Comparative safety of inhaled medications in patients with chronic obstructive pulmonary disease: systematic review and mixed treatment comparison meta-analysis of randomised controlled trials

Dong, Yaa Hui; Lin, Hsien Ho; Shau, Wen Yi; Wu, Yungang; Chang, Chia‐Hsuin; Lai, Mei‐Shu

doi:10.1136/thoraxjnl-2012-201926

Cited by 127 publications

(127 citation statements)

References 25 publications

Supporting

Mentioning

121

Contrasting

Unclassified

Order By: Relevance

“…Despite this, the two meta-analyses, which reported data on the 5 mg preparation alone, both reported an increased risk of death of 1.46 (95% CI 1.01-2.10) [3] ( fig. 1) and 1.46 (95% CI 1.01-2.14) [5], respectively, and a 5 mg dose was also associated with an increased risk of cardiovascular death, OR 2.18 (95% CI 1.15-4.41) [5].…”

Section: Inclusion Of 10 Mg Datamentioning

confidence: 97%

“…Previous research has shown that allocation of the cause of death in clinical trials of tiotropium is not straightforward and that ''all-cause'' mortality may be a stronger endpoint than cause-specific mortality because of diagnostic uncertainty [18]. Despite this, both the BMJ and Thorax systematic reviews found an increased risk of cardiovascular death with tiotropium Respimat compared with placebo, RR 2.05 (95% CI 1.06-3.99) [3], and OR 1.96 (95% CI 1.07-3.60) [5], respectively. This twofold increase in cardiovascular mortality accounts for about half the increase in all-cause mortality.…”

Section: All-cause Mortality and Cause-specific Mortalitymentioning

confidence: 99%

“…Both the Cochrane [4] and Thorax [5] meta-analyses have reported no effect of tiotropium HandiHaler on mortality risk, and a significant difference in mortality risk between the HandiHaler and Respimat inhalers. It has been suggested that this difference may weaken the evidence of mortality risk with tiotropium Respimat [12].…”

Section: Differential Risk With Tiotropium Productsmentioning

confidence: 99%

“…Tiotropium Respimat significantly increased the risk of mortality, OR 1.47 (95% CI 1.04-2.08). In contrast there was no increased risk of mortality with tiotropium HandiHaler, OR 0.92 (95% CI 0.80-1.05).In 2012 Thorax published a systematic review with direct comparison and mixed treatment comparison meta-analyses of randomised controlled trials of medications used in the treatment of COPD that provided data about overall or cardiovascular death, and were a minimum 6 months in trial duration [5]. In the direct comparison meta-analysis, tiotropium Respimat increased the risk of death compared with placebo, OR 1.49 (95% CI 1.05-2.11).…”

mentioning

confidence: 99%

“…Tiotropium Respimat should not be prescribed in COPD http://ow.ly/mzPGL Systematic reviews and meta-analyses of randomised controlled trials of medications provide a high standard of evidence to inform clinical practice, and can be considered the ''gold standard'' for assessing the risk/benefit profile of treatments [1,2]. Three systematic reviews and meta-analyses (including a Cochrane Review) of randomised placebo-controlled trials of tiotropium Respimat, each using different methods, have demonstrated a 50% increased risk of mortality, with its use in patients with chronic obstructive pulmonary disease (COPD) [3][4][5]. These analyses provide substantive evidence that tiotropium Respimat increases mortality in the treatment of COPD [6,7].…”

mentioning

confidence: 99%

See 4 more Smart Citations

Tiotropium Respimat increases the risk of mortality: pro

Beasley

2013

Eur Respir J

View full text Add to dashboard Cite

@ERSpublications Tiotropium Respimat increases mortality risk. First do no harm. Tiotropium Respimat should not be prescribed in COPD http://ow.ly/mzPGL Systematic reviews and meta-analyses of randomised controlled trials of medications provide a high standard of evidence to inform clinical practice, and can be considered the ''gold standard'' for assessing the risk/benefit profile of treatments [1,2]. Three systematic reviews and meta-analyses (including a Cochrane Review) of randomised placebo-controlled trials of tiotropium Respimat, each using different methods, have demonstrated a 50% increased risk of mortality, with its use in patients with chronic obstructive pulmonary disease (COPD) [3][4][5]. These analyses provide substantive evidence that tiotropium Respimat increases mortality in the treatment of COPD [6,7]. It is informative to review each of the systematic reviews and the issues that have been raised relevant to their interpretation.In 2011 the British Medical Journal (BMJ) published the first systematic review and meta-analysis, which included all parallel-group, randomised, placebo-controlled trials of tiotropium Respimat in the treatment of COPD that had reported data on mortality and were of a minimum 30-day duration [3] (table 1 [ [8][9][10]). Five trials were included in the analysis, two 12-week trials and three 12-month trials, studying 6522 participants. All five trials were judged to be at low risk of bias. Tiotropium Respimat significantly increased the risk of all-cause mortality, relative risk 1.52 (95% CI 1.06-2.16). There was an apparent dose-response effect on all-cause mortality, with RR 1.46 (95% CI 1.01-2.10) and 2.15 (95% CI 1.03-4.51), for the 5-mg and 10-mg preparations, respectively ( fig. 1). The overall estimates were not substantially changed by sensitivity analyses using the random effects model, limiting the analysis to three trials of 1-year duration period each, or the inclusion of additional preliminary data on tiotropium Respimat from an unpublished study. An accompanying editorial calculated, based on these figures, that one excess death is expected for every 121 (COPD) patients treated with a 5 mg dose of tiotropium by Respimat for 12 months [11].The 2012 Cochrane Review of tiotropium included the same five randomised placebo-controlled clinical trials of tiotropium Respimat, but used the Peto method for pooled estimation of odds ratio, which is arguably more appropriate for the combined analysis of rare events such as death [4]. Tiotropium Respimat significantly increased the risk of mortality, OR 1.47 (95% CI 1.04-2.08). In contrast there was no increased risk of mortality with tiotropium HandiHaler, OR 0.92 (95% CI 0.80-1.05).In 2012 Thorax published a systematic review with direct comparison and mixed treatment comparison meta-analyses of randomised controlled trials of medications used in the treatment of COPD that provided data about overall or cardiovascular death, and were a minimum 6 months in trial duration [5]. In the direct comparison meta-analysis, ti...

show abstract

Section: Inclusion Of 10 Mg Datamentioning

confidence: 97%

Section: All-cause Mortality and Cause-specific Mortalitymentioning

confidence: 99%

Section: Differential Risk With Tiotropium Productsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Tiotropium Respimat increases the risk of mortality: pro

Beasley

2013

Eur Respir J

View full text Add to dashboard Cite

show abstract

Effect of Aclidinium Bromide on Major Cardiovascular Events and Exacerbations in High-Risk Patients With Chronic Obstructive Pulmonary Disease

Wise

Scirica

Bhatt

et al. 2019

JAMA

View full text Add to dashboard Cite

IMPORTANCE There is concern that long-acting muscarinic antagonists increase cardiovascular morbidity or mortality in patients with chronic obstructive pulmonary disease (COPD). OBJECTIVE To determine the cardiovascular safety (noninferiority) and efficacy (superiority) of aclidinium bromide, 400 μg twice daily, in patients with COPD and cardiovascular disease or risk factors. DESIGN, SETTING, AND PARTICIPANTS Multicenter, randomized, placebo-controlled, double-blind, parallel-design study conducted at 522 sites in North America. A total of 3630 patients with moderate to very severe COPD and either a history of cardiovascular disease or at least 2 atherothrombotic risk factors were randomized; follow-up occurred for up to 3 years until at least 122 major adverse cardiovascular events (MACE) occurred. The first patient was enrolled on October 16, 2013 and the last on August 22, 2016. The final patient completed follow-up on September 21, 2017. INTERVENTIONS Patients were randomized to receive aclidinium (n = 1812) or placebo (n = 1818) by dry-powder inhaler, twice daily for up to 3 years. MAIN OUTCOMES AND MEASURES The primary safety end point was time to first MACE over up to 3 years (hazard ratio [HR] 1-sided 97.5% CI noninferiority margin = 1.8). The primary efficacy end point was the annual COPD exacerbation rate during the first year of treatment. Secondary outcomes included an expanded MACE definition (time to first MACE or serious cardiovascular event of interest) and annual rate of exacerbations requiring hospitalization. RESULTS Among 3589 patients analyzed (mean age, 67.2 years; 58.7% male), 2537 (70.7%) completed the study. Of these, 69 (3.9%) aclidinium and 76 (4.2%) placebo patients had a MACE (HR, 0.89; 1-sided 97.5% CI, 0-1.23); the expanded MACE definition included 168 (9.4%) aclidinium vs 160 (8.9%) placebo patients with events (HR, 1.03; 1-sided 97.5% CI, 0-1.28). Annual moderate to severe exacerbation rates (aclidinium, 0.44; placebo, 0.57; rate ratio, 0.78; 2-sided 95% CI, 0.68-0.89; P < .001) and rate of exacerbations requiring hospitalization (aclidinium, 0.07; placebo, 0.10; rate ratio, 0.65; 2-sided 95% CI, 0.48-0.89; P = .006) decreased significantly with aclidinium vs placebo. The most common adverse events were pneumonia (aclidinium, 109 events [6.1%]; placebo, 105 events [5.8%]), urinary tract infection (aclidinium, 93 events [5.2%]; placebo, 89 events [5.0%]), and upper respiratory tract infection (aclidinium, 86 events [4.8%]; placebo, 101 events [5.6%]). CONCLUSIONS AND RELEVANCE Among patients with COPD and increased cardiovascular risk, aclidinium was noninferior to placebo for risk of MACE over 3 years. The rate of moderate to severe COPD exacerbations was reduced over the first year.

show abstract

Double-edged Sword?

Woodruff

2013

JAMA Intern Med

View full text Add to dashboard Cite

Comparative safety of inhaled medications in patients with chronic obstructive pulmonary disease: systematic review and mixed treatment comparison meta-analysis of randomised controlled trials

Cited by 127 publications

References 25 publications

Tiotropium Respimat increases the risk of mortality: pro

Tiotropium Respimat increases the risk of mortality: pro

Effect of Aclidinium Bromide on Major Cardiovascular Events and Exacerbations in High-Risk Patients With Chronic Obstructive Pulmonary Disease

Double-edged Sword?

Contact Info

Product

Resources

About