High‐throughput screening for prescribing cascades among real world statin initiators

Abstract

Purpose Statins are among the most prevalent medications prescribed and associated with adverse events that may prompt additional treatment (i.e., a prescribing cascade). No comprehensive assessment of statin‐related prescribing cascades has been performed to our knowledge. Methods We utilized sequence symmetry analysis to iteratively screen prescribing sequences of all therapeutic classes (“marker” classes) based on Level 4 Anatomical Therapeutic Chemical codes among adult statin initiators, using IBM Marketscan commercial and Medicare supplemental claims databases (2005–2019). Order of initiation and secular trend‐adjusted sequence ratios were calculated for each statin‐marker class dyad, among marker class initiators ±90 days of statin initiation. Among signals classified as prescribing cascades, we calculated naturalistic number needed to harm (NNTH) within 1 year as the inverse of the excess risk among exposed. Results We identified 2 265 519 statin initiators (mean ± SD age, 56.4 ± 12.0 years; 48.7% women; 7.5% with cardiovascular disease). Simvastatin (34.4% of statin initiators) and atorvastatin (33.9%) were the most commonly initiated statins. We identified 160 significant statin‐marker class dyad signals, of which 35.6% (n = 57) were classified as potential prescribing cascades. Of the top 25 strongest signals (lowest NNTH), 12 were classified as potential prescribing cascades, including osmotically acting laxatives (NNTH, 44, 95% CI 43–46), opioids + non‐opioid combination analgesics (81, 95% CI 74–91), and first‐generation cephalosporins (204, 95% CI 175–246). Conclusions Using high‐throughput sequence symmetry analysis screening, we identified previously known prescribing cascades as well as potentially new prescribing cascades based on known and unknown statin‐related adverse events.

Modifiable statin characteristics associated with potential statin‐related prescribing cascades

“…We conducted a secondary analysis of a previously published study, in which high-throughput SSA screening was used to identify potential statin-related prescribing cascades. 14 Briefly, highthroughput SSA is a hypothesis-free pharmacovigilance tool used for detecting new adverse drug events or evaluating known side effects. 21 Due to its case-only, self-controlled nature, SSA has the advantages of eliminating time-invariant confounders (e.g., sex) and dimension reduction by concentrating on the sequence of drug prescriptions.…”

“…[6][7][8][9][10][11][12][13] In addition, a highthroughput sequence symmetry analysis (SSA) approach was used to screen a nationally representative sample of commercially insured U.S. patients. 14 This screening approach identified several new potential statin-related prescribing cascades including osmotically acting laxatives (presumably for statin-related constipation) and opioids in combination with non-opioid analgesics (presumably for statinrelated muscle pain).…”

“…drug prescriptions, drug-related side effects and adverse reactions, hydroxymethylglutaryl-CoA reductase inhibitors published, 14 and interactive results can be viewed at https:// public.table au.com/app/profi le/cvmed lab/viz/Resul tsoft hehig hthrou ghput SSAsc reeni ng/Table ofCon tents Flowc hart. Briefly, we included adults aged ≥20 years, who initiated a statin (i.e., "index" class) between 2007 and 2018, and who were continuously enrolled in the same health care plan for at least 720 days before and 360 days after statin initiation.…”

“…Because this study focuses on risk factors for potential statin-related prescribing cascades, we only included drug class dyads with an aSR of >1. 14 Among the 57 signals classified as potential prescribing cascades, we restricted the present analysis to 42 statin-marker dyad subcohorts with ≥500 patients (Table S2). Among patients experiencing at least 1 of the 42 included prescribing cascades, we measured their baseline characteristics within −360 days of statin initiation, as well as characteristics of the statin regimen started on day 0, to assess the differential risk for each potential prescribing cascade by statin regimen characteristic, adjusted for patients' baseline characteristics.…”

“…Seven statin‐related prescribing cascades have been reported in previous studies including prochlorperazine for dizziness, quinine for nocturnal leg cramps, medications for managing lower urinary tract symptoms, hypnotic drugs for sleep disturbances, antidementia drugs, hepato‐protective drugs, anti‐staphylococcal antibiotics for skin infections, and antidiabetic drugs 6–13 . In addition, a high‐throughput sequence symmetry analysis (SSA) approach was used to screen a nationally representative sample of commercially insured U.S. patients 14 . This screening approach identified several new potential statin‐related prescribing cascades including osmotically acting laxatives (presumably for statin‐related constipation) and opioids in combination with non‐opioid analgesics (presumably for statin‐related muscle pain).…”