Discussion

This study found small increased risks of stroke, MI and angina along with a decreased risk of mortality with tiotropium. Individual studies are often too small to identify with certainty associations between specific medications and rare adverse events, and these findings should be considered in context with other evidence.

In 2002, the Lung Health Study, the first large placebo-controlled randomised trial of an inhaled anticholinergic agent reported an increased incidence in the ipratropium group of hospitalisation due to SVT, angina, MI and death due to coronary heart disease.18 Observational studies have reported associations between ipratropium and stroke,19 cardiovascular hospitalisation20 and death.21

Tiotropium has a similar mechanism of action to ipratropium, and in 2008, the FDA issued an early communication after a pooled analysis of placebo-controlled clinical trials revealed an excess risk of stroke with tiotropium.22 Subsequently, the Uplift trial reported a decreased risk of total mortality, MI and no increased risk of stroke with tiotropium.23 As in other studies, the stroke end point was a composite end point that included ischaemic and hemorrhagic stroke,23 and the incidence of ischaemic stroke in the Uplift study was slightly greater in the tiotropium group than the placebo group.24 25 In addition, the Uplift study showed an increased risk with tiotropium of certain tachyarrhythmias26 and serious angina.23

A pooled analysis of randomised trials reported an increased rate of arrhythmias with tiotropium compared with placebo or LABAs and increased risks with tiotropium of both cardiovascular and cerebrovascular serious adverse events (RR=1.71, 95% CI 0.76 to 3.89).27 A randomised trial comparing tiotropium with salmeterol in combination with fluticasone reported increased cardiac adverse events with tiotropium.28 An observational study reported increased risk of mortality with tiotropium compared with LABA.29 Pooled analyses of placebo-controlled tiotropium clinical trials have reported small increased rates with tiotropium of palpitations, SVT, angina and stroke and lower rates of MI, cardiovascular mortality and total mortality.30–32

Perhaps the most relevant study is the recent ‘POET’ study, the largest tiotropium randomised trial conducted to date, with 7376 COPD patients.33 The POET Study is similar to this study in that, it compared tiotropium HandiHaler with salmeterol. The POET Study also found fewer deaths for tiotropium (n=64) compared with salmeterol (n=78), although there was no decrease in cardiac deaths (eight tioptropium vs six salmeterol)33 (supplementary appendix). The POET Study reported no increased risk of stroke but found an increased risk with tiotropium of several serious cardiovascular adverse events including angina (nine tiotropium vs five salmeterol), myocardial ischaemia (11 tiotropium vs six salmeterol) and MI (20 tiotropium vs 13 salmeterol).33 34

Recently, safety concerns have been raised about increased mortality with the mist inhaler formulation of tiotropium (Respimat®), which is available in several countries but which was not approved for marketing in the USA.35 (Tiotropium Respimat was not available in the UK at the time of this analysis.) It was hypothesised that the increased risk of deaths, which were mostly cardiac and sudden or unexplained deaths, may be the result of the device delivering a greater dose than the powder formulation.36 Tiotropium Respimat is also associated with a dose-related increased risk of angina and cardiac ischaemic events, but not MI.37 38

The decreased risk of mortality observed in this study with tiotropium is in agreement with the results reported in the Uplift23 and POET33 studies, but not in the ipratropium Lung Health Study18 or several large tiotropium trials using the Respimat device.37 39 These drugs have virtually identical safety profiles,2 3 40 so it would be an oversimplification to suggest that they have either beneficial or harmful effects on mortality based solely on the device delivering similar active ingredients. Heterogeneity of results should be considered in light of both causal and non-causal explanations. For composite end points, interpretation often can be clarified by evaluating components, especially cardiovascular deaths. Thus, the POET Study reports fewer total deaths with tiotropium33 but more cardiac deaths.34

The results for angina, MI and stroke reported here and in other studies of inhaled anticholinergic drugs are usually not statistically significant. The absence of statistical significance in studies that lack the power to detect small effects should be expected and does not indicate the absence of an effect.41 42 For instance, repeated findings of an increased risk of angina of a similar magnitude in studies of different design and locations make chance an unlikely explanation for this finding.

Non-randomized studies must always be concerned with possible bias arising from differences in baseline risks between treatment groups. We used propensity scores and multivariate models to control efficiently for available risk factors. Nevertheless, certain variables, such as lung function results, were unavailable and could not be controlled. We found that more LABA patients than tiotropium patients had an asthma diagnosis in addition to their COPD diagnosis. The decreased risk of asthma exacerbations in the tiotropium group is consistent with a greater proportion of patients in the LABA group having an asthma component to their COPD. Nevertheless, COPD diagnoses and exacerbations were similar between groups, suggesting similar severity of COPD. Nevertheless, it is possible that tiotropium patients had more severe COPD than LABA patients despite our efforts to control for baseline risk factors. More severe COPD might account for higher rates of cardiovascular events, although the decreased mortality in the tiotropium group is inconsistent with this hypothesis. Increased risks of ischaemic cardiovascular events in randomised trials also argue against confounding as an explanation.

All tiotropium effect estimates in this study are relative to effects of LABA. A valid effect estimate indicating a higher rate with tiotropium means that tiotropium increases risk more than LABA but both drugs could be either increasing or decreasing risk. To the extent that LABA may increase the risk of cardiovascular adverse events, such an effect would attenuate an increased risk that might also exist for tiotropium.

Among non-cardiovascular and non-respiratory end points, results showed an increased risk of dry mouth with tiotropium, but not for other anticholinergic end points including constipation and urinary retention. The incidence of these less serious events was low; however, and it is likely that only a small proportion of these cases are reported to GPs and recorded in the database. Under-reporting of non-serious AEs could introduce misclassification that would dilute RR estimates for events such as dry mouth and constipation.15 Misclassification could have occurred for more serious end points as well, although we would expect that completeness of the medical record would be better for more serious cardiovascular events. Misclassification of certain serious end points still is a concern, however, as we examined total mortality and total strokes, but not cardiovascular mortality or ischaemic strokes. Finally, tiotropium HandiHaler is available in one dose, and this study was unable to evaluate dose–response. However, among patients using therapy for at least 6 months, the associations with angina, MI and stroke became stronger, while the association with mortality became weaker.

Results of this study should be interpreted cautiously, but they lend modest support to a considerable body of evidence of a serious cardiovascular safety risk with inhaled anticholinergic drugs. Nevertheless, with regard to safety of inhaled anticholinergic drugs, the FDA recently concluded that ‘data from Uplift adequately addressed the potential safety signal of stroke and adverse cardiovascular outcomes.’43 A few points help explain these divergent conclusions. First, we consider the entire body of evidence pertaining to class effects, and we consider each study on its merits. In particular, studies should not be disregarded merely because they are not randomised19–21 29 or they include an another medication as a control group instead of a placebo group.28 33 Second, when considering the evidence pertaining to small effects on rare adverse events, we do not assume that results that are not statistically significant provide evidence against an increased risk.41 42 This is especially important when increases in risk are small or studies were not large enough to detect such risks as statistically significant. It is important to consider the magnitude of effect estimates and the precision with which they are measured.41 42 The Uplift study, for instance, describes higher rates of serious angina and ischaemic stroke with tiotropium than placebo24 and so can hardly provide reassurance about the absence of such risks. In addition, results from composite end points do not necessarily apply to each of their components. Thus, decreased rates of total mortality and total stroke can mask increased rates of cardiovascular mortality24 or ischaemic stroke.34 Finally, adverse effects do not occur in every patient and may not be apparent in every population or every study. Heterogeneity of results is not evidence against a causal effect but is an interesting finding that should be interpreted in consideration of the impact of both non-causal as well as causal explanations; the latter include differences in populations, durations of follow-up and doses. Thus, the absence of an increased risk of MI in the Uplift study does not negate increases in risk of MI in the Lung Health Study,18 POET Study34 or this study, especially when each of these studies indicates an increased risk of angina.

Inhaled anticholinergic drugs are effective treatments in COPD and treatment decisions must balance benefits with risks for individual patients. It has long been suggested that older people are especially susceptible to anticholinergic effects, and angina has been described previously as a severe anticholinergic effect secondary to tachyarrhythmias.1 4 5 Subsequently, increased risks of tachyarrhythmias and angina have been reported in association with inhaled anticholinergic drugs in non-randomised and randomised studies, of various sizes and durations, with ipratropium and tiotropium, compared with placebo and active comparators, and using different devices. Pharmacological and clinical evidence, therefore, supports these cardiovascular events as class effects of inhaled anticholinergic drugs. Small increased rates of stroke have been observed fairly consistently across studies, while MI, and cardiovascular death, have been associated in different studies both positively and negatively with anticholinergic medication. Additional research is needed to understand the full extent of cardiovascular effects of inhaled anticholinergic medications and the patients who may be susceptible.