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European Journal of Heart Failure 2005 7(5):874-877; doi:10.1016/j.ejheart.2005.03.002
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© 2005 European Society of Cardiology

Do metoprolol and carvedilol have equivalent effects on diurnal heart rate in patients with chronic heart failure?

John E. Sanderson*, Leata Y.C. Leung, Skiva K.W. Chan, Gabriel W.K. Yip, Jeffrey W.H. Fung and C.M. Yu

Division of Cardiology, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, 9th Fl Clinical Science Bldg Prince of Wales Hospital, Hong Kong SAR

* Corresponding author. Tel.: +852 2632 2064; fax: +852 2637 2396. E-mial address: john.sanderson{at}uhns.nhs.uk


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Carvedilol exerted a greater reduction in mortality than metoprolol tartrate in the Carvedilol or Metoprolol European Trial (COMET). However, it is unclear if the degree and time course of β1-blockade during a 24-h period was similar with each agent at the doses used. Therefore we analyzed 24-h ECG Holter recordings from a study which compared the long-term clinical efficacy of metoprolol tartrate to carvedilol in chronic heart failure patients using the same dosing regimen as in COMET.

Methods and results: Fifty-one patients with chronic heart failure with a mean LVEF 26+1.8% were randomized in a double-blind fashion to receive metoprolol tartrate 50 mg bid or carvedilol 25 mg bid. 24-h ECG monitoring (Holter) was performed at baseline, 12 weeks and 1 year. Adequate quality recordings for analysis were obtained from 43 subjects at baseline, 42 at 12 weeks and 29 subjects at 1 year. Both drugs produced a fall in average 24-h heart rate from baseline at 12 weeks and at 1 year: metoprolol 88+3 to 71+2 and 69+3 bpm; carvedilol 83+3 to 70+2 and 70+3 bpm respectively (all p<0.001). The pattern of suppression of heart rate during the 24-h period was similar for both drugs.

Conclusion: Metoprolol tartrate 50 mg bid and carvedilol 25 mg bid had similar effects on 24-h heart rate. This result suggests that the degree of β1-blockade produced by these two drugs in these doses is comparable and the superior survival effect of carvedilol compared to metoprolol seen in COMET is likely to be due to actions of carvedilol other than β1-blockade.

Key Words: Heart failure • Beta-blockers • Metoprolol • Carvedilol

Received August 20, 2004; Revised January 22, 2005; Accepted March 24, 2005


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Three β-blockers, metoprolol, carvedilol and bisoprolol, have been shown to prolong survival [1–4]. Whether there are clinically significant differences between these β-blockers is controversial. Carvedilol and metoprolol have been compared in a large, long-term mortality trial, Carvedilol Or Metoprolol European Trial (COMET), which found that patients with heart failure treated with carvedilol had a 17% lower risk of death than those treated with metoprolol [5]. Several explanations have been offered for this difference including additional anti-adrenergic effects of carvedilol (which blocks {alpha}1-, β1- and β2-receptors unlike metoprolol and bisoprolol which are β1-receptor selective), possible direct anti-fibrotic effects [6] and antioxidant activity [7,8]. However, immediate release metoprolol tartrate was used in COMET rather than the slow-release metoprolol succinate CR/XL preparation that was used in MERIT-HF trial. The former preparation may not produce a similar degree of β1-receptor blockade as carvedilol especially 7–12 h after tablet ingestion [3,9]. Indeed there was a small but significant difference in heart rates at 4 months in COMET (1.6 beats per minute lower with carvedilol), although after 16 months there was no significant difference for the remainder of the trial [5]. However, measurements of heart rate were only done 2–6 h after ingestion of the medicine and it is possible that much larger differences in heart rate would have been observed at other times of the day. We conducted a double-blind randomized controlled trial of carvedilol versus metoprolol in chronic heart failure using the same dosing regime as in the COMET trial [10]. Now we present the full results of 24-h ambulatory ECG monitoring in those subjects done at baseline, 3 months and after 1 year treatment [11].


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
This was a double-blind controlled trial [10] of patients with symptoms of heart failure on standard therapy with diuretics, digoxin and angiotensin-converting enzyme inhibitors and an LV ejection fraction < 0.45 (measure by radionuclide ventriculography) without contra-indications to β-blockers [10]. Baseline measurements included Minnesota Quality of Life Heart Failure Questionnaire, 6-min walking test, blood tests, LV ejection fraction by radionuclide ventriculography, standard Doppler-echocardiography and 24-h ambulatory ECG (Holter) monitoring. ECG analysis was undertaken using a Marquette (Milwaukee Wisconsin) MARS 8000 analyzer. Mean, maximum and minimum heart rates for each hourly period were recorded as well as for the total 24 h. Patients were randomized to carvedilol or metoprolol in identical capsules with a 4-week dose titration period increasing the dose of carvedilol from 3.125 mg to 25 mg twice daily and metoprolol from 6.25 mg to 50 mg daily. The final dose was maintained for 1 year. Baseline measurements were repeated at 12 weeks and at 1 year.

Differences between the treatment groups were carried out by repeated-measures analysis of variance for continuous variables (ANOVA) with Barlets test with homogeneity test if p<0.05, Friedman's test for non-parametric data and Fisher exact test for differences between proportions. Differences between baseline and 1 year, week 12 and 1 year within groups were tested by paired t-tests, and Wilcoxon matched pairs signed ranks test for non-parametric data. The results are expressed as mean±S.E.M. Differences were considered significant if p<0.05.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
Fifty-one patients with a mean LV ejection fraction of 26±1.8% were recruited and 26 were randomized to metoprolol and 25 to carvedilol. No differences in the baseline characteristics between groups were observed [10]. The majority had idiopathic dilated or ischaemic cardiomyopathy. Over 90% of patients were taking an angiotensin-converting enzyme inhibitor or angiotensin II receptor antagonist at week 12. At the end of week 12, there were 23 patients in the metoprolol group and 20 patients in the carvedilol group. The maintenance dose of each drug was continued for a total of 1 year. In the metoprolol group, 6 patients did not complete the 1-year study after week 12. Two patients were withdrawn because of stroke. Two patients had worsening of symptoms mainly dyspnoea and dizziness. One patient was withdrawn because of impotence and one defaulted follow up for unknown reasons. In the carvedilol group, 6 patients did not complete the study after week 12. Two patients died, suspected to be arrhythmic deaths. Four patients stopped the drug because of increasing dyspnoea. Two of them were switched to metoprolol but were not included in the metoprolol group for subsequent analysis. There was no difference between carvedilol and metoprolol in withdrawal rate.

3.1. Symptoms
The results of the symptom (quality of life) questionnaire score at baseline, 12 weeks and 1 year are shown in Table 1. Both drugs had improved symptoms to a similar extent at 12 weeks. This effect was maintained but did not increase further up to 1 year.


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  		Table 1 Results of the symptom (quality of life) questionnaire score at baseline, 12 weeks and 1 year

 
3.2. Exercise capacity
There was little increase in exercise capacity with either beta-blocker. Between group comparisons showed no difference in exercise capacity between agents at 12 weeks or 1 year.

3.3. LV systolic function
LV ejection rose progressively and to a similar extent with each agent (Fig. 1).


Figure 1
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  		Fig. 1 Change of left ventricular ejection fraction with treatment by metoprolol and carvedilol. *p<0.01, and NS=non-significant.

 
3.4. 24-h heart rate monitoring
24-h heart rate was similar in both groups at baseline (Table 1 and Fig. 2a). Both drugs reduced average 24-h (Table 1) and maximum heart rates (Table 1) at week 12 compared to baseline. There was little further change between week 12 and 1 year. The distribution of hourly heart rate was also similar at week 12 and 1 year for carvedilol and metoprolol (Fig. 2b and c). There was no obvious loss of heart rate reduction by metoprolol IR during the 24-h period.


Figure 2
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  		Fig. 2 (a) Mean hourly heart rates over 24 h at baseline. (b) Mean hourly heart rates over 34 h after 12 weeks of therapy. (c) Mean hourly heart rates over 24 h after 1 year of therapy.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
This is the first study to assess heart rate over a 24-h period after long-term treatment with metoprolol tartrate and carvedilol in patients with heart failure. The effects of these two agents on 24-h ambulatory heart rates were similar. It appears, therefore, that metoprolol IR produces the same degree of β1-blockade as carvedilol if the heart rate can be considered to be a reliable marker of β1-blockade. However, the relationship between β1-receptor stimulation and heart rate is complicated in heart failure as there is a relative increase in the proportion of β2-receptors and blockade of these receptors may have additional inhibitory effects on exercise heart rate [11]. Therefore, it might be expected that non-selective β-receptor blockade may produce a greater effect on exercise heart rate in patients with heart failure but we did not find this. In addition, the 24-h maximum heart rate will be influenced by the intensity of exercise and it is possible that metoprolol may be superior to carvedilol in this respect [10], although our study did not show a difference in exercise capacity. It has been suggested that twice daily metoprolol tartrate IR is not an effective treatment for heart failure because dosing 3–4 times daily is required to provide a continuous 24-h action [12]. However, many trials of twice daily metoprolol tartrate IR showed beneficial effects on LV ejection fraction, symptoms and exercise capacity which argue against this idea [10,13]. Our study shows that the dose of metoprolol tartrate used in COMET does suppress heart rate throughout 24 h to a similar degree as carvedilol. Kukin et al. found that the difference in resting heart rate at trough and peak effect after 3 months treatment with metoprolol tartrate 50 mg twice daily was small and with similar trough effects (12 h) as those achieved by controlled-release metoprolol [14,15]. It seems that fluctuations in blood levels of metoprolol tartrate that may occur with short-term treatment are not observed with long-term treatment.

Thus if the degree of β1-blockade is similar with metoprolol IR and carvedilol in the doses used in COMET it requires additional hypotheses to explain the superior effect of carvedilol compared to metoprolol on survival. Carvedilol may have properties other than β1-receptor blockade that may be relevant including more comprehensive sympathetic blockade, antioxidant activity, anti-fibrotic activity, inhibition of apoptosis, free-radical scavenging, and improved insulin sensitivity [6–9,16,17]. A differential effect on the renin–angiotensin system is unlikely as we have shown that the effect of metoprolol and carvedilol on plasma renin is temporary and neither had a significant effect on aldosterone levels [18]. Differences in vascular effects, as suggested by the slightly lower systolic BP with carvedilol treatment (–1.8 mm Hg) in COMET [5] and our initial study [10], may also be important.

Although both drugs significantly reduced resting and maximum heart rates it is noteworthy that the mean maximum heart rate was still 108 and 109 bpm for metoprolol and carvedilol respectively at 12 weeks indicating that even at these doses there was still an exercise related tachycardia. These results therefore raise the possibility that present recommended doses being used for metoprolol and carvedilol are still insufficient to provide complete beta-blockade. It is unclear whether higher doses would lead to greater clinical benefits.

One limitation of the study is the relatively small number of patients and relatively high withdrawal rate in both treatment groups [18].

In summary, in this study we have shown that metoprolol tartrate IR in a dose of 50 mg twice daily and carvedilol 25 mg twice daily have similar effects on hourly heart rate over a 24-h period. This result suggests that the intensity of β1-blockade produced by these two drugs in these doses is also comparable.


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

  1. Packer M., Bristow M.R., Cohn J.N., et alThe US Carvedilol Heart Failure Study Group. Effect of carvedilol on morbidity and mortality in chronic heart failure. N Engl J Med (1996) 334:1349–1355.[Abstract/Free Full Text]
  2. CIBIS-II Investigators and Committees. The cardiac insufficiency bisoprolol study-II (CIBIS-II): a randomized trial. Lancet (1999) 353:9–13.[CrossRef][Web of Science][Medline]
  3. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL randomized intervention trial in congestive heart failure. Lancet (1999) 343:2001–2007.
  4. Packer M., Coats A.J., Fowler M.B., et al. For the carvedilol prospective randomized cumulative survival study group effect of carvedilol on survival in severe chronic heart failure. N Engl J Med (2001) 344:1651–1658.[Abstract/Free Full Text]
  5. Poole-Wilson P.A., et alfor the COMET investigators. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomized controlled trial. Lancet (2003) 362:7–13.[CrossRef][Web of Science][Medline]
  6. Wei S., Chow L.T., Sanderson J.E. Effect of carvedilol in comparison with metoprolol on myocardial collagen postinfarction. J Am Coll Cardiol (2000) 36:276–281.[Abstract/Free Full Text]
  7. Lysko P.G., Webb C.L., Ohlstein E.H., Ruffolo R.R., Yue T.L. A comparison of carvedilol and metoprolol antioxidant activities in vitro. J Cardiovasc Pharmacol (2000) 36:277–281.[CrossRef][Web of Science][Medline]
  8. Arumanayagan M., Chan S., Tong S., Sanderson J.E. Antioxidant properties of carvedilol and metoprolol in heart failure: a double-blind randomized controlled trial. J Cardiovasc Pharmacol (2001) 37:48–54.[CrossRef][Web of Science][Medline]
  9. Hjalmarson A., Waagstein F. COMET: a proposed mechanism of action to explain the results and concerns about dose. Lancet (2003) 362:1077.[Web of Science][Medline]
  10. Sanderson J.E., Chan S.K.W., Yip G., et al. Beta-blockade in heart failure: a comparison of carvedilol with metoprolol. J Am Coll Cardiol (1999) 34:1522–1528.[Abstract/Free Full Text]
  11. Do Packer M. β-Blockers prolong survival in heart failure only by inhibiting the β1-receptor? A perspective on the results of the COMET trial. J Card Fail (2003) 9:429–441.[CrossRef][Web of Science][Medline]
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  13. Packer M., Antonopoulos G.V., Berlin J.A., Chittams J., Konstam M.A., Udelson J.E. Comparative effects of carvedilol and metoprolol on left ventricular ejection fraction in heart failure: results of a meta-analysis. Am Heart J (2001) 141:899–907.[CrossRef][Web of Science][Medline]
  14. Kukin M.L., Kalman J., Mannimo M.M. Beta blockade in congestive heart failure: persistent adverse haemodynamic effects during chronic treatment with subsequent doses. Heart (1997) 78:444–449.[Abstract/Free Full Text]
  15. Kukin M.L., Mannimo M.M., Freudenberger R.S, et al. Hemodynamic comparison of twice daily metoprolol tartrate with once daily metoprolol succinate in congestive heart failure. J Am Coll Cardiol (2000) 35:45–50.[Abstract/Free Full Text]
  16. Rossig L., Haendeler J., Mallat Z., et al. Congestive heart failure induces endothelial cell apoptosis: protective role of carvedilol. J Am Coll Cardiol (2000) 36:2081–2089.[Abstract/Free Full Text]
  17. Jacob S., Rett, Wicklmayr M., Agrawal B., Augustine H.J., Dietze G.J. Differential effect of chronic treatment with two beta-blocking agents on insulin sensitivity: the carvedilol–metoprolol study. J Hypertens (1996) 14:489–494.[Web of Science][Medline]
  18. Fung J.W.H., Yu C.M., Yip G., et al. Effect of beta blockade (carvedilol or metoprolol) on activation of the renin–angiotensin–aldosterone system and natriuretic peptides in chronic heart failure. Am J Cardiol (2003) 92:406–410.[CrossRef][Web of Science][Medline]

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