Skip Navigation

European Journal of Heart Failure 2007 9(11):1128-1135; doi:10.1016/j.ejheart.2007.07.014
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Remme, W. J.
Right arrow Articles by Swedberg, K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Remme, W. J.
Right arrow Articles by Swedberg, K.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 2007 European Society of Cardiology

Effect of carvedilol and metoprolol on the mode of death in patients with heart failure

Willem J. Remmea,*, John G. Clelandb, Leif Erhardtc, Phillip Sparkd, Christian Torp-Pedersene, Marco Metraf, Michel Komajdag, Christine Moulleth, Mary Ann Lukasi, Philip Poole-Wilsonj, Andrea Di Lenardak and Karl Swedbergl

a Sticares Cardiovascular Research Foundation P.O. Box 882, 3160 AB Rhoon, The Netherlands
b Department of Cardiology, Castle Hill Hospital, University of Hull Kingston upon Hull, UK
c Cardiology Research Unit, University Hospital MAS Malmö, Sweden
d Nottingham Clinical Research Group Nottingham, UK
e Department of Cardiology, Bispebjerg University Hospital Copenhagen, Denmark
f Department of Cardiology, University of Brescia Brescia, Italy
g Department of Cardiology, CHU Pitié-Salpétrière Paris, France
h F. Hoffmann-LaRoche, Basel, Switzerland
i GlaxoSmithKline, Philadelphia, Pennsylvania, USA
j Department of Cardiac Medicine, National Heart & Lung Institute London, UK
k University of Trieste Trieste, Italy
l Sahlgrenska Hospital Gothenburg, Sweden

* Corresponding author. Tel.: #x002B;31 10 485 51 77; fax: +31 10 485 48 33. E-mail address:w.j.remme{at}sticares.org


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 A.1. Sudden death
 A.2. Circulatory failure
 A.3. Stroke death
 A.4. Other cardiovascular death
 A.5. Non-cardiovascular death
 References
 
Background: In the COMET study, carvedilol improved survival compared to metoprolol tartrate in 3029 patients with NYHA II–IV heart failure and EF <35%, followed for an average of 58months.

Aims: To evaluate whether the effect on overall mortality was specific for a particular mode of death. This may help to identify the mechanism of the observed difference.

Methods: Of the 1112 total deaths, 972 were adjudicated as cardiovascular, including 480 sudden, 365 circulatory failure (CF) and 51 stroke deaths. For each mode of death, the effect of pre-specified baseline variables was assessed, including sex, age, NYHA class, aetiology, heart rate, systolic blood pressure, EF, atrial fibrillation, previous myocardial infarction or hypertension, renal function, concomitant medication, and study treatment allocation.

Results: In multivariate Cox regression analyses, compared to metoprolol, carvedilol reduced cardiovascular (RR 0.80, CI 0.7–0.91, p=0.0009), sudden (RR 0.77, CI 0.64–0.93, p=0.0073) and stroke deaths (RR 0.37, CI 0.19–0.71, p=0.0027) with a non-significant trend for CF death (RR 0.83, CI 0.66–1.04, p=0.07). Treatment benefit with carvedilol did not differ between modes of death, except for a greater reduction in stroke death with carvedilol (competing risk analysis, p=0.0071 vs CF death). There were no interactions between treatment allocation and baseline characteristics.

Conclusion: Mortality reduction with carvedilol compared to metoprolol appears relatively non-specific and could be consistent with a superior effect of carvedilol on cardiac function, arrhythmias or, in view of the greater reduction in stroke deaths, on vascular events.

Key Words: Heart failure • β-blockade • Cardiovascular mortality • Sudden death • Stroke death • Circulatory failure death

Received December 19, 2006; Revised June 21, 2007; Accepted July 24, 2007


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 A.1. Sudden death
 A.2. Circulatory failure
 A.3. Stroke death
 A.4. Other cardiovascular death
 A.5. Non-cardiovascular death
 References
 
Beta-blockers improve survival and symptoms of patients with chronic heart failure due to left ventricular dysfunction [1-5]. Benefits have been shown for different beta-blocking drugs, including the beta-1 selective agents, metoprolol, bisoprolol and nebivolol, and the non-selective beta- and alpha-1 antagonist, carvedilol. In addition to comprehensive adrenergic blockade, carvedilol has anti-oxidant effects, anti-arrhythmic properties, a possible effect on plasma potassium and stimulates alternative signalling pathways linked to the beta-2 receptor.

The COMET study showed that carvedilol reduced mortality compared to metoprolol tartrate in patients with mild-moderate heart failure and left ventricular systolic dysfunction [6]. The mechanism for the observed difference is unclear. No data on long-term ventricular function or arrhythmia monitoring were collected. Mode of death could provide some clues to the mechanism for the observed difference. A predominant effect on worsening heart failure might suggest a greater effect on cardiac function. A reduction in sudden death might suggest an effect on arrhythmias or vascular events. Although there were fewer deaths on carvedilol compared to metoprolol tartrate, over one third of patients on carvedilol died over the 5 year follow-up. Identification of the mode of death in these patients might help determine what additional therapies might improve longevity.

Here we report the effects of carvedilol and metoprolol tartrate on mode of death in COMET, and the possible interaction of pre-specified subgroup characteristics at baseline.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 A.1. Sudden death
 A.2. Circulatory failure
 A.3. Stroke death
 A.4. Other cardiovascular death
 A.5. Non-cardiovascular death
 References
 
The COMET study was a randomised, double-blind comparison of carvedilol and metoprolol tartrate, during an average 58 month follow-up period, in 3029 patients with chronic symptomatic heart failure and systolic left ventricular dysfunction. The study design, rationale and inclusion criteria have been published in detail [7].

In summary, patients with stable heart failure, in NYHA class II-IV, with a left ventricular ejection fraction =35%, treated with ACE inhibitors and diuretics, who had been hospitalized for cardiovascular reasons during the preceding year and who were eligible for treatment with beta-blockers were enrolled. Patients were excluded if they had recent (<2 months) unstable angina, myocardial infarction, coronary revascularization or stroke, symptomatic or sustained persisting ventricular arrhythmias despite anti-arrhythmic drug therapy, implantation of an ICD, uncontrolled hypertension or haemodynamically significant valvular disease.

Patients were also excluded if there was a contra-indication to the use of a beta-blocker or a change in therapy within the last 2 weeks.

2.1. Trial and adjudication procedures
At randomization, patients were assigned blindly to carvedilol 3.125 mg BID or to metoprolol tartrate, 5 mg BID. The dose of each beta-blocker was doubled at 2 weekly intervals until the target dose of 25 mg carvedilol, twice daily, or 50 mg metoprolol, twice daily, was reached. The investigator was free to change the dose throughout the study if there were side effects.

All deaths were adjudicated by an events committee consisting of 3 persons (JGFC, LE, WJR), blinded to study drug allocation. Every death was adjudicated by 2 members of the committee, based on information contained in the CRF. When two reviewers disagreed, the case was considered by the full committee. Where necessary, further documentation was sought from the investigator. Deaths were first classified as cardiovascular, non-cardiovascular or as unable to assign a cause. Cardiovascular deaths were subsequently classified as sudden death, death due to circulatory failure, stroke death and death due to other cardiovascular reasons. The respective definitions are provided in Appendix 1. Myocardial infarction was considered an event preceding death rather than as a mode of death and had to be documented by ECG, biochemical markers or autopsy evidence.

2.2. Events preceding death
The CRF required the investigator to note specific events which preceded death. These included: worsening of HF, chest pain, stroke, myocardial infarction, syncope or arrhythmias. The CRF also required information on whether the death was witnessed, occurred during sleep, routine activities or heavy exertion, whether the patient died in hospital and information on the last known NYHA class. The definition of witnessed death included cases where the patient's death was directly observed or occurred in close proximity to another person. Patients who were found dead in bed by their spouse or died, for instance, in the bathroom when their spouse was in another room were counted as witnessed.

2.3. Statistical analyses
The study was event driven, to be stopped when 1020 deaths had occurred. Details on power calculation and the statistical analyses of the two co-primary endpoints, all-cause mortality and the combination of all-cause mortality and all-cause hospitalization have been published [7].

Differences between the treatment groups were assessed using Cox proportional hazard models. All analyses presented here are based on the intention to treat principle. All patients were followed until the end of the study irrespective of whether blinded study treatment was continued or not. Patients who withdrew consent or were lost to follow-up were censored on the day of last contact or day of withdrawal of consent. Patients undergoing heart transplantation were not censored and continued in the study.

To assess whether treatment affected the 5 modes of death differently, we fitted a competing risks Cox regression analysis [8] and assessed the magnitude of the treatment by mode of death interaction. If evidence of an interaction existed, we assessed the pair-wise comparisons between the various modes of death using the parameter estimates from the fitted model.

For each mode of death, exploratory analyses comparing the effect of carvedilol and metoprolol in pre-specified subgroups were carried out.

Subgroups were defined by the following baseline variables: sex, age, NYHA class, ischaemic aetiology, heart rate, systolic blood pressure, LV ejection fraction, idiopathic dilated cardiomyopathy, Body Mass Index, diabetes mellitus, atrial fibrillation, previous myocardial infarction, a history of hypertension, haemoglobin, serum creatinine, serum sodium, use of ACE inhibitors, spironolactone, digitalis glycosides, aspirin, anticoagulant therapy and statins.

Cox regression analysis was used to assess any interactions for each mode of death between randomised therapy and the subgroups. Events preceding death were analysed for each mode of death using chi-squared tests. In order to assess the impact of baseline characteristics on our conclusions, we developed a multivariate model for all cause mortality using bootstrap methods. Two forms of internal validation were undertaken. In the first part of the validation, 200 samples of 3029 patients (sampling with replacement) were taken and a backwards stepwise procedure was run on each sample. For each sample, the variables selected were recorded. Variables appearing in 70% or more of all models are included in our final multivariate model. In the second internal validation step, the bootstrap was used to assess the parameter estimation. Two hundred bootstrap samples were created, and, for each of the samples, the model was refit and the regression parameters and risk ratios were estimated. The sample mean and SD of the 200 risk ratios for each parameter were computed and used to formulate confidence intervals about the risk ratio. These estimates were compared with those quantities obtained in the final Cox model. Our estimates are a good representation of the true effect size.

Baseline characteristics of patients dying a specific death (regardless of treatment allocation) were compared to all other deaths using t-tests for continuous variables and the chi-squared test for categorical data.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 A.1. Sudden death
 A.2. Circulatory failure
 A.3. Stroke death
 A.4. Other cardiovascular death
 A.5. Non-cardiovascular death
 References
 
Of the 1511 patients randomised to carvedilol and the 1518 patients randomised to metoprolol, 512 and 600 respectively, died (hazard ratio [HR] 0.83, 95% confidence intervals ([CI] 0.74-0.93, p=0.0017). Of these deaths, 74 in patients assigned to carvedilol and 66 in those assigned to metoprolol were attributed to a non-cardiovascular cause, approximately 50% of which in each group were due to cancer (Table 1). Carvedilol reduced the risk of cardiovascular death, with 438 patients dying in the carvedilol group vs 534 patients on metoprolol (HR 0.80, CI 0.70-0.90, p=0.0004). Sudden death occurred in 218 patients (14.4%) assigned to carvedilol and in 262 (17.3%) assigned to metoprolol (HR 0.81, CI 0.68-0.97, p=0.0216), death due to circulatory failure in 168 patients (11.1%) assigned to carvedilol vs 197 (13%) assigned to metoprolol (HR 0.83, CI 0.67-1.02, p=0.0702) and death due to stroke in 13 patients assigned to carvedilol compared to 38 assigned to metoprolol (HR 0.33, CI 0.18-0.62, p=0.0006). Few patients died of other CV causes, 19 assigned to carvedilol and 26 assigned to metoprolol (HR 0.71, CI 0.39-1.29, p=0.261). Kaplan Meier plots of time to cardiovascular death, sudden death, death due to circulatory failure and stroke death indicate that the curves widened over time, indicating that the better effect of carvedilol as compared to metoprolol on these modes of death was constant over time. (Fig. 1). No definite cause could be assigned to 20 deaths amongst those assigned to carvedilol and 11 assigned to metoprolol.


View this table:
[in this window]
[in a new window]

  		Table 1 Distribution of non-cardiovascular deaths by treatment group

 


Figure 01
View larger version (19K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Kaplan Meier estimates for all-cause mortality, cardiovascular death, sudden death, death due to worsening heart failure (circulatory failure death), stroke death and death due to other cardiovascular causes.

 
In multivariate Cox regression analyses, compared to metoprolol, carvedilol reduced all-cause mortality (RR 0.80, 95% CI 0.71-0.91, p=0.0007), cardiovascular mortality (RR 0.80, CI 0.70-0.91, p=0.0009), sudden death (RR 0.77, CI 0.64-0.93, p=0.0073) and stroke death (RR 0.37, CI 0.19-0.71, p=0.0027). Only a non-significant trend was observed for death due to worsening heart failure (RR 0.83, CI 0.66-1.04, p=0.0702).

3.1. Competing risks analysis
The competing risks Cox regression analysis for mode of death is presented in Table 2. There is strong evidence (p=0.0086) that the impact of treatment with carvedilol compared to metoprolol differed for the modes of death. For the reference mode of death in this table, circulatory failure, the difference between carvedilol and metoprolol was similar to that seen for the study as a whole (RR=0.83). The relative reduction in sudden and other causes of cardiovascular death was similar to the effect on circulatory failure death. However, there was evidence for a greater effect on stroke death than of death due to circulatory failure (RR=0.40, p=0.0071). For unknown mode of death and non-cardiovascular death there was no evidence of a treatment benefit of carvedilol.


View this table:
[in this window]
[in a new window]

  		Table 2 Competing risks analysis of mode of death

 
3.2. Subgroup analysis
Baseline characteristics in patients who died were generally similar between the treatment groups; however, patients who died from stroke in the metoprolol group were older than those in the carvedilol group (71 vs 66 years, respectively).

There were no differences between unadjusted relative risk reductions or when adjusted for those parameters which were important in the bootstrap models (Fig. 2).


Figure 02
View larger version (13K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2 Relative risks of the different modes of death, unadjusted (solid line) and adjusted for parameters important in the bootstrap models (dotted line).

 
In univariate analyses, carvedilol consistently reduced total and cardiovascular mortality, sudden death and stroke death more than metoprolol in all pre-defined subgroups. Hazard ratios for total deaths varied between 0.81 and 0.85, for cardiovascular deaths between 0.78 and 0.81, for sudden death between 0.78 and 0.82 and for stroke deaths between 0.31 and 0.35 (Fig. 3). In contrast, the trend for carvedilol to reduce deaths due to worsening heart failure was not statistically significant overall, including most subgroups.


Figure 03
View larger version (16K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 3 Hazard ratios of cardiovascular death, sudden death, worsening HF (circulatory failure) death and stroke death by pre-specified subgroups. There is a consistent benefit of carvedilol treatment irrespective of baseline parameters.

 
3.3. Events preceding death
Events preceding death, regardless of treatment allocation are presented in Table 3. Approximately half of the sudden deaths were witnessed and occurred in 58% during routine activities, in 40% while sleeping and in only 2% during heavy exertion. There were few premonitory symptoms or events amongst patients who died suddenly and most patients were reported to be in NYHA class II or III prior to death (Fig. 4). In contrast, patients dying from circulatory failure were, as expected, reported to be predominantly in NYHA class IV (74%) and to have preceding worsening of heart failure. The pattern was similar in the two treatment groups.


View this table:
[in this window]
[in a new window]

  		Table 3 Specific events reported by investigators which preceded deatha

 


Figure 04
View larger version (7K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 4 Percentage distribution of different modes of cardiovascular death: sudden death, circulatory failure death and stroke death in NYHA I-II, III and IV heart failure, respectively. Sudden death predominates in NYHA class I-II and class III (85% and 68%, respectively), whereas circulatory failure death is the leading mode of death in severe heart failure, NYHA IV (85% of deaths).

 
Amongst patients assigned to carvedilol, 222 (46.3%) deaths were out of hospital and 258 (53.7%) were in the hospital. Respective data for metoprolol were 283 (48.8%) out of hospital and 297 (51.2%) deaths in hospital. The location of death was unknown for 32 deaths in patients assigned to carvedilol and 20 deaths in patients assigned to metoprolol.

230 patients were withdrawn from carvedilol prior to death, 201 (87.4%) >30 days and 18 (7.8%) 7-30 days prior to death. Respective data for metoprolol were 256 patients, 206 (80.5%) >30 days and 28 (10.9%) 7-30 days prior to death.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
A.1. Sudden death
 A.2. Circulatory failure
 A.3. Stroke death
 A.4. Other cardiovascular death
 A.5. Non-cardiovascular death
 References
 
This analysis suggests that the greater reduction in overall mortality with carvedilol compared to metoprolol cannot be explained by a reduction in any single mode of death. The greater reductions in mortality with carvedilol were significant and robust for all-cause, all cardiovascular, sudden and stroke death, whereas the difference in effect on death for circulatory failure bordered on significance. However, the relative differences in sudden deaths and circulatory failure deaths appeared similar. The differences in effects occurred early, except for death due to worsening heart failure and were constant over time. Differences were consistent for all pre-specified subgroups.

A consistent better survival effect of carvedilol was found overall. The effect difference between carvedilol and metoprolol with respect to circulatory death was similar to that observed for the study as a whole, as shown in the competing risks analysis, and the relative risks reductions with carvedilol on sudden and other cardiovascular death did not differ from this effect. However, the risk reduction in stroke death was significantly greater in patients treated with carvedilol than with metoprolol. This observation may provide some support for a reduction in vascular events as a reason for the observed difference in mortality [9].

The superior effect of carvedilol on mortality in COMET was due entirely to a reduction in cardiovascular deaths. About half of all cardiovascular deaths were sudden, over 80% occurring out of hospital, and accounting for about 50% of the treatment effect of carvedilol. About 40% of deaths were from circulatory failure, over 80% occurring in-hospital, and <10% due to stroke but each accounted for about 25% of the treatment effect of carvedilol. These data show that out of hospital sudden death remains the single most common mode of death in patients with mild to moderate heart failure. It is not clear what proportion of these were due to primary arrhythmias or due to vascular events with or without secondary arrhythmias.

Patients assigned to carvedilol had a lower risk of vascular events including myocardial infarction, unstable angina and stroke [9]. Other studies have reported a greater improvement in ventricular function with carvedilol compared to metoprolol [10-12], which could have reduced the risk of sudden death and account for the trend to fewer deaths from worsening heart failure. The comprehensive adrenergic blockade of carvedilol leads to a greater sympatho-inhibitory effect than metoprolol [13-15] and may better improve cardiac function and prevent disease progression and death than β-1 blockade alone. Moreover, carvedilol, but not metoprolol leads to persistent beta-blockade beyond its plasma elimination, due to binding to an allosteric site of human β-adrenoceptors with slower kinetics [16]. Blockade of beta-2 receptors might reduce arrhythmias by preventing hypokalaemia during periods of sympathetic activation and, possibly, may prevent apoptosis by altering signal transduction through the beta-2 receptor blockade of alpha-adrenergic receptors and the anti-oxidant and anti-endothelin effects of carvedilol could also play a role in improving ventricular function, reducing arrhythmias or both. A reduction of ventricular arrhythmias has been reported in heart failure patients who switched from metoprolol to carvedilol as compared to those who stayed on metoprolol [17]. Also, carvedilol may normalize QT variability in heart failure patients to a greater extent than metoprolol [18].

The greater improvement in ventricular function with carvedilol than metoprolol reported in previous studies [10-12] should translate into a greater reduction in progressive heart failure and less death due to worsening heart failure in patients treated with carvedilol in COMET. While there was a trend in this direction, there was no significant difference (p=0.0702). Although speculative, this may have been a question of time, as suggested by the late divergence of the Kaplan-Meier curves for death due to worsening heart failure.

When considering events preceding death, a picture arises that is consistent with specific modes of death in the overall patient population. Thus, progressive heart failure precedes death due to worsening heart failure and stroke precedes deaths due to stroke. Such deaths are likely to be well documented in hospital and occur during sleep or, at least, lack of consciousness. Sudden deaths are generally poorly documented, occur outside hospital, are often not witnessed, and occur most often during routine activities rather than heavy exertion. Sudden deaths are often classified as such because of circumstantial rather than direct evidence. Arrhythmias, syncope or myocardial infarction preceding death were reported in relatively few cases in patients dying with each mode of death, but were rarely reported for out of hospital deaths, most of which were classified as sudden. Clinically unrecognized acute coronary findings have been reported at autopsy in heart failure patients dying suddenly [19]. Among patients who died, the pattern of preceding events was not different between carvedilol and metoprolol.

The consistently better effect of carvedilol on the different modes of death compared to metoprolol are well explained by the different pharmacological profiles described above, and are in our view not the result of formulation and/or dose, and hence, possible different levels of beta-1 blockade by carvedilol and metoprolol in COMET. The small differences in heart rate after 4 months therapy between the two drugs are unlikely to explain the difference in effect [6,20]. Moreover, a recent analysis indicated that the difference in mortality, observed between carvedilol and metoprolol tartrate in COMET is independent of heart rate at 4 months or changes herein from baseline [21]. Also, in this analysis no interaction was observed between different achieved dosages of metoprolol and carvedilol and the beneficial effects of carvedilol.

In conclusion, this analysis suggests that the greater reduction in mortality with carvedilol compared to metoprolol was due to cardiovascular causes, but otherwise relatively non-specific. Numerically, the greatest effect was in reducing sudden death, but with a large relative reduction in deaths attributed to stroke. The observed differences in mortality could reflect a greater effect of carvedilol on vascular events compared to metoprolol, but might also be explained by differences in effect on arrhythmias and ventricular function.


   A.1. Sudden death
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 A.1. Sudden death
A.2. Circulatory failure
 A.3. Stroke death
 A.4. Other cardiovascular death
 A.5. Non-cardiovascular death
 References
 

  1. witnessed death in the absence of pre-existing circulatory failure (see below) or other modes of death, or
  2. unwitnessed death in the absence of pre-existing circulatory failure or other modes of death, or
  3. patients resuscitated from a cardiac arrest in the absence of pre-existing circulatory failure or other modes of death and who die within 24 h or similar patients who die during an attempted resuscitation


   A.2. Circulatory failure
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 A.1. Sudden death
 A.2. Circulatory failure
A.3. Stroke death
 A.4. Other cardiovascular death
 A.5. Non-cardiovascular death
 References
 
The presence at the time of death of at least one of the following:

  1. cardiogenic shock (that is hypotension for >15 min resulting in a failure to maintain normal renal or cerebral function prior to death), or
  2. pulmonary oedema sufficient to cause tachypnoea and distress, or
  3. heart failure symptoms or signs requiring continuous intravenous therapy or oxygen administration, or
  4. confinement to bed but only if confinement is due to heart failure symptoms


   A.3. Stroke death
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 A.1. Sudden death
 A.2. Circulatory failure
 A.3. Stroke death
A.4. Other cardiovascular death
 A.5. Non-cardiovascular death
 References
 

  1. the rapid onset of localizing neurological symptoms or signs leading to death, or
  2. sudden loss of consciousness without circulatory failure leading to death and no other reason for loss of consciousness identified


   A.4. Other cardiovascular death
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 A.1. Sudden death
 A.2. Circulatory failure
 A.3. Stroke death
 A.4. Other cardiovascular death
A.5. Non-cardiovascular death
 References
 
Other cardiovascular death including, but not limited to, peri-operative death, mesenteric infarction, peripheral vascular occlusion, etc.


   A.5. Non-cardiovascular death
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 A.1. Sudden death
 A.2. Circulatory failure
 A.3. Stroke death
 A.4. Other cardiovascular death
 A.5. Non-cardiovascular death
References
 
Non-cardiovascular death including, but not limited to, death due to infection, cancer, etc.


   Acknowledgements
 
COMET was supported by F. Hoffmann La Roche and GlaxoSmithKline.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 A.1. Sudden death
 A.2. Circulatory failure
 A.3. Stroke death
 A.4. Other cardiovascular death
 A.5. Non-cardiovascular death
 References
 

  1. CIBIS II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS II): a randomised trial. Lancet (1999) 353:9–13.[CrossRef][Web of Science][Medline]
  2. Packer M., Bristow M.R., Cohn J.N., et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med (1996) 334:1349–1355.[Abstract/Free Full Text]
  3. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in congestive heart failure (MERIT-HF). Lancet (1999) 353:2001–2007.[CrossRef][Web of Science][Medline]
  4. Packer M., Coats A.J.S., Fowler M.B., et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med (2001) 344:1651–1658.[Abstract/Free Full Text]
  5. Flather M., Shibata M., Coats A., et al. Randomised trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J (2005) 26:215–225.[Abstract/Free Full Text]
  6. Poole-Wilson P.A., Swedberg K., Cleland J.G.F., 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) 362:7–13.[CrossRef][Web of Science][Medline]
  7. Poole-Wilson P.A., Cleland J.G., Di Lenarda A., et al. Rationale and design of the carvedilol or metoprolol European trial in patients with chronic heart failure: COMET. Eur Heart J (2002) 4:321–329.[CrossRef]
  8. Wei L.J., Lin D.Y., Weissfeld L. Regression analysis of multivariate incomplete failure time data by modelling marginal distribution. J Am Stat Assoc (1989) 84:1065–1073.[CrossRef][Web of Science]
  9. Remme W.J., Cleland J.G., Di Lenarda A., et al. Carvedilol better protects against vascular events than metoprolol in heart failure: results from COMET. J Am Coll Cardiol (2007) 49:963–971.[Abstract/Free Full Text]
  10. Di Lenarda A., Sabbadini G., Salvatore L., et al. Long-term effects of carvedilol in idiopathic dilated cardiomyopathy with persistent left ventricular dysfunction despite chronic metoprolol. The Heart-Muscle-Disease Study Group. J Am Coll Cardiol (1999) 33:1926–1934.[Abstract/Free Full Text]
  11. Metra M., Gibbini R., Nodari S., Boldi E., Modena M.G., Dei Cas L. Differential effects of beta-blockers in patients with heart failure. A prospective, randomized, double-blind comparison of the long-term effects of metoprolol versus carvedilol. Circulation (2002) 102:546–551.
  12. Packer M., Antonopoulos G.V., Berlin J.A., Chittams J., Konstam M.A., Udelson J.E. Comparative effects or carvedilol and metoprolol on left ventricular ejection fraction in heart failure: a meta-analysis. Am Heart J (2001) 141:899–907.[CrossRef][Web of Science][Medline]
  13. Azevedo E.R., Kubo T., Mak S., et al. Nonselective versus selective β-adrenergic receptor blockade in congestive heart failure. Differential effects on sympathetic activity. Circulation (2001) 104:2194–2199.[Abstract/Free Full Text]
  14. Gilbert E.M., Abraham W.T., Olsen S., et al. Comparative hemodynamic, left ventricular functional, and antiadrenergic effects of chronic treatment with metoprolol versus carvedilol in the failing heart. Circulation (1996) 94:2817–2825.[Abstract/Free Full Text]
  15. Kurz T., Richardt D., Gorge B., et al. Differential effects of carvedilol on norepinephrine release in normoxic and ischemic heart. J Cardiovasc Pharmacol (2000) 36:96–100.[CrossRef][Web of Science][Medline]
  16. Kindermann M., Maack C., Schaller S., et al. Carvedilol but not metoprolol reduces β-adrenergic responsiveness after complete elimination from plasma in vivo. Circulation (2004) 109:3182–3189.[Abstract/Free Full Text]
  17. Di Lenarda A., Remme W.J., Charlesworth A., et al. Exchange of β-blockers in heart failure patients. Experiences from the poststudy phase of COMET (the Carvedilol or Metoprolol European Trial). Eur J Heart Fail (2005) 7:640–649.[Abstract/Free Full Text]
  18. Piccirillo G., Quaglione R., Nocco M., et al. Effects of long-term beta-blocker metoprolol or carvedilol) therapy on QT variability in subjects with chronic heart failure secondary to ischemic cardiomyopathy. Am J Cardiol (2002) 90:1113–1117.[CrossRef][Web of Science][Medline]
  19. Uretsky B.F., Thygesen K., Armstrong P.W., et al. Acute coronary findings at autopsy in heart failure patients with sudden death. Results from the Assessment and Treatment with Lisinopril And Survival (ATLAS) trial. Circulation (2000) 102:611–616.[Abstract/Free Full Text]
  20. Torp-Pedersen C., Poole-Wilson P.A., Swedberg K., et al. Effects of metoprolol and carvedilol on cause-specific mortality and morbidity in patients with chronic heart failure — COMET. Am Heart J (2005) 149:370–376.[CrossRef][Web of Science][Medline]
  21. Metra M., Torp-Pedersen C., Swedberg K., et al. Influence of heart rate, blood pressure, and beta-blocker dose on outcome and the differences in outcome between carvedilol and metoprolol tartrate in patients with chronic heart failure: results of the COMET trial. Eur Heart J (2005) 26:2259–2268.[Abstract/Free Full Text]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 ANN INTERN MEDHome page
F. A. McAlister, N. Wiebe, J. A. Ezekowitz, A. A. Leung, and P. W. Armstrong
Meta-analysis: {beta}-Blocker Dose, Heart Rate Reduction, and Death in Patients With Heart Failure
Ann Intern Med, June 2, 2009; 150(11): 784 - 794.
[Abstract] [Full Text] [PDF]

Home page
 Circ Heart FailHome page
P. J. Hauptman
Does It Matter Why and How Patients With Heart Failure Die?: A Debate That Lives On
Circ Heart Fail, July 1, 2008; 1(2): 89 - 90.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Remme, W. J.
Right arrow Articles by Swedberg, K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Remme, W. J.
Right arrow Articles by Swedberg, K.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?