Magnitude of and Characteristics Associated With the Treatment of Calcium Channel Blocker–Induced Lower-Extremity Edema With Loop Diuretics

Abstract

IMPORTANCE Calcium channel blockers, specifically dihydropyridine calcium channel blockers (DH CCBs, eg, amlodipine), may cause lower-extremity edema. Anecdotal reports suggest this may result in a prescribing cascade, where DH CCB-induced edema is treated with loop diuretics. OBJECTIVE To assess the magnitude and characteristics of the DH CCB prescribing cascade. DESIGN, SETTING, AND PARTICIPANTS This cohort study used a prescription sequence symmetry analysis to assess loop diuretic initiation before and after the initiation of DH CCBs among patients aged 20 years or older without heart failure. Data from a private insurance claims database from 2005 to 2017 was analyzed. Use of loop diuretics associated with initiation of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and other commonly used medications was used as negative controls. Data were analyzed from March 2019 through October 2019. EXPOSURES Initiation of DH CCB or negative control medications. MAIN OUTCOMES AND MEASURES The temporality of loop diuretic initiation relative to DH CCB or negative control initiation. Secular trend-adjusted sequence ratios (aSRs) with 95% CIs were calculated using data from 360 days before and after initiation of DH CCBs. RESULTS Among 1 206 093 DH CCB initiators, 55 818 patients (4.6%) (33 100 [59.3%] aged <65 years; 32 916 [59.0%] women) had a new loop diuretic prescription 360 days before or after DH CCB initiation, resulting in an aSR of 1.87 (95% CI, 1.84-1.90). An estimated 1.44% of DH CCB initiators experienced the prescribing cascade. The aSR was disproportionately higher among DH CCB initiators who were prescribed high doses (aSR, 2.20; 95% CI, 2.13-2.27), initiated amlodipine (aSR, 1.89; 95% CI, 1.86-1.93), were men (aSR, 1.96; 95% CI, 1.91-2.01), and used fewer antihypertensive classes (aSR, 2.55; 95% CI, 2.47-2.64). The evaluation of ACE inhibitors or ARBs as negative controls suggested hypertension progression may have tempered the incidence of the prescribing cascade (aSR for ACE inhibitors and ARBs, 1.27; 95% CI, 1.24-1.29). CONCLUSIONS AND RELEVANCE This study found an excessive use of loop diuretics following initiation of DH CCBs that cannot be completely explained by secular trends or hypertension progression. The prescribing cascade was more pronounced among those initially prescribed a high dose of DH CCBs.

Prescribing cascades in community-dwelling adults: protocol for a systematic review

“…Prescribing cascades are a contributor to problematic polypharmacy but are not captured within the numerous prescribing indicator sets aimed at reducing the use of inappropriate medications. Known prescribing cascades include those resulting from commonly used medications such as antihypertensives, NSAIDs and cholinesterase inhibitors 16,17,24,25 . Calcium channel blockers, particularly dihydropyridine calcium channel blockers, have been shown to result in a prescribing cascade whereby the resultant lower extremity oedema is treated with loop diuretics 16,17 .…”

“…Known prescribing cascades include those resulting from commonly used medications such as antihypertensives, NSAIDs and cholinesterase inhibitors 16,17,24,25 . Calcium channel blockers, particularly dihydropyridine calcium channel blockers, have been shown to result in a prescribing cascade whereby the resultant lower extremity oedema is treated with loop diuretics 16,17 . A dry cough is a common side effect of ACE inhibitors and has been shown to result in the prescription of a cough suppressant and antibiotics 24 .…”

“…If the ADR is misinterpreted as a new medical condition and results in the subsequent prescription of another medication, an unintentional prescribing cascade occurs 15 . An example of an unintentional prescribing cascade is the prescribing of a loop diuretic to treat lower extremity oedema caused by calcium channel blockers 16,17 . Intentional prescribing cascades occur when the ADR is recognised and attributed to the first medication and a subsequent medication is intentionally prescribed to combat this ADR or is prescribed at the same time as the first medication in order to prevent it 15 .…”

Drug-induced peripheral edema: an etiology-based review

“…It may become more severe during long-term therapy (Makani, Bangalore, Romero, Htyte, et al, 2011;Messerli, 2002). Faced with these edema, many pharmacoepidemiologic studies have shown that a very frequent therapeutic reflex consists in initiating diuretics (Savage et al, 2020;Vouri et al, 2019). Indeed, 2.3% of patients over 65 years of age newly treated with DHP experience this prescription cascade within one year of initiation (Vouri et al, 2019).…”

“…Faced with these edema, many pharmacoepidemiologic studies have shown that a very frequent therapeutic reflex consists in initiating diuretics (Savage et al, 2020;Vouri et al, 2019). Indeed, 2.3% of patients over 65 years of age newly treated with DHP experience this prescription cascade within one year of initiation (Vouri et al, 2019). Compared to renin angiotensin aldosterone system (RAAS) inhibitor prescription, this risk is significantly increased by 2.4 after a 3-month treatment (Savage et al, 2020).…”