Confounding by indication distorts drug-outcome associations so that treatment looks “bad” or “harmful,” while the healthy user bias distorts drug-outcome associations so that treatment looks “good” or “beneficial.” The relative importance of these biases depends upon the specific drug-outcome association and population of interest.Ĭontributions from Occupational Epidemiology The impact of (1) confounding by indication and (2) the healthy user bias (the combination of the healthy initiator and healthy adherer biases) works in opposite directions. As placebo could not plausibly have any effect on mortality, the observed reduction in mortality can be solely attributable to selection bias. This study reported that patients who adhered to placebo had substantially reduced mortality compared with patients who were non-adherent to placebo. One of the most striking examples of the healthy adherer bias was demonstrated in a meta-analysis evaluating the effect of adherence to placebo in randomized controlled trials (RCTs). Individuals who adhere to preventive treatments over prolonged periods are as follows: (1) more likely to adhere to other healthy behaviors and preventative care and (2) less likely to have experienced changes in frailty (or underlying health status) compared with their non-adherent counterparts. One common form of selection bias that occurs in pharmacoepidemiologic studies is the healthy adherer bias, which extends the healthy initiator and frailty bias to patients who adhere to treatment. This type of channeling has led a number of non-experimental studies to report implausibly strong preventive effects of influenza vaccination on all-cause mortality in the range of a 50 % relative risk reduction.
Older adults and particularly those with severe comorbid illness and decreased physiologic reserves are unlikely to receive influenza vaccination but are at an increased risk for death. The healthy initiator bias has been documented in studies of influenza vaccine effectiveness in older adults and other populations in poor health. Under both scenarios, the healthy initiator bias will lead to spurious associations, where the beneficial effect of a given drug will be exaggerated. The second involves the selective channeling of treatments away from frail individuals, who are at an increased risk of adverse outcomes. The first involves the selective initiation of preventive treatments among healthy and health-conscious patients, who, through the effects of their healthy lifestyle, are also at decreased risk of a number of adverse health outcomes. This bias can arise through two distinct pathways. Through incremental restriction of the study cohort, the authors demonstrate a large shift in the overall estimate when new statin users were compared with new users of an unrelated preventive treatment (anti-glaucoma medication) instead of non-users, indicating a large reduction in bias.Īnother type of confounding bias common in pharmacoepidemiologic studies is the healthy initiator bias. Schneeweiss and colleagues provide support for this concern in a study evaluating the association between statin use and 1-year mortality among adults aged 65+ years. In general, confounding by indication is likely to be of greatest concern in studies that compare initiators of treatments to non-initiators.
Such confounding would tend to make beta-agonists appear as though they were associated with asthma mortality.
Asthma patients with severe disease are more likely than patients with less severe disease to receive beta-agonists and to die from their asthma. Confounding by indication can be illustrated using a hypothetical study seeking to estimate the effect of beta-agonists on asthma-related mortality among asthma patients. The indication for treatment leads to selective prescribing of treatments, and in pharmacoepidemiologic studies, confounding by indication may arise if the indication for the treatment is also related to prognosis (the risk of the outcome). In routine clinical practice, treatments are administered to patients for a specific reason (i.e., the medical indication)-to prevent an adverse health outcome from occurring or to treat an adverse health outcome that has already occurred (and to prevent future occurrences).
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