Cardiovascular Risks of Inhaled Anticholinergics

1
Cardiovascular Risks of Inhaled Anticholinergics

• Suzy Lim MD
• Family and Community Medicine
• UCSF/SFGH
• October 17 2008

2
Introduction

• COPD is the 4th leading cause of chronic
  morbidity and mortality in the United States
• COPD is projected to rank 5th in burden of
  disease worldwide

3
Introduction

• Anthonisen et al., 2002 unexpected tendency for
  coronary and CVD to be more common in COPD
  patients receiving tiotropium vs. placebo
• Kesten et al., 2006 overall mortality,
  cardiovascular mortality, cardiac arrest, and
  myocardial infarction, did not occur more
  frequently in patients receiving tiotropium
• US Food and Drug Administration, 2008 patient in
  the inhaled tiotropium group experience a
  possible increased risk of stroke.

4
Introduction

• Inhaled tiotropium is the most widely prescribed
  agent for COPD, with more than 8 million patients
  world having used it since its approval in 2002
• Therefore, it is important to establish the
  complete cardiovascular safety profile of inhaled
  anticholinergics in patients with COPD

5
Study Objective

• To ascertain the cardiovascular risks (myocardial
  infarction, stroke, and cardiovascular death)
  associated with inhaled anticholinergics compared
  with control therapies in patients with COPD in
  randomized controlled trials

6
Methods

• Inclusion Criteria for trials
• Study design consisting of an RCT for any inhaled
  anticholinergics with more than 30 days of
  follow-up
• Study participants with a diagnosis of COPD of
  any severity
• An inhaled anticholinergic as the intervention
  drug vs. control (placebo or inhaled B-agonist or
  inhaled steroid B-agonist combination)
• Trial had to report data on incidence of serious
  cardiovascular adverse events

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Methods

• Study Selection
• 2 reviewers independently and in duplicate
  searched for and scanned all potential titles and
  abstracts, then independently assessed
  eligibility from full-text articles.
• Disagreements regarding eligibility were resolved
  with a third reviewer through consensus
• Validity Assessment
• Same 2 reviewers independently and in duplicate
  assessed each study for reporting of allocation
  concealment, the use of blinding, loss to
  follow-up, withdrawal rates, and strength of
  adverse event monitoring

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Methods

• Outcome Measures
• Primary outcome measure
• Composite of nonfatal MI, nonfatal stroke, and
  cardiovascular death
• Secondary outcome measure
• Risk of all-cause mortality
• Data Synthesis and Sensitivity Analysis
• RR with 95 CI calculated
• Statistical heterogeneity assessed
• NNH calculated
• Sensitivity analyses

9
Results

• Study Selection
• From 703 potentially relevant citation, 17 trials
  fulfilled the inclusion criteria
• 12 trials evaluated inhaled tiotropium vs.
  control
• 5 trials evaluated inhaled ipratropium vs.
  control
• 9 trials evaluated inhaled anticholinergics vs.
  placebo
• 7 trials evaluated inhaled anticholinergics
  vs. comparators
• 5 trials were long-term (48wks to 5y)
• 12 trials were short-term trials (6 wks to 26
  wks)

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Results

• Primary Outcome
• Inhaled anticholinergics significantly increased
  the risk of cardiovascular death, MI, or stroke
• RR 1.6 (95 CI 1.2-2.1), P lt0.001
• Inhaled anticholinergics significantly increased
  the risk of cardiovascular death
• RR 1.8 (95 CI 1.2-2.8), P 0.008
• Inhaled anticholinergics significantly increase
  the risk of MI
• RR 1.5 (95 CI 1.1-2.2), P 0.03
• Inhaled anticholinergics did not significantly
  increased the risk of stroke
• RR 1.5 (95 CI 0.8-2.6), P 0.20

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Results

• Secondary Outcome
• Inhaled anticholinergics did not significantly
  increase the risk of all-cause mortality
• RR 1.3 (95 CI 1.0-1.6), P 0.06

12
Results
13
Results

• Sensitivity Analysis
• Analysis by agent
• Tioprium vs. control
• RR 2.1 (95 CI 1.2-3.7), P 0.008
• Ipratropium vs, control
• RR 1.6 (95 CI 1.1-2.3), P 0.02
• Analysis by duration of trial
• 5 long-term trials, gt6mo
• RR 1.7 (95 CI 1.3-2.4), P lt0.001
• 12 short-term trials, lt26wk
• RR 1.2 (95 CI 0.7-2.0), P 0.60

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Results

• Sensitivity Analysis
• Excluded 5 trials for which data on some
  individual end points of the composite were
  unavailable
• RR 1.6 (95 CI 1.2-2.2), P lt 0.001
• Excluded the trial that contributed to more than
  50 of the weight in the fixed-effects model
• RR 1.6 (95 1.1-2.3), P 0.02

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Results

• Estimated NNH with Inhaled Anticholinergics
• for Cardiovascular death
• NNH 40/year (95 CI 18-185 per year)
• for MI
• NNH 174/year (95 CI 75-1835 per year)

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Discussion

• Inhaled anticholinergics significantly increases
  the risk of combined endpoint of cardiovascular
  death, MI, or stroke. This increase is
  particularly manifest in long-term trials

17
Discussion

• The significant increase in the risk of
  cardiovascular death, MI, or stroke, without a
  significant increase in all-cause mortality, may
  have some possible explanations
• 1. lack of statistical power to detect
  differences in all-cause mortality
• Even though difference in number of deaths from
  any cause was greater then difference in number
  of cardiovascular deaths, relative risk was lower
  due to dilutional effect of non-cardiovascular
  deaths
• 2. protective effects of inhaled B-agonists or
  inhaled steroid B-agonists
• However, clinical trial evidence suggests that
  inhaled B-agonists or inhaled steroid and
  B-agonists may, on the contrary, increase risk of
  cardiovascular adverse events

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Discussion

• The findings of this study need to be
  distinguished from other meta-analyses of
  short-term trials that failed to find a
  significant effect of inhaled anticholinergics on
  MI, cardiovascular mortality, respiratory
  mortality, and all-cause mortality
• Other meta-analyses have also failed to find any
  effect of inhaled anticholinergics on all-cause
  mortality

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Discussion

• Biological mechanisms by which inhaled
  anticholinergics increase risk of cardiovascular
  death, MI, or stroke among patients with COPD are
  uncertain
• A study found an increased incidence of
  supraventricular tachycardia with inhaled
  ipratropium
• Another study found increased sputum IL-8 with
  use of inhaled tiotropium. Inflammatory
  cytokines may play a role in mediating
  cardiovascular effects

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Study Strengths

• 2 separate reviewers, with a 3rd reviewer
  mediating
• Large study consisting of 17 RCTs and 14,783
  patients
• The results of subgroup analyses support the
  finding of the meta-analysis
• Results were clinically important and highly
  significant

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Study Limitations

• The adverse events measured (cardiovascular
  death, MI, stroke) were not common, resulting in
  few events. Therefore, the 95 CI are wide,
  resulting in some uncertainty as to the precise
  magnitude of the observed risk
• None of the trials were specifically designed to
  monitor the risk of cardiovascular events
• Patient enrolled in clinical trials may differ
  from our patients. Paper does not provide
  patient characteristics (other then gender and
  age).

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Bottom Line

• Clinicians and patients should carefully balance
  the risk and benefits of inhaled anticholinergics
  
• The Benefits increase in exercise capacity,
  reduction in frequency of exacerbation, fewer
  hospitalization, improvement in quality-of-life
• NNT 21 (95 CI 13-50) to prevent 1 COPD
  exacerbation
• NNT 20 (95 CI 14-34) to prevent 1
  COPD-related hospitalization
• The Risks increase in cardiovascular death and
  MI
• NNH 40 (95 CI 18-185) to cause 1
  cardiovascular death
• NNH 174 (95 CI 75-1835) to cause 1 MI

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Reference

• Sonal S, Loke YK, Furberg CD. Inhaled
  Anticholinergics and Risk of Major Adverse
  Cardiovascular Events in Patients With Chronic
  Obstructive Pulmonary Disease A Systematic
  Review and Meta-analysis. JAMA. 
  2008300(12)1439-1450.