© 2004 European Society of Cardiology
Tolerability of carvedilol and ACE-Inhibition in mild heart failure. Results of CARMEN (Carvedilol ACE-Inhibitor Remodelling Mild CHF EvaluatioN)
a Institut de Cardiologie, Centre Hospitalier GH Pitié-Salpêtrière, 47-83 Bld de l'Hôpital 75013, Paris Cedex 13, France
b F. Hoffmann-La Roche Basel, Switzerland
c Hospital de Santa Maria Lisboa, Portugal
d Aarhus University Hospital Aarhus, Denmark
e Hospital Le Molinette Torino, Italy
f Frederiksberg Hospital Frederiksberg, Denmark
g St. Antonius Hospital Nieuwegein, The Netherlands
h University of Regensburg Regensburg, Germany
i Karolinska Hospital Stockholm, Sweden
j University Hospital Vall d'Hebron Barcelona Spain
k Sticares Foundation Rhoon, The Netherlands
* Corresponding author. Tel.: +33-1-42-17-68-14; fax: +33-1-42-17-68-00. E-mail address: Veronique.villareal{at}chups.jussieu.fr
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Abstract |
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 Top Abstract 1. Introduction2. Methods3. Results4. DiscussionA.1. CARMEN investigatorsA.2. Executive steering...A.3. Endpoint committeeA.4. Data and safety...A.5. SponsorAcknowledgmentsReferences |
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Background: Management guidelines for heart failure recommend ACE-I and β-blockers. The perception of difficult up-titration might have added to the slow uptake of β-blockers despite their mortality and morbidity benefits.
Aims: CARMEN offered a possibility to study safety and tolerability of enalapril against carvedilol and their combination.
Methods: Five hundred and seventy-two patients were blindly up-titrated on carvedilol (target 25 mg bid) and/or enalapril (target 10 mg bid), and continued for 18 months. In the combination arm, carvedilol was up-titrated before enalapril.
Results: There was no group related difference in adverse events during up-titration. Withdrawal rates were 31, 30 and 30%, and serious adverse events 28, 29 and 34% in the combination, carvedilol and enalapril arms. Mortality was similar in all groups (all-cause N=14, 14 and 14; cardiovascular N=9, 13 and 14). All-cause and cardiovascular hospitalizations occurred in 26, 27 and 32%, and in 12, 16 and 22% in the combination, carvedilol and enalapril arms, respectively.
Conclusion: The safety profile was similar in all treatment arms. In contrast to common perception, there was no difference in tolerability between the ACE-I and carvedilol. This result is even more remarkable as the high prestudy use of ACE-I (65%) might have introduced a bias by selecting ACE-I tolerant patients, who were only switched from their former ACE-I to enalapril.
Key Words: Carvedilol • Enalapril • Heart failure • Tolerability • CARMEN
Received October 10, 2003; Accepted December 10, 2003
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1. Introduction |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionA.1. CARMEN investigatorsA.2. Executive steering...A.3. Endpoint committeeA.4. Data and safety...A.5. SponsorAcknowledgmentsReferences |
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Current management guidelines for chronic heart failure (CHF) [1,2] recommend the combined use of ACE inhibition (ACE-I) and β-blockers in a broad spectrum of patients with symptomatic CHF. The recommended order is to start with ACE-I and to follow up with β-blockade.
The use of ACE-I in CHF has increased considerably over recent years. In contrast, β-blockers remain under-utilised. Recent surveys report prescription rates ranging from 8% in the primary care setting [3] up to 37% in the hospital setting [4]. A possible explanation is the more recent introduction of β-blockers in CHF treatment, but historical emphasis on their contraindication may also be a reason. Worsening CHF has been cited as an important treatment risk [3]. Despite compelling evidence for the beneficial effects of β-blockers on mortality and morbidity, the need to add β-blockade may still be perceived as less urgent, particularly in mild CHF, as the fear of side effects attributable to β-blocker introduction prevails.
The CARMEN trial compared carvedilol alone, enalapril alone and their combination with the primary objective to study left ventricular (LV) remodelling in patients with mild to moderate CHF [5]. After 18 months the combination of carvedilol and enalapril reduced LV end systolic volume index (LVESVI) significantly as compared to enalapril alone. In the within-treatment arm comparison with baseline both carvedilol alone and in combination with enalapril significantly reduced LV remodelling.
Presently, CARMEN is the only trial of an adequate size and length to provide safety data in a head to head comparison of a β-blocker and an ACE-I in CHF. The purpose of this paper is to compare safety and tolerability of treatment with carvedilol alone, enalapril alone and their combination.
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2. Methods |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionA.1. CARMEN investigatorsA.2. Executive steering...A.3. Endpoint committeeA.4. Data and safety...A.5. SponsorAcknowledgmentsReferences |
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CARMEN is a double-blind, randomised, parallel-group study in patients with chronic LV dysfunction and symptoms of mild CHF. Effects on LV remodelling constituted the primary endpoint. Safety parameters were assessed throughout the study. Detailed reports on the study protocol [6] and the primary results [5] have been given elsewhere. A summary of pertinent parts is provided below.
2.1. Patients
Patients with stable mild CHF, 
18 years, of either sex, with at least a 2 month history of symptoms and a LVEF <40% were eligible if they were on stable CHF medication and free from cardiovascular hospitalisations for at least 2 weeks prior to randomisation. In total 745 patients were screened at 65 centres in 13 European countries.
Exclusion criteria were related to the study aim of LV remodelling (excluding patients with confounding factors, e.g. recent or planned coronary revascularisation), and to safety, excluding patients with contraindications for β-blocker therapy. Ongoing ACE-I treatment was stopped between 2 and 14 days and angiotensin II receptor antagonists, 
-blockers and β-blockers were stopped 4 weeks before randomisation.
The safety population included all randomised patients who received at least one dose of trial medication.
The study was approved by the appropriate Ethical Review Boards and conducted according to principles as outlined in the Declaration of Helsinki. All patients gave their informed, written consent to study participation.
2.2. Study design
Included patients were randomized to one of the three treatment arms (Fig. 1).
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In phase A (Fig. 1), patients were up-titrated on either carvedilol (Groups C+E and C) or enalapril (Group E) in a blinded fashion until the maximum tolerated dose of carvedilol (target: 25 mg bid for patients <85 kg, 50 mg bid for patients
85 kg) or enalapril (target: 10 mg bid) was reached. Carvedilol/matching placebo tablets were given at equivalent doses of 3.125, 6.25, 12.5, 25 or 50 mg bid while enalapril/placebo capsules were taken at equivalent doses of 2.5, 5 or 10 mg bid. During phase B patients were up-titrated on enalapril (Group C+E) or matching placebo (Groups C and E) in a blinded fashion until the maximum tolerated or target dose was reached. Study medication was continued during the maintenance phase for 18 months. At study completion and following down-titration of study drugs the patients received optimal open-label therapy at the discretion of the investigator. The drug code was kept at the independent randomisation centre only to be released after completion of all trial related activities or in case of an emergency. Patients were followed for 30 days after completion or withdrawal from study as regards mortality and hospitalisations.
2.3. Safety endpoints
An endpoint committee of three experienced cardiologists, blinded to treatment, reviewed all events involving death, hospitalisations or CHF medication changes.
Deaths were classified as cardiovascular (sub-categories: sudden cardiac death, worsening of CHF, acute myocardial infarction or other fatal cardiovascular events) or non-cardiovascular. Hospitalisations were classified as cardiovascular (sub-categories: worsening of CHF, or other reasons) or non-cardiovascular.
Criteria for changes in CHF medication as a result of increasing symptoms were predefined and included
- Addition of a diuretic to existing therapy.
- Change of current diuretic therapy (thiazide or aldosterone antagonist) to a loop diuretic.
- Introduction of any other medication for treatment of CHF.
- An increase in dose of 50% of any CHF medication sustained at least for 30 days.
Changes in CHF medication, which occurred in the context of a hospitalisation for CHF, were only counted as hospitalisations.
An independent Data Safety Monitoring Board supervised all safety aspects. At no point during the conduct of the study did any safety concern occur and the study proceeded to its planned end.
All reports of adverse events were included irrespective of the investigators assessment of their causality with respect to treatment. Adverse events that were fatal or life-threatening, required or prolonged hospitalisation, or resulted in persistent or significant disability or incapacity were classified as serious.
2.4. Statistical analyses
The statistical analyses of safety parameters were two-sided and tested at the 5% significance level, without adjustment for multiple comparisons. All safety analyses were performed on the safety population. Between-group differences in the Kaplan–Meier survival and morbidity curves were tested for significance by the log-rank statistic.
Three pairwise comparisons were performed to investigate the differences between groups. Changes from baseline to follow up were analysed to elucidate the development over time. T-tests were used to compare the changes between treatment groups
As patients in Group C+E and Group C received blinded carvedilol during up-titration phase A, results representing this phase were summarised for both groups combined.
2.5. Role of the funding source
Study data are in a Roche database. The Steering Committee had unlimited access to all data and was free to interpret and publish the results.
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3. Results |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionA.1. CARMEN investigatorsA.2. Executive steering...A.3. Endpoint committeeA.4. Data and safety...A.5. SponsorAcknowledgmentsReferences |
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3.1. Trial profile and baseline data
A total of 572 patients (safety population, C+E=191; C=191; E=190) were randomised. Baseline characteristics were similar in all groups (Table 1). The median duration of the observation period (treatment start to last visit) was approximately 22 months and similar in all three groups. The median length of up-titration in each group was between 59 and 61 days during period A and 42 or 43 days during period B.
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3.2. Early withdrawal
Withdrawal rates were similar in the three groups (Table 2). ‘Adverse event’ was the most frequent reason (113 patients or 19.8%), followed by ‘other’ reasons (30 patients or 5.2%, including withdrawal of consent in 24/30 cases), and ‘protocol deviations’ (20 patients or 3.5%). Patient withdrawal was most frequent during up-titration phase A. During this phase withdrawal rates were similar during enalapril up-titration (14%) and during carvedilol up-titration (14%).
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Enalapril up-titration immediately preceded by carvedilol up-titration was unproblematic, as suggested by the smaller number of drop-outs compared to the enalapril alone (4% (C+E) vs. 14% (E)). However, the three treatment arms were similar with respect to incidence, reasons and study phase of withdrawal.
3.3. Dose of study medication
Most patients were successfully up-titrated in all treatment arms. Mean total daily dosages over the treatment period did not differ between the monotherapy arms and the combination arm. Mean doses were 47.9 mg (C) vs. 48.7 mg (C+E) of carvedilol and 16.8 mg (E) vs. 14.9 mg (C+E) of enalapril. Target maintenance doses were reached for almost all patients entering the maintenance phase, and were similar between treatment arms and for carvedilol 149/157 (94.9% Group C+E), 147/157 (93.6% Group C) and 154/160 (96.3%, placebo, Group E), and for enalapril 151/157 (96.2% Group C+E), 147/157 (93.6%, placebo, Group C) and 153/160 (95.6%, Group E), respectively.
3.4. Mortality and hospitalisation
Mortality data and hospitalisation frequency showed a similar pattern (Table 3, Fig. 2). A trend towards a beneficial effect on cardiovascular and CHF events was observed with combined therapy.
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3.5. Adverse events
Three quarters of the patients experienced at least one adverse event during the trial period (Table 3). Serious adverse events, the majority hospitalisations, occurred in approximately 30% of patients.
Adverse events most frequently related to the study drugs’ hypotensive properties (dizziness, hypotension) or the underlying condition (heart failure) and its symptoms (dyspnoea, asthenia) (Table 4). More carvedilol treated patients had at least one non-serious episode of bradycardia (7%; serious=1%), as compared to the enalapril alone arm (1%; serious=0%), but had less cough than enalapril treated patients. Combination therapy resulted in a decrease in CHF events and a slight increase of non-serious hypotensive episodes, which did not affect withdrawal rates (Tables 3, 4 and 2).
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Heart failure was the most frequent serious adverse event (Table 4, numbers in brackets) followed by sudden death (investigator assigned) in 3%, 4% and 3% and unstable angina pectoris in 2%, 3% and 3% of the patients in the combination, carvedilol and enalapril arms, respectively.
3.6. Changes in heart failure medication
Only 14% of patients needed medication adjustments for worsening CHF without hospitalisation (Table 2). When hospitalisations for CHF were taken into account, the combination group needed less interventions (N=27/191 or 14.1%) compared to each of the monotherapy arms (carvedilol N=39/191 or 20.4%, enalapril N=40/190 or 21.1%).
3.7. Blood pressure
All treatment options induced changes in blood pressure (Fig. 3). Significant reductions from baseline in systolic blood pressure were observed at the end of the up-titration periods (–3.8, –8.3 mmHg in Group C+E; –3.3, –5.2 mmHg in Group C and –4.1, –6.1 mmHg in Group E at the end of up-titration A, up-titration B, respectively; P<0.01 for all changes from baseline). However, at the end of the maintenance period systolic blood pressure had returned to baseline levels. The incidence of low systolic blood pressure (<80 mmHg) was 
1% in each group during the entire study.
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Reductions in diastolic blood pressure from baseline were significant at the end of the up-titration periods (–2.4, –6.5 mmHg in Group C+E; –3.6, –4.5 mmHg in Group C and –1.8, –3.6 mmHg in Group E at the end of up-titration A, up-titration B, respectively, P<0.05 for all changes from baseline). In the monotherapy arms diastolic blood pressure was not different from baseline at the end of the maintenance period, while a significant reduction (–2.3 mmHg; P<0.05) persisted in Group C+E. There were no differences between the three arms, except that by the end of up-titration B means diastolic blood pressure was lower in the combination than in the enalapril arm (–2.9 mmHg; P<0.05). The overall incidence of low diastolic blood pressure (<60 mmHg) was 14%, 6% and 10% in the combination, the carvedilol and the enalapril groups, respectively.
3.8. Heart rate
Carvedilol treatment resulted in a significant reduction of heart rate (Fig. 4). There was no difference between the two groups receiving carvedilol who had a lower heart rate (P<0.001) than Group E at all time points. The incidence of low heart rate (<50 bpm) during the study period was 5%, 8% and 3% in the combination, carvedilol and enalapril groups, respectively.
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3.9. Renal function as assessed by serum creatinine
Mean serum creatinine levels increased slightly from baseline to end of maintenance in enalapril treated patients (+2.3 µmol/l in Group C+E, +3.3 µmol/l in Group E) and decreased to a similar extent in Group C (–2.5 µmol/l).
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4. Discussion |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionA.1. CARMEN investigatorsA.2. Executive steering...A.3. Endpoint committeeA.4. Data and safety...A.5. SponsorAcknowledgmentsReferences |
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CARMEN is the first study showing that the β-blocking agent carvedilol can be safely initiated before the institution of an ACE-I (enalapril) in CHF. Moreover, carvedilol treatment was as well tolerated as enalapril and resulted, in contrast to ACE inhibitor therapy alone, in a reversal of LV remodelling [5]. The combination of an ACE-I and carvedilol resulted in more favourable effects as compared to either carvedilol or ACE-I therapy alone.
The present data support a therapeutic strategy in which the institution of β-blockade should not be delayed for fear of intolerance and provide an additional mandate for prescribing the combination of both agents early in mild CHF. This is of special importance as β-blockers still are significantly under utilised despite recommendations in treatment guidelines for CHF [1,2]. However, β-blockers are generally well tolerated when added to standard therapy with diuretics and ACE-I [7–9]. The use of β-blockers in CHF has increased slightly over the last few years but the prescription of β-blockers to all eligible patients remains an important goal. CARMEN can add to this by supplying further evidence of the safety of β-blockade in mild to moderate CHF.
Uptitration with Carvedilol was as well tolerated as up-titration with an ACE-I as indicated by similar adverse event profiles and withdrawal rates in the three treatment regimens (Table 2). These findings suggest that the tolerability of carvedilol in mild CHF patients does not depend on concomitant ACE-I treatment providing an adequate afterload reduction to offload the failing heart before initiating β-blockade. Also, they indicate that the order in which the combination of carvedilol and ACE-I is instituted in mild CHF may be at the discretion of the clinician. Whether these findings can be extended to other conventional, non-vasodilating β-blockers needs further investigation. Previous studies have confirmed that carvedilol, but not β–1 selective blockers, provides afterload reduction [10–12].
Possibly due to the study design with its complex, blinded uptitration scheme, the highest withdrawal rate was observed during up-titration phase A. During this period there were uncertainties for the investigators (blinded titration of carvedilol or enalapril) and changes for the patient (in many cases discontinuation of pre-study treatment followed by initiation of study therapy). During phase B, enalapril (an established CHF treatment) or placebo were up-titrated, thus reducing potential uncertainties and changes. This may explain why fewer withdrawals were reported during this second phase of the study. The withdrawal rate between the three treatment regimens during the up-titration phases was, however, similar.
Also, during the maintenance phase there were no differences between the three treatment regimens as regards safety and tolerability. As shown by previous studies [13,14], addition of β-blockers to standard therapy including ACE-I resulted in an improvement of CHF symptoms and CHF related adverse events. This effect usually became apparent after a few weeks on drug. CARMEN confirms these observations as the combination group tends to have less CHF related events.
The lack of a difference in adverse events between the two active compounds carvedilol and enalapril in the mono study therapy arms, is a clear indication that carvedilol is safe and as well tolerated as an ACE-I in mild to moderate CHF. These results are even more remarkable as 65% of the patients had been on an ACE-I prior to study start, thereby having demonstrated prior tolerance to ACE-I treatment.
CARMEN was not designed as a mortality/morbidity trial and we observed no difference in morbidity and mortality. However, a significant survival benefit and reduced morbidity of carvedilol in addition to ACE-I treatment in CHF have been clearly demonstrated in several large controlled trials [15–17]. Our results also indicate that the combination therapy had less cardiovascular and worsening CHF events than the two other study arms. The significant reversal of LV remodelling, a strong predictor of outcome [18], in the combination therapy arm [6] supports the earlier outcome trials, underlining the importance of early combination therapy in mild CHF patients.
Both ACE-I and β-blockers have hypotensive properties resulting from different, independent pharmacologic modes of action. As could be expected, a slight increase in (non-serious) hypotensive adverse events was observed in the combination arm compared to the monotherapy arms. This was not a cause for more withdrawals from the study. The more frequent but mild events were obviously outbalanced by the treatment benefits.
4.1. Limitations
It cannot be ruled out that the extensive prior use of ACE-I may have influenced the safety results. This was unavoidable since such therapy was already an established evidence-based treatment in CHF and as such not possible to eliminate but for a short up-titration period. The enalapril arm may have benefited as patients pre-treated with ACE-I did not undergo long-term withdrawal and received a treatment that they previously tolerated. Still the main message of this study, that early institution of the β-blocker carvedilol was safe and well tolerated, is not blunted by this limitation. As the primary endpoint on which the sample size was based concerned remodelling parameters, the number of patients in the study is too small to give definitive answers concerning outcome data.
4.2. Conclusions and clinical implications
The safety results of CARMEN are of interest. In contrast to common perception, which suggests that β-blockers are less well tolerated than ACE-I in heart failure, neither the combination of carvedilol and enalapril nor carvedilol therapy alone resulted in an increase of adverse events or withdrawals as compared to enalapril treatment. Moreover, there were no significant differences between the three study arms regarding vital signs such as blood pressure and the only observed difference was, as expected, in heart rate. The mean daily dosages reached and the number of patients achieving target dose were comparable between the treatment arms. Accordingly, the decision of initiating β-blocker therapy should be taken as early as possible in heart failure. As such, the results of CARMEN expand current guidelines, which recommend adding β-blockade to ACE-I only if patients remain symptomatic. The order in which this combination is initiated could be left to the clinician's discretion.
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A.1. CARMEN investigators |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionA.1. CARMEN investigatorsA.2. Executive steering...A.3. Endpoint committeeA.4. Data and safety...A.5. SponsorAcknowledgmentsReferences |
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Austria Demschik, Gessner; Czech Republic Stanek, Hradec/Kral, Spinar, Ceral, Rybka, Gorican; Denmark Hildebrandt, Torp-Pedersen, Skagen, Sykulski, Egstrup, Pedersen, Jespersen; Estonia Eha, Teesalu; Germany Gaudron, Kandziora, Scheinpflug, Braun; Iceland Ragnarsson/Hognason; Ireland Sugrue, Barton, Quigley, Moore, Crean, Meany; Italy Alunni, Villa, Bobbio, Sega, Borgo, Nicolino, Trinchero, Donadon; Lithuania Grabuskiene, Kibarskis, Stankevicius; Netherlands Ascoop, Louritz, Stevens, Haan; Poland Kuch, Cholewa, Wojciechowski, Jaworska, Piwowarska, Tracz, Krzeminska-Pakula, Janion; Romania Cristodorescu, Dorobantu, Candea; Sweden Hofman-Bang, Hoglund, Carlsson, Wahlstrom/Ljungstrom, Sandstrom, Nicol, Akesson, Hofvendahl/Lofdahl, Ellstrom, Wagner, Andersson/Saldeen/Hornestam
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A.2. Executive steering committee |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionA.1. CARMEN investigatorsA.2. Executive steering...A.3. Endpoint committeeA.4. Data and safety...A.5. SponsorAcknowledgmentsReferences |
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W.J. Remme (Chairman and Principal Investigator, The Netherlands), G. Riegger (Deputy Chairman, Germany), M. Bobbio (Italy), J. Bounhoure (France), M. Komajda (France), P. Hildebrandt (Denmark), W. Jaarsma (The Netherlands), L. Rydén (Sweden), J. Soler-Soler (Spain).
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A.3. Endpoint committee |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionA.1. CARMEN investigatorsA.2. Executive steering...A.3. Endpoint committeeA.4. Data and safety...A.5. SponsorAcknowledgmentsReferences |
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M. Komajda (France), H. Madeira (Portugal), K. Thygesen (Denmark).
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A.4. Data and safety monitoring board |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionA.1. CARMEN investigatorsA.2. Executive steering...A.3. Endpoint committeeA.4. Data and safety...A.5. SponsorAcknowledgmentsReferences |
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J. Kjekshus (Norway), A. Bayes de Luna (Spain), S.J. Pocock (UK)
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A.5. Sponsor |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionA.1. CARMEN investigatorsA.2. Executive steering...A.3. Endpoint committeeA.4. Data and safety...A.5. SponsorAcknowledgmentsReferences |
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Initially SmithKline Beecham sponsored the CARMEN study. However, as a result of new commercial arrangements, Roche assumed full responsibility for the study in February 1999. Sponsor representatives participated in steering committee meetings as non-voting members.
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Acknowledgments |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionA.1. CARMEN investigatorsA.2. Executive steering...A.3. Endpoint committeeA.4. Data and safety...A.5. SponsorAcknowledgmentsReferences |
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We would like to thank George Stein for preparing and conducting the statistical analysis.
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References |
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- Remme W.J., Swedberg K. 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) 22:1527–1560.
[Free Full Text] - Hunt S.A., Baker D.W., Chin M.H., et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult. Circulation (2001) 104:2996–3007.
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[Abstract/Free Full Text] - Remme W.J., Soler-Soler J., Ryden L., et al. Replacement of angiotensin converting enzyme inhibition by carvedilol results in long-term reversed left ventricular remodeling in mild heart failure and is well tolerated: results of the CARMEN (Carvedilol ACE-inhibitor remodeling in mild heart failure evaluation) Study. J Am Coll Cardiol (2003) 41:205A.
- Remme W.J. The Carvedilol and ACE-Inhibitor Remodelling Mild Heart Failure EvaluatioN trial (CARMEN) – rationale and design. Cardiovasc Drugs Ther (2001) 15:69–77. on behalf of the CARMEN Steering Committee and Investigators.[CrossRef][Web of Science][Medline]
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