Evaluation of a Beta-Blocker-Edema-Loop Diuretic Prescribing Cascade: A Prescription Sequence Symmetry Analysis.

BACKGROUND: Drug-related adverse events associated with antihypertensive therapy may result in subsequent prescribing of other potentially harmful medications, known as prescribing cascades. The aim of this study was to assess the magnitude and characteristics of a beta-blocker-edema-loop diuretic prescribing cascade. METHODS: A prescription sequence symmetry analysis was used to assess loop diuretic initiation before and after initiation of beta-blockers among patients 20 years or older without heart failure, atrial fibrillation, other arrythmias, or use of calcium channel blocker within a U.S. private insurance claims database (2005-2018). The temporality of loop diuretic initiation relative to a beta-blocker or negative control (renin-angiotensin system blocker) initiation was tabulated. Secular trend-adjusted sequence ratios (aSRs) with 95% confidence intervals (CIs) compared the initiation of loop diuretic 90 days before and after initiation of beta-blockers. RESULTS: Among 988,675 beta-blocker initiators, 9,489 patients initiated a new loop diuretic prescription 90 days after and 5,245 patients before beta-blocker initiation, resulting in an aSR of 1.78 (95% CI, 1.72-1.84). An estimated 1.72 beta-blocker initiators per 100 patient-years experienced the prescribing cascade in the first 90 days. The aSR was disproportionately higher among older adults (aSR 1.97), men (aSR 2.25), and patients who initiated metoprolol tartrate (aSR 2.48), labetalol (aSR 2.18), or metoprolol succinate (aSR 2.11). Negative control results (aSR 1.09, 95% CI, 1.05-1.13) generally corroborated our findings, but suggested modest within-person time-varying confounding. CONCLUSIONS: We observed excess use of loop diuretics following beta-blocker initiation that was only partially explained by secular trends or hypertension progression.

Evaluating the use of prescription sequence symmetry analysis as a pharmacovigilance tool: A scoping review.

BACKGROUND: The (prescription) sequence symmetry analysis (PSSA) design has been used to identify potential prescribing cascade signals by assessing the prescribing sequence of an index drug relative to a marker drug presumed to treat an adverse drug event provoked by the index drug. OBJECTIVES: This review aimed to explore the use of the PSSA design as a pharmacovigilance tool with a particular focus on the breadth of identified signals and advances in PSSA methodology. METHODS: We searched Embase, PubMed/Medline, Google Scholar, Web of Science and grey literature to identify studies that used the PSSA methodology. Two reviewers independently extracted relevant data for each included article. Study characteristics including signals identified, exposure time window, stratified analyses, and use of controls were extracted. RESULTS: We identified 53 studies which reported original results obtained using PSSA methodology or quantified the validity of components of the PSSA design. Of those, nine studies provided validation metrics showing reasonable sensitivity and high specificity of PSSA to identify prescribing cascade signals. We identified 340 unique index drug - marker drug signals published in the PSSA literature, representing 281 unique index - marker pharmacological class dyads (i.e., unique fourth-level Anatomical Therapeutic Chemical [ATC] classification dyads). Commonly observed signals were identified for index drugs acting upon the nervous system (34%), cardiovascular system (21%), and blood and blood-forming organs (15%), and many marker drugs were related to the nervous system (25%), alimentary tract and metabolism (23%), cardiovascular system (17%), and genitourinary system and sex hormones (14%). Negative controls and positive controls were utilized in 21% and 13% of studies, respectively. CONCLUSIONS: The PSSA methodology has been used in 53 studies worldwide to detect and evaluate over 300 unique prescribing cascades signals. Researchers should consider sensitivity analyses incorporating negative and/or positive controls and additional time windows to evaluate time-varying biases when designing PSSA studies.