Beta-blockers may reduce mortality and risk of
exacerbations in patients with chronic
obstructive pulmonary disease
Frans H. Rutten, Nicolaas P. A. Zuithoff, EelkoHak, Diederick
E. Grobbee, Arno W. Hoes
Arch Intern Med. 2010;170(10):880-887.
Introduction: Prevalence and
Definition
4th leading cause of death in the US, also a major cause of
diability
Estimated 12 million in US diagnosed, another estimated 12
million in US remain undiagnosed
(http://www.nhlbi.nih.gov/health/public/lung/copd/index.htm)
Key components of the COPD definition by The GOLD (Global
Initiative for Chronic Obstructive Lung Disease):
(http://www.goldcopd.com/)
• preventable and treatable disease significant extrapulmonary
effects
• pulmonary component is characterized by airflow limitation that is
not fully reversible
– airflow limitation is usually progressive and associated with an
abnormal inflammatory response of the lungs to noxious particles or
gases
Introduction: Diagnosis
Suspect in all patients with chronic cough, chronic sputum
production, dyspnea (at rest or with exertion), and/or history
of inhalational exposure
Confirm with spirometry:
GOLD: FEV1/FVC <0.70
Hopkins: FEV1/FVC actually differs 5 or more percent from
predicted
Note: make sure no alternative diagnosis such
as bronchiectasis, vocal cord paralysis, or
tracheal stenosis which can mimic PFTs of
COPD
Introduction: Therapy
http://www.spirometrie.info/img/gold_therapy.jpg
Introduction: Question: Does long-term beta
blocker use improve survival and reduce the risk
of exacerbations in patients with COPD?
• Beta blockers improve survival in patients with heart
failure, IHD
• Meta-analyses show that cardioselective beta-blockers
are well-tolerated in COPD; no significant effect of
FEV1, beta-agonist response, inhaler use, or respiratory
symptoms
Salpeter SS, Ormiston T, Salpeter E, Poole P, Cates C. Cardioselective beta-blockers for chronic
obstructive pulmonary disease. Cochrane Database Syst Re. 2002;(2):CD003566.
• Prior study showing that beta-blockers had a nonsignificant tendency to reduce all-cause mortality in
patients with HTN and COPD
Au DH, Bryson CL, Fan VS, et al. Beta-blockers as single-agent therapy hypertension and the risk
of mortality among patients with chronic obstructive pulmonary disease. Am J Med.
2004;117(12):925-931.
Methods: Study Design
•Goal: Does long-term B-blocker use improve survival and
reduce risk of COPD exac in COPD pts including those
without CV disease.
• Observational Cohort of 2230 patients from the GP
network database in Utrecht, Netherlands.
• 23 practices – 35 GPs from 1995 to 2005.
• Inclusion criteria: >= 45yrs, incident or prevalent
diagnosis of COPD.
•Exclusion criteria: Patients who moved or lost to f/u,
database doesn’t have nursing home residents.
• Outcomes: All cause mortality, 1st COPD exac during
study period.
Methods: Definitions
• COPD : by ICD 9 codes for chronic bronchitis,
COPD/emphysema, sx of dyspnea/cough/sputum
for at least 3 mon/yr for 2 consecutive yrs and
rhonchii on exam (70% of COPD cases conform to
GOLD criteria).
• COPD exac: pulsed-dose prescription of steroids
during 7-10 days and/or hospitalization for exac.
• Overt CV disease: Angina, MI, CABG, PCI, Afib,
CHF, PAD, CVA, DM (Htn not included)
Methods: Data Analysis
• Cox proportional hazards regression used to calculate
crude and adjusted hazard ratios for risk of all cause
death and COPD exac with use of all beta blockers and
then with cardioselective and non-cardioselective beta
blockers.
• Missing smoking data: performed imputation and
sensitivity analyses to compare to imputation data –
were similar
• To adjust for confounding medication and improving
power, they used Propensity score and Subgroup
analysis
Patient Characteristics
-Small % of non-HTN
pts in no β-blocker
group
-More pts with CV
comorbidities in the βblocker group
-Could pts with CV dz
not on β-blocker be
undertreated? Could
they represent more
severe COPD?
Patient Characteristics
-Significantly more pts NOT on β-blocker ARE on inhaled β2 agonist
-More β-blocker pts treated with anticholinergics
-Are pts w/ COPD being treated for COPD appropriately?
-Do pts on inhaled β2 agonists but not on β-blockers have more severe COPD?
Mortality and β-blocker use
All CI < 1
All CI cross 1;
higher point
estimates
Mortality and subgroup analysis
• Subgroups included:
– No overt cardiovascular disease
(defined as no angina, MI, ischemic heart dz, afib, CHF,
CVA, PAD; note HTN is missing)
– Pts taking meds:
• 2 or more pulmonary drugs
• β2 agonists
• inhaled anticholinergics
– Incident cases of COPD
– Pts referred to pulmonologist
Subgroup analysis
“Patients without (overt) cardiovascular
comorbidities in our study still had HTN
as the reason for β-blocker use”
-Note very low mortality rate, 19.6%
-All other subgroups had mortality ranging
from 29.8 – 40.5%
-Implies healthier patients, greater
functional reserve, fewer CV
Comorbidities
-Incident cases of COPD may indicate less
severe disease at onset
-75% of pts included were “incident
cases”
-Could incident COPD mean less severe?
Subgroup analysis
-Surprisingly few patients on β2 agonists
treated with β-blocker
-Is use of 2 or more pulmonary drugs really
a surrogate of severe COPD?
(i.e. β-agonist and inhaled steroids)
-Again, are pts being treated optimally for
their underlying COPD?
Survival in COPD patients according to βblocker use
Change
in survival
No significant
mortality
effect rate
at ~60 after
months
until >20 months
initiation
parallel to no β-blocker
Subgroup analysis
-Referral to pulmonologist as surrogate for
severity of COPD
-β-blocker shows no improvement in
mortality in pts expected to have severe
COPD
-No convincing evidence of harm either
-Note that all of the CI cross 1, but all
point estimates <1
- Point estimates of HR are significantly
higher than other subgroups
Survival in COPD patients referred to
pulmonologist
Change in slope at
~60 months in pts
with severe COPD
Alternative hypothesis:
Pulmonologist HARM patients with COPD as corroborated below:
Referral to Kevin Gibbs
No
Yes
Kevin Gibbs and IPF
Kevin Gibbs and IPF treatment
No
Yes
*www.facebook.com
Kevin Gibbs and sepsis
Kevin Gibbs and sepsis treatment
No
Yes
*www.facebook.com, Levy et al. ANN INTERN MED
2008;148:801-809
COPD exacerbation and β-blocker use
All CI < 1 and point estimates
are similar
COPD exacerbations sub group analysis
All CI < 1 except for one
-smaller % of COPD exacerbations in pts with
no overt CV disease and incident cases of COPD
indicating less severe disease burden vs. those
referred to pulmonologist
Discussion Point #1:
Confounding Issues
primary CM
CHF
hypertension
COPD
Pulm HTN
A. fib/flutter
CAD/IHD
Smoking
asthma
Discussion Point #2:
What historical factors may have influenced
treatment during the study period?
• Prevailing theories on beta blocker use
• Available medications
Discussion Point #3:
Would this change your practice?
Why or why not?
Discussion Point #4:
What else do you want to know? What would
you hope to see addressed in a clinical trial?