Adams S, G., Anzueto A, Briggs DD, J r, et al. Evaluation of withdrawal of maintenance tiotropium in COPD. Respiratory Medicine 2009;103:1415-20
PubMed link: https://www.ncbi.nlm.nih.gov/pubmed/19523796
| Methods | Study design: Non-randomized controlled study (parent study was a randomized controlled study, but participants were not re-randomized at the completion of the parent study) with a parallel-design
Number of groups: Two groups |
| Participants | Number of participants: 921 enrolled, 713 completed
· Active group: 550 randomized for the original study, 445 enrolled in this study, 445 completed · Control group: 371 randomized for the original study, 268 enrolled in this study, 268 completed Age: 65.2 ± 8.7 years Sex: 322 females, 599 males Participants with dementia: No Inclusion criteria: · Either sex · 40-yearss-old or above · Clinical diagnosis of Chronic Obstructive Pulmonary Disease (COPD), as defined by the American Thoracic Society · At least a ten pack-years smoking history · Clinically stable airway obstruction, · Forced expiratory volume in one second of at least 65% of predicted normal values · At least 70% of forced vital capacity Exclusion criteria: · History of asthma · History of allergic rhinitis · History of atopy · Total blood eosinophil count of >600 cells/mm-3 · Required regular daytime supplemental oxygen · On doses exceeding the equivalent of 10 mg prednisone daily during the month beforeentering the study · Recent history of myocardial infarction (<1 years) · Recent history of heart failure (<3 years) · Cardiac arrhythmia requiring drug therapy Concomitant medicines: · Albuterol metered dose inhaler, as-needed · Stable doses of theophylline (i.e. stable doses usedfor up to 6 weeks before entry) · Inhaled glucocorticosteroids · Equivalent of <10 mg/day-1 oral prednisone throughout the study period Country: Country not specified, but authors based in Canada, United States of America and England Setting: 50 trial centers |
| Interventions | Medicine: Inhaled tiotropium in lactose (18 mg) each morning via a dry powder inhaler device
Withdrawal schedule: Not described Comparator: Inhaled lactose each morning via a dry powder inhaler device |
| Outcomes | Medicine use at 3 weeks after deprescribing
Dyspnea Peak Expiratory Flow Rate (morning and evening) Health-related quality of life measured using the St George’s Respiratory Questionnaire |
| Dates | Dates: Not described
Follow-up duration: 12 months total (48 weeks tiotropium treatment, 3-weekdeprescribing) |
| Funding sources | Boehringer-Ingelheim Pharmaceuticals, Inc. |
| Notes | Another paper reports on the same study:
Casaburi R, Mahler DA, Jones PW, et al. A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease. Eur Respir J 2002;19:217e24. |
Risk of bias table
| Bias | Authors’ judgment | Support for judgment |
| Random sequence generation (selection bias) | High risk | Non-randomized study.
Although the original study was randomized, this follow-up study was an observational study. Participants remained in the same groups they had been during the original study, so the study did not assess if participants health status altered if the administered tiotropium was deprescribed compared to those who continued to receive tiotropium. All patients had tiotropium ceased. Because tiotropium was not commercially available at the time of the study, no patients were taking this medication at the 3-week posttreatmentfollow-up visit. Also, there were no significant differences in respiratory medications at this final visit. |
| Allocation concealment (selection bias) | High risk | The original study was placebo-controlled. This study, however, was an opencessation of medicine across all participants. |
| Blinding of participants and personnel (performance bias) | 5 out of 5 | The original study was placebo-controlled. This study, however, was an opencessation of medicine across all participants. |
| Blinding of outcome assessment (detection bias) | 5 out of 5 | There is no clear missing outcome data. |
| Incomplete outcome data (attrition bias) | 3 out of 5 | There is no pre-specified protocol available. However, the described outcomes are all reported. However, the deprescribing study appears to be an opportunistic description of study health outcome after study discontinuation rather than a planned intervention and follow-up. |
| Selective reporting (reporting bias) | 2 out of 5 | There is no pre-specified protocol available. However, the described outcomes are all reported. However, the deprescribing study appears to be an opportunistic description of study health outcome after study discontinuation rather than a planned intervention and follow-up. |
| Confounding (non-randomized) | 5 out of 5 | The study reports two groups. The first group had taken a placebo in the main study and then ceased. The second group had used the active drug in the main study and then ceased. Therefore, there is no opportunity to compare the cessation of active drug with the continued active drug to know if longer treatment durations are of increased benefit than shorter treatment durations.
3 weeks was a short-termfollow-up. No crossover. No description of whether there was a changein seasons or weather. |
| Other bias | High risk | Industry-sponsored study. |
| Newcastle-Ottawa scale | ||
| Selection bias | Representativeness of the exposed cohort | Somewhat representative of the average COPD sufferer who previously smoked who discontinues their tiotropium treatment (broadexclusion criteria). |
| Selection of the non-exposedcohort | Selection of the non-exposed cohort drawn from a different source (initiallymatched at baseline for the original study, but now different as they had different interventions in the original study). | |
| Ascertainment of exposure | Ascertainment of exposure was by securerecord. | |
| Demonstration that outcome of interest was not present at start of study | Yes, study environment was controlled. | |
| Comparability bias | Comparability of cohorts on the basis of the design or analysis | The study controlled for the cessationof active tiotropium compared to the cessationof placebo. |
| Outcome bias | Assessment of outcome | Outcome assessment was an independent blind assessment. |
| Was follow-up long enough for outcomes to occur | The follow-upperiod was probably adequate for the outcomesto occur. Follow-up period is longer than five half-lives. Therefore, this study adequately assesses if the effects of tiotropium cease once the drug is clearedfrom the body. | |
| Adequacy of follow-up of cohorts | Completefollow-up – all subjects accounted for. | |