Inclusion Criteria

Interventions

Included interventions are listed in Table 1.

Table 1

Included interventions

Literature Search

To identify articles relevant to each key question for each version of this report, we searched Medline, the Cochrane Library, and reference lists of review articles. For the original report we also searched EMBASE (1980-July week 3 2005). For the current update, we searched Medline and the Cochrane Library through December 2008. In electronic searches, we used broad searches, only combining terms for drug names with terms for relevant research designs. (See Appendix B for complete search strategy). We have attempted to identify additional studies through searches of reference lists of included studies and reviews, the US Food and Drug Administration website, and dossiers submitted by pharmaceutical companies for the current review. All citations were imported into an electronic database (EndNote XI).

Study Selection

Selection of included studies was based on the inclusion criteria created by the Drug Effectiveness Review Project participants, as described above. Two reviewers independently assessed titles and abstracts of citations identified through literature searches for inclusion using the criteria below. Full-text articles of potentially relevant citations were retrieved and again were assessed for inclusion by 2 reviewers. Disagreements were resolved by consensus. Results published only in abstract form were not included because lack of detail prevented quality assessment.

Trials that evaluate one anticholinergic drug against another provide direct evidence of comparative effectiveness and adverse event rates. In theory, trials that compare these drugs with placebos or with other drugs used to treat overactive bladder can also provide evidence about efficacy. However, the efficacy of drugs in different trials can be difficult to interpret because of significant differences in key characteristics of the patient populations. Comparison of results across trials (direct comparisons or indirect comparisons) is difficult due to differing outcome measures.

Data Abstraction

The following data were abstracted from included trials: study design; setting; population characteristics (including sex, age, ethnicity, diagnosis); eligibility and exclusion criteria; interventions (dose and duration); comparisons; numbers screened, eligible, enrolled, and lost to follow-up; method of outcome ascertainment; and results for each outcome. We recorded intention-to-treat results if they were available and the trial did not report high overall loss to follow-up. Data were abstracted by one reviewer and checked for accuracy by a second.

Validity Assessment

We assessed the internal validity (quality) of trials based on the predefined criteria listed in Appendix C. These criteria were based on the US Preventive Services Task Force and the National Health Service Centre for Reviews and Dissemination (United Kingdom) criteria for assessing study quality. In rating the internal validity of each trial we assessed the methods used for randomization, allocation concealment, and blinding; the similarity of compared groups at baseline; maintenance of comparable groups; adequate reporting of dropouts, attrition, crossover, adherence, and contamination; loss to follow-up; and the use of intention-to-treat analysis. Trials that had a fatal flaw were rated poor-quality; trials that met all criteria were rated good-quality. The remainder were rated fair-quality. As the fair-quality category was broad, studies with this rating varied in their strengths and weaknesses; the results of some fair-quality studies were likely to be valid, while others were only possibly valid. Poor-quality trials were not valid: The results were at least as likely to reflect flaws in the study design as a true difference between the compared drugs. A fatal flaw is reflected by failure to meet combinations of items on the quality assessment checklist.

Appendix C also shows the criteria we used to rate observational studies of adverse events. These criteria reflect aspects of study design that are particularly important for assessing adverse event rates. We rated observational studies as good-quality for adverse event assessment if they adequately met 6 or more of the 7 predefined criteria, fair-quality if they met 3 to 5 criteria, and poor-quality if they met 2 or fewer criteria.

Included systematic reviews were also rated for quality based on predefined criteria (see Appendix C), which assessed the research questions(s) and inclusion criteria, adequacy of search strategy and validity assessment, adequacy of detail provided for included studies, and appropriateness of the methods of synthesis.

The overall strength of evidence for a particular key question or outcome reflected the risk of bias of the studies (based on quality and study design) and the consistency, directness, and precision of the studies relevant to the question. Strength of evidence was graded as insufficient, low, moderate, or high.

Data Synthesis

We constructed evidence tables showing the study characteristics, quality ratings, and results for all included studies. We reviewed studies using a hierarchy-of-evidence approach, in which the best evidence was the focus of our synthesis for each question, population, intervention, and outcome addressed. Data reported on a ‘per 24 hour’ basis were converted to ‘per week’ to allow comparison to other data.

In addition to qualitative discussion of studies’ findings, meta-analyses were conducted, where possible. Forest plots of the risk difference for efficacy measures or adverse events are presented (where possible) to display data comparatively. Forest plots were created using StatsDirect (CamCode, UK) software. Results are reported as differences between drugs in mean change in number of micturitions or episodes of incontinence per day or per week. Differences in rates of adverse events and withdrawals due to adverse events are expressed as the “percent risk difference,” which is the difference between the proportions with the event in 2 groups of patients at a given time-point. For example, if 20% of patients in group A and 25% of patients in group B report an adverse event, then the groups show a 5% risk difference. The 95% confidence interval (CI) is reported as a measure of the variance around the estimate of risk difference. If the 95% CI includes 0, then the difference is not statistically significant. Risk differences are plotted on forest plots, always presenting the difference of the first drug minus the second named drug. The size of the box indicating the point estimate is determined by the variance, such that larger studies generally have larger boxes relative to smaller studies.

Peer Review and Public Comment

The Original report underwent a review process that involved solicited peer review from 3 clinical experts. Their comments were reviewed and, where possible, incorporated into the final document. The comments received and the author’s proposed actions were reviewed by the representatives of the participating organizations of the Drug Effectiveness Review Project prior to finalization of the report. Names of peer reviewers for Drug Effectiveness Review Project reports are listed at www.ohsu.edu/drugeffectiveness.

Each version of the report has been posted in draft form to the Drug Effectiveness Review Project website for public comment. Key stakeholders were notified of these postings. For Update 4 we received comments from 3 stakeholders (Novartis, Pfizer, and Orth-McNeil Janssen). The comments received and the author’s proposed actions were reviewed by the representatives of the participating organizations of the Drug Effectiveness Review Project prior to finalization of the report.