Abstract 4142268: Calcium channel blocker-induced prescribing cascades: Signal detection using high-throughput sequence symmetry analysis

Background: Dihydropyridine calcium channel blockers (DHCCBs) are effective first-line therapy for hypertension but can cause adverse effects (AEs) leading to the prescription of a new drug, i.e., a ‘prescribing cascade.’ Aim: To identify potential DHCCB-induced prescribing cascades using high throughput sequence symmetry analysis (HTSSA). Methods: Using claims from 5% (2011-15) and 15% (2016-20) samples of Medicare fee-for-service beneficiaries, we identified new DHCCB users aged > 66 y with continuous enrollment > 360 days pre- and > 180 days post-CCB initiation. We screened for the initiation of 446 other ‘marker’ drug classes (based on WHO Anatomical Therapeutic Classification level 4 codes) within + 90 days of DHCCB initiation. Adjusted sequence ratios (aSRs), representing proportions of DHCCB initiators starting the marker class after vs. those starting before DHCCB were calculated, with 95% CIs >1 considered significant; for significant signals, the number needed to harm (NNTH) was also calculated. Independent clinical reviewers classified signals as potential prescribing cascades or not based on biological plausibility. Results: We identified 388,862 DHCCB initiators (mean + SD age 77 + 7.5 years; 62% female and 92% with hypertension). Of the 446 marker classes assessed, we identified 82 signals that warranted further exploration (aSR > 1). After clinical review, 29 (35.36%) signals were classified as potential prescribing cascades (Figure 1). The top 3 potential prescribing cascades ranked by aSR were other systemic hemostatics (aSR 2.99 [1.10-8.16]), other nasal preparations (aSR 1.99 [1.47-2.70]), and drugs used in erectile dysfunction (aSR 1.85 [1.27-2.70]). Other clinically relevant signals included electrolyte solutions (NNTH 216, aSR 1.35), osmotically acting laxatives (NNTH 710, aSR 1.13), and sulfonamides (NNTH 104, aSR 1.50). Conclusion: HTSSA is a novel approach to identify DHCCB-induced potential prescribing cascades. Using this method, we identified known and underrecognized AEs of CCBs in this nationally-representative Medicare cohort. More research is needed to evaluate clinical outcomes attributed to these prescribing cascades.