Download Tolerability of Conversion from Carvedilol to Metoprolol

original Research
Tolerability of Conversion from Carvedilol to
Metoprolol Succinate in Patients with Heart Failure
Chadwick K. Mellen, BA, and Joseph P. Rindone, PharmD
Abstract
• Objective: To ascertain the tolerability and safety
of changing carvedilol to metoprolol in patients with
heart failure.
• Design: Observational, retrospective review.
• Setting: Outpatient clinic.
• Participants: Patients with diagnosis of heart failure
or ejection fraction < 40% who were taking carvedilol
for at least 6 months before conversion to metoprolol.
• Measurements: Blood pressure, heart rate, weight,
and percentage of patients requiring urgent care
and/or hospitalization for heart failure before and
after conversion. Background heart failure drug
therapy was recorded before and after conversion.
• Results: 142 patients were reviewed. There was
no statistical difference in any parameter measured.
108 patients had no problem with the conversion,
and 4 patients had evidence of worse heart failure
after conversion. 30 other patients changed back to
carvedilol, 8 cases due to worsening heart failure.
• Conclusion: The majority of patients with heart failure can be switched from carvedilol to metoprolol
without adverse sequelae.
C
arvedilol is a β-blocking agent with proven benefits
in heart failure [1]. In early 2006, there was a national
shortage of carvedilol, which posed a clinical dilemma in patients with heart failure. At the time, it was unclear
when shipments of carvedilol would resume, meaning that
many patients with heart failure might exhaust their supply
of the drug. Since stopping β blockers either abruptly or by
taper can be dangerous in patients with heart failure, our
facility decided to change all patients to metoprolol succinate to circumvent the possibility of β-blocker outage [2].
Since there are no data describing the safety and tolerability
of changing β blockers in patients with heart failure, we retrospectively collected outcome data in these patients before
and after the conversion.
Methods
The medical records of patients converted from carvedilol to
metoprolol in January 2006 were reviewed. To be included in
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the analysis, all the patients had to have the diagnosis of heart
failure and or an ejection fraction less than 40% noted in the
medical record. The dose of metoprolol was twice the total
daily dose of carvedilol and administered once daily. There
was no titration phase when changing to metoprolol. Data
collected were the number of urgent care visits and/or hospitalizations (for heart failure–related symptoms) 6 months before and 6 months after the conversion. Patients had to be on
carvedilol at least 6 months before conversion to be included
in the analysis. The most recent systolic/diastolic blood pressure readings, heart rate, and weight were recorded before
and after the conversion. Doses of carvedilol and metoprolol
just before and after conversion were noted. Other concomitant heart failure drugs were also recorded while on both
b blockers. Noncontinuous variables were compared between
groups using a McNemar’s test. Continuous variables were
compared be­tween groups using a paired t test. Statistical
analysis was performed using SigmaStat 3.0 software (SPSS,
Inc, Chicago, IL). Statistical significance was set at an alpha
of < 0.05.
Results
The review included 142 patients. All patients were male
with a mean age of 73 ± 8 years. The mean dose of carvedilol
and metoprolol immediately before and after conversion was
30 mg ± 18 and 60 mg ± 36, respectively. Background drug
therapy for heart failure was similar before and after conversion (Table 1 and Table 2). No statistical differences were
noted between groups with regard to blood pressure, heart
rate, and weight (Table 3). There was no statistical difference
between groups in patients requiring an urgent care visit or
hospitalization for heart failure; only patients who were on
metoprolol were analyzed for this outcome measure.
One hundred eight (76%) patients underwent the conversion with no problems (Figure). Four patients had worsening heart failure on metoprolol but stayed on the drug. The
dose ranged from 25 to 100 mg/day and onset was 1 to
3 months after conversion in these patients. Thirty patients were changed back to carvedilol for various reasons
From the Northern Arizona Veterans Affairs Health Care System, Prescott, AZ.
Vol. 14, No. 2 February 2007 JCOM 99
CHANGING b
BLOCKERS IN HEART FAILURE
Table 1. Percentage of Patients on Other Heart Failure
Drugs Before and After Conversion
Table 3. Patient Clinical Characteristics Before and After
Conversion
Carvedilol
Metoprolol
P Value
Carvedilol
Metoprolol P Value
Furosemide or hydro-
chlorothiazide
53%
52%
0.60
Systolic blood pressure, mm Hg
123 ± 17
124 ± 17
0.57
66 ± 11
66 ± 11
0.71
Lisinopril or losartan
62%
61%
0.61
Spironolactone
25%
24%
0.72
Diastolic blood pressure,
mm Hg
Digoxin
32%
30%
0.68
Heart rate, bpm
71 ± 12
73 ± 13
0.14
Weight, kg
88 ± 17
88 ± 18
0.72
5.2
3.5
0.74
Patients requiring urgent
care/hospitalization for heart failure, %
Table 2. Mean Doses of Background Heart Failure
Drugs Before and After Conversion
Mean Dose (mg/day)
Carvedilol
Metoprolol
P Value
Furosemide
41 ± 33
40 ± 22
0.50
Spironolactone
23 ± 14
26 ± 13
0.19
Lisinopril
19 ± 16
17 ± 16
0.06
Losartan
50 ± 35
58 ± 33
0.29
0.170 ± 0.07
0.155 ± 0.07
0.10
15 ± 14
25
0.17
Digoxin
Hydrochlorothiazide
(Figure). Eleven of these were for cardiac side effects, 8 of
which were due to worsening heart failure. This made for
a total of 12 patients (8%) who had worsening heart failure
with the conversion, whether they stayed on metoprolol or
changed back to carvedilol. Of those who changed back to
carvedilol because of worsening heart failure, 3 had continued heart failure symptoms and died during the review
period. The details of these deaths are unknown. Another
patient had worsening symptoms that required hospitalization. There were no data in the medical record regarding
the outcome of the other 4 patients who made the change
back to carvedilol because of worsening heart failure. Eight
patients refused to take metoprolol either on their own volition or per instruction by the primary physician.
Discussion
This is the first observational study that reports the tolerability and safety of changing β blockers in patients with
heart failure. Our results show that the majority of patients
can undergo this change without adverse events. Eight
percent of patients reported worsening of heart failure with
metoprolol. It is not known if this deterioration was due
to the change in the b blocker or a reflection of the natural
history of heart failure. Our observations suggest that the
deterioration was from a natural course, since 4 patients had
a continued decline in heart function after the switch back
to carvedilol. In addition, we found no difference in urgent
care/hospitalizations before and after conversion.
100 JCOM February 2007 Vol. 14, No. 2
Although 21% of patients changed back to carvedilol,
closer review showed that many of these patients were
changed for dubious reasons. One patient had increasing
angina, which could have been compensated by increasing the metoprolol dose. Another patient had hypotension,
which may have resolved with dose reduction of metoprolol.
Four patients reported noncardiac side effects that were
unusual and looked suspicious as to real cause and effect
(eg, blindness, smell disturbance, rash, arthritis).
Our study is limited in that it was observational and
retro­spective. To accurately gauge the tolerability of changing carvedilol to metoprolol would involve a randomized
blinded study done in a crossover fashion using a relatively
large number of patients. Whether such a study will be done
is doubtful. Our results do reflect the real-world conversion
of carvedilol to metoprolol in patients with heart failure.
Our program to change β blockers could be criticized
based on our dose conversion. We used a 2:1 ratio (metoprolol/
carvedilol) based on guidelines published by the Veterans Affairs Pharmacy Benefits Management Group. This conversion
was somewhat arbitrarily set, based on standard doses for
both drugs. One small crossover study compared short-acting
metoprolol to carvedilol in patients with heart failure using a
dose conversion of approximately 4:1 (metoprolol/carvedilol)
[3]. Overall, there was no difference in New York Heart Association functional class or various hemodynamic variables at
rest between β blockers. However, 21% of patients developed
hypotension, bradycardia, or worsening of symptoms after
switching from carvedilol to metoprolol. This suggests that the
dose conversion may have been excessive in this series.
Many patients refused to use anything but carvedilol,
based either on their own volition or by recommendation of
their primary physician. This may be due to the belief that
carvedilol is a superior drug to metoprolol for heart failure.
The COMET study showed superiority in overall survival in
heart failure patients with carvedilol versus metoprolol [4].
However, there have been criticisms of this study, including the relatively low dose of metoprolol used and that a
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original Research
Patients converted to metoprolol
142
Remained on metoprolol
112
No problems
108
Deterioration of heart failure
4
Changed back to carvedilol
30
Noncardiac side effects on metoprolol
7
Cardiac side effects on metoprolol
11
Physician requested
6
Angina
1
Worsening heart failure
8
Hypotension
2
Unknown
4
Patient refused
2
Figure. Patient flowchart.
short-acting form was used instead of a long-acting product,
like the succinate salt [5]. A long-acting form of metoprolol
was used in the MERIT-HF study, which showed a significant mortality benefit versus placebo [6]. These criticisms of
COMET may in part explain why the American Heart
Association guidelines on heart failure treatment do not advocate carvedilol over metoprolol succinate as the preferred
b blocker in heart failure [7]. This was a major reason for our
change to metoprolol as the formulary b blocker for heart
failure at our facility.
Corresponding author: Joseph P. Rindone, Northern Arizona Veterans
Affairs Health Care System, 500 N Hwy 89, Prescott, AZ 86313,
[email protected].
Financial disclosures: None.
Author contributions: conception and design, JPR; analysis and interpretation of data, CKM, JPR; drafting of the article, JPR; critical
revision of the article, CKM; collection and assembly of data, CKM.
References
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