A signal of increased risk of hypoglycaemia with angiotensin receptor blockers caused by confounding

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Spontaneous reporting is a valuable way to provide early detection for safety signals related to drug use. • Due to the increasing size of pharmacovigilance databases, data-mining and other automated methods for signal generation are more and more often used.• Even if these methods are very useful, they do not allow, for every particular association, an automated exploration of the multiple sources of confounding. WHAT THIS STUDY ADDS• An association between angiotensin receptor blockers use and hypoglycaemia was found in the French pharmacovigilance database.• This signal disappeared after stratification on antidiabetic drug use, suggesting confounding by indication.• The association between hypoglycaemia and angiotensin receptor blocker use was actually less than expected in concomitant antidiabetic drug users. AIMSTo study reporting of hypoglycaemia in angiotensin receptor blocker (ARB) users, and to investigate the possibility of confounding. METHODSThe French pharmacovigilance database was examined for an association between hypoglycaemia and ARBs or other drugs using reports notified between 1996 and 2005. This association was also tested in patients taking or not taking antidiabetic agents (ADAs) using reporting odds ratios (ROR). RESULTSHypoglycaemia was mentioned in 807 of the 174 595 reports entered during the study period. Overall hypoglycaemia was associated with the use of ARBs [ROR 2, 95% confidence interval (CI) 1, 3] and with the use of ADAs (ROR 32, 95% CI 27, 37). Moreover, the use of ARBs was associated with the use of ADAs (OR 7, 95% CI 6,8). Considering separately reports with and without ADA, the association of ARB use with a higher risk of hypoglycaemia disappeared (OR 0.4, 95% CI 0.2, 0.8 and OR 2, 95% CI 1, 3, respectively). CONCLUSIONA signal indicating an association between ARB use and hypoglycaemia was found in the French pharmacovigilance database. This signal disappeared after stratification on ADA use, thus suggesting confounding by indication. Moreover, the association between ARB use and hypoglycaemia was negative in ADA users.

Association between Selective Serotonin Reuptake Inhibitor Therapy and Suicidality: Analysis of U.S. Food and Drug Administration Adverse Event Reporting System Data

“…[17][18][19] Because depression is one of the risk factors associated with suicidality, 24) we evaluated the intraclass RORs of the depression patient subset. For the calculation of the intraclass ROR, we defined a subset of depressed patients from the whole FAERS data.…”

“…Non-cases consisted of patients associated with all other reports. 17,[25][26][27][28] In the present study, the association between SSRIs and suicidal or self-harm events was calculated as an ROR. The RORs were calculated from two-by-two contingency tables of counts that indicated the presence or absence of a particular drug and a particular adverse event in the case reports, and were expressed as point estimates with 95% confidence intervals (CIs).…”

“…[14][15][16] Furthermore, subset analysis, which mitigates bias and the influence of confounding variables, can be applied in the evaluatation of drug-adverse event associations in disproportionality analyses using the ROR. [17][18][19] To the best of our knowledge, the relationship between SSRI and suicidality has not yet been evaluated in terms of age-stratified patient groups from the FAERS database. In this study, we evaluated the possible relationship between SSRI use and suicidality from data available in the FAERS database using a logistic regression model and subset analysis, and obtained information regarding confounding factors from the reported cases such as age, sex, and drug use.…”

Data Mining Techniques in Pharmacovigilance: Analysis of the Publicly Accessible FDA Adverse Event Reporting System (AERS)

“…The latter approach is needed to avoid the confounding by indication that occurs when a given class of drugs is preferentially used in subjects who have a priori higher or lower risk of presenting the event under investigation [74].…”

“…Indeed, one of the most important aspect and a compelling need for a clinician is to identify safer molecules within therapeutic classes. Moreover, this strategy helps to mitigate the so-called "confounding by indication bias" [74], by limiting the analysis to a population of patients that presumably share at least a set of common risk factors and diseases. Nonetheless, the so-called "channeling bias" (i.e., the possibility that drugs may be differently prescribed in relation to the severity of disease) still remains.…”