Effect of β blockers in treatment of chronic obstructive pulmonary disease: a retrospective cohort study
BMJ 2011; 342 doi: https://doi.org/10.1136/bmj.d2549 (Published 10 May 2011) Cite this as: BMJ 2011;342:d2549
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While exactly the same comments are once again made by de Vries
regarding immortal time bias for the overall analysis of effects of beta-blockers (ie irrespective of treatment step), pointedly our analysis
showed additive effects of beta-blockers over all treatment steps, which
we believe was the key finding here. We therefore firmly stand by the
results of our original peer reviewed data analysis which remain valid. Furthermore in the original article we acknowledged that any results from
a retrospective analysis should not be used a recommendation to change
clinical practice, but more to act a catalyst to stimulate further
research. As De Vries will fully appreciate, results from a retrospective
health informatics analysis can never be any substitute for a proper
randomised controlled control. Challenging clinical equipoise is always
going to be difficult, and we therefore would prefer to focus on the
positive aspects of our study as elegantly outlined by Israel in the
accompanying editorial, perhaps leading to a definitive prospective
randomised placebo controlled trial of beta-blockers in COPD. In this way
we may as clinicians actually progress further as was shown to be the case
in heart failure, to the ultimate benefit of patients.
Competing interests: No competing interests
To the Editor,
with the greatest interest I have read the recent retrospective
cohort study on the use of beta-blocker in COPD. Analyzing a large
longitudinal Scottish database the authors describe a significant and
robust reduction in morbidity and mortality in patients with COPD being
prescribed a beta blocker 1. Importantly lung function did not
deteriorate. Concerning the underlying pathophysiology the authors
discussed "that up-regulation of beta2 adrenoceptors by chronic beta
blockade may improve the effectiveness of beta2 agonists". While this is
certainly appealing, the concept of neurohumoral activation might
contribute to the positive effects of beta blockade in COPD as detailed
below.
With a variety of methods we and others described striking
neurohumoral activation in patients with COPD 2 3 4. From patients with
heart failure it is well known, that beta blocker reduce mortality and
morbidity by their impact on sympathetic and neurohumoral activation. Thus
it is intriguing to speculate that beta blocker exerts their beneficial
effects in COPD patients via the autonomic nervous system. Indeed, also
ACE inhibitors and angiotensin receptor blocker (being successfully used
to treat heart failure) also show positive effects in COPD 5 6.
One might consider historic parallels concerning the use of beta
blocker in heart failure and COPD. Only two decades ago beta blocker were
considered contraindicated in patients with heart failure due to their
negative inotropic and chronotropic effects. Large randomized controlled
trials have subsequently clearly demonstrated positive effects of beta
blockade in patients with heart failure. These positive results being
explained by the blockade of maladaptive neurohumoral activity on the
cardiovascular system 7. Of note pharmacologic therapy coined at
neurohumoral activation needs more than a few weeks to reveal its overall
positive effects. The present study informs us about the need and how to
perform a randomized controlled trial of beta blocker in COPD 8.
Yours sincerely
Stefan Andreas
Prof. Dr. med. Stefan Andreas
Lungenfachklinik Immenhausen, Krs Kassel
Gastprofessor
Universitaetsmedizin Goettingen
Abteilung Kardiologie und Pneumologie
www.herzzentrum-goettingen.de
References
1. Short PM, Lipworth SI, Elder DH, Schembri S, Lipworth BJ. Effect
of beta blockers in treatment of chronic obstructive pulmonary disease: a
retrospective cohort study. Bmj 2011;342:d2549.
2. Andreas S, Anker SD, Scanlon PD, Somers VK. Neurohumoral
activation as a link to systemic manifestation of chronic lung disease.
Chest 2005;128:3618-3624.
3. Raupach T, Bahr F, Herrmann P, Luethje L, Heusser K, Hasenfuss G,
et al. Slow breathing reduces sympathoexcitation in COPD. Eur Respir J
2008;32(2):387-392.
4. Luethje L, Raupach T, Michels H, Unsold B, Hasenfuss G, Kogler H,
et al. Exercise intolerance and systemic manifestations of pulmonary
emphysema in a mouse model. Respir Res 2009;10(1):7.
5. Raupach T, Luethje L, Koegler H, Duwe C, Schweda F, Hasenfuss G,
et al. Effects of angiotensin II type 1 receptor blockade on pulmonary and
systemic manifestations in an emphysema mouse model. Pulm Pharmac Ther
2011 24:215-20.
6. Mortensen EM, Copeland LA, Pugh MJ, Restrepo MI, de Molina RM,
Nakashima B, et al. Impact of statins and ACE inhibitors on mortality
after COPD exacerbations. Respir Res 2009;10:45.
7. Schrier RW, Abraham WT. Hormones and hemodynamics in heart
failure. N Engl J Med 1999;341:577-85.
8. Kazani S, Israel E. Treatment with beta blockers in people with
COPD. Bmj 2011;342:d2655.
Competing interests: No competing interests
Immortal time bias explained 64% of the reduction of mortality with
beta blocker use in Scottish COPD patients [1,2]. The distorted, 22%
reduced risk of mortality was published by the BMJ on 10 May 2011 [1].
Correction for immortal time bias resulted in an only 8% reduced risk [2],
that could still be the result of residual confounding or healthy user
bias. "Immortal time in observational studies can bias the results in
favour of the treatment group, but it is not difficult to identify and
avoid". This was the sub header of a manuscript on research methodology,
that was published in this journal one year earlier. It emphasizes the
"detrimental impact that such biased findings can have on clinical
practice and health policy by promoting the use of potentially ineffective
therapies or interventions" [3]. We highly appreciate the efforts by Dr
Short and colleagues to reanalyze their key findings. But they have not
shown the impact of removal of immortal time bias on the other findings.
In the original manuscript, the biased reduction in mortality has not been
corrected by the editorial staff either. Currently, it only shows up in
this online discussion and is therefore less likely to be picked up by
readers. Because we have spotted a potential immortal time bias in a
similar observational study that was published in the Archives of Internal
Medicine, [4] we are worried that the distorted risk reductions will be
included in future meta-analyses. This may then further inflate the bias,
and promote the potential use of beta blockers in patients with COPD. For
the other manuscript, we have notified the first author in order to
discuss a reanalysis of their data [4]. In the meantime, we would suggest
that the BMJ will publish a new DOI version of the manuscript by Short et
al, with complete removal of immortal time bias [1].
Kind regards,
Arief Lalmohamed
Frank de Vries
[1] Short PM, Lipworth SIW, Elder DHJ, Schembri S, Lipworth BJ.
Effect of beta blockers in treatment of chronic obstructive pulmonary
disease: a retrospective cohort study. BMJ 2011;342:d2549.
[2] http://www.bmj.com/content/342/bmj.d2549.short/reply, accessed 25
August 2011
[3] Levesque LE, Hanley JA, Kezouh A, Suissa S. Problem of immortal
time bias in cohort studies: example using statins for preventing
progression of diabetes. BMJ 2010;340:b5087.
[4] Rutten FH, Zuithoff NP, Hak E, Grobbee DE, Hoes AW. Beta-blockers
may reduce
mortality and risk of exacerbations in patients with chronic obstructive
pulmonary disease. Arch Intern Med. 2010;170(10):880-7.
Competing interests: The Department of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute of Pharmaceutical Sciences, employing authors AL and FV, has received unrestricted funding for pharmacoepidemiological research from GlaxoSmithKline, Novo Nordisk, the private-public funded Top Institute Pharma (www.tipharma.nl, includes co-funding from universities, government, and industry), the Dutch Medicines Evaluation Board, and the Dutch Ministry of Health.
Cox Regression with time dependent analysis comparing patients
exposed to beta-blocker or no beta-blocker assessing effects on all-cause
mortality, shows a significant overall effect; HR 0.92 (95%CI 0.85-0.96).
Pointedly our study revealed that irrespective of concurrent inhaled
treatment for COPD, beta-blockade conferred significant additivity on
outcomes including mortality, exacerbations and hospitalisations. As such
we believe our observations support the hypothesis that beta-blockers may
be a useful adjunct for treating patients with COPD.
Competing interests: No competing interests
Short et al. reported a reduction of 22% in all cause mortality and
38-69% in exacerbations with beta blocker use in Scottish COPD patients
[1]. However, the study may be subject to immortal time bias [2]. Patients
exposed to beta blockers may have had a substantial period of "immortal
time". They had to survive the period from their inclusion (a
hospitalization for COPD) until the second beta blocker prescription to be
considered exposed.
In addition, immeasurable time bias may be an issue in
this study [3]. In-hospital medication use could not be measured within
this database. As a result, hospitalized patients (severe COPD) may have
been misclassified as unexposed. Both biases will result in an artificial
benefit of beta blocker use (or of any other drug), as compared to non-users. This has been described previously for mortality in COPD patients
with use of inhaled corticosteroids [3-5].
Immortal time bias could have
been addressed with a time-dependent Cox analysis that also addresses the
period of "immortal time" [2,5] or with a nested case control approach.
Immeasurable time bias could have been quantified by assessing the person-years affected by "immeasurable time" in each group [3].
References
1. Short PM, Lipworth SIW, Elder DHJ, Schembri S, Lipworth BJ. Effect
of beta blockers in treatment of chronic obstructive pulmonary disease: a
retrospective cohort study. BMJ 2011;342:d2549.
2. Suissa S. Immortal time bias in observational studies of drug
effects. Pharmacoepidemiol Drug Saf 2007;16:241-249.
3. Suissa S. Immeasurable time bias in observational studies of drug
effects on mortality. Am J Epidemiol 2008;168:329-335.
4. Sin DD, Man SF, Tu JV. Inhaled glucocorticoids in COPD: immortal
time bias. Am J Respir Crit Care Med 2003;168:126-127.
5. Suissa S. Effectiveness of inhaled corticosteroids in chronic
obstructive pulmonary disease: immortal time bias in observational
studies. Am J Respir Crit Care Med 2003;168:49-53.
Competing interests: The Department of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute of Pharmaceutical Sciences, employing authors AL and FV, has received unrestricted funding for pharmacoepidemiological research from GlaxoSmithKline, Novo Nordisk, the private-public funded Top Institute Pharma (www.tipharma.nl, includes co-funding from universities, government, and industry), the Dutch Medicines Evaluation Board, and the Dutch Ministry of Health. DS and MD have no conflicts of interest to declare.
Competing interests: No competing interests
Dear Editor,
The study from Short et al raises interesting questions as to how
beta-blockers might reduce mortality in COPD(1). One other possibility
that should be considered is reduction in multifocal atrial tachycardia
and other supraventricular arrhythmias by beta-blockade, independent of
ischaemic heart disease or cardiac failure. In one large cohort study, 40%
of COPD patients were noted to have atrial tachycardia even before
treatment with a long-acting beta agonist(2). These arrhythmias are well
documented in COPD related to a variety of possible factors including
atrial distension, autonomic dysfunction, drugs (including theophyllines),
electrolyte changes, hypertension, acidosis and raised catecholamine
levels due to hypoxia. Multifocal atrial tachycardia in particular has
been associated with an inpatient hospital mortality approaching 50% and a
poor prognosis in COPD(3).
References
1. Short PM, Lipworth SIW, Elder DHJ, Schembri S, Lipworth BJ. Effect
of beta-blockers in treatment of chronic obstructive pulmonary disease: a
retrospective cohort study. BMJ 2011:342:d2549.
2. Hanrahan JP, Grogan DR, Baumgartner RA, Wilson A, Cheng H,
Zimetbaum PJ, Morganroth J. Arrhythmias in patients with chronic
obstructive pulmonary disease (COPD): occurrence frequency and the effect
of treatment with the inhaled long-acting beta2-agonists arformoterol and
salmeterol. Medicine (Baltimore). 2008;87(6):319-28.
3. Payne, RM. Management of arrhythmias in patients with severe lung
disease. Clin Pulm Med 1994; 1:232-7.
Competing interests: No competing interests
Re: Effect of β blockers in treatment of chronic obstructive pulmonary disease: a retrospective cohort study
Dear Editor,
Your study mentioned that with the exception of tiotropium, combination treatments involving long acting bronchodilators and inhaled corticosteroids have failed to show any significant improvement in mortality (1, 2).
Reviewing, the above mentioned references; Crim et al and Rodrigo et al did not assume that treatment of COPD patients with tiotropium showed improvement in mortality (1, 2).
Wedzicha et al reported that mortality was significantly lower in COPD patients treated with salmetrol/fluticasone proprionate compared with those treated with tiotropium propionate (3).
The UPLIFT study, reported that treatment with tiotropium over 4 years was associated with decreased mortality, but patients in the placebo group in this study were using other non study inhaled medication and there was no statistical significant difference in overall mortality (HR, 0.89 [CI, 0.79 to 1.02]) (4, 5).
Kind regards,
Christian Ghattas
References:
1. Crim C, Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, et al. Pneumonia risk in COPD patients receiving inhaled corticosteroids alone or in combination: TORCH study results. Eur Respir J. 2009 Sep;34(3):641-7.
2. Rodrigo GJ, Castro-Rodriguez JA, Plaza V. Safety and efficacy of combined long-acting beta-agonists and inhaled corticosteroids vs long-acting beta-agonists monotherapy for stable COPD: a systematic review. Chest. 2009 Oct;136(4):1029-38.
3. Wedzicha JA, Calverley PM, Seemungal TA, Hagan G, Ansari Z, Stockley RA. The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide. Am J Respir Crit Care Med. 2008 Jan 1;177(1):19-26.
4. Celli B, Decramer M, Kesten S, Liu D, Mehra S, Tashkin DP. Mortality in the 4-year trial of tiotropium (UPLIFT) in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2009 Nov 15;180(10):948-55.
5. Qaseem A, Wilt TJ, Weinberger SE, Hanania NA, Criner G, van der Molen T, et al. Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society. Ann Intern Med. 2011 Aug 2;155(3):179-91.
Competing interests: No competing interests