Tiotropium Handihaler and the risk of cardio- or cerebrovascular events and mortality in patients with COPD

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Abstract

Background

Tiotropium has been associated with an increased risk of mortality and/or cardiovascular events. Recent data from RCTs suggests tiotropium Handihaler to be safe, but its safety has not yet been fully investigated under real-life circumstances.

Methods

We conducted 2 nested case-control studies in a COPD cohort from the Dutch IPCI database. In the first case-control study, cases had a cardiovascular or cerebrovascular endpoint (CCVE): stroke and transient ischemic attack (TIA), myocardial infarction, heart failure and/or ventricular arrhythmia. In the second, cases were all patients who died. Cases were matched to controls on age, sex and index date. Conditional logistic regression analysis was used to calculate adjusted odds ratios (ORadj) with 95% confidence intervals (CI) for tiotropium vs. long-acting beta-agonists (LABA).

Results

Within a cohort of 6788 COPD patients, 784 CCVE’s and 1032 deaths were reported. Compared to current LABA use, use of tiotropium Handihaler was neither associated with an increased risk of a CCVE (ORadj 0.89, 95% 0.55–1.44) nor with an increased risk of death (ORadj 0.79, 95% CI 0.49–1.28).

Conclusions

In real life, use of tiotropium Handihaler in COPD patients is not associated with an increased risk of a CCVE or mortality compared to LABA.

Highlights

► There is conflicting evidence on the cardiovascular safety of tiotropium in patients with COPD. ► The safety of tiotropium has not yet been fully investigated under real-life circumstances. ► Results from our case-control study, nested in a large cohort of COPD patients, demonstrate that current use of tiotropium Handihaler does not increase the risk of cardiovascular events compared to current use of long-acting β2-agonists (LABA). ► Our nested case-control study shows that current use of tiotropium Handihaler does not increase the risk of mortality compared to current use of LABA in patients with COPD.

Introduction

Chronic obstructive pulmonary disease (COPD) is a major cause of chronic morbidity and mortality worldwide. According to data from the World Health Organization (WHO), COPD is expected to become the third leading cause of death by 2020. Bronchodilators are the mainstay of symptomatic management of COPD and include β2-agonists, anticholinergics (AC), and methylxanthines, used alone or in combination.[1] Long-acting bronchodilators are more effective and convenient than the short-acting agents [1]. Tiotropium is a long-acting inhaled AC bronchodilator developed for the long term, once daily, maintenance treatment of COPD. The efficacy and safety of tiotropium have been described in RCTs, with imprecise reductions for mortality and a significantly lower risk for COPD exacerbations [2].

In March 2008, the FDA made an early communication on a small excess risk of stroke with tiotropium over placebo based on a pooled analysis of 29 RCTs. That same year, 2 other publications reported an increased risk for mortality and/or cardiovascular (CV) events in patients on inhaled ACs (ipratropium or tiotropium) [3], [4]. In 2008 the results of the UPLIFT study (Understanding Potential Long term Impacts on Function with Tiotropium) were published showing a reduced risk of cardiovascular events for tiotropium Handihaler as compared to placebo (RR 0.84, 95% CI 0.73–0.98). In addition, this study showed a non-significant trend for a decrease of death from any cause in tiotropium Handihaler treated patients compared to placebo treated patients (HR 0.89, 95% CI 0.79–1.02) in the intention to treat analysis [5], [6]. In November 2009, the FDA concluded that the risk of stroke, heart attack or death is not increased in COPD patients using tiotropium Handihaler [7].

As tiotropium continues to be used in a wider population, there is a need to better examine safety under non-experimental real-life conditions. For this reason, we studied the cardiovascular and cerebrovascular safety and risk of mortality of tiotropium Handihaler compared to LABA in a cohort of well-defined COPD patients from the general population.

Section snippets

Setting

The study was conducted in the Integrated Primary Care Information Project (IPCI) database. IPCI is a population-based longitudinal database that contains the complete computer-based medical records of more than 400 General Practitioners (GPs) throughout the Netherlands [8]. In the Dutch healthcare system, patients are registered with a single GP who acts as a gatekeeper of medical care and of information from primary care visits, hospital admissions and outpatient visits. At present, the ICPI

COPD cohort

From the source population of 185,325 individuals, 40 years and older, 6788 patients were diagnosed with COPD of which 23% had incident COPD. The median follow-up time per COPD patient was 3.5 years, with a total follow-up time of 23.930 person-years. Baseline characteristics of the COPD cohort are described in Table 1. As IPCI is a primary care database, up to 80% of patients had mild or moderate COPD at cohort entry. Since COPD has lately been recognized as a systemic disease, we thoroughly

Discussion

Pooled analysis of data from RCTs provided conflicting information on the potential cardiovascular risk of tiotropium. We conducted a nested case-control study in a COPD cohort to further elaborate the potential cardiovascular risks of tiotropium used under real-life circumstances. We did not observe an increased risk for a cardiovascular or cerebrovascular endpoint and/or mortality in COPD patients currently treated with tiotropium compared with LABA.

The debate on the potential association

Conflict of interest

This research was supported by an unconditional grant from Pfizer/Boehringer-Ingelheim. As this research grant was unconditional, this meant that the sponsor was not actively involved in the design of the study, gathering of data, analyses and interpretation of the data or in the writing of the manuscript.

KV has been involved as project leader in analyses contracted by various pharmaceutical companies and received unconditional research grants from Pfizer and Yamanouchi, none of which are

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