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25 March 2010
A US cohort study in patients with COPD found an increased risk of CV events associated with the use of ipratropium within the past six months. In contrast, a report on the CV safety of tiotropium from Boehringer Ingelheim’s pooled safety database found tiotropium was associated with a statistically significant reduction in the risk of all-cause mortality, CV mortality and CV events.
Level of evidence:
Level 2 (limited quality patient-oriented evidence) according to the SORT criteria.
Action
Cardiovascular (CV) safety concerns about ipratropium (and to a lesser extent tiotropium) come from observational studies and retrospective pooled analyses of data. These have inherent limitations and only flag up potential safety issues, not confirm them. The UPLIFT trial and the recent report from the tiotropium trial database are reassuring about the safety of tiotropium. However, continued monitoring of both ipratropium and tiotropium is required.
Prescribers should continue to follow NICE guidance on the management of patients with COPD, which is due to be updated in June 2010. When decisions are made around which bronchodilator to use, choice in individual patients should take account of their response to a trial of the drug, the drug’s side effects, patient preference and cost. These new safety data, as well as the potential benefits from treatment, should also feature in these decisions. Considering each drug in terms of its efficacy, safety, patient factors and cost may provide a starting point for discussions with patients about which treatment to trial first. However, the individual choice will probably depend more on whether they can use the inhaler device, tolerate the drug and how effective the medication is for their symptoms. COPD is a heterogeneous disease that affects different patients in different ways, and the management of an individual patient’s disease should be guided by the symptoms and disability that they experience.
What is the background to this?
The cardiovascular safety of inhaled anticholinergics in patients with COPD was discussed in some detail in MeReC Bulletin Volume 19, Number 4, April 2009. In 2008, a meta-analysis by Singh et alraised concerns that short- and long-acting anticholinergics may be associated with increased CV events and CV mortality in patients with COPD. However, the large four-year randomised controlled trial (RCT), UPLIFT, was reassuring about the safety of tiotropium. In the November 2008 issue of Drug Safety Update, the MHRA concluded that it was difficult to draw firm conclusions on the risk of all-cause mortality, CV death, or stroke associated with inhaled anticholinergics in COPD, and further analyses are needed to shed light on any possible increased risk.
Two more articles relating to anticholinergics and CV safety in COPD were published in the January issue of Chest. These were a cohort study in US Veterans looking at CV events associated with ipratropium, and a report on the CV safety of tiotropium from Boehringer Ingelheim’s pooled trial safety database.
What do these studies claim?
The US cohort study in 82,717 Veterans with a new diagnosis of COPD found an increased risk of CV events (acute coronary syndrome, heart failure or cardiac dysrhythmia) associated with the use of anticholinergics within the past six months (99.98% of prescriptions for anticholinergics were for ipratropium and just 0.02% were for tiotropium). There was no increased risk if ipratropium was used more than six months prior. Compared with no exposure to anticholinergics within the past year, exposure to four or less 30-day equivalents of ipratropium within the past six months was associated with a 40% increase in CV events (adjusted hazard ratio [HR] 1.40, 95% confidence interval [CI] 1.30 to 1.51). Exposure to more than four 30-day equivalents of ipratropium within the past six months was associated with a 23% increase in CV events (adjusted HR 1.23, 95%CI 1.12 to 1.35). Across the entire cohort, the absolute rate of CV events was 2.2 per 100 patient years. There is no information given in the paper about the absolute rates in patients either exposed to or not exposed to anticholergics.
The report on the CV safety of tiotropium included 8,699 patients receiving placebo and 10,846 patients receiving tiotropium from 30 RCTs of at least four weeks duration (including 5,992 patients from the four-year UPLIFT trial). Based on adverse event reporting from these trials, tiotropium was associated with a statistically significant reduction in the risk of all-cause mortality, CV mortality and CV events. The incident rate (IR) for all-cause mortality was 3.44 per 100 patient-years with tiotropium vs. 4.10 per 100 patient-years with placebo (relative risk [RR] 0.88, 95%CI 0.77 to 1.00, P<0.05). For the composite CV endpoint (CV death, non-fatal myocardial infarction [MI], non-fatal stroke, sudden/cardiac death) the IR was 2.15 per 100 patient-years with tiotropium vs. 2.67 per 100 patient-years with placebo (RR 0.83, 95%CI 0.71 to 0.98); and for CV mortality it was 0.91 per 100 patient-years with tiotropium vs. 1.24 per 100 patient-years with placebo (RR 0.77, 95%CI 0.60 to 0.98).
So what?
The US cohort study, adds further weight to the concern that inhaled short-acting anticholinergics, i.e. ipratropium, may be associated with increased CV events in patients with COPD. This observational study does have several limitations, including a lack of data on patients dying or being admitted for emergency CV events outside Veterans Affairs hospitals. However, its results are consistent with earlier studies. An earlier Veterans Affairs observational study found patients taking ipratropium had a significantly increased risk of CV and all-cause mortality compared with patients not taking this drug (odds ratio [OR] CV death 1.34, 95%CI 1.22 to 1.47, OR for all-cause mortality 1.11, 95%CI 1.08 to 1.15,). Likewise, a meta-analysis by Singh et al found that inhaled anticholinergics (ipratropium or tiotropium) significantly increased the composite outcome of CV death, MI and stroke compared with control therapy (1.8% vs. 1.2%; RR 1.58, 95%CI 1.21 to 2.06). When ipratropium and tiotropium were analysed separately, a significant increase in the composite outcome was seen with ipratropium in pooled analyses of short-term trials (<6 months duration), long-term trials (>6 months duration), and all trials combined. For tiotropium, an increase in the composite outcome was seen in pooled analyses of the four long-term trials, but not in the short-term trials or all tiotropium trials combined. This meta-analysis has been criticised on methodological grounds, particularly because it pooled results for short- and long-acting anticholinergics, integrated placebo-controlled and active-controlled trials and did not take into account differential discontinuation. More detail on the Singh meta-analysis, including its limitations, can be found in a previous blog.
The report on the CV safety of tiotropium adds to the evidence that tiotropium, unlike ipratropium, does not increase the risk of CV events. Indeed, adverse event reporting from the tiotropium trial database suggests that tiotropium actually reduces, not increases, the risk of CV events. In the UPLIFT trial, which randomised 5,993 people with COPD to tiotropium or placebo for four years, no increase in all-cause mortality and rates of MI and stroke were reported (HR for all-cause mortality 0.89, 95%CI 0.79 to 1.02; RR for MI 0.73, 95%CI 0.53 to 1.00; RR for stroke 0.95, 95%CI 0.70 to 1.29). When adverse events rather than efficacy outcomes were analysed from UPLIFT, there was a statistically significant reduction in fatal events with tiotropium compared with placebo (12.8% vs. 13.7%; HR 0.84, 95%CI 0.73 to 0.97). This is similar to what has been seen in this latest report which included 30 RCTs of tiotropium, one of which was UPLIFT (fatal adverse events 3.44 per 100 patient-years vs. 4.10 per 100-patient years; RR 0.88, 95%CI 0.77 to 1.00, P<0.05).
These data are reassuring about the CV safety of tiotropium. However, it should be remembered that none of the trials included in the recent report, including UPLIFT, were specifically designed to look at any CV endpoints; and the data reported are based on adverse event reporting, not efficacy endpoints. Also of note is the fact that patients with a recent history of MI, arrhythmia or heart failure were excluded from UPLIFT (and possibly other studies) therefore, it is not known whether these patients may be at an increased risk of any drug-related CV events in a real-world setting. Further details of the UPLIFT study are available in an earlier blog.
In the November 2008 issue of Drug Safety Update, the MHRA concluded that it was difficult to draw firm conclusions on the risk of all-cause mortality, CV death, or stroke associated with inhaled anticholinergics in COPD, and further analyses are needed to shed light on any possible increased risk. These recent publications add to the concerns about ipratropium, and the reassurance about tiotropium. However, it is unclear why short-acting anticholinergics would affect the CV system differently to long-acting anticholinergics (see editorial in Chest for further discussion).
Current NICE guidance for COPD recommends that short-acting bronchodilators (either a short-acting beta2 agonist e.g. salbutamol or terbutaline, or ipratropium), as necessary, should be the initial empirical treatment for the relief of breathlessness and exercise limitation. Patients who remain symptomatic should have their inhaled treatment intensified to include long-acting bronchodilators (either a long-acting beta2 agonist e.g. formoterol or salmeterol, or tiotropium) or combined therapy with a short-acting beta2-agonist and ipratropium. Long-acting bronchodilators should be used in patients who remain symptomatic despite treatment with short-acting drugs, and also in patients who have two or more exacerbations per year. This guidance is due to be updated in June 2010 and the NICE website should be consulted for updates.
When decisions are made around which bronchodilator to use, NICE advises that choice in individual patients should take account of their response to a trial of the drug, the drug’s side effects, patient preference and cost. This new safety data, as well as the potential benefits from treatment, should also feature in these decisions. Considering each drug in terms of its efficacy, safety, patient factors and cost may provide a starting point for discussions with patients about which treatment to trial first (see Table 1 in MeReC Bulletin Volume 19, Number 4) However, the individual choice will probably depend more on whether they can use the inhaler device, tolerate the drug and how effective the medication is for their symptoms. COPD is a heterogeneous disease that affects different patients in different ways, and the management of an individual patient’s disease should be guided by the symptoms and disability that they experience. The management of severe COPD has a large palliative element and focuses on symptom control and optimising quality of life.
Study details –
Ogale SS, et al. Cardiovascular events associated with ipratropium bromide in COPD. Chest 2010;137:13–19
Design
Cohort study
Patients
82,717 US Veterans with a new diagnosis of COPD between 1999 and 2002. Subjects followed until first hospitalisation for a CV event (acute coronary syndrome, heart failure, or cardiac dysrhythmia), death, or end of the study period (September 30, 2004).
Intervention and comparison
Cumulative anticholinergic exposure calculated as number of 30-day equivalents (ipratropium bromide) within the past year. Compared with no exposure to anticholinergics within the past year.
Outcomes and results
6,234 CV events identified (44% heart failure, 28% acute coronary syndrome, 28% dysrhythmia. See above for further details.
Sponsorship
Funded by US Department of Veteran Affairs Health Services Research and Development
Celli B, et al. Cardiovascular safety of tiotropium in patients with COPD. Chest 2010;137:20-30
Design
Report on Boehringer Ingelheim’s pooled safety database of 30 completed clinical trials of tiotropium in COPD to September 2008. Included trials were placebo-controlled, double-blind, parallel-group, at least 4 weeks duration
Patients, Intervention and comparison
19,545 patients randomised: 10,846 to tiotropium and 8,699 to placebo. Mean FEV1 = 1.15 ± 0.46L (41 ± 14% predicted), 76% men, mean age = 65 ± 9 years. Cumulative exposure to study drug: 13,146 patient-years with tiotropium and 11,095 patient-years with placebo.
Outcomes and results
The IR for all-cause mortality was 3.44 per 100 patient-years with tiotropium vs. 4.10 per 100 patient-years with placebo (relative risk [RR] 0.88, 95%CI 0.77 to 1.00, P<0.05). For the composite CV endpoint (CV death, non-fatal myocardial infarction [MI], non-fatal stroke, sudden/cardiac death) the IR was 2.15 per 100 patient-years with tiotropium vs. 2.67 per 100 patient-years with placebo (RR 0.83, 95%CI 0.71 to 0.98). The IR for CV mortality excluding nonfatal MI and stroke was 0.91 per 100 patient-years with tiotropium vs. 1.24 per 100 patient years with placebo (RR 0.77, 95%CI 0.60 to 0.98). For total MI, cardiac failure, and stroke the RRs were 0.78, 95%CI 0.59 to 1.02, 0.82, 95%CI 0.69 to 0.98, and 1.03, 95%CI 0.79 to 1.35, respectively.
Sponsorship
Boehringer Ingelheim and Pfizer
More information on COPD can be found on the COPD section of NPC
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