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European Journal of Heart Failure 2001 3(4):463-468; doi:10.1016/S1388-9842(01)00146-5
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© 2001 European Society of Cardiology

Effect of metoprolol CR/XL on exercise tolerance in chronic heart failure — a substudy to the MERIT-HF trial

Lars Gullestada,*, Cord Manhenkeb, Torbjørn Aarslandb, Rita Skårdala, Hans Fagertunc,1, John Wikstrandd and John Kjekshusa,2

a Department of Cardiology, Division of Heart and Lung Diseases Rikshospitalet, 0027 Oslo, Norway
b Hjertelaget Research Foundation Stavanger, Norway
c Scandinavian Statistical Services Oslo, Norway
d Wallenberg Laboratory for Cardiovascular Research, Gøteborg University Gothenburg, Sweden

* Corresponding author. Medical Department, Baerum Hospital, 1306 Baerum Postterminal, Norway. Tel.: +47-67809400; fax: +47-67809556. E-mail address: lagulles{at}online.no (L. Gullestad).


   Abstract
Top
 Notes
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Background: β-Blockade usually causes a slight reduction in exercise capacity among healthy subjects, while more variable results have been observed in chronic heart failure (CHF), probably related to patients studied, methods and agent used. The effect of metoprolol controlled release/extended release (CR/XL) on peak oxygen uptake (peak VO2) in this patient population has not previously been investigated.

Aims: We examined the effect of long-term treatment with the selective β1-receptor blocker metoprolol CR/XL once daily on exercise capacity in patients with CHF.

Methods: Ninety-four patients (70 males and 24 females; mean age 63.6±10.6 years) with chronic symptomatic heart failure in New York Heart Association (NYHA) functional class II–IV, and with ejection fraction ≤40%, stabilized on optimum standard therapy were randomized to metoprolol CR/XL or placebo in a double-blind trial. Exercise capacity was evaluated by peak VO2 at baseline, after 3 months and at the end of study (mean follow-up 11.4±0.4 months).

Results: Compared with placebo metoprolol CR/XL produced a significant decrease in heart rate by 11 beats/min at rest and 18 beats/min at peak exercise. There was a tendency for a temporal decline in peak VO2 after 3 months of therapy in both groups, but altogether peak VO2 remained unchanged from baseline with no difference between the groups at 1 year.

Conclusions: In patients with moderate to severe CHF, 11.4 months of β1-blockade with metoprolol CR/XL had no effect on exercise capacity when compared with placebo or baseline.

Key Words: β-Blockade • Exercise • Oxygen uptake

Received October 10, 2000; Revised February 12, 2001; Accepted February 20, 2001


   1. Introduction
Top
 Notes
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
During recent years β-blockers have become standard therapy for patients with chronic heart failure (CHF) with systolic dysfunction. Among such patients the addition of β-blockers have proven, through several large-scale double blind, placebo-controlled trials, to increase functional status and cardiac performance and to reduce mortality and morbidity [1–4]. Their effect on exercise capacity has, however, been variable.

Treatment with β-blockers usually results in reduced exercise capacity among healthy subjects [5,6], although to a lesser extent with β1-blockade than with non-selective β-blockade. Previous trials related to the effect of β-blockers on exercise capacity among patients with CHF have been conflicting. While some studies have reported an improvement in exercise duration or peak VO2 [7–10], others have found no effect [11–17] or even a decrease compared with placebo [18,19]. However, many of the trials with β-blockers were conducted before angiotensin converting enzyme inhibitors became standard therapy for the disease. Although ACE-inhibitors usually improve exercise capacity [20] also with impact on survival and hospitalization among patients with CHF [21,22], recent studies have demonstrated that such patients have progressive loss of exercise capacity with time [23]. We therefore hypothesized that the addition of a β1-blocker to standard optimal treatment among patients with CHF would prevent progression and attenuate the expected decline in exercise capacity. In the present study we examined the effect of the β1-selective blocker metoprolol CR/XL once daily on maximal oxygen uptake in 94 patients enrolled in the MERIT-HF trial [3].


   2. Methods
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusions
 References
 
2.1. Patients
The present study was conducted at two experienced centers, Rikshospitalet and Rogaland Central Hospital, in Norway as a substudy to the MERIT-HF randomized, placebo-controlled, double-blind multicenter trial study in which the effect of the β1-selective blocker metoprolol CR/XL was tested in patients with chronic symptomatic heart failure and with depressed left ventricular function (left ventricular EF<40%) [3]. The study included 94 patients (70 males and 24 females; mean age 63.6±10.6 years). They were all optimally treated for heart failure including angiotensin converting enzyme (ACE) inhibitors and diuretics (Table 1). Their clinical and hemodynamic situation was stable during the 2-week placebo run-in phase. The main exclusion criteria included acute myocardial infarction or unstable angina pectoris within 28 days before randomization; severe decompensated heart failure; indication or contraindication to treatment with a β-blocker, systolic blood pressure below 100 mmHg, or heart rate below 68 beats/min. All patients gave written informed consent.


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  		Table 1 Clinical characteristics of the CHF patients receiving metoprolol CR/XL or placebo

 
2.2. Study design
The study design for the main study has previously been described [3]. Briefly, 94 patients, were entered into a placebo run-in period for 2 weeks. They were then randomized to metoprolol CR/XL or placebo in a double blind fashion. The starting dose was 12.5–25 mg given once daily. The dose was gradually increased during 8 weeks with a target dose of 200 mg daily. Dose regimen could be modified according to the judgement of the investigator. The International Steering Committee stopped the study early on the recommendation of the independent safety committee [3], resulting in a mean follow up of 11.4±0.4 months in the present study.

2.3. Exercise testing
Exercise testing was carried out using an electrically braked cycle ergometer in the sitting position with simultaneous gas exchange and hemodynamic monitoring at baseline, after 3 months of therapy and at the end of study. In a subset of 30 patients, two baseline tests, 1–2 weeks apart, were carried out. The test protocol consisted of a starting work rate of 20 W increasing by 20 W every second minute until exhaustion (defined as an inability to keep the pedalling rate steady at 60 rev./min). Exercise tests were considered acceptable if the patients were limited by dyspnoea, or general or leg fatigue and if the respiratory exchange ratio (R value) increased by at least 0.1 from the lowest R value [24]. Patients were excluded if the patient had anginal chest pain or claudication on exercise. Gas exchange was monitored during exercise. In one center (Rikshospitalet) gas exchange was measured with a mixing chamber using the EOS/SPRINT system and in the other center (Rogaland) with breath-by-breath analysis using the Medical Graphics Corp. 2001 system. Gas exchange was recorded at 30-s intervals, and peak VO2 calculated from the final 30 s of exercise. The analysers were calibrated every morning. Heart rate was recorded continuously from an electrocardiograph, and cuff blood pressure was measured non-invasively with an automatic blood pressure recorder before and during each workload of exercise. The subjective perception of fatigue (Borg scale) [25] was recorded during exercise.

2.4. Statistical analyses
The SAS Statistical package was used for statistical analysis. Analysis of Covariance (ANACOVA) was used to compare the two treatment groups at 3 months and end of study using the baseline value as covariate. Continuously distributed variables are given as mean with 95% C.I. of mean or mean with S.D., while categorical variables are given with frequency and rates. P values are two-sided and considered significant when less or equal to 0.05.


   3. Results
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusions
 References
 
Of the 94 patients entering the study, 11 failed to complete before the study was stopped. Six patients discontinued in the metoprolol CR/XL group (two died, one underwent cardiac transplantation, and 3 withdrew for other reasons) and five in the placebo group (four died and one withdrew for another reason). Thus, 83 patients completed the study, 43 on metoprolol and 40 on placebo. The clinical characteristics of the two treatment groups are given in Table 1. The two groups were similar with respect to key demographic and clinical signs of CHF.

In order to test the reproducibility of the exercise testing 30 patients underwent two baseline tests. The mean difference for peak VO2 was –0.8 (95% C.I. of –2.8, 1.1) ml/kg per min which suggests sufficient reproducibility. The mean peak respiratory exchange ratios >1.0 confirm adequate effort and provide evidence of anaerobic exercise.

Heart rate was significantly reduced at rest by 11 beats/min and by 18 beats/min at peak exercise while systolic blood pressure remained unchanged during metoprolol CR/XL treatment (Table 2). These variables remained unchanged during placebo treatment (Table 2). Oxygen pulse, an indirect index of combined cardiopulmonary oxygen transport, increased both at rest from 3.5±1.2 to 4.2±1.3 ml/beat and at maximal exercise from 8.5±2.7 to 9.9±3.1 ml/beat during treatment with metoprolol CR/XL, at baseline and end of study respectively. In contrast, no changes were observed during placebo (3.3±1.2 and 3.3±0.92 ml/beat at rest; 8.3±2.5 and 8.2±2.7 ml/beat at maximal exercise at baseline and end of study, respectively).


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  		Table 2 Change in exercise variables during treatment from baseline to end of studya

 
Peak exercise performance measured as maximal work load or peak VO2 decreased slightly during the first 3 months (ns) and increased thereafter towards baseline at the end of study in both treatment groups (Table 2, Fig. 1). There was no difference in exercise response among those with a history of coronary artery disease vs. those with non-ischemic etiology for heart failure. Since duration of treatment could be a confounding factor, we analyzed the exercise response in patients divided into follow up below or above median duration of follow up, but there was no difference in peak VO2. All other gas exchange exercise variables remained unchanged in both groups during treatment (Table 2).


Figure 1
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  		Fig. 1 Change in peak oxygen uptake (peak VO2) from baseline to 3 months and end of study (mean 11.4 months) during treatment with metoprolol CR/XL or placebo. Data are given as mean change and S.E.

 

   4. Discussion
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusions
 References
 
In the present study we demonstrated that selective β1-blockade with metoprolol CR/XL did not change maximal exercise performance compared with placebo or baseline during long term-treatment among patients with chronic heart failure.

Previous trials have in general demonstrated impaired exercise performance during β-blocker treatment in healthy subjects and patients with hypertension [5,6], while the results in patients with heart failure have been more variable. Some studies have reported an improvement [7–10] or a decrease [18,19], while most studies have found no change in exercise capacity compared with placebo [11,13–17,26,27].

Some previous trials among patients with heart failure have demonstrated increased exercise capacity after metoprolol treatment compared with placebo [7–10,28] while exercise capacity was unchanged in the present study. The discrepant results may be related to both patients studied and method used. In the study of Engelmeier et al. [7] and in The Metoprolol in Dilated Cardiomyopathy (MDC) study [8] only relatively young patients with dilated cardiomyopathy were included while most of the patients in our study were older with ischemic etiology for heart failure. Furthermore, in most of these trials [7,8,10,11] exercise capacity was assessed by exercise duration, which is a less robust parameter compared with peak VO2 as used in the present study. Recently Kukin et al. [9] measured peak VO2 and demonstrated a significant improvement of approximately 1 ml/kg per min after 6 months of treatment with metoprolol or carvedilol. However, the study differed from the present in that younger patients (mean age 57 vs. 63 years) with more compromised cardiac function (mean EF 18 vs. 26%, and lower peak VO2 of 10.8 vs. 15.3 ml/kg/min) were included, and a different dose and formula of metoprolol were used [9]. Furthermore, Kukin et al. [9] did not include a placebo arm.

Another important difference is related to dosing and properties of metoprolol. While the above mentioned studies used short acting metoprolol in a relatively low dose, we used the slow release formulation of metoprolol CR/XL in a higher dose which was reflected in a larger decrease in maximal heart rate. While peak heart rate was reduced by 18 beats/min in the present study, Engelmeier et al. [7] did not observe any effect on this parameter. Since there appears to be a relationship between the changes in peak heart rate and changes in exercise performance during β-blockade in heart failure [19,29], a greater reduction in heart rate could explain a lack of effect on exercise capacity in the present study. One could wonder why a relatively large reduction in heart rate compared with placebo would not be associated with reduced exercise capacity. However, a reduction in heart rate could be compensated for by increased stroke volume and/or increased a-VO2 difference which is in line with the present study showing an increased oxygen pulse with metoprolol CR/XL.

Some authors have advocated the use of the third generation β-blockers carvedilol and bucindolol partly because of the vasodilating effects [1,14] which could contribute to better tolerance and improved submaximal exercise capacity [15]. However, most studies with these agents have shown no effect on either submaximal [16,17,27] or maximal exercise capacity [13–16,27] compared with placebo. In some studies with bucindolol even a decrease in peak exercise performance has been reported [18,19]. Since both bucindolol and carvedilol are non-selective β-blockers it is likely that exercise capacity is negatively influenced by blockade of vasodilating β2-adrenoceptors in the skeletal muscles and by blockade of β2 –receptors in the heart with decreased chronotropic response [30]. Furthermore, β2-blockade negatively influences energy release to the working muscles [31]. Thus the degree of reduction of peak heart rate and the influence of peripheral factors may determine exercise tolerance during β-blockade in heart failure patients.

Although peak VO2 is considered a robust prognostic indicator of prognosis in congestive heart failure, the prognostic importance of changes in peak VO2 or changes observed during treatment remains uncertain. We have previously shown that serial changes in peak VO2 among heart failure patients have limited prognostic value [32], and some positive inotropic drugs that have a beneficial effect on exercise capacity may in fact have a negative effect on survival [33]. The present and most other studies with β-blockers in heart failure have shown no effect on exercise capacity despite a substantial improvement in mortality and morbidity with these agents. Alterations in exercise capacity is therefore not necessarily translated into an effect on prognosis, and an effect on exercise capacity cannot be used as a surrogate for prognosis in heart failure.

4.1. Limitation
The present study was planned for 120 patients to give a sufficient degree of power. However, based on the observed standard deviation of two repeat tests, the present study had a power of 0.80 to detect a difference in 25% in peak O2 uptake. Another limitation is that the main trial was stopped early resulting in a shorter than planned follow-up of 18 months. Previous placebo controlled trials in heart failure among patients receiving ACE-inhibitors but with no β-blockade have demonstrated an initial stabilization for up to 12 months, followed by a progressive deterioration in cardiac performance and exercise capacity [24]. In the MDC trial [8] a significant difference between metoprolol treated and placebo treated patients in exercise capacity was observed after 12 months of follow up but not after 6 months. Although we did not expect to see an improvement in exercise capacity with metoprolol CR/XL, we had hoped to demonstrate that a beneficial effect on ventricular remodelling that has been observed during β-blockade [34] would translate into improved exercise tolerance. Thus, although exercise capacity was not influenced by follow-up time in the present study, it is possible that improved cardiac performance, as observed with β-blockers in CHF, would eventually translate into improved or maintained exercise performance, but this remains to be established.


   5. Conclusions
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
References
 
The present study demonstrated that exercise capacity was unchanged during one year of treatment with metoprolol CR/XL compared with placebo and baseline among symptomatic patients with CHF. It remains to be determined if an improvement can be observed during extended follow-up.


   Acknowledgements
 
AstraZeneca, Norway provided financial support for this study.


   Notes
Top
 Notes
Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
1 JW is also a senior medical advisor for AstaZeneca, Mølndal, Sweden. Back

2 On behalf of the MERIT-HF Study Group. Back


   References
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 

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