Tiotropium: Do the findings of a CV safety signal in the meta-analyses have implications for all drugs to treat COPD? Lorcan McGarvey MD FRCP Queen s University Belfast CSRC Outcomes Think Tank meeting: Washington 19 th February 2014
Background - weight of the evidence Anti-cholingergics (SAMA) mainstay of symptomatic relief for COPD patients 2004: FDA approved use of Tiotropium Handihaler (HH) first LAMA 2007: possible drug related increase in stroke first reported to FDA by Boehringer Ingelheim Pooled data from 29 placebo controlled Tiotropium trials Early Communication issued by FDA
Background weight of the evidence Sept 2008: Singh et al publish meta-analyses of 17 trials evaluating CV safety of inhaled anti-cholinergics (SAMAs and LAMAs) RR of CV event 1.6 (95% [CI], 1.22 to 2.10) They concluded: use of inhaled anticholinergics associated with a significantly increased risk of major cardiovascular event including death from myocardial infarction and stroke Singh S et al. JAMA 2008; 300: 1439-50
Background weight of the evidence Boehringer Ingelheim report increased mortality (all cause) in 3 placebo controlled 1- year studies of Tiotropium (Respimat inhaler) RR for death (5µg Tio compared with placebo) 1.7 (95% CI, 1.1 to 2.8) adjusted to 1.4 (95% CI, 0.9to 2.0)
Tashkin DP et al. N Eng J Med 2008; 359:1543-54 Contrasting findings in the big COPD trials - UPLIFT and TIOSPIR Understanding Potential Long term Impacts of Tiotropium on Lung Function (UPLIFT) 4-year randomised, placebo controlled clinical trial of Tiotropium Handihaler (HH) Results available end 2008: 17,721 patient years exposure Independent Mortality Adjudication Committee No increase in myocardial Infarction, CV or any cause death
Summary table of comparison between pooled analysis and the UPLIFT study Michele TM et al. N Eng J Med 2010
TIOtropium Safety and Performance In Respimat (TIOSPIR) 17,135 COPD patients (including patients with stable cardiac disease) Tiotropium Respimat at once daily dose of 2.5µg and 5µg compared with 18µg Tiotropium Handihaler Primary endpoint: Risk of death with 2.5µg or 5µg Respimat versus 18µg HH Key results: mean follow up 2.3 years Respimat at either dose non-inferior wrt death vs HH No increased mortality in participants with preexisting stable CV disease Wise RA et al. N Eng J Med 2013
Mechanism based mode of action Anti-cholinergics suppress parasympathetic control and potentially increase the risk of tachyarrhythmia Tiotropium (unlike atropine) is a quaternary ammonium structure (poorly absorbed) should potentially limit systemic effects Class effect? Pharmacokinetics of other compounds differ (half life, rapid hydrolysis in plasma)
LAMAs: Meeting a medical need Sustained 24-hour bronchodilatation Improved symptoms & QoL Reduction in COPD exacerbations Emerging concerns around anti-inflammatory therapy (inhaled corticosteroids) A number of similar compounds now available Alone and in combination with LABAs Prominent place in current treatment/management guidelines (GOLD)
GOLD classification of COPD ICS/LABA or LAMA ICS/LABA or LAMA SAMA prn SABA prn LABA or LAMA
My thoughts on the question Not all drugs to treat COPD (Inhaled corticosteroids have their own issues and the issue of LABAs perhaps more pertinent for asthma) Why and of what do COPD patients die from in clinical (including CV) trials Even large well conducted clinical trials can t be expected to inform completely on post-market drug safety How representative can a clinical trial be? (TIOSPIR excluded MI in previous 6/12 and NYHA class III & IV heart failure) Changing demographics (aging co-morbid population) provide challenges now and future
Summary Slide What Was The CV Safety Issue Leading to Outcome Study Requirement Weight of Evidence Presence of a Likely MOA for Risk Benefit:Risk Relationship for Drug? Is perceived risk: Generalizable to Other Drugs in Class or with Same Efficacy MOA? Lesions Learned Reported excess of CV deaths in meta-analysis of Inhaled anti-cholinergics (including Tiotropium) Currently large RCTs do not suggest increased CV risk withtiotropium Yes anti-cholinergic suppression of parasympathetic control theoretically increases risk of tachyarrhythmia Need to consider this in low and high risk populations No. There are differences in pharmacokinetics Caution in interpreting results of metanalyses but balance this against the generalizability of RCTs