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The renin-angiotensin-aldosterone system (RAAS) is an intricate physiological pathway involving numerous enzymes and hormones, including renin, angiotensin-converting enzyme (ACE), angiotensin I and II, and aldosterone. Imbalances within this system increase the production of angiotensin II and aldosterone. Increased angiotensin II levels promote vasoconstriction and blood pressure elevation. Concurrently, higher aldosterone levels stimulate sodium and water reabsorption in the kidneys,...
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High-Throughput Screening for Prescribing Cascades Among Real-World Angiotensin-Converting Enzyme Inhibitor

Asinamai M Ndai1,2,3, Kayla Smith1,2,3, Shailina Keshwani1,2,3

  • 1Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, Gainesville, Florida, USA.

Pharmacoepidemiology and Drug Safety
|March 18, 2025
PubMed
Summary

Angiotensin-converting enzyme inhibitor (ACEI) adverse effects may lead to prescribing cascades. This study identified potential ACEI-induced prescribing cascades in Medicare beneficiaries, highlighting risks like corticosteroid and sympathomimetic use.

Keywords:
ACE inhibitors (ACEIs)Medicare beneficiariesadverse eventsantihypertensive drugsolder adultsprescribing cascadessequence symmetry analysis

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Area of Science:

  • Pharmacovigilance
  • Drug Safety
  • Health Services Research

Background:

  • Angiotensin-converting enzyme inhibitors (ACEIs) are widely prescribed antihypertensive medications.
  • Adverse drug events associated with ACEIs can lead to the initiation of new medications, a phenomenon known as a prescribing cascade (PC).
  • Identifying ACEI-induced PCs is crucial for improving patient safety and optimizing medication management.

Purpose of the Study:

  • To identify potential prescribing cascades initiated by Angiotensin-converting enzyme inhibitors (ACEIs).
  • To utilize high-throughput sequence symmetry analysis for detecting these drug-induced prescribing patterns.
  • To assess the clinical plausibility and quantify the risk of identified ACEI-induced PCs.

Main Methods:

  • Analysis of national Medicare claims data from 2011-2020 for beneficiaries aged 66 years and older.
  • Screening for the initiation of 446 non-antihypertensive drug classes within 90 days of ACEI initiation.
  • Calculation of adjusted sequence ratios (aSRs) and naturalistic number needed to harm (NNTH) for significant signals, followed by clinical review.

Main Results:

  • Over 308,000 ACEI initiators were analyzed.
  • Eighty-one significant signals were detected, with 42 classified as potential ACEI-induced prescribing cascades after clinical review.
  • Strongest signals included corticosteroids (NNTH 313) and serotonin 5-HT3 antagonists (NNTH 496), and sympathomimetics (aSR 1.97).

Conclusions:

  • The study identified potential prescribing cascades linked to known and possibly underrecognized ACEI adverse events.
  • These findings suggest that ACEI use may contribute to subsequent prescriptions for other drug classes.
  • Further research is warranted to confirm the extent and clinical impact of these identified prescribing cascades on patient outcomes.