Dose-dependent relationships in potential prescribing cascades: a cohort study using community pharmacy dispensing data

Abstract Introduction Prescribing cascades occur when new medications are initiated to treat adverse drug reactions (ADRs) caused by an initial medication (index). Although using lower dose of the index medication is often recommended as a general strategy to address adverse drug reactions that may trigger potential prescribing cascades, evidence supporting a dose-dependent relationship for many prescribing cascades is limited. Aim The aim was to examine the dose-dependent relationship across a range of index medications related to various potential prescribing cascades, for which the dose-dependent relationship between the index medication and the ADR was not yet known. Method A cohort study was conducted using prescription sequence symmetry analysis with data from over 600 Dutch community pharmacies (2015–2020). We assessed 18 potential prescribing cascades involving ACE inhibitors (ACEIs), statins, antidepressants, dihydropyridine calcium channel blockers (DCCBs), and other drug classes. Index medication doses were categorized based on the World Health Organization (WHO) Defined Daily Dose (DDD) into low ( 1.50 DDD). The adjusted sequence ratio (aSR) quantified the likelihood of marker drug initiation after vs. before the index drug, corrected for prescribing trends; aSR > 1 indicated a potential prescribing cascade. Results Twelve of the 18 potential prescribing cascades showed a dose-dependent relationship. All angiotensin converting enzyme inhibitor (ACEI) related cascades demonstrated increasing aSRs with higher doses. ACEIs associated with cough showed increasing aSRs, from 0.86 to 2.09 at low dose to 1.29 to 2.78 at high dose across four cascades. Dose-dependent relationships were also found for statins, antidepressants, and DCCBs. 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 potential prescribing cascades. Healthcare professionals should be aware of the potential contribution of dose to prescribing cascade development. The study design precludes causal inference, and confirmation is needed to support further clinical recommendations.