reviewed outcomes in the trial at regular intervals and was responsible for informing the study organizers of the appropriateness of the trial’s continuation.
Patients were potentially eligible for inclusion in the trial if they had (1) chronic stable heart failure due to ischemic heart disease (defined as a documented history of myocardial infarction, typical angina, an exercise ECG positive for ischemia, or angiographic evidence of coronary disease), (2) LV ejection fraction by radionuclide ventriculography <45%, and (3) current New York Heart Association (NYHA) functional class II or III or previous NYHA class II-IV. Exclusion criteria included current NYHA class IV; heart rate <50 beats per minute (bpm), sick sinus syndrome; second- or third-degree heart block; blood pressure <90 mm Hg systolic or >160/100 mm Hg; treadmill exercise duration <2 or >18 minutes (modified Naughton protocol); coronary event or procedure (myocardial infarction, unstable angina, coronary artery bypass surgery, or coronary angioplasty) within the previous 4 weeks; primary myocardial or valvular disease; current treatment with a β-blocker, β-agonist, or verapamil; insulin-dependent diabetes mellitus; chronic obstructive airways disease; hepatic disease (serum transaminase >3 times normal); renal impairment (serum creatinine >250 μmol/L); or any other life-threatening noncardiac disease.
Design and Study Treatment
Potentially eligible patients were clinically evaluated and had baseline measurements of LV function, LV size, and maximal and submaximal exercise performance during a 4-week period before the commencement of study treatment. After this period, patients who remained eligible were registered and began a 2- to 3-week prerandomization phase on open treatment with carvedilol. A first dose of carvedilol 3.125 mg was administered with observation for 2 hours, continuing thereafter with 3.125 mg BID for 1 to 2 weeks and, if tolerated, progressing to 6.25 mg BID for a further week. The purpose of this open treatment phase was to identify before randomization those patients who were unable to tolerate a low dose of carvedilol or who were unlikely to comply with treatment or follow-up requirements.
Compliant patients who tolerated carvedilol 6.25 mg BID were then randomized, double blind, to receive continued treatment with carvedilol or matching placebo. Randomization was performed by telephone call to the Clinical Trials Research Unit randomization service in Auckland; treatment assignment was provided by computer, stratifying for clinical center and using a minimization algorithm16 to ensure balance for ejection fraction, treadmill exercise duration, and exercise-limiting myocardial ischemia (termination of baseline exercise test due to angina or ECG ST-T changes). Then followed a flexible 2- to 5-week dose titration period with weekly assessment, the aim being to increase the dose of carvedilol to a maximum of 25 mg BID (or the equivalent dose of matching placebo) or to the highest dose tolerated. Maintenance treatment then continued with carvedilol 6.25 to 25 mg BID or matching placebo and with clinical assessments at 5 weeks, 3 months, and at three monthly intervals thereafter. Compliance with treatment was assessed by tablet count at each visit.
End Points and Assessment
The primary study end points were changes in LV ejection fraction and treadmill exercise duration from baseline (before commencing study treatment) to 6 months after randomization. Secondary study end points were changes in LV dimensions, 6-minute walk distance, and symptoms of heart failure and angina. LV ejection fraction was determined by radionuclide ventriculography, and treadmill exercise duration was determined using a modified Naughton protocol with 2-minute stages. The patient’s perceived level of exertion was assessed at the end of each stage of the protocol using the Borg scale.17 Submaximal exercise performance was assessed using a 6-minute walk test.18 LV dimensions were assessed using two-dimensionally guided M-mode echocardiography, and all measurements were made from videotapes (ImageVue, Nova Microsonics) at a central laboratory (University of Auckland) according to American Society of Echocardiography standards for LV dimensions.19 Symptoms were assessed using NYHA functional class, the Specific Activity Scale (SAS),20 the Canadian Cardiovascular Society angina scale,21 and a patient health self-assessment scale (grades of response: very well, well, fair, or poor).
The study protocol specified that data on these primary and secondary study end points would be analyzed and reported after all patients had been followed up for 6 months after randomization. It was also specified that at that time, a decision would be made as to whether double-blind treatment and follow-up of patients should continue. In light of the results presented here and with the approval of the chairman of the data monitoring committee, the decision was made to continue treatment and follow-up of study patients with the main objective of determining the effects, if any, of treatment with carvedilol on the frequency and duration of hospital admission. This extended follow-up phase is scheduled to continue until all patients have been followed for 18 months.
A sample size of 200 to 225 patients per group was estimated to provide more than 80% power at the .05 level of statistical significance to detect (1) an absolute change in LV ejection fraction of 2% or more between groups (assuming a standard deviation of change in ejection fraction of about 6%) and (2) a change in treadmill exercise duration of 1 minute or more between groups (assuming a standard deviation of change in treadmill exercise duration of about 3 minutes).
Principal outcome analyses involved all patients grouped according to their original randomized treatment allocation (ie, by the intention to treat). In planned subsidiary analyses, treadmill exercise duration was analyzed separately in the subgroup of patients whose performance in the baseline exercise test was not limited by myocardial ischemia. Differences in LV ejection fraction, treadmill exercise duration, LV dimensions, 6-minute walk distance, blood pressure, and heart rate were analyzed using two-sample t tests. Each of the symptom scales was analyzed using χ2 tests. All statistical analyses were performed using s-plus software.22
Prerandomization Open Treatment Phase
After baseline evaluation, 442 potentially eligible patients were registered and entered the open treatment phase, in which all patients received low-dose carvedilol for 2 to 3 weeks. No patient was intolerant of the test dose of carvedilol 3.125 mg. During the remainder of this phase, 27 patients (6%) were withdrawn for various reasons. The main events that led to withdrawal were worsening heart failure (8), hypotension (8), and death (2 sudden deaths and 1 due to brain tumor). All cases of worsening heart failure and hypotension resolved after treatment withdrawal. The mean time to treatment withdrawal was 11 days.
Baseline Characteristics of Randomized Patients
Of the 442 patients who entered the open treatment phase, 415 (94%) were randomized to continued treatment with carvedilol (207) or placebo (208). The two groups were well matched at entry for most patient characteristics (Table 1⇓). Overall, 70% of patients were classified as being in NYHA functional class II or III, although 43% had previously been classified as class IV. At entry to the trial, 95% of patients were receiving drug treatment of some kind for the management of heart failure, and 85% were receiving ACE inhibitor therapy. The average LV ejection fraction at entry was 28.6%, and the average treadmill duration was 10.5 minutes.
Postrandomization Treatment and Follow-up
In the 6 months after randomization, a total of 11 patients died (3 sudden deaths, 2 progressive heart failures, 4 myocardial infarctions, 1 heart failure after laparotomy for perforated peptic ulcer, and 1 sepsis after peripheral vascular surgery). Of the 404 survivors, 6-month follow-up data were obtained from 392 (97%), and the outcome results reported here are based on those data. A total of 361 patients (90% of survivors) completed 6 months of treatment; the reasons for withdrawal of treatment in the other 43 surviving patients are shown in Table 2⇓. About 40% of withdrawals were the result of patient decisions (without any known medical reason), and the remainder were the result of medical decisions, of which about half were for worsening heart failure or bradycardia. More patients in the carvedilol group than the placebo group were withdrawn from treatment (30 versus 13; 2P=.01), but no single reason for withdrawal accounted for this difference. The average time from randomization to treatment withdrawal was 14 days shorter in the carvedilol group than in the placebo group, but this difference was not statistically significant (2P>.4).
Among the 361 patients continuing to take study treatment at 6 months, the mean doses taken were similar in the two study groups: 41 mg daily in the carvedilol group and the equivalent of 46 mg daily in the placebo group. At 6 months, among all of those 207 patients assigned treatment with carvedilol, 17% had died or were no longer receiving study treatment, 8% were taking 6.25 mg BID, 19% were taking 12.5 mg BID, and 56% were taking 25 mg BID. Among those receiving frusemide, there was no significant change in the mean dose of frusemide between the study groups during follow-up; overall, the average daily doses at baseline and at 6 months were 92 mg and 94 mg, respectively. Similarly, among those receiving an ACE inhibitor, there were no significant changes in the mean doses of captopril and enalapril between study groups (these drugs accounted for 82% of total ACE inhibitor use among study participants); overall, the average daily doses of captopril at baseline and at 6 months were both 53 mg, and the average daily doses of enalapril were 12 mg and 11 mg, respectively.
Heart Rate, Blood Pressure, and Rate-Pressure Product
From baseline to 6 months, supine and standing heart rates fell by 7.5 and 9.8 bpm, respectively, in the carvedilol group compared with the placebo group (Table 3⇓). At maximum exercise, heart rate fell by 25 bpm in the carvedilol group compared with the placebo group. Supine and standing systolic blood pressures declined by 5.6 and 8.1 mm Hg, respectively, in the carvedilol group over the same period, and supine and standing diastolic blood pressures declined by 4.5 and 4.4 mm Hg, respectively. The falls in exercise blood pressures in the carvedilol group compared with the placebo group were of similar size to those observed at rest. The supine, standing, and exercise rate-pressure products fell by 13%, 17%, and 23%, respectively, in the carvedilol group compared with the placebo group.
Left Ventricular Function and Size
During follow-up, LV ejection fraction increased by 5.2% in the carvedilol group compared with the placebo group (95% confidence interval, 3.7% to 6.8%), reflecting an increase from 28.4% at baseline to 33.7% at 6 months among patients assigned carvedilol (Table 4⇓ and Fig 1⇓). There were independently significant increases in ejection fraction for patients assigned carvedilol in each of the three tertiles of ejection fraction at baseline (all 2P<.0005) (Fig 1⇓). LV end-diastolic and end-systolic dimensions were reduced by 1.3 mm (2P=.048) and 2.6 mm (2P=.0004), respectively (Fig 2⇓), and fractional shortening was increased by 2.5% (2P<.0001) in the carvedilol group compared with the placebo group (Table 4⇓).
Maximal and Submaximal Exercise Performance
At 6 months, there was no significant change in treadmill exercise duration between carvedilol and placebo groups (mean difference, −22 seconds; 95% confidence interval, −59 to 15 seconds) (Table 4⇑ and Fig 3⇓). There were no significant changes in this end point between groups either for patients with exercise-limiting myocardial ischemia on the first treadmill test (2P>.5) or for patients without such ischemia (2P>.5). For all patients, at maximum exercise there was no change between the carvedilol and placebo groups in the Borg score at 6 months. Finally, there was no significant change in 6-minute walk distance between carvedilol and placebo groups (mean difference, −6 m; 95% confidence interval, −18 to 6 m).
In both treatment groups, the NYHA and SAS functional classes of two thirds of all patients remained unchanged during follow-up (Table 5⇓). However, there was a borderline-significant trend toward less improvement and more frequent worsening of NYHA functional class in the carvedilol group compared with the placebo group. Consistent with this was a conventionally significant adverse change in functional capacity assessed by the SAS in the carvedilol group compared with the placebo group. The likelihood of an adverse change in symptoms did not appear to be related to functional class at entry into the study. There were no significant differences between groups for the angina scale or the patient self-assessment scale.
The results of this randomized trial provide, for the first time, clear evidence that treatment with a β-blocker improves LV function in patients with heart failure due to ischemic heart disease. Treatment with carvedilol resulted in increased LV ejection fraction, reduced LV dimensions, and increased LV fractional shortening. There was no clear evidence of an effect of treatment on either maximal or submaximal exercise performance, but symptoms assessed by the NYHA and SAS scales of functional class appeared to be mildly adversely affected by carvedilol. Despite this, however, the overall tolerability of treatment with carvedilol, as judged by the number of treatment withdrawals, appeared to be good. About 4% of patients failed to tolerate initial low-dose treatment with 6.25 mg BID, and during longer-term double-blind treatment, only 8% more patients were withdrawn from carvedilol than from placebo. Such tolerability compares favorably with that of other drugs such as ACE inhibitors used frequently in patients with heart failure.5 6
The 5% increase in LV ejection fraction observed in this trial among patients with heart failure of ischemic etiology is almost identical to that observed in a recent overview of previous trials of β-blockers in patients with heart failure of mostly idiopathic etiology.11 Moreover, the effects on LV function in this trial appeared to be similar across a wide range of baseline ejection fractions, and these effects were obtained in a patient population in which 86% were receiving concurrent treatment with an ACE inhibitor. The reduction in LV dimensions indicates that the effect of carvedilol on LV ejection fraction was not solely an effect of heart rate slowing and suggests an improvement in intrinsic myocardial contractility. Whether the improvement in LV function produced by carvedilol represents an effect of β-adrenergic blockade alone or a combined effect of this and α1-receptor–mediated vasodilation cannot be determined reliably from this study. However, a primary role of β-adrenergic blockade is suggested by the similarity of the effects on LV ejection fraction observed in this study and in other studies of nonvasodilating β-blockers such as metoprolol23 and by the absence in other studies of any sustained effect on LV function of α1-blocking drugs such as prazosin.24 It is also possible that reduced myocardial ischemia25 and improved diastolic function26 may have contributed to the observed changes.
The absence of a clear effect of carvedilol on treadmill exercise duration in this trial is consistent with the equivocal evidence about the effects of β-blocker therapy on maximal exercise performance in previous trials in patients with heart failure.11 The results of the present study indicate that during treatment with carvedilol, maximum exercise capacity was preserved despite a marked reduction in maximum exercise heart rate. That exercise performance was maintained at a lower rate-pressure product suggests improved cardiac efficiency and is consistent with the increased LV ejection fraction and reduced LV dimensions. The absence of an effect of carvedilol on 6-minute walk distance indicates that submaximal exercise performance also was unaffected by the decline in exercise heart rate. This contrasts with reports from some small studies in which increases in 6-minute walk distance or submaximal exercise duration have been reported in patients with more severe symptoms treated with β-blockers including carvedilol.27 28 However, in the present study, there was no evidence of a beneficial effect of carvedilol on 6-minute walk distance either in the subgroup of 66 patients with NYHA class III symptoms at baseline (mean difference, −5 m; 2P>.5) or in the subgroup of 137 patients in the lowest tertile of 6-minute walk distance at baseline (mean difference, −4 m; 2P>.5).
During follow-up in this study, most patients in both carvedilol and placebo groups experienced little or no change in symptoms assessed by the NYHA and SAS functional classes. However, among the remainder, there was a small excess of patients in the carvedilol group with worsening symptoms and a deficit of patients with improving symptoms. It is uncertain whether this represents an adverse effect of treatment on the symptoms of heart failure or simply the typical side effects of β-blocker therapy (ie, tiredness, fatigue). In this regard, it is of note that there was no increase in the dose of frusemide or ACE inhibitors prescribed to patients in the carvedilol group. Moreover, although there was a small but significant excess of patients withdrawn from carvedilol compared with placebo during double-blind follow-up, only 5 patients (2%) were withdrawn from active treatment because of worsening heart failure.
The results of this trial indicate improved LV function and unchanged exercise performance after treatment with carvedilol, but it remains uncertain whether such treatment will ultimately confer reduced morbidity or mortality from heart failure and whether any such potential benefits would outweigh the potential minor disadvantage suggested by the changes in symptoms. Data on hospitalizations and mortality from the extended follow-up of patients in the present study may provide useful information in this regard. However, these questions will only be reliably answered by the conduct of large-scale trials of the effects of β-blockers on mortality and serious morbidity in patients with heart failure. The mortality results of trials of β-blockers in patients with a history of myocardial infarction are encouraging in that they suggest that the survival benefits of these drugs may extend to some patients with heart failure of ischemic etiology.11 13 14 However, definitive conclusions about the value of β-blocker therapy for patients with heart failure are limited by the exclusion of many patients with heart failure from enrollment to these studies. It is therefore important that new large-scale trials in heart failure be initiated to resolve this uncertainty. Two such trials (BEST [Betablocker Evaluation of Survival Trial] and CHOICE [Congestive Heart Failure Mortality: Investigation of Carvedilol’s Efficacy]) are now planned and together will involve a total of more than 6000 randomized patients. Results from these trials should provide reliable evidence about the balance of benefits and risks conferred by β-blocker therapy in patients with heart failure.
Australia–New Zealand Heart Failure Research Collaborative Group
Australia. Austin Hospital, Melbourne (H. Krum, A. Tonkin,1 A. Trotter); Fremantle Hospital, Fremantle (R. Burton, J. Garrett, G. Lane1); Illawarra Regional Hospital, Wollongong (D. Owensby,* J. Ryan); Launceston Hospital, Tasmania (J. Shepherd, B. Singh1); Preston and Northcote Community Hospital, Melbourne (B. Jackson,1 G. Rudge); Princess Alexandra Hospital, Brisbane (J. Stephensen, S. Woodhouse1); Prince Henry Hospital, Sydney (T. Davidson, J. Turner, W. Walsh1); Repatriation Hospital, Melbourne (J. Bradbury, A. Hamer1); Royal Brisbane Hospital, Brisbane (D. Cross,1 C. Hall); Royal Hobart Hospital, Hobart (V. Kimber, A. Thomson1); Sir Charles Gairdner Hospital, Perth (M. Croot, P. Thompson1); The Queen Elizabeth Hospital, Adelaide (J. Horowitz,1 S. Leslie, Y. Zhang); Wesley Hospital, Brisbane (D. Colquhoun,1 B. Hicks); Woden Valley Hospital, ACT (I. Jeffery,* P. Taverner).
New Zealand. Auckland Hospital, Auckland (C. Bond, R.N. Doughty,1 J. Murphy, N. Sharpe1); Christchurch Hospital, Christchurch (C. Hall, H. Ikram,1 M. Richards*); Dunedin Hospital, Dunedin (C. Low,* D. Scott); Napier Hospital, Napier (G. Brown, G. Lewis1); Tauranga Hospital, Tauranga (J. Bruning, L. Nairn1); Waikato Hospital, Hamilton (A. Clayton, J. Crawford, H. McAlister1).
Clinical Trials Research Unit, Department of Medicine, University of Auckland, Auckland, New Zealand (N. Sharpe,2 S. MacMahon,2 R.N. Doughty, J. Murphy, C. Bond, T.W. Yee, A. McCulloch, A. Milne, R. Prasad, H. Bartram).
Central Echocardiography Laboratory (R.N. Doughty, G. Whalley).
Data Monitoring Committee (I. Reid, Chairman).
This study was funded by a grant from SmithKline Beecham; however, the study was initiated, conducted, analyzed, and reported by the ANZ Heart Failure Research Collaborative Group independently of the sponsor. Dr Stephen MacMahon is the recipient of Senior Research Fellowship from the Health Research Council of New Zealand. The assistance of Kathy Bos in the production of the data collection forms used in this study is gratefully acknowledged.
- Received February 1, 1995.
- Revision received April 10, 1995.
- Accepted April 16, 1995.
- Copyright © 1995 by American Heart Association
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