European Journal of Heart Failure 2004 6(4):449-451; doi:10.1016/j.ejheart.2004.01.015
© 2004 European Society of Cardiology
Beta-blocker induced bradycardia—should we pace?
Uta C. Hoppe
Department of Internal Medicine III, University of Cologne Cologne, Germany
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1. Beta-blocker therapy in guidelines
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Beta-blockade improves survival, reduces hospitalisations for
heart failure, and improves left ventricular function when given
over a long period of time to patients with symptomatic systolic
heart failure in the functional classes NYHA II–IV. Current
international guidelines recommend the initiation of beta-blocker
therapy in all stable symptomatic patients with systolic heart
failure, using one of the three beta-blockers (bisoprolol, carvedilol
or metoprolol), which have been shown to reduce morbidity and
mortality in outcome trials. In asymptomatic patients in functional
class NYHA I, the European Society of Cardiology recommends
beta-blocker therapy following myocardial infarction, while
the American Heart Association extends the recommendation to
all asymptomatic patients with systolic dysfunction. Beta-blocker
medication should be started at a very low dose and should be
titrated up to the high maintenance dosages shown to be effective
in large outcome trials. However, from clinical experience and
data of intervention trials, it is evident that some patients
cannot be up-titrated due to the induction of bradycardia. Indeed,
in the US Carvedilol program, the CIBIS study and the MERIT-HF
trial, bradycardia was one of the most common reasons, why patients
could not be up-titrated to the target dose (
Table 1). In mildly
and moderately symptomatic patients in the US Carvedilol trail,
bradycardia was documented as an adverse event during the double
blind up-titration and maintenance phase in 12.9% and 9% of
the carvedilol group compared to 0.7% and 1% in the placebo
group, respectively
[1,
2]. In the MERIT HF trail metoprolol
CR/XL could not be fully titrated due to bradycardia in 9.1%
of patients in NYHA class II, while bradycardia was observed
in 2.4% receiving placebo. In more symptomatic patients (NYHA
III/IV) bradycardia was even more frequent (11.3% in the metoprolol
CR/XL group vs. 3.3% in the placebo group)
[3]. Discontinuation
of the beta-blocker due to low heart rate, however, was rather
rare in the large outcome trials (0.3–0.9%) (
Table 2).
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2. Do we have to titrate up beta-blocker therapy in heart failure patients?
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The MOCHA trial (
n=345) is the only randomized endpoint study
comparing different beta-blocker dosages (carvedilol 2
x6.25
mg vs. 2
x2.5 mg vs. 2
x25 mg) in heart failure patients
[4].
No dose-related difference in the primary endpoint of exercise
tolerance was found. The dose response of the change in ejection
fraction from baseline was completely flat in patients with
ischemic heart disease, the most common cause of heart failure.
Survival improved significantly in the low-, medium-, and high-dose
carvedilol groups compared with placebo. Though linear regression
analysis suggested a dose-related reduction of all-cause mortality,
no significant difference of survival benefit was provided between
the individual dose groups (respective mortality rates of 6.0%,
6.7%, and 1.1% with increasing doses of carvedilol vs. 15.5%
in the placebo group).
In a subgroup analysis of the CIBIS II trial, patients were classified according to the last tolerated dose (low dose 1.25–3.75 mg, moderate dose 5–7.5 mg, and high dose 10 mg of bisoprolol or placebo) [5]. Patients tolerating only low doses (of bisoprolol or placebo) were significantly older with more severe NYHA functional class and a higher frequency of co-morbidities. The heart rate reduction with bisoprolol was similar regardless of the tolerated dose. The probability of all-cause mortality was reduced in high and moderate dose groups of both bisoprolol and placebo compared with the respective low dose groups. However, compared to placebo, survival was significantly improved in all bisoprolol groups regardless of the dose level achieved.
These findings are consistent with a subgroup analysis of the MERIT-HF trial [6]. Patients were divided according to the maximal tolerated metoprolol dose (
100 mg vs. >100 mg). Baseline heart rate was similar in the low dose and high dose groups. The maximal tolerated beta-blocker dosages lead to a comparable heart rate reduction. In the low dose and high dose groups a similar reduction of total mortality, sudden cardiac death and death from worsening heart failure was observed. These results indicate that the maximal tolerated beta-blocker dose results in a similar degree of β1-blockade in an individual patient and in a significant risk reduction.
Although these retrospective data and subgroup analyses may not be used to choose the dose of a beta blocker they suggest that patients who can only tolerate small doses of beta-blockers may be more sensitive to their effects and get a greater bradycardia for the same dose. Currently, no evidence supports that when a beta-blocker causes bradycardia titrating the dose up further will provide any additional benefit in chronic systolic heart failure.
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3. Pacing in heart failure: good or bad?
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The number of patients not tolerating a minimal beta-blocker
dose in clinical practice is higher than suggested by the withdrawal
rate of 0.6–0.9% in randomised trials as a baseline heart
rate <60–68 bpm was an exclusion criterion in these
studies. Thus, it is of interest whether pacing per se is good
or harmful in heart failure. First data indicating that pacing
might be harmful in heart failure was provided by Saxon et al.
who showed that heart failure patients requiring pacemakers
had a significantly higher risk for death or urgent transplantation
compared with matched controls
[7]. In recent years, evidence
from basic research and clinical trials is growing that stimulation
of the right ventricular (RV) apex not only acutely leads to
a reduction of the stroke volume due to pacing-induced ventricular
desynchronization but also results in long term deterioration
of left ventricular function. During a follow-up over 9 years,
young adults with RV pacing developed a significant reduction
of the ejection fraction compared to age matched controls
[8].
In patients with sick-sinus-syndrome and normal left ventricular
function, ventricular pacing, even when AV synchrony is preserved,
increases the risk of heart failure hospitalization and atrial
fibrillation
[9].
In heart failure, further evidence is provided by the DAVID trial in which patients with an ejection fraction 40%, an indication for ICD therapy but no bradycardia were randomised to either a VVI-ICD with backup stimulation (40 bpm) or a DDDR-ICD with a stimulation rate of 70 bpm [10]. The DDDR-ICD group had a significantly greater cumulative right ventricle pacing rate (55.7%) compared to the VVI-ICD group (2.9%). This was associated with a significant increase in death or first hospitalisation for new or worsening heart failure in the double chamber ICD group. Similar results where obtained in a surveillance trial comparing dual-chamber to single-chamber ICDs in patients with severe ischemic cardiomyopathy. Patients with a double-chamber ICD had a significantly higher rate of all-cause mortality. The most important independent predictor for mortality was RV pacing. These results indicate that RV pacing in heart failure further alters left ventricular function, and increases mortality and hospitalization due to new or worsened heart failure.
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4. Conclusions
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- – Patients who tolerate a minimal beta-blocker dose should be up-titrated guided by the individual patient's tolerability and heart rate response. These patients should not be paced to achieve a higher beta-blocker dose.
- – In patients not tolerating a minimal beta-blocker dose due to sinus node dysfunction, atrial pacing (i.e. AAI) might be considered in individual patients to initiate a beta-blocker therapy.
- – Although development of significant AV block with the use of a beta-blocker suggests that there is disease of the conduction system, in patients not tolerating a minimal beta-blocker dose due to AV-block, right ventricular pacing should be avoided. Currently, no data are available supporting biventricular pacing or HIS pacing to enable a beta-blocker therapy in this population.
- – In patients not tolerating beta-blockers who have left bundle branch block (>130 ms) and severe heart failure, biventricular pacing should be considered.
However, clinical trials addressing these questions are definitely warranted.
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References
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- Colucci W.S., et al. Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure. Circulation (1996) 94(11):2800–2806. US Carvedilol Heart Failure Study Group.[Abstract/Free Full Text]
- Packer M., et al. for the US Carvedilol Heart Failure Study Group. 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]
- Gottlieb S.S., et al. Tolerability of beta-blocker initiation and titration in the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). Circulation (2002) 105(10):1182–1188.[Abstract/Free Full Text]
- Bristow M.R., et al. Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. MOCHA Investigators. Circulation (1996) 94(11):2807–2816.[Abstract/Free Full Text]
- Simon T., Mary-Krause M., Funck-Brentano C., Lechat P., Jaillan P. Bisoprolol dose-response relationship in patients with congestive heart failure: a subgroup analysis in the cardiac insufficiency bisoprolol study (CIBIS II). Eur Heart J (2003) 24(6):552–559.[Abstract/Free Full Text]
- Wikstrand J., Stevenson W.G., Middlekauff H.R., Stevenson L.W. Dose of metoprolol CR/XL and clinical outcomes in patients with heart failure: analysis of the experience in metoprolol CR/XL randomized intervention trial in chronic heart failure (MERIT-HF). J Am Coll Cardiol (2002) 40(3):491–498.[Abstract/Free Full Text]
- Saxon L.A., et al. Increased risk of progressive hemodynamic deterioration in advanced heart failure patients requiring permanent pacemakers. Am Heart J (1993) 125(5 Pt1):1306–1310.[CrossRef][Web of Science][Medline]
- Tantengco M.V., Thomas R.L., Karpawich P.P. Left ventricular dysfunction after long-term right ventricular apical pacing in the young. J Am Coll Cardiol (2001) 37(8):2093–2100.[Abstract/Free Full Text]
- Sweeney M.O., et al. Adverse effect of ventricular pacing on heart failure and atrial fibrillation among patients with normal baseline QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction. Circulation (2003) 107(23):2932–2937.[Abstract/Free Full Text]
- Wilkoff B.L., et al. Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial. J Am Med Assoc (2002) 288(24):3115–3123.[Abstract/Free Full Text]
- CIBIS Investigators, A randomized trial of beta-blockade in heart failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS). CIBIS Investigators and Committees. Circulation, 1994; 90(4): pp. 1765–1773.
- Krum H., et al. Effects of initiating carvedilol in patients with severe chronic heart failure: results from the COPERNICUS Study. J Am Med Assoc (2003) 289(6):712–718.[Abstract/Free Full Text]
- Hjalmarson A., et al. Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestive heart failure (MERIT-HF). J Am Med Assoc (2000) 283(10):1295–1302. MERIT-HF Study Group.[Abstract/Free Full Text]
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