Metoprolol better than atenolol in therapy of cardiac failure! Role of peripheral NPY!?

The Effects of Atenolol and Metoprolol on Survival Rate of Patients with Mild-to-Moderate Chronic Heart Failure: A Comparative Study

Vera Celic, Biljana Pencic, Milica Dekleva, Sinisa Dimkovic, Maksimilijan Kocijancic

Clinical Medical Centre ”Dr. Dragisa Misovic” – Dendinje, Belgrade

Srp Arh Celok Lek. 133(5-6):242-7, 2005 May-Jun. Translation from Serbian.


Regardless of its grounds and hospital treatments the sum of death outcomes caused by cardiovascular reasons is an indicator of survival rate for patients with mild-to-moderate chronic heart failure and is characterized as a combined case.  The aim of this study was to investigate influence of metoprolol and atenolol on the combined case in patients with chronic heart failure.  The study was comparative, prospective and randomised.  The criteria for including in the study were: age of 70 years or less, NYHA functional class II and III, left ventricular ejection fraction ≤40%.  One hundred and fifty patients who had been treated by angiotensin converting enzyme inhibitor and by diuretics were divided into three numerically equal therapeutic groups: patients treated by atenolol (”the atenolol group”), patients treated by metoprolol (”the metoprolol group”) and a control group of patients who were not treated by beta blockers.  Effects of the treatment were observed for 12 months.  The results were analyzed by the SPSS 10.0 statistical software.  The cumulative survival rate of patients treated by metoprolol (88%) and by atenolol (78%) was greater than survival rate of patients from the control group (48%).  Survival rate of patients treated by metoprolol was also greater then survival rate of patients treated by atenolol.  Metoprolol significantly reduced the risk for occurrence of combined cases (71%) compared to atenolol (53%).  Results of the study have shown that metoprolol and atenolol have a positive effect on the survival rate of patients with chronic heart failure though metoprolol’s effect is significantly better compared to atenolol.

Key words: chronic heart failure; beta-blockers; metoprolol; atenolol


The most important pathophysiological process of chronic heart failure (CHF) is the process of remodeling of the heart ventricles.  The remodeling starts and develops primarily due to angiotensins and catecholamines activities [1, 2].  The hypothesis that the medicines that inhibit or reverses the remodeling can prolong CHF patients’ lives got confirmed by the results of large studies on the angiotensin-converting enzyme inhibitors (ACE inhibitors) and beta blockers (β blockers).  A long-term use of β blockers has a surprisingly positive effect on overall cardiovascular mortality and morbidity [3-5].  These effects have a solid confirmation only for carvedilol, metoprolol and bisoprolol at mild and moderate CHF, even though according to the professor John G. F. Cleland’s statements, atenolol, propranolol, acebutolol, bisoprolol and betaxolol are used in Europe and US as well [6, 7].  The main question is do different β blockers have a significantly different effect on the CHF patient’s survival rate [7, 8].  Results from the comparative studies (COMET and other) as well as from our study could give the answer on that question in the years that follow [9, 10].

Aim of the work

Aim of the study was to investigate and compare effect of atenolol and metoprolol on the survival rate of patients with CHF of NYHA (New York Heart Association) functional class II and III by observing the combined case as clinical indicator of survival rate.  A combined case is defined as the total of death outcomes due to cardiovascular reasons regardless of its grounds and hospital treatments.


The CHF diagnosis was set based on the guideline of the European Society of Cardiology’s Task Force for Diagnosis and Treatment of Chronic Heart Failure [6].  Echocardiografic examination was performed according to the standardized assessment protocol of American Society of Echocardiography [11].  The criteria for including in the study were: age of 70 years or less, NYHA functional class II and III, left ventricular ejection fraction ≤40%.  The criteria for excluding from the study were: systolic blood pressure of 100 mm Hg or less, bradicardia (heart frequency of up to 60 beats per minute) and all degrees of atrioventricular block or sinoatrial node disease, instable angina or myocardial infarct in the last three months, percutan coronar intervention or aortocoronary bypass in the last six months, obstructive or restrictive cardiomyopathies, congenital heart disorder, primary valvular disease or artificial valves, terminal diseases of other systems or organs, all known contraindications to beta-blockers application and the information about current treatment by β blockers.  Patients were divided into three numerically equal therapeutic groups: patients treated by ACE inhibitor and diuretic – the control group (50 patients), patients treated by atenolol, ACE inhibitor and diuretic – the atenolol group (50 patients) and patients treated by metoprolol, ACE inhibitor and diuretic – the metoprolol group (50 patients).

The study was comparative, prospective and randomised.  β blockers application start was determined by the phase when a patient was clinically ”dry” for two weeks.  The initial atenolol dose was 25 mg once daily and initial dose of metoprolol tartrate was 25 mg divided in two daily doses.  Farther titrational scheme was individual; target dose for both atenolol and metoprolol was 100 mg daily.  The therapeutic effect has been followed for 12 months.  The control examinations were performed after 1, 3, 6 and 12 months from start of the treatment.  The study has been ongoing for 39 months.  At each control we followed: possible negative effects of the β blockers treatment (symptomatic aggravation of CHF, symptomatic hypotension, symptomatic bradycardie), new cardiovascular diseases and new additional diseases independent of the cardiovascular system, bad compliance, death of a patient regardless of the cause.  During the study we excluded from examinations all patients who had permanently discontinued intake of β blockers due to bad compliance or due to new additional disease independent of the cardiovascular system.

The statistical analyses were performed in the SPSS 10.0 program package and they comprised: X2-test, analysis of variance for investigation of differences in demographic characteristics and frequency of unfavorable events, Kaplan-Meier survival model curve for distribution of combined cases as function of time, equality test performed by log-rank statistics, Wilcoxon statistics for the determination of survival rate between two patients groups, Cox regression model FW (Forward Wald) for examination of relative risk for occurrence of combined case in the three groups of patients. In the beginning of study there were no significant differences in age, gender, systolic blood pressure and heart frequency, etiology CHF, NYHA class, ejection fraction, i.e. other diseases as hypertension and diabetes, between the CHF patients from three therapeutic groups (Table 1).


The differences in deaths rates between the examined CHF patients groups were not statistically significant (Table 2).  A statistical significant difference among the patients from the three therapeutic groups was found in the number (frequency) of hospitalisations due to cardiovascular diseases and in the number (frequency) of the combined cases.  Frequency of hospitalisation in the metoprolol group (4%) was significantly less compared to the atenolol group (12%) and compared to the control group (26.3%). Combined case frequency in the metoprolol group (8%) was significantly less compared to the atenolol group (16%) and compared to the control group (26.3%) (Table 2).  Kaplan-Meier’s survival rate curves were significantly different for different therapeutic groups of patients (log-rank 16.46; df=2; p=0.0003) as shown in the Graph 1.  In the end of investigation the cumulative survival rate in the metoprolol group was 0.88 (88%), in the atenolol group 0.78 (78%) and in the control group 0.48 (48%).  The survival rate of patients treated by atenolol was significantly greater compared to control group  while the survival rate of patients treated by metoprolol was significantly greater compared to the control group as well compared to patients treated by atenolol (Table 3).  It was determined that metoprolol significantly reduces the relative risk for emerging of combined cases (71.3%; ExpB 0.287; p=0.020) compared to atenolol (53.4%; ExpB 0.466; p=0.050).  In the end of the study average daily doses of atenolol were 50±12.25 mg and average daily doses of metoprolol were 65.50±20 mg.


Results of our study are further confirmation of the β1 selective antagonists’ favorable effect on development and outcome of chronic heart failure.  The ground for this favorable effect lies in the deformations of adrenergic signaling in insufficient myocardium [1, 12].  A long and intensified stimulation by catecholamines leads to devastating biological effects on the myocytes level due to stimulation of β adrenergic receptors.  These effects cause remodeling signals and evolution of malignant arrhythmia [12, 13].  As the ratio of β1 receptors and β2 receptors in the heart ventricles is 80:20% and due to the fact that noradrenalin performs its effects mainly through the β1 receptors, the adaptation of myocytes against the exaggerated stimulation happens foremost by reducing the number and sensitivity of β1 receptors.  Another adaptive response of the myocytes is stimulation of iRNA and β adrenoceptor kinase (β-ARK) activities, as well as stimulation of activity of inhibitory subunit guanin-protein (Gi), what causes phosphorylisation of β receptors and prevents connecting to agonist (so called, functional uncoupling).  These transformations in β adrenergic signaling explicitly disturb ability of the heart to increase its contractility to meet the hemodynamic needs.  Application of the β1 blockers establishes a beneficial balance in so called cross-talk of the β1 and β2 receptor molecules, as proved in many studies [12-16].  The primary aims of the large studies as the total or cardiovascular mortality, cardiovascular morbidity or hospitalisation due to CHF progression and combined cases, have proved as acceptable clinical indicators of survival rate.  More than 90% of the patients who were treated by β blockers, from the studies performed so far, had been previously treated by ACE inhibitor and diuretic [17, 18].  Reports from all finished studies confirm that β blockers significantly reduce mortality and morbidity.  Results of our study are just another contribution to the previous studies.  The most recent meta-analysis of the β blockers in CHF, published in 2000, includes 22 randomised, placebo-controlled studies, comprising more than 10,000 patients.  The authors have concluded that treatment by β blockers reduces occurrence of combined case (the total mortality and hospitalisation due to CHF) by almost a 100% among the patients of NYHA class II and III.  What practically means 3.8 saved lives out of 100 treated patients.  At the same time β blockers reduce number of hospitalisations by four out of a 100 treated patients [1, 19].  The main question is do different β blockers have a significantly different effect on the CHF patient’s survival rate.

Results from the biggest comparative study (COMET) as well as the other smaller studies show that carvedilol has a more favorable effect on the survival rate than metoprolol.  Number of death outcomes by all causes in the COMET study was significantly lower among the carvedilol patients group (34%) compared to the metoprolol group (40%), but numbers of the combined cases (death and hospital treatments regardless of its grounds) were not significantly different between patients treated by carvedilol (74%) and metoprolol (76%) [9].  The assumption that carvedilol’s ”advantage” over metoprolol lies ”outside” β1 blockade was disturbed by the observation that extent of β1 blockade by metoprolol (tartrate formulation, average daily dose 85 mg) in the COMET study was significantly lower than in the previous studies in which patients were treated by metoprolol.  This observation impels carefulness while estimating some β blockers’ ”advantage” and opens a question about dosage and formulation of the medicine in other comparative studies, regardless of applied β blocker [20].

In our study we compared the effects of metoprolol-tartrate, a β1 blocker, with another β1 blocker – atenolol.  This way we observed the effects of adrenoreceptor antagonists on combined case only within the β1 blockade.  The both β1 blockers showed positive effect on the clinical development and outcome of CHF among the patients from the control group.  While the effect of metoprolol (tartrate formulation, average daily dose 65.50±20 mg) was significantly better compared to atenolol’s effect (average daily dose 50±12.25 mg).  It is possible that reasons for the variance could be connected to the different moduling of β adrenergic signaling.  Namely, metoprolol has dominant β1 receptor activity and proved ability to recover the number and sensitivity of β1 adrenoreceptors [12].  Regardless of the negative inotropic effect, metoprolol in some way makes the β2 receptors sensible, redirects adrenergic signaling towards the β2 receptors, normalises the β-ARK and Gi activity and puts into balance the receptorial stimulation and inhibition of myocytes [1, 12, 21, 22].  Atenolol normalises β1 adrenergic signaling as well.  But the β1 and β2 receptorial activities ratio is much greater.  The expected result of such receptorial activity could be symptomatic bradycardia or symptomatic deterioration of CHF i.e. reduced drug tolerance.  Which mechanisms initiate the favorable and which initiate the unfavorable occurrences during the β1 blockade is not clear yet [1, 21, 22].  Metoprolol tartrate, unlike atenolol, is liposoluble i.e. can easily pass emato-encefalic barrier.  It has been proved that its primarily effect can prevent occurrence of lethal arrhythmia [23].  All the stated influences that metoprolol has on adrenergic signaling can – to some extend – explain the better tolerance and more favorable effects of metoprolol on the survival rate of patients with mild-to-moderate CHF, compared to atenolol, even though the molecular mechanisms that lie as a ground for the different effects of these β blockers of the same generation, are for the time being not sufficiently investigated.


In patients with chronic heart failure NYHA functional class II and III of different etiologies, previously treated by ACE inhibitors and diuretics, both of the β1 blockers (metoprolol-tartrate and atenolol) reduce the total mortality and cardiovascular morbidity compared to the control group of patients, while the metoprolol’s effect on the survival rate is significantly better and the application safer compared to the effect and application of atenolol.


1. Hermann DD. Beta-adrenergic blockade 2002: A pharmacologic

odyssey in chronic heart failure. CHF 2002; 8(5):262-9.

2. Bristow MR. Why does the myocardium fail? Insights from basic

science. Lancet 1998; 352(Suppl I):8-14.

3. SOLVD Investigators. Effect of enalapril on survival in patients

with reduced left ventricular ejection fraction and congestive heart

failure. N Engl J Med 1991; 325:293-302.

4. CONSENSUS Trial Study Group. Effects of enalapril on mortality

in severe congestive heart failure: results of the Cooperative North

Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J

Med 1987; 316(23):1429-35.

5. MetraM, Nodari S, D’AloiaA, et al. A rationale for the use of betablockers

as standard treatment for heart failure. Am Heart J 2000;


6. The Task Force for the Diagnosis and Treatment of Chronic Heart

Failure, European Society of Cardiology. Guidelines for the diagnosis

and treatment of chronic heart failure. Eur Heart J 2001;


7. Adams KF.Which beta blocker for heart failure? Am Heart J 2001;


8. Bristow MR.What type of beta blocker should be used to treat

chronic heart failure. Circulation 2000; 102:484-6.

9. Poole-Wilson PA, Swedberg K, Cleland JG, et al. Comparison of

carvedilol and metoprolol on clinical outcomes in patients with

chronic heart failure in the Carvedilol Or Metoprolol European

Trial (COMET): randomised controlled trial. Lancet 2003;


10. Metra M, Giubbini R, Nodari S, et al. Differential effects of betablockers

in patients with heart failure: a prospective, randomized,

double-blind comparison of the long-term effects of metoprolol

versus carvedilol. Circulation 2000; 102:546-51.

11. Shiller N, Shah PM, Crawford M, et al. Recommendations for

quantitation of the left ventricle by two dimensional echocardiography.

J Am Soc Echocardiography 1989; 2:358-68.

12. Brodde OE, Michel MC. Adrenergic and muscarinic receptors in

the human heart. Pharmacological Reviews 1999; 51(4):651-90.

13. Remme WJ. The sympatetic nervous system and ischaemic heart

disease. Eur Heart J 1998; 19(Suppl F):F62-F71.

14. Ceconi C, Curello S, Ferrari R. The neuroendocrine and sympathetic

nervous systemin congestive heart failure. Eur Heart J 1998;

19(Suppl F):F45-F51.

15. Liggett SB. β-adrenergic receptors in the failing heart: the good, the

bad, and the unknown. J Clin Invest 2001; 8:947-8.

16. Houser SR, Margulies KB. Is depresed myocyte contractility centrally

involved in heart failure? Circ Res 2003; 92:350-8.

17. Eichhorn EJ. Experience with beta blockers in heart failure mortality

trials. Clin Cardiol 1999; 22:(Suppl V):V21-V29.

18. Lechat P, Packer M, Chalon S, et al. A meta-analysis of doubleblind,

placebo-controlled, randomized trials. Circulation 1998;


19. Brophy JM, Joseph L, Ruleau JL. Beta blockers in congestive heart

failure. A Bayesian meta-analysis. Ann Intern Med 2001;


20. Dogrell SA. Has COMET solved the controversy as to whether

carvedilol is better than metoprolol in heart failure. Expert Opinion

on Pharmacotherapy 2004; 5(1):205-8.

21. BristowMR.Mechanismof action of beta-blocking agents in heart

failure. Am J Cardiol 1997; 80:26L-40L.

22. Sabbah HN. The celluar and physiologic effects of beta blockers in

heart failure. Clin Cardiol 1999; 22(Suppl V):V16-V20.

23. Hjalmarson A. Prevention of sudden cardiac death with beta

blockers. Clin Cardiol1999; 22(Supll V):V11-V15.

Bengt Åblad comment:  This interesting paper contains three tables and one figure ( see below).

Etiketter: , ,

36 svar to “Metoprolol better than atenolol in therapy of cardiac failure! Role of peripheral NPY!?”

  1. google keyword report Says:

    Hey! I know this is kinda off topic but I’d figured I’d ask.
    Would you be interested in trading links or maybe guest authoring a
    blog post or vice-versa? My blog covers a lot of
    the same subjects as yours and I believe we could greatly
    benefit from each other. If you might be interested feel free to send me an
    email. I look forward to hearing from you! Terrific blog by the way!

  2. Dewey Says:

    Fabulous, what a webpage it is! This weblog presents
    helpful data to us, keep it up.

  3. Zara Says:

    Attractive element of content. I just stumbled upon your blog and in accession capital to claim that I acquire actually
    enjoyed account your blog posts. Anyway I will be subscribing in your augment or even I success you get right
    of entry to constantly quickly.

  4. bancuri cu alinuta Says:

    Hello, this weekend is nice designed for me, as this time i am reading this impressive informative paragraph here
    at my house.

  5. Devin Says:

    Heya i am for the first time here. I found this board and I in finding It truly useful & it helped me out a lot.

    I’m hoping to offer something again and aid others like you aided me.

  6. shingles treatment medication acyclovir Says:

    Unquestionably imagine that that you stated. Your
    favorite reason appeared to be on the internet the simplest thing to understand of.
    I say to you, I certainly get annoyed while other folks think about issues that they just don’t realize about. You controlled to hit the nail upon the top as neatly as outlined out the entire thing with no need side effect , other folks can take a signal. Will probably be again to get more. Thanks

  7. webpage Says:

    Definitely believe that which you said. Your favorite
    reason appeared to be on the internet the simplest
    thing to be aware of. I say to you, I definitely get irked while people think about worries that they just do
    not know about. You managed to hit the nail upon the top and also defined out the whole thing without having side-effects , people
    can take a signal. Will likely be back to get more. Thanks

  8. Says:

    Howdy! Quick question that’s completely off topic. Do you know how to make your site mobile friendly? My weblog looks weird when browsing from my apple iphone. I’m trying to find
    a theme or plugin that might be able to fix this problem.

    If you have any recommendations, please share. With thanks!

  9. the diet solution Says:

    If some one wants expert view concerning blogging afterward i advise him/her to go to see
    this weblog, Keep up the fastidious work.

  10. Alejandra Says:

    It’s an remarkable article in favor of all the web visitors; they will obtain benefit from it I am sure.

  11. Says:

    Useful information. Lucky me I discovered your web site accidentally, and I am stunned why this twist of fate
    did not happened in advance! I bookmarked it.

  12. anxiety disorder Says:

    Hi there to every one, the contents existing at this web site
    are truly awesome for people experience, well, keep up
    the nice work fellows.

  13. pompy głębinowe Says:

    I enjoy what you guys are up too. This kind of clever work and reporting!
    Keep up the terrific works guys I’ve added you guys to my own blogroll.

  14. american heart association Says:

    If you desire to grow your knowledge just keep visiting this site and be updated with the hottest gossip posted here.

  15. Get More Leads Says:

    Pretty section of content. I just stumbled upon your site and
    in accession capital to assert that I get
    in fact enjoyed account your blog posts. Any way I’ll be subscribing to your augment and even I achievement you access consistently quickly.

  16. keyword research Says:

    Admiring the commitment you put into your site
    and in depth information you offer. It’s good to come across a blog every once in a while that isn’t the same unwanted rehashed information.
    Excellent read! I’ve bookmarked your site and I’m adding your RSS feeds to my Google account.

  17. Says:

    Great post. I was checking continuously this blog
    and I am impressed! Very useful information specially the last part :) I care
    for such info a lot. I was looking for this particular info for a long time.
    Thank you and good luck.

  18. Ross Says:

    Hey, I think your blog might be having browser compatibility issues.

    When I look at your blog in Chrome, it looks fine
    but when opening in Internet Explorer, it has some overlapping.
    I just wanted to give you a quick heads up! Other then that, very good blog!

  19. Where to buy Garcinia Cambogia Says:

    Heya i am for the first time here. I came across this board and I find
    It really useful & it helped me out a lot. I hope to give something back and help others like you helped me.

  20. red cedar properties Says:

    My pal advised I could such as this web site. Your dog has been totally proper. This kind of submit basically built my personal time. You cannot envision the amount of time I needed invested with this information and facts! Thanks a lot!

  21. more information Says:

    Typically I really don’t understand posting on sites, having said that i want to express that this kind of write-up quite forced my family to think about as well as achieve this! A person’s publishing preference continues to be stunned my family. Appreciate it, pretty good post.

  22. Actos settlement class action Says:

    Wonderful website. A lot of useful information here. I’m sending it to some pals ans additionally sharing in delicious.
    And certainly, thanks to your effort!

  23. Ckassroom Decorations Says:

    Hello, i think that i saw you visited my website thus i came to “return the favor”.I am attempting to find things to improve my website!I suppose its ok to use
    a few of your ideas!!

  24. Emilio Says:

    It’s an amazing article designed for all the online people; they will take advantage
    from it I am sure.

  25. mischa barton cellulite Says:

    I could nnot resist commenting. Verry well written that I read this evening and I do love it.
    But also, in my view,I think you could write it better if you can add more pictures at beginning.
    At this moment I am ready to do my breakfast, afterward having my breakfast coming yet again too read further news.

  26. gerd diets Says:

    Awesome! Its genuinely awesome piece of writing,
    I have got much clear idea about from this paragraph.

  27. Sung Says:

    Good information. Lucky me I found your blog by accident
    (stumbleupon). I have saved as a favorite for later!

  28. Says:

    Excellent post. I was checking continuously this
    blog and I am impressed! Very useful info particularly the last part :) I care for such information a lot.
    I was looking for this certain info for a long time.
    Thank you and best of luck.

  29. experience Says:

    Very great post. I just stumbled upon your blog and wanted to mention that I have truly enjoyed surfing around your weblog posts.
    After all I will be subscribing on your feed and I’m hoping
    you write again soon!

  30. Startup Videos Says:

    Thanks for ones marvelous posting! I quite enjoyed reading it, you can be a great author.I will
    make sure to bookmark your blog and may come back down
    the road. I want to encourage you to definitely continue your great
    job, have a nice holiday weekend!

  31. garis panduan tender Says:

    I have learn some excellent stuff here. Definitely value bookmarking for revisiting.
    I wonder how much effort you set to create the sort of fantastic informative site.

  32. making Says:

    Hi there! I simply want to offer you a huge thumbs up for your great info you’ve got right here on this
    post. I will be coming back to your blog for more soon.

  33. Prix vérandas 20m543 à Moriviller - 54830 - Dép. Meurthe-et-Moselle Says:

    Hi there! I could have sworn I’ve been to this website before but after checking through some of the post
    I realized it’s new to me. Anyhow, I’m definitely delighted I found it
    and I’ll be book-marking and checking back frequently!

  34. pay per download Says:

    Hi there, just wanted to tell you, I loved this article.

    It was helpful. Keep on posting!

  35. Says:

    Great website. A lot of helpful info here. I’m sending it to some
    pals ans also sharing in delicious. And obviously, thanks in your effort!


Fyll i dina uppgifter nedan eller klicka på en ikon för att logga in: Logo

Du kommenterar med ditt Logga ut / Ändra )


Du kommenterar med ditt Twitter-konto. Logga ut / Ändra )


Du kommenterar med ditt Facebook-konto. Logga ut / Ändra )

Google+ photo

Du kommenterar med ditt Google+-konto. Logga ut / Ändra )

Ansluter till %s


Få meddelanden om nya inlägg via e-post.

%d bloggers like this: