Response to Wise <i>et al</i>. (Tiotropium safety in real life populations)

We appreciate the comments made by Wise et al. 1 regarding the limited generalizability of the Tiotropium Safety and Performance in Respimat (TIOSPIR) trial 2 found in our study 3. As Wise et al. 1 pointed out, Miravitlles et al. 4 compared baseline characteristics and comorbidities of patients included in tiotropium treatment examining randomized controlled trials (RCTs) vs. observational studies including chronic obstructive pulmonary disease (COPD) patients (irrespective of treatment). Summing up these comparisons as only ‘similar’ is, at least to some extent, a simplification. For example, the pooled prevalence estimates for hypertension were 39.4% (n = 28 HandiHaler® trials) and 40.0% (n = 7 Respimat® trials), whereas for five large observational studies, prevalence estimates were between 40.1% and 60.6% 4. Of course, comparing pooled and non-pooled prevalence results 4 should be interpreted with caution and methodological differences between observational studies should be taken into account. We agree with Wise et al. 1 mentioning that there is no reason to believe that patients with milder COPD would be at any additional specific risk of adverse cardiac effects. However, one of our main concerns regarding the generalizability of the TIOSPIR trial 2 was the exclusion of patients on account of relevant comorbidities, which might be more relevant in elderly, multimorbid patients suffering from severe COPD 3. By excluding those patients, safety signals might have been overlooked to a relevant extent. Verhamme et al. 5 found a 27% increased risk of deaths among patients using Respimat® compared with HandiHaler®. Interestingly, no significant association was found for patients with normal renal function, whereas for patients with GFR <60 ml min–1 1.73 m–2 BSA, the use of Respimat® was associated with increased mortality (aHR=1.52, 95% CI 1.02, 2.28) 6. In contrast, no clear trend was found when comparing (S)AE incidence rate ratios of placebo-controlled studies examining HandiHaler® or Respimat® in patients with normal renal function, mild or moderate renal impairment 7. For severe renal impairment, results were limited because of the low number of patients. However, only renal function at baseline was taken into account but a time-dependent analysis might be more appropriate. Regarding cardiovascular risk factors, Loke et al. found, in a post hoc analysis of the TIOSPIR trial 8, an increased risk of myocardial infarctions comparing Respimat® (combined analysis of the two treatment groups) with HandiHaler® users. Recently, some data were published regarding cardiac adverse events occurring after an initial on-treatment cardiac event in the UPLIFT trial and the TIOSPIR trial 9, 10. Wise et al. 1 mentioned that no increase in risk was found for subsequent mortality or cardiac events in patients receiving tiotropium vs. placebo (UPLIFT 9) or tiotropium Respimat® vs. tiotropium HandiHaler® (TIOSPIR 10). We agree that these data are relevant but, unfortunately, they do not fully cover our concerns. Underlining the assumption that initiating an antimuscarinic treatment might be the period with the highest risk of developing (S)AEs 11, Lee et al. 12 found an increased risk of tachyarrhythmias in patients starting a long acting β2-adrenoceptor agonist (LABA) or antimuscarinic (LAMA) treatment. On the other hand, in a post hoc analysis of the TIOSPIR trial, no differential effects of anticholinergic-naïve patients at baseline vs. the total study population were reported 13. However, excluding high risk patients due to major cardiovascular events, as conducted in the TIOPSPIR trial 2, limits the generalizability of these results too. Antimuscarinic and β2-adrenergic co-medication is of particular interest with regard to cardiovascular side effects. In the protocol of the TIOSPIR trial 2, the concurrent use of short acting muscarinic antagonists was not explicitly stated as an exclusion criterion (and, henceforth, was not included in our generalizability analysis). However, the intake of antimuscarinic compounds was ‘not allowed during the randomization period’ 2. Taking into account the cumulative anticholinergic drug burden, not allowing ipratropium intake may have decreased the risk of cardiovascular (and other) side effects, and it should be taken into account that ipratropium intake was present in approximately 5% of our ‘real life’ population 3. With regard to β2-adrenergic co-medication (which is frequently prescribed to asthma patients), there is some evidence showing a trend towards an increased risk of cardiovascular and cerebrovascular side effects from a combination of LABA and LAMA compared with LABA or LAMA alone 14, but the data are conflicting 11. We totally agree that ‘real world’ observational studies are useful to generate questions, whereas RCTs are necessary to answer these questions 1. However, there are far too many possible combinations of comorbidities and co-medications to be answered by RCTs, underlining the need for well-conducted observational studies. According to the evidence currently available, tiotropium Respimat® seems to have an overall safety profile comparable with tiotropium HandiHaler®, whereas an increased risk of cardiovascular (S)AEs in certain vulnerable patients receiving tiotropium Respimat® cannot be excluded 5, 11. All authors have completed the Unified Competing Interest form at ww.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work. SS reports personal fees from Rottapharm Madaus (Cologne, Germany) and travel costs for an investigator meeting were reimbursed by Bayer HealthCare AG (Leverkusen, Germany) outside the submitted work. PT reports personal fees from Rottapharm Madaus (Cologne, Germany) outside the submitted work.

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