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European Journal of Heart Failure 2005 7(4):640-649; doi:10.1016/j.ejheart.2004.09.010
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© 2005 European Society of Cardiology

Exchange of β-blockers in heart failure patients. Experiences from the poststudy phase of COMET (the Carvedilol or Metoprolol European Trial)

Andrea Di Lenardaa,*, Willem J. Remmeb, Andrew Charlesworthc, John G.F. Clelandd, Beatrix Lutigere, Marco Metraf, Michel Komajdag, Christian Torp-Pedersenh, Armin Scherhage, Karl Swedbergi, Philip A. Poole-Wilsonj and for the COMET investors

a Department of Cardiology, Ospedale di Cattinara Strada di Fiume 447, 34100 Trieste, Italy
b Sticares Cardiovascular Research Foundation Rhoon, The Netherlands
c Stat Nottingham Clinical Research Group (NCRG) Nottingham, UK
d Department of Cardiology, University of Hull Kingston upon Hull, UK
e F. Hoffmann La Roche Basel, Switzerland
f Cattedra di Cardiologia, Università di Brescia, Italy
g Department of Cardiology, La Pitié-Salpétrière Hospital Paris, France
h Department of Cardiology, Bispebjerg University Hospital Copenhagen, Denmark
i Dept. of Medicine, Sahlgrenska University Hospital/Östra Göteborg, Sweden
j National Heart and Lung Institute, Imperial College London UK

* Corresponding author. Tel.: +39 040 3994866; Fax: +39 040 3994878. E-mail address: dilenar{at}univ.ts.it


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: The Carvedilol or Metoprolol European Trial (COMET) reported a significant survival benefit for carvedilol, a β1-, β2- and {alpha}1-blocker, vs. metoprolol tartrate, a β1-selective blocker, in patients with mild-to-severe chronic heart failure (CHF). Patients on treatment with metoprolol might benefit from switching to carvedilol.

Aim: To investigate the safety and tolerability of switching β-blockers in CHF.

Methods: At the end of COMET, the Steering Committee recommended that study medication was stopped without unblinding, and patients were commenced on open-label β-blockade at a dose equivalent to half the dose of blinded therapy, with subsequent titration to target or maximum tolerated dose. Patients were followed for 30 days.

Results: 1321 out of 1440 patients were transitioned to open-label treatment (76.8% to carvedilol). Serious adverse and CHF-related events were respectively 9.4% and 4.7% in those switching from carvedilol to metoprolol and 3.1% and 1.5% in patients switching from metoprolol to carvedilol. Patients who switched from carvedilol to metoprolol showed the highest mortality or hospitalisation rate (12.3%) in comparison with those who switched from metoprolol to carvedilol (3.1%, p<0.001) or who stayed on the same drug (carvedilol: 2.5%, p<0.001; metoprolol: 4.2%, p=0.04). Reducing the initial dose of the second β-blocker maximised the safety of this strategy. Event rate was higher in patients with more severe heart failure and in those withdrawing from β-blockade.

Conclusion: Our data show that switching β-blockers is a practical, safe and well-tolerated strategy to optimise treatment of CHF. Patients who switched to carvedilol showed the lowest rate of adverse events. A closer clinical monitoring is recommended during transition in high-risk patients.

Key Words: Heart failure • β-blockers • Carvedilol • Metoprolol • Dosage • Adverse event

Received April 5, 2004; Revised September 9, 2004; Accepted September 20, 2004


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Three β-blockers have been proven to reduce mortality and morbidity in patients with chronic heart failure (CHF) in placebo-controlled trials on top of diuretic and ACE-inhibitor therapy [1–4]. Recently, the Carvedilol or Metoprolol European Trial (COMET) reported a 17% survival benefit for carvedilol, a β1-, β2- and {alpha}1-blocking agent, over metoprolol tartrate, a β1-selective blocker, indicating that β-blockers may differ in their effect on outcome [5]. As a consequence, physicians may choose to change existing β-blocking therapy to carvedilol in heart failure patients. The manner in which this can be done safely is as yet unknown.

Whereas withdrawal of β-blockade in patients with CHF may trigger worsening of heart failure symptoms and arrhythmias [6,7], only limited information is available on the transition from one β-blocker to another without down-titration of the initial agent. Currently, there are only data from two small randomised controlled studies in which clinically stable CHF patients were switched from one agent to another [8,9].

The Steering Committee of COMET proposed that, at the end of the study, all patients should continue to receive β-blocker therapy, as recommended by the ESC guidelines for CHF treatment [10]. Based on prior evidence [8,9], procedures were suggested for a safe transition from blinded study medication to open-label β-blocker therapy. We present here the data on safety and tolerability of exchanging blinded study medication for open β-blocker therapy in patients with stable heart failure and still on treatment at the end of COMET.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
COMET was a double-blind randomised controlled parallel-group study of carvedilol vs. metoprolol in patients with mild-to-severe CHF. The study protocol has been described in detail elsewhere [11], and the primary results were recently published [5]. COMET compared the effect of carvedilol at a dose of 25 mg BID, with metoprolol tartrate, 50 mg BID, on two primary endpoints: total mortality and the combined endpoint of total mortality and all-cause hospitalisation in 3029 patients with NYHA class II–IV CHF over a period of 58 months, in addition to treatment with ACE-inhibitors and diuretics. Carvedilol resulted in a 17% survival improvement as compared to metoprolol. The second primary endpoint and all-cause hospitalizations did not differ between groups.

Before the end of the study, the COMET Steering Committee proposed that patients should not be down-titrated from blinded study medication on completion of the study but, if possible, should switch to open β-blocking therapy, in accordance with the ESC guidelines for the treatment of CHF. Based on the results of two smaller studies investigating the effect of switching from one β-blocker to another [8,9], a scheme was proposed in which patients could be transitioned to any approved β-blocking agent for CHF immediately after the study ends (Table 1).


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  		Table 1 Equivalent dose levels suggested for different β-blocking agents

 
At the final visit, after the cut off date of the study on November 15, 2002, it was recommended that patients on study medication were switched to one of the β-blockers approved for CHF in the respective country. Investigators selected the β-blocker deemed by them as the most appropriate for the individual patient. The study treatment code (carvedilol or metoprolol) was not available to the investigators at the time of this transition. Previous studies [8,9] on practical, safe and well-tolerated strategies for patients with clinically stable CHF suggested that such transition from blinded study medication to a new agent needed to be carried out under careful clinical observation.

After evaluation of the patient's stability, investigators were advised to stop study treatment (the last dose was to be taken at 20:00 h) the day before the final visit, at which time the new agent was introduced. It was proposed that the first dose of the new β-blocker be administered at the final visit (12–20 h after the last dose of study medication), and that the patient should remain under clinical observation for at least 2 h thereafter. In order to maximise the safety of such a transition, the first dose of the new agent had to be equivalent to one-half of the last dosage of blinded study medication (for example, a patient who was taking the 4th dose level of COMET study medication was to be switched to the dose of the chosen β-blocker corresponding to the 3rd level, as described in Table 1). The dosage of the new β-blocker was then doubled every 7–14 days until the maximum recommended [10] or tolerated dose was reached. Intermediate steps or a slower up-titration schedule could be employed according to the judgement of the treating investigator. Special consideration was given to patients whose COMET study medication was maintained at level 1 and to those with more severe heart failure (NYHA III–IV), hypotension (systolic blood pressure ≤90 mm Hg) or bradycardia (heart rate <50 beats/min). To minimise the risks of side effects, including worsening heart failure, in these higher risk patients, it was recommended that they should have a longer (48–72 h) withdrawal period between the last dose of study medication and be monitored more closely (e.g., with more frequent visits) after the test dose of the selected β-blocker. In addition, the treatment code could be broken in case of safety concerns.

The patients were then followed up for 30 days after the last dose of study medication to detect all-cause mortality and all-cause hospitalisation and any adverse event or worsening heart failure. All the events were classified according to the definition used in the COMET trial.

Worsening CHF was defined as increasing symptoms of CHF which required additional or intensified diuretic treatment, addition of digoxin (not for control of atrial fibrillation) or introduction of intravenous inotropes. Out-patient visits for worsening symptoms requiring such changes of CHF treatment were also considered as an event. Worsening CHF was defined as serious when it was fatal, acutely life-threatening or required hospitalisation.

Due to the fact that many investigators decided to introduce the poststudy β-blocker at an equivalent dose level as the last study medication, the adverse event pattern in this group was compared with the group receiving a reduced dosage.

2.1. Statistical analysis
Differences between the treatments for continuous variables were performed using t-tests or analysis of variance, as appropriate, and using the chi-squared test for categorical variables. Where cell frequencies were small in 2x2 tables, differences were assessed using Fisher's Exact Test as indicated in the text. All calculations were produced in SAS 8.2 or S-PLUS 6.0.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Patient characteristics and dosing of study medication
After a mean study period of 4.8±0.5 years (range 3.9 to 6.0 years), 1440 (47.5%) of the 3029 enrolled patients were alive and on study medication. After the cut off date for COMET (Fig. 1), all but 119 patients (n=1321, 91.7%) had their study medication exchanged for open β-blocker therapy. The baseline clinical characteristics of the 1321 patients receiving poststudy β-blockade and the 108 patients not receiving β-blockade are presented in Table 2. Eleven patients were not followed up. Patients randomised to carvedilol had a lower left ventricular (LV) ejection fraction at baseline, with more frequent atrial fibrillation but less previous coronary artery bypass grafts (CABG) compared with those patients randomised to metoprolol.


Figure 1
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  		Fig. 1 Patient disposition: * one patient received Practolol, ** three patients received Atenolol, Sotalol and Practolol. BB—β-blocker.

 


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  		Table 2 Baseline characteristics at enrolment in COMET of subjects on study medication at the end of the study

 
Clinical findings at the prefinal visit, which took place about 3 months before study treatment was stopped, are presented in Table 3A. Compared to baseline, patients in both treatment groups (carvedilol and metoprolol) had improved CHF symptoms and a lower heart rate and blood pressure. There were no differences in clinical findings and in dosage level of study treatment between the groups, with the exception of systolic blood pressure, which was lower in the carvedilol-treated patients. Before the transition, patients were receiving a mean dosage level of 3.5 (see Table 1 for definition of dosage levels) in both groups (mean daily dose 41±15 mg of carvedilol vs. 82±30 mg of metoprolol), with 71.2% of patients on the target dose of carvedilol and 72.2% of patients receiving the target dose of metoprolol.


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  		Table 3A Findings at the prefinal visit before the patients were to be switched to poststudy β-blockade

 
3.2. Patient characteristics according to poststudy β-blockade and dosing
Most of the patients transitioned to carvedilol (n=1014, 76.8%; Fig. 1). Significantly, fewer switched to metoprolol (n=201, 15.2%) or bisoprolol (n=102, 7.7%). The type of metoprolol (tartrate or succinate) was specified by investigators only in a minority of patients. Table 3B presents clinical findings and dosage levels of the study medication at the transition visit according to poststudy treatment. Patients not receiving poststudy β-blockade tended to have more advanced CHF, as indicated by their NYHA classification, and had received lower doses of study medication. Patients who switched to carvedilol had a significantly higher diastolic blood pressure and tended to be less symptomatic than those receiving poststudy metoprolol.


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  		Table 3B Clinical findings at the final visit by poststudy β-blockade

 
Almost all patients (99%) had their poststudy β-blockade introduced without any delay (i.e., within one day of the last study medication dose). Mean initial doses were 33±16 mg/day for carvedilol, 72±40 mg/day for metoprolol and 4.8±2.5 mg/day for bisoprolol (Table 4).


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  		Table 4 Poststudy β-blocker dosing

 
The majority of the patients who switched to carvedilol (63%) was treated immediately at full dose, 35% at half of the equivalent dose and 2% at a higher dose (Table 4). A similar distribution of poststudy metoprolol dose levels was observed, while more patients (36%) were switched to a higher dose level of bisoprolol.

Patients who switched to an equivalent or higher dosage of poststudy drug had a significantly higher heart rate (70.1±12.3 vs. 68.4±12.1 beats/min, p=0.019) and lower dose level (dose level 4: 16.3% vs. 34.5%, p<0.001) at their last visit, as compared to patients who were treated with half of the equivalent dose.

3.3. Adverse event profiles, hospitalisation and mortality
Adverse events within the 30-day follow-up period were reported in 11.5% of patients. In general, the rate of adverse events reported after 30 days was lower in patients who continued with the same β-blocker (8.7% in patients remaining on carvedilol and 7.4% in those remaining on metoprolol) and higher in those switching to a different poststudy β-blocker treatment (15.1% in patients switching from carvedilol to metoprolol, 14.1% in those switching from metoprolol to carvedilol, 14.8% from carvedilol to bisoprolol and 12.5% from metoprolol to bisoprolol; Fig. 2A). Patients who did not receive poststudy β-blocker treatment had the highest adverse event rate (22.2%), which was similar in both study treatment groups (23.5% and 21.1% in the carvedilol and metoprolol groups, respectively; Table 5). Most adverse events occurred in the first week after the transition to poststudy treatment (Fig. 2 and 3).


Figure 2
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  		Fig. 2 (A) Adverse Events by frequency over time (later assessments include earlier events, i.e., 7 days is included in 14 days). (B) Type of adverse events at 30 days. Please note that the bradycardia event in "C->B" group represents only one patient. C—Carvedilol; M—Metoprolol; B—Bisoprolol.

 


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  		Table 5 Primary endpoints, total and serious 30-day adverse events after withdrawal or transition to open β-blockade at the end of COMET

 


Figure 3
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  		Fig. 3 (A) Serious adverse events frequency over time. (B) Serious heart failure events. C—Carvedilol; M—Metoprolol; B—Bisoprolol. Later assessments include earlier events, i.e., 7 days is included in 14 days.

 
The overall serious adverse event rate was 3.1%, and it was lower in patients who stayed on carvedilol (2.1%) or metoprolol (3.2%) or in those changing from metoprolol to carvedilol (3.1%) but significantly higher in those switching from carvedilol to metoprolol (9.4%) (Fig. 3A).

Again, patients not receiving poststudy β-blocker treatment had the highest serious adverse event rate (11.1%); the rate was higher in patients in whom carvedilol was withdrawn as compared to metoprolol (13.3% vs. 8.8%, respectively; Table 5).

The overall rates of adverse events and serious adverse events after transition were less than one-third than were reported in the first 30 days of COMET (37.8% and 11.3%, respectively).

Worsening CHF was the most prominent adverse event (n=29, 2.0%) and was classified as serious in 22 cases (1.5%). Most patients suffered this condition after switching from carvedilol to metoprolol (10/106, 9.4%, 4.7% serious). Eleven of 484 patients complained of worsening CHF after changing from metoprolol to carvedilol (2.3%, 1.5% serious), and 2/108 (1.9%, 1% serious) who withdrew from study medication. The 30-day rate of serious worsening CHF after transition (1.5%) was lower than that reported in the first month after enrolment in COMET (4.4%). Bradycardia and hypotension were reported in less than 1% of all patients (Fig. 2B).

In total, all-cause hospitalisation was documented during the 30-day observation period in 49 patients (3.4%), 27 (2.7%) on carvedilol, 12 (6.0%) on metoprolol, five (4.7%) on bisoprolol or other β-blockers and five (4.6%) among those who withdrew β-blockade. The highest rate of hospitalisation were observed in patient who switched from carvedilol to metoprolol (8.5%) or bisoprolol (5.6%) and in those who withdrew β-blockade (4.6%).

Nine patients (0.7%) died during the 30-day observation period, two (0.2%) on carvedilol, five (2.5%) on metoprolol and two (1.9%) among those who were withdrawn from β-blockade. Six of the fatal events were classified as sudden death and three as circulatory failure by the endpoint committee. Of the 484 patients who switched from metoprolol to carvedilol, two (0.4%) died. Among those on metoprolol, four of the 106 patients (3.8%) who switched from carvedilol to metoprolol and one of the 95 patients (1.1%) who stayed on metoprolol died. Two patients (one switched to carvedilol and one to metoprolol) died 2 days after the transition from randomised treatment to open-label β-blocker.

Combining all-cause death and all-cause hospitalisation (Table 5), 50 patients (3.8%) died or were hospitalised among those who switched to open β-blockade (28, 2.8% on carvedilol; 17, 8.5% on metoprolol and five, 4.7% on bisoprolol or other β-blockers), while six (5.6%) died or were hospitalised among those who were withdrawn from β-blockade.

Patients who switched from carvedilol to metoprolol showed a higher mortality or hospitalisation rate (12.3%) in comparison with those who switched from metoprolol to carvedilol (3.1%, p<0.001) or who stayed on the same drug (carvedilol: 2.5%, p<0.001; metoprolol: 4.2%, p=0.04).

Special consideration was given to more severe CHF patients and those on lower dose of study medication. A trend towards a higher rate of death or hospitalisation, total and serious adverse events was seen in those in NYHA III or IV, systolic blood pressure ≤90 mm Hg and on dose level 1 of the study drug (Table 5).

During the 30-day observation period, treatment codes were broken in only four cases (0.3%), on average of 12 days (4–22) after the transition to carvedilol (n=3) or withdrawal of study drug (n=1).

3.4. Adverse event profiles according to dose of poststudy β-blockade
Patients who were switched from metoprolol to a reduced dose of poststudy carvedilol seemed to experience fewer adverse events than those who switched to an equivalent dose of carvedilol (Fig. 4). In particular, worsening of heart failure occurred in none of the patients who switched to reduced dose of carvedilol but in 17 (2.7%, 11 serious) of those transitioning to an equivalent dose (p=0.08). Similarly, death or hospitalisation rate was also lower in those who switched to a reduced dose (1.2%) than to an equivalent dose of carvedilol (3.3%).


Figure 4
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  		Fig. 4 (A) Adverse events frequency by dosage at 30 days. (B) Serious heart failure event frequency by dosage at 30 days. C—Carvedilol; M—Metoprolol; B—Bisoprolol.

 
Patients who switched to metoprolol showed a higher rate of 30-day adverse events, with no differences between those transitioning to a reduced dose and those treated with an equivalent dose of poststudy drug (Fig. 4).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The present study reports the outcome of β-blocker exchange in over 1300 CHF patients following the closure of the COMET study and the transition from study medication to open-label β-blocking therapy without unblinding. The results provide a practical, safe and well-tolerated strategy to switch from existing β-blocking medication to the β-blocker which the clinician deems optimal in individual patients. The COMET study reported a 17% survival benefit for carvedilol, a β1-, β2- and {alpha}1-blocking agent, over metoprolol tartrate, a β1-selective blocker [5], suggesting that more comprehensive adrenergic blockade might confer additional benefits. As a consequence, clinicians may wish to change existing β-blocking therapy. The present study indicates that exchanging metoprolol for carvedilol was well-tolerated, with fewer serious adverse events than when patients were switched from carvedilol to metoprolol.

Until now, only limited information was available on the transition from one β-blocker to another without down-titration of the initial agent, as was done in COMET. Di Lenarda et al. [8] studied 30 patients with idiopathic dilated cardiomyopathy with persistent left ventricular dysfunction and reduced exercise tolerance in spite of a chronic tailored treatment with metoprolol. In that study, the transition to half of the equivalent dose of carvedilol was well-tolerated by all patients without significant worsening CHF, hypotension or bradycardia. In the study by Maack et al. [9], in 44 patients with ischaemic or idiopathic cardiomyopathy treated with metoprolol or carvedilol, the transition from metoprolol to carvedilol was well-tolerated in all patients. In contrast, the switch from carvedilol to an equivalent or higher dose of metoprolol was not tolerated in five patients (21%) due to hypotension and/or bradycardia.

The withdrawal of β-blockade may precipitate worsening CHF and arrhythmias [6,7,12,13]. Consequently, at the end of the COMET, the Steering Committee recommended switching stable patients on study medication to one of the β-blockers approved for the treatment of CHF without unblinding of study drug. By design, almost all patients were switched to an open-label β-blocker within 1 day from withdrawal of study treatment. This strategy proved to be safe and generally well-tolerated even in higher risk patients with more advanced heart failure, hypotension and bradycardia and in those on low dosages of study medication. The 30-day total and serious adverse events posttransition (respectively 11.5% and 3.1%) were less one-third than those reported at the beginning of COMET (37.8% and 11.3%) and were similar to the average event rates reported in the all trial (12.2% and 5.8% per month). The death rate was also similar to that seen during blinded treatment (7.5 vs. 7.6 deaths/100 patient–years in the COMET). Nevertheless, the higher rate of adverse events in patients who switched to another β-blocker compared with those who stayed on the same medication clearly indicates the need for closer monitoring during the transition process and the following titration period, particularly during the first week when nearly half of all adverse events occurred. Clinical monitoring should be particularly careful in higher risk patients, as in those with NYHA III–IV, hypotension or low dosage of β-blockade, and allow for a longer withdrawal period before the transition, prolonged observation after dose assumption and more frequent clinical visits in the first days after transition, eventually as inpatient in case of clinical instability.

Compared with patients staying on the same drug, the transition to another β-blocker was associated with a higher risk of adverse events. The most frequent adverse event was worsening heart failure. Bradycardia and hypotension occurred infrequently. The rate of serious adverse events was higher in patients who were switched to metoprolol. In these patients, the risk of worsening CHF was three times higher than in those who switched to carvedilol.

Similarly, using the same combined endpoint of COMET, patients who switched from carvedilol to metoprolol, in comparison with those who switched from metoprolol to carvedilol or who stayed on the same drug, showed a significantly higher rate of all-cause mortality or hospitalisation. The sudden death rate was also higher in patients receiving metoprolol than in those treated with carvedilol, but the number of arrhythmic events was too low to allow any conclusion on the different effects of the two drugs on arrhythmic death.

The better short-term tolerability of carvedilol compared with metoprolol may be related to the very different pharmacological profiles of the drugs. First, the {alpha}1-blocking properties of carvedilol result in systemic vasodilatation, unloading of the failing left ventricle and improving cardiac function, counteracting the negative inotropic effect of β1-blockade. Consequently, switching from metoprolol to carvedilol is more likely to be better tolerated in terms of cardiac dysfunction than changing the order of administration to the other way around. Secondly, although the lack of up-regulation of β1-receptors in patients treated with carvedilol could favourably influence the haemodynamic tolerability in patients who switched to metoprolol, the negative haemodynamic effect of metoprolol may be related to its greater inverse agonist activity compared with carvedilol [14], resulting in lower cellular cyclic adenosine monophosphate production and thus less cardiac inotropy and chronotropy. Short- and long-term comparisons of the haemodynamic effects of both drugs in patients with heart failure indicate that cardiac output is better preserved with carvedilol than with metoprolol [15–17].

Finally, as recent data suggest, due to the prolonged β-blocking effect of carvedilol, far beyond its elimination in plasma, the higher rate of CHF-related events in patients abruptly switching from carvedilol to metoprolol could also be explained by the additive β-blocking effect of the two drugs [18].

Thus, when switching from carvedilol to metoprolol, the absence of {alpha}1-blockade, the higher inverse agonist activity and the possible early accumulation of β-blocking effect may predispose to worsening heart failure and should be prevented by a longer withdrawal period, reduced initial dose of metoprolol and closer clinical monitoring.

In COMET, carvedilol was compared with the conventional metoprolol tartrate and not with the controlled release formulation of metoprolol succinate[3], inasmuch as this preparation was not available to us when the trial was initiated. In comparison with metoprolol tartrate, metoprolol succinate showed a 30–35% reduced systemic availability [19]. According to these data, it is possible that our scheme of dosage equivalence (Table 1) may result in an initial underdosing with controlled release metoprolol in comparison with metoprolol tartrate. However, a higher initial dose of open β-blockade was associated in our study to a higher rate of adverse events (mainly worsening CHF), and the overall rate of sudden death was relatively small in the study period with only two events (one in carvedilol and one in metoprolol) occurring in the first week after transition. Moreover, the type of metoprolol was specified only in a minority of patients, not allowing any comparison between the two types of preparations.

In previous reports, [7,12,13], the withdrawal of β-blocker treatment in CHF patients was frequently associated with deterioration of symptoms and occasionally with death, mainly sudden. Abrupt discontinuation of β1-blockade with metoprolol tartrate may be associated with a rapid shift of the autonomic balance towards a sympathetic tone within 24 h [6]. This could imply a potential risk for arrhythmias and sudden deaths when abruptly discontinuing β-blocking therapy. In our study, the highest rate of adverse events was seen in patients in whom β-blockade was withdrawn at the end of the COMET study and particularly in patients who had been randomised to carvedilol. Previous experiences suggested a high risk of worsening heart failure or arrhythmic events lasting several months after β-blocker withdrawal [20]. The high rate of adverse events documented in our study may also be explained by the more severe clinical stage of the disease in these patients.

On the basis of previous studies on β-blocker exchange [8,9] and, in order to maximise the safety of such a transition, the Steering Committee recommended that the first dose of poststudy β-blockade should have been equivalent to one-half of the last dosage of blinded study medication. Most investigators started their patients on poststudy β-blockade at equivalent dosage to study medication, probably basing their decision on the clinical status of the patient. This strategy was associated with a higher rate of total and serious adverse events and particularly of worsening heart failure. The transition to carvedilol at half of the equivalent blinded β-blocker dose used in the COMET study maximised the safety of our strategy. The number of adverse events in patients changing from metoprolol to a reduced dose of carvedilol was similar to the low rate seen in patients staying on the same β-blocker. Thus, according to the data presented here, the switch from metoprolol to carvedilol and the subsequent titration of the latter could be easily tolerated by most patients, at least, as well as the initiation and titration of the initial β-blocking treatment in patients with CHF.

4.1. Limitations of the Study
At the end of COMET, it was recommended that patients on study medication were switched to the most appropriate available β-blocker. Such transition could not be blind, inasmuch as randomised comparison was not possible before unblinding of the COMET treatment. The result was an unbalanced switch, with most patients being treated with carvedilol and a minority with metoprolol and particularly with bisoprolol. Inasmuch as there were minor differences in symptoms and diastolic blood pressure, we cannot exclude that the result of the transition could have been partially influenced by baseline characteristics. Nevertheless, the decision to which open-label treatment to change was made before unblinding of study medication, inasmuch as the treatment code was broken in a minority of patients.

Only scant information could be derived from the small group of patients treated with bisoprolol. It is possible that due to its lower inverse agonism [21], a transition from carvedilol to bisoprolol could be better tolerated than a switch from carvedilol to metoprolol. However, no short- and long-term haemodynamic comparisons are available on bisoprolol in comparison with other β-blockers.

4.2. Conclusion
These data considerably expand the current knowledge and provide the clinician with a practical, safe and well-tolerated strategy to optimise β-blocker therapy in patients with CHF. Reducing the initial dose of the second β-blocker maximises the safety of this strategy. Close clinical monitoring is recommended during transition in higher risk patients as in those with NYHA III–IV, hypotension or low dosage of β-blockade.

Abrupt withdrawal of β-blockade in patients with CHF is associated with a high rate of serious adverse events, including in some cases, death. The transition from carvedilol to metoprolol should be carried out under strict clinical monitoring to minimise the possible negative initial pharmacologic effect. The possibility of transition to other β1-blockers needs further investigation. On the other hand, patients can be safely switched to carvedilol to benefit from the survival advantage demonstrated in the COMET study.


   Acknowledgements
 
We thank all the patients who participated in this trial and all the physicians and nurses whose work made the trial possible. The study was supported by F. Hoffmann-La Roche and GlaxoSmithKline.


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

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