High-Throughput Screening for Prescribing Cascades Among Real-World Angiotensin-II Receptor Blockers (ARBs) Initiators

Objective: Angiotensin-II Receptor Blockers (ARBs) are commonly prescribed; however, their adverse events may prompt new drug prescription(s), known as prescribing cascades. We aimed to identify potential ARB-induced prescribing cascades using high-throughput sequence symmetry analysis. Methods: Using claims data from a national sample of Medicare beneficiaries (2011-2020), we identified new ARB users aged ≥66 years with continuous enrollment ≥360 days before and ≥180 days after ARB initiation. We screened for initiation of 446 other (non-antihypertensive) 'marker' drug classes within ±90 days of ARB initiation, generating sequence ratios (SRs) reflecting proportions of ARB users starting the marker class after versus before ARB initiation. Adjusted SRs (aSRs) accounted for prescribing trends over time, and for significant aSRs, we calculated the naturalistic number needed to harm (NNTH); significant signals were reviewed by clinical experts for plausibility. Results: We identified 320,663 ARB initiators (mean ± SD age 76.0 ± 7.2 years; 62.5% female; 91.5% with hypertension). Of the 446 marker classes evaluated, 17 signals were significant, and three (18%) were classified as potential prescribing cascades after clinical review. The strongest signals ranked by the lowest NNTH included benzodiazepine derivatives (NNTH 2130, 95% CI 1437-4525), adrenergics in combination with anticholinergics, including triple combinations with corticosteroids (NNTH 2656, 95% CI 1585-10074), and other antianemic preparations (NNTH 9416, 95% CI 6606-23784). The strongest signals ranked by highest aSR included other antianemic preparations (aSR 1.7, 95% CI 1.19-2.41), benzodiazepine derivatives (aSR 1.18, 95% CI 1.08-1.3), and adrenergics in combination with anticholinergics, including triple combinations with corticosteroids (aSR 1.12, 95% CI 1.03-1.22). Conclusion: The identified prescribing cascade signals reflected known and possibly under-recognized ARB adverse events in this Medicare cohort. These hypothesis-generating findings require further investigation to determine the extent and impact of these prescribing cascades on patient outcomes.