The OT analysis of the SERVE-HF trial shows that the increase in cardiovascular mortality seen in patients randomised to ASV in the ITT analysis mainly occurs during periods of device usage, suggesting a causal relationship between ASV use and cardiovascular death, although the risk did not appear to be proportional to the nightly duration of device usage. OT analyses of trial data initially analysed on an ITT basis are usually performed to distinguish between the direct effects of a treatment and indirect effects occurring during periods of non-adherence or treatment interruptions, which are frequently seen as avoidable. However, because the decision to stop a treatment is not independent of personal preferences and past experiences of physicians and patients, the comparison of periods with and without use of a treatment may be biased. This bias may even be stronger than the direct treatment effect. OT analyses are thus generally considered to provide less robust evidence than ITT analyses, similar to cohort studies. To attenuate or even eliminate the bias in OT analyses, epidemiological methods developed for the analysis of prospective observational studies can, and should, be applied, such as adjustment for baseline covariates or explicit modelling of selection effects.
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