β Blockade after myocardial infarction: systematic review and meta regression analysis
BMJ 1999; 318 doi: https://doi.org/10.1136/bmj.318.7200.1730 (Published 26 June 1999) Cite this as: BMJ 1999;318:1730
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In the paper "beta Blockade after myocardial infarction: systematic
review and meta regression analysis" the authors of a review of randomized
controlled trials fail to consider the possible adverse effects of beta
Blockade, particularly in the elderly patient.1
In a review of 7 trials, that included 13,796 patients, beta blockers
such as metoprolol, a beta blocker mentioned in the review, were associated
with a 41% increase in the risk of hypotension. A significant risk of
dizziness was reported in 4 trials that included 7,789 patients and a
significant risk of brachycardia was reported in 7 trials that included
13,796 patients. 2 Metoprolol is metabolized by cytochrome P450 2d6. A
subset of the patient population, with genetic polymorphisms in the
cytochrome p450 2d6 gene, are poor metabolizers of metoprolol and that
subset has a 5-fold higher risk for developing adverse effects.3
5 to 10% of whites are poor metabolizers of metoprolol. 4 Perhaps
this is one reason that beta Blockers are underused. A significant risk of
falls was associated with hypotension in a group of 70 men and women aged
62-92 years old.5 Pharmacogenetic testing is now available for use in
clinical practice to test for genotypic differences in patients with
different CYP2D6 genotypes.6 It would seem that these tests could be used
prior to prescribing â blockers for older patients with heart disease and
consistent with the optimum safe usage of beta blockade to reduce morbidity
and mortality after myocardial infarction.
1. Freemantle N, Cleland J, Young P, et al. â Blockade after
myocardial infarction: systematic review and meta regression analysis. BMJ
June 1999; 26 June;318:1730-37.
2. Ko DT, Hebert PR, Coffey CS et al. Adverse effects of Beta-Blocker
therapy for patients with heart failure. Arch Intern Med, 2004;164:1389-
1394.
3. Wuttke H, Rau T, Heide R, et al. Increased frequency of
cytochrome P450 2D6 poor metabolizers among patients with
metoprolol-associated adverse effects. Clin Pharmacol Ther 2002;72:29-37.
4. Wilkinson GR. Drug Metabolism and Variability among patients in Drug
Response. N Engl. J Med 2005; 352:2211-21.
5. Heittarachi E, Lord SR, Meyercort P, et al. Blood Pressure changes on
upright tilting predict falls in older people. Age and Ageing 2002;31:181-
186.
6. de Leon J, Armstrong SC, Cozza KL. Clinical guidelines for the use of
pharmacogenetic testing for CYP450 2D6 and CYP450 2C19. Psychosomatics.
2006 Jan-Feb; 47(1):75-85.
Competing interests:
None declared
Competing interests: No competing interests
Two questions:
Is there any evidence of benefit when beta-blockers are started many years
after the MI? I have a number of patients who have had MIs twenty to
thirty years ago and who have been perfectly well since with no angina.
Do they now merit treatment?
Once the beta-blocker has been started should it be carried on for
life? (if tolerated and no contra-indications emerge).
Many thanks.
Competing interests: No competing interests
Editor - The conclusions drawn by Freemantle et al (1) from their
systematic review of trials of b blockers after acute myocardial
infarction support the meta-analysis published by Yusuf et al. in 1985
(2). However, the key issue in understanding the variable uptake of this
form of treatment into clinical practice is not efficacy but
generalisability. The trials did not study "unselected patients", since
those thought likely to be intolerant of b blockade were excluded either
by protocol or on clinical judgement. Can the results be extrapolated to
the whole clinical population of patients with acute myocardial
infarction? What is the 'right' level of use in routine practice? This can
be explored indirectly using observational data from that population.
The European Secondary Prevention Study Group (3) examined treatment of a
truly representative sample of patients (n=4,035), admitted to hospital
with acute myocardial infarction, from 11 geographically defined European
regions during 1993-4. Overall, 20% of patients (range 6-38%) had no
recorded contraindications but were discharged without a b blocker.
Importantly, analysis of treatment continuation to six months gave no
evidence that high prevalence of b blockade at discharge was associated
with a high discontinuation rate. The converse was true; the odds ratio
for continued use at 6 months for a 10% increase in b blocker use at
discharge was 1.33 (95% CI 1.22 - 1.47) after controlling for potential
confounding by age and sex. Therefore, discontinuation of b blocker
treatment at 6 months was significantly less likely in regions where the
proportion of patients given b blockers at discharge was high (>70%).
The documented long-term tolerability of b blockers in most post-infarct
patients supports their wider use. As Freemantle et al point out, the case
is further strengthened by accumulating evidence that cautious
introduction of b blockade reduces mortality in patients with heart
failure.
Diane Ketley
Clinical Governance Programme Leader
Centre for Best Practice
Leicester Royal Infirmary
Kent L Woods
Professor of Therapeutics
Department of Medicine and Therapeutics
University of Leicester
The authors have no conflicting interests.
References
1. Freemantle N, Cleland J, Young P, Mason J, Harrison J. Beta
blockade after myocardial infarction: systematic review and meta
regression analysis. BMJ 1999;318:1730-7.
2. Yusuf S, Peto R, Lewis J, Collins R, Sleight P. Beta blockade
during and after myocardial infarction: an overview of the randomized
trials. Progr Cardiovasc Dis 1985; 27:335-71.
3. Woods KL, Ketley D, Lowy A, Augusti A, Hagn C, Kala R et al (The
European Secondary Prevention Study Group). Beta-blockers and
antithrombotic treatment for secondary prevention after acute myocardial
infarction. Eur Heart J 1998; 19:74-79.
Competing interests: No competing interests
As I read through Freemantle et al's excellent systematic review of
beta blockade after myocardial infarction 1, I looked particularly for
evidence about the effectiveness of atenolol. In my practice, atenolol is
our first choice of beta blocker for hypertension, angina and secondary
prevention because it is convenient (once daily dose), cheap, and
relatively free from side effects in most patients.
After the promising, if inconclusive, results of early short term
trials of atenolol (pooled OR 0.93, 95%CI 0.85 to 1.02) it was frustrating
to find that there were so few long term trials that the results (OR 1.02,
95%C 0.52 to 1.99) were meaningless. The wide confidence intervals of the
long term trials reflect the weight of 1.6% for long term trials of
atenolol compared to 74.2% for the short term trials, and the authors
rightly conclude that atenolol has been inadequately evaluated for long
term use.
This gives me and thousands of other GPs a dilemma. Should we switch
patients from atenolol to propranolol (inconvenient dosage or expensive
sustained release preparations, plus more side effects) or timolol, which
is also considerably more expensive than atenolol? If we are to follow the
available evidence, then we should. On the other hand, absence of evidence
of effectiveness is not the same as evidence of absence of effectiveness,
and it is possible that atenolol is, in reality, as effective as
propranolol or timolol. That we lack evidence one way or the other for the
effectiveness of so ubiquitous a drug as atenolol in so important a
clinical area as secondary prophylaxis of myocardial infarction represents
a failure in research and development planning and policy.
Why was work on atenolol virtually abandoned after the promising
early results? Was it just that newer compounds seemed more exciting than
older ones? This seems unlikely, given that there is adequate evidence
about propranolol, an even older drug. It is more likely that the research
agenda was driven not only by the clinical need for evidence, but by the
need for pharmaceutical companies to obtain evidence supportive of their
products in order to increase sales. Perhaps atenolol, no longer under
patent, was just too unprofitable to justify adequate research funding?
I am worried that the principles of evidence-based medicine can be
manipulated by pharmaceutical companies. They have the financial resources
to carry out large randomised controlled trials, seeking outcomes which
show their products in the most favorable light, while research on equally
important questions remains underfunded.
1. Freemantle N, Cleland J, Young P, Mason J, Harrison J. Beta
blockade after myocardial infarction: systematic review and meta
regression analysis. BMJ 1999;318:1730-7
Competing interests: No competing interests
The authors fail to consider possible adverse effects of Beta Blockade, particularly in the elderly patient
In the paper "Beta Blockade after myocardial infarction: systematic
review and meta regression analysis" the authors of a review of randomized
controlled trials fail to consider the possible adverse effects of beta
blockade, particularly in the elderly patient.1
In a review of 7 trials, that included 13,796 patients, beta blockers
such as metoprolol, a beta blocker mentioned in the review, were
associated with a 41% increase in the risk of hypotension. A significant
risk of dizziness was reported in 4 trials that included 7,789 patients
and a significant risk of brachycardia was reported in 7 trials that
included 13,796 patients. 2 Metoprolol is metabolized by cytochrome P450
2d6. A subset of the patient population, with genetic polymorphisms in the
cytochrome p450 2d6 gene, are poor metabolizers of metoprolol and that
subset has a 5-fold higher risk for developing adverse effects.3
5 to 10% of whites are poor metabolizers of metoprolol. 4 Perhaps
this is one reason that beta blockers are underused. A significant risk
of falls was associated with hypotension in a group of 70 men and women
aged 62-92 years old.5 Pharmacogenetic testing is now available for use in
clinical practice to test for genotypic differences in patients with
different CYP2D6 genotypes.6 It would seem that these tests could be used
prior to prescribing beta blockers for older patients with heart disease
and consistent with the optimum safe usage of beta blockers to reduce
morbidity and mortality after myocardial infarction.
1. Freemantle N, Cleland J, Young P, et al. Beta Blockade after
myocardial infarction: systematic review and meta regression analysis. BMJ
June 1999; 26 June;318:1730-37.
2. Ko DT, Hebert PR, Coffey CS et al. Adverse effects of Beta-Blocker
therapy for patients with heart failure. Arch Intern Med, 2004;164:1389-
1394.
3
. Wuttke H, Rau T, Heide R, et al. Increased frequency of cytochrome P450
2D6 poor metabolizers among patients with metoprolol-associated adverse
effects. Clin Pharmacol Ther 2002;72:29-37.
4. Wilkinson GR. Drug Metabolism and Variability among patients in Drug
Response. N Engl. J Med 2005; 352:2211-21.
5. Heittarachi E, Lord SR, Meyercort P, et al. Blood pressure changes on
upright tilting predict falls in older people. Age and Ageing 2002;31:181-
186.
6. de Leon J, Armstrong SC, Cozza KL. Clinical guidelines for the use of
pharmacogenetic testing for CYP450 2D6 and CYP450 2C19. Psychosomatics.
2006 Jan-Feb; 47(1):75-85.
Competing interests:
None declared
Competing interests: No competing interests