Dose-dependent relationships observed for prescribing cascades: a cohort study

Background: Prescribing cascades occur when new medications are initiated to treat adverse drug reactions (ADRs) caused by an initial medication (index). Although dose reduction of the index medication is often recommended, evidence supporting a dose-dependent relationship is limited. Objectives: To investigate dose-dependent relationships in prescribing cascades where such evidence is currently insufficient or lacking. Methods: A cohort study was conducted using prescription sequence symmetry analysis with data from over 600 Dutch community pharmacies. We assessed 18 prescribing cascades involving ACE inhibitors (ACEIs), statins, antidepressants, calcium channel blockers, and other drug classes. Index medication doses were categorized based on the WHO Defined Daily Dose (DDD) into low (<0.50 DDD), medium (0.50–1.50 DDD), and high (>1.50 DDD). Adjusted sequence ratios (aSRs) were calculated per dose category; aSRs >1 indicated the presence of a prescribing cascade. Results: Twelve of the 18 prescribing cascades showed a dose-dependent relationship. All ACEI-related cascades demonstrated increasing aSRs with higher doses. For example, for ACEI potentially causing cough, followed by various medications in four cascades, aSRs increased from 0.86-2.09 for low doses to 1.29-2.75 for high doses. Dose-dependent relationships were also found for statins, antidepressants, and dihydropyridine calcium channel blockers. No such relationship was observed for cascades involving proton pump inhibitors, diuretics, and non-steroidal anti-inflammatory drugs. Conclusion: Medication dose can play a significant role in prescribing cascades. Clinicians should be aware of potential ADRs at higher doses and consider dose reduction as a strategy to prevent or reverse certain cascades.