Evaluation of a Common Prescribing Cascade of Calcium Channel Blockers and Diuretics in Older Adults With Hypertension
Authors: Jessica D Visentin
Vasily Giannakeas
Wei Wu
Susan E Bronskill
Xuesong Wang
Paula A Rochon
Miles J Luke
Andrea Gruneir
Jun Guan
Kenneth Lam
Lynn Zhu
Lisa M McCarthy
Nathan M Stall
Rachel D Savage
Stephanie H Read
Journal: JAMA Internal Medicine (2020)
Discipline: CLINICAL MEDICINE
Keywords: Calcium channel blockers; peripheral edema; prescribing cascade; loop diuretic; older adults
Affiliations: Women's College Research Institute, Women's College Hospital, Toronto, Ontario, Canada., ICES, Toronto, Ontario, Canada., Institute of Health Policy, Management and Evaluation, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada., Department of Family Medicine, University of Alberta, Edmonton, Alberta, Canada., Division of Geriatric Medicine, Department of Medicine, University of Toronto, Toronto, Ontario, Canada., Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.

Abstract:  Importance: Calcium channel blockers (CCBs) are commonly prescribed agents for hypertension that can cause peripheral edema. A prescribing cascade occurs when the edema is misinterpreted as a new medical condition and a diuretic is subsequently prescribed to treat the edema. The extent to which this prescribing cascade occurs at a population level is not well understood. Objective: To measure the association between being newly dispensed a CCB and subsequent dispensing of a loop diuretic in older adults with hypertension. Design, setting, and participants: A population-based cohort study was performed using linked health administrative databases of community-dwelling adults 66 years or older with hypertension and new prescription drug claims from September 30, 2011, to September 30, 2016, in Ontario, Canada. The dates of analysis were September 1, 2018, to May 30, 2019. Exposures: Individuals who were newly dispensed a CCB were compared with the following 2 groups: (1) individuals who were newly dispensed an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker and (2) individuals who were newly dispensed an unrelated medication. Main outcomes and measures: Hazard ratios (HRs) with 95% CIs were estimated for individuals who were dispensed a loop diuretic within 90 days of follow-up using Cox proportional hazards regression models. Results: The cohort included 41 086 older adults (‚â?6 years) with hypertension who were newly dispensed a CCB, 66 494 individuals who were newly dispensed another antihypertensive medication, and 231 439 individuals who were newly dispensed an unrelated medication. At index (ie, the dispensing date), the mean (SD) age was 74.5 (6.9) years, and 191 685 (56.5%) were women. Individuals who were newly dispensed a CCB had a higher cumulative incidence at 90 days of being dispensed a loop diuretic than individuals in both control groups (1.4% vs 0.7% and 0.5%, P &lt; .001). After adjustment, individuals who were newly dispensed a CCB had increased relative rates of being dispensed a loop diuretic compared with individuals who were newly dispensed an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker (HR, 1.68; 95% CI, 1.38-2.05 in the first 30 days after index [days 1-30]; 2.26; 95% CI, 1.76-2.92 in the subsequent 30 days [days 31-60]; and 2.40; 95% CI, 1.84-3.13 in the third month of follow-up [days 61-90]) and individuals who were newly dispensed unrelated medications (HR, 2.51; 95% CI, 2.13-2.96 for 1-30 days after index; 2.99; 95% CI, 2.43-3.69 for 31-60 days after index; and 3.89; 95% CI, 3.11-4.87 for 61-90 days after index). This association persisted, although slightly attenuated, from 90 days to up to 1 year of follow-up and when restricted to a subgroup of individuals who were newly dispensed amlodipine. Conclusions and relevance: Many older adults with hypertension who are newly dispensed a CCB subsequently receive a loop diuretic. Given how widely CCBs are prescribed, interventions are needed to raise clinicians' awareness of this common prescribing cascade to reduce the prescribing of potentially unnecessary medications that may cause harm. 

Retracted: No

PubPeer comments:
 ### Loop diuretics for the treatment of calcium channel blocker-induced lower leg edema: a frequent and avoidable prescribring cascade A prescribing cascade [1] begins when an adverse drug reaction is not identified and misinterpreted as a symptom of a disease. In order to  treat this supposed disease, additional drugs are then often used instead of discontinuing or changing the causal drug. Calcium channel blockers (CCB) of the dihydropyridine type are among the first choice in the therapy of arterial hypertension. A typical side effect of CCB (especially amlodipine) is lower leg edema, which can occur in up to a quarter of all patients treated.[2] These edemas are pathophysiologically based on arteriolar dilatation with consecutive extravasation of fluid. Hypervolemia is explicitly not present. If loop diuretics are used for volume deprivation by increased diuresis, this is a typical example of a prescription cascade and is regarded as a false indication.[3] In a retrospective cohort study, the clinical significance of this prescription cascade was investigated based on data from the public health insurance system in the Canadian province of Ontario. The study included 41,086 patients with arterial hypertension aged 65 years who were prescribed CCB for the first time in the period 2011-2016. The comparison groups were hypertensive patients who were prescribed ACE inhibitors (ACEI) or angiotensin receptor blockers (ARB) for the first time during the study period (ACEI ARB comparison group, N = 64,494), as well as patients with any new drug prescription apart from antihypertensives (general comparison group, N = 231,439). Antihypertensively or diuretically pretreated patients as well as patients with heart failure or end-stage renal disease were excluded. The primary endpoint of the study was the new prescription of loop diuretics within 90 days after initial prescription of CCB. This occurred significantly more frequently in the group of CCB patients compared to the comparison groups (1.4% vs. 0.7% in the ACEI ARB comparison group and 0.5% in the general comparison group). The risk for a diuretic prescription was still significantly increased in the CCB group even after 12 months (adjusted HR 1.19; 95% KI 1.06-1.32 for the ACEI ARB control group and adjusted HR 2.23; 95% KI 2.02-2.48 for the general control group). Future studies should show which further consequences - such as diuretic-induced side effects, unnecessary cardiac follow-up examinations or additional costs - are associated with such a prescription cascade. Conclusion for clinical practice: Especially in elderly patients with newly appeared symptoms, it should first be examined whether these could be side effects of an existing drug therapy before prescribing new drugs. --- [1]: [Rochon, Gurwitz: Optimising drug treatment for elderly people: the prescribing cascade. In: BMJ. Band: 315, Nummer: 7115, 1997] [2]: [Makani et al.: Peripheral edema associated with calcium channel blockers: incidence and withdrawal rate u2013 a meta-analysis of randomized trials. In: Journal of Hypertension. Band: 29] [3]: [Sica: Calcium Channel Blockeru2010Related Peripheral Edema: Can It Be Resolved?. In: The Journal of Clinical Hypertension. Band: 5, Nummer: 4, 2003] ,