A large meta-analysis of randomised controlled trials (RCTs) suggests that anticholinergic drugs (ipratropium, tiotropium) increase the risk of cardiovascular (CV) events in people with chronic obstructive pulmonary disease (COPD) compared with placebo or active comparators (inhaled corticosteroids and/or beta-agonists). However, the precise magnitude of this increased risk is uncertain. Early data from a further RCT (UPLIFT) does not report an increased CV risk for tiotropium versus placebo, but we await full publication of this data. Recent observational data signalled an increased CV risk with ipratropium.
This recent meta-analysis provides a signal about the possibility of increased CV risk with inhaled anticholinergics in people with COPD, but this cannot be regarded as definitive. Further data will be available in the near future, and we anticipate that regulatory authorities will be reviewing this area. For the present, patients and prescribers should weigh this new data in discussions. The number needed to treat (NNT) with tiotropium to prevent one exacerbation is estimated to be 21 (95% CI 13-50), and for COPD-related hospitalisation is around 20 (14-34) per year. The new data indicated a number needed to harm (NNH) for myocardial infarction (MI) of 174 (75-1835) per year with inhaled anticholinergics – assuming a baseline MI event rate of 10.9 per 1000 person years.
What is the background to this?
There are existing concerns about inhaled anticholinergics in people with COPD and an increase in CV events. Earlier this year, the FDA announced a safety review of the anticholinergic bronchodilator tiotropium. This followed the announcement to the FDA by the manufacturers, that ongoing safety monitoring had identified a possible increased risk of stroke in patients taking it.
Earlier this month a nested case–control study in people with newly diagnosed COPD in the U.S. Veterans Health Administration health care system using 32,130 case patients and 320,501 control participants found adjusted odds ratios (ORs) for all-cause mortality of 0.80 (95% CI, 0.78-0.83) for inhaled corticosteroids, 1.11 (1.08-1.15) for ipratropium, 0.92 (0.88 to 0.96) for long-acting β-agonists, and 1.05 (0.99-1.10) for theophylline. Ipratropium was associated with increased cardiovascular deaths (OR, 1.34 [1.22-1.47]), whereas inhaled corticosteroids were associated with reduced risk for cardiovascular death (OR, 0.80 [0.72-0.88]). Results were consistent across sensitivity analyses.
What does this study claim?
This recent study was a systematic review and meta-analysis of ipratropium and tiotropium, focussing on the CV safety of these drugs. In the analysis of all 17 RCTs (n=14,783), inhaled anticholinergics increased the risk of a composite of CV death, MI or stroke by 58% compared to control therapy: 1.8% vs. 1.2% for control; relative risk (RR)1.58 (1.21-2.06; P<0.001. There was no evidence of statistical heterogeneity among the included trials (I2 = 0%). In the short-term trials no statistically significant increased risk was seen, but it was seen in the five longer-term RCTs (n=7267): 2.9% vs. 1.8% for control; RR 1.73 (1.27-2.36; P<0.001). In the analysis of these five trials an increased risk was seen with both ipratropium (RR 1.57 [1.08 to 2.28]; P=0.02) and tiotropium (RR 2.12, [1.22-3.67]; P=0.008). Analysis of all 17 RCTs did not show that anticholinergics statistically significantly increased the risk of all-cause mortality (RR 1.26, [0.99-1.61], P=0.06).
The two greatest limitations of this study are the mix of treatments in the control arms (but note the comparator in most of the five long term trials was placebo) and the inability to take account of differences in CV risk factors such as diabetes, smoking history, use of statins and other drugs.
In addition, none of the RCTs were designed to look for CV outcomes, so there may have been discrepancies between trials in how these outcomes were reported. The number of events was small, so the confidence intervals are wide: e.g. looking at the result from the five long-term trials, we can only say with reasonable (95 in 100) certainty that the increased risk is somewhere between 27% and 136%.
A possible limitation of all meta-analyses is the possibility that important trials have not been included, despite the rigorous search strategy used – this is known as inclusion bias. The authors of this study estimate that they would have to have “missed” 16 long-term studies, each of about 1,450 patients and each showing no significant risk, for the finding from the five longer-term studies to be incorrect, i.e. for the observed increased risk to have been due to inclusion bias when in reality there is no increased risk. In addition, when the authors repeated the analysis of all trials but excluded the one trial (of ipratropium) which contributed more than 50% of the data, the observed risk of CV events was similar to the results of the 17-trial and 5-trial analyses (RR 1.58 [1.08-2.33]; P=0.02)
As the authors say, a long term RCT specifically designed to look at CV outcomes is necessary to confirm and quantify any increased CV risk with inhaled anticholinergics in people with COPD.
The results of a further relevant RCT (UPLIFT) are expected to be reported at the Annual Meeting of the European Respiratory Society on 5th October. The UPLIFT study (n=5,993) evaluates both the efficacy and safety of tiotropium in COPD. Some results from UPLIFT have been released early in a press release, which appears to provide some reassurance of the cardiovascular safety of tiotropium:
- During treatment, fatal events occurred in 12.8% of the tiotropium group, compared with 13.7% in the placebo group: hazard ratio (HR) 0.84 (0.73-0.97)
- There was no increased risk of cardiovascular death during treatment: risk ratio 0.73 (0.56-0.95)
- Myocardial infarction developed in 67 patients in the tiotropium group and 85 patients in the placebo group: RR 0.73 (0.53-1.00)
- Stroke developed in 82 patients in the tiotropium group and 80 patients in the placebo group: RR 0.95 (0.70-1.29)
Fully published data are required before we can evaluate these reported results of UPLIFT.
The recently reported Veterans observational data offers some support for a possible increased CV risk, but is a lower form of evidence than RCTs or meta-analyses of RCTs.
Patients: 14,783 patients from 17 RCTs of inhaled anticholinergics in COPD, which reported on serious CV events, including MI, stroke and CV death. All RCTs that recruited patients with asthma were excluded.
Intervention and comparison: The authors searched for published and unpublished data which met their eligibility criteria. Nine RCTs compared ipratropium or tiotropium with placebo, five compared an anticholinergic with salmeterol (a long-acting beta2 agonist), two compared tiotropium with salmeterol and fluticasone and one compared ipratropium with salbutamol. Five of the RCTs were for between 48 weeks and five years (one of ipratropium against placebo, three of tiotropium against placebo, and one of tiotropium against salmeterol and fluticasone), and 12 trials lasted between six and 26 weeks. Allocation concealment was adequate in 4 RCTs and unclear in the remaining 13 RCTs.
Outcome and results: The primary outcome for the meta-analysis was a composite of CV death, MI or stroke. The secondary outcome was all-cause mortality. See text for results.
Sponsorship: None disclosed.