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Evaluation of Clinical Outcomes and Costs Based on Prescribed Dose Level of Renin-Angiotensin-Aldosterone System Inhibitors
Murray Epstein, MD; Paula J. Alvarez, RPh, MPH, MBA; Nancy L. Reaven, MA; Susan E. Funk, MBA, FACHE; Karen J. McGaughey, PhD; Melanie S. Brenner, PharmD, BCPS; Wade Benton, PharmD; and Ladan Golestane

Evaluation of Clinical Outcomes and Costs Based on Prescribed Dose Level of Renin-Angiotensin-Aldosterone System Inhibitors

Murray Epstein, MD; Paula J. Alvarez, RPh, MPH, MBA; Nancy L. Reaven, MA; Susan E. Funk, MBA, FACHE; Karen J. McGaughey, PhD; Melanie S. Brenner, PharmD, BCPS; Wade Benton, PharmD; and Ladan Golestane
Renin-angiotensin-aldosterone system (RAAS) inhibitors, including angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARBs), and mineralocorticoid receptor antagonists, have been shown to reduce mortality and slow disease progression in patients with heart failure (HF), chronic kidney disease (CKD), and diabetes.1-6 Current evidence-based guidelines consider RAAS inhibitors as integral components in the management and treatment of patients with HF7,8 and CKD9,10 and of patients with diabetes and comorbid hypertension or renal impairment.11,12 However, concerns related to hyperkalemia risk and other risks with the use of RAAS inhibitors have contributed to sub-therapeutic dosing, discontinuation, and avoidance of RAAS inhibitors when clinically indicated.13-15 As a result, there is a large gap between guideline recommendations and real-world clinical practice in the use of RAAS inhibitors.16-21
To better elucidate this treatment gap, we recently published a comprehensive retrospective analysis of an electronic medical records database covering more than 1.7 million patients to evaluate 3 pivotal concerns: (1) whether RAAS inhibitors are being prescribed according to treatment guidelines for HF, CKD, and diabetes; (2) what happens to prescriptions for RAAS inhibitors after hyperkalemia events; and (3) whether clinical outcomes are affected in patients who are prescribed doses below guideline recommendations or whose RAAS inhibitors are discontinued.22 We identified a substantial gap between guideline recommendations and real-world prescribing patterns for RAAS inhibitors, with 58% to 65% of patients prescribed lower-than-recommended doses and approximately 15% discontinued from RAAS inhibitor therapy. The prescribing patterns for RAAS inhibitors appeared to be significantly altered by the development of hyperkalemia. An association was found between RAAS inhibitor dose and the development of serious adverse outcomes or death, favoring the use of RAAS inhibitors at guideline-recommended doses, when possible. Taken together, these findings highlight the challenge behind RAAS inhibitor prescribing decisions in which clinicians attempt to balance treatment benefits against the risk of provoking hyperkalemia.
This treatment decision process takes place in a healthcare environment with juxtaposing objectives of balancing therapeutic quality with spiraling medical costs. To balance these objectives, there is a need to better understand the implications of care on costs. Therefore, in the current study, we expanded our previous investigation by examining medical system costs in relation to RAAS inhibitor use in the same patient populations, as well as the influence of hyperkalemia as a determinant of RAAS inhibitor use and cost. We compared annualized all-cause medical and pharmacy costs from a payer perspective for patients classified by whether they were prescribed the recommended dose of RAAS inhibitor per each agent’s product label, were prescribed a lower-than-recommended dose, or had been discontinued from their RAAS inhibitors.
Study Population and Cohorts
The original study22 involved selecting patients who had at least 2 potassium test results between 2007 and 2012 from a large US database of electronic health records (EHRs) (Humedica). Records from patients with sufficient data and without preindex end-stage renal disease (ESRD), who had one or more RAAS inhibitor prescriptions prior to the fixed index date of July 1, 2009, were examined (specific medications and their dose levels included in each dose category are listed in eAppendix Box 1). The current analysis further excluded patients with less than 90 days of postindex data and those to whom RAAS inhibitor doses exceeding the maximum recommended dose listed in the package insert were prescribed.
Age was used to assign patients to 2 payer categories: those covered by Medicare (age ≥65 years) and those covered by commercial insurance (age <65 years, including 373 patients whose ages were unspecified). Nonexclusive cohorts of patients with CKD (stages 3a, 3b, or 4, identified by estimated glomerular filtration rate [eGFR] or diagnosis code), HF (by diagnosis code), or diabetes (by single diagnosis code, glycated hemoglobin [A1C]  ≥6.5%, or single outpatient written prescription for a hypoglycemic agent) were analyzed separately for each payer category. (All hypoglycemic agents used to identify diabetes are listed in eAppendix Box 2, available at Only 4% of diabetes was identified through a drug prescription alone.)
As in the previous study, adverse outcomes included stroke, acute myocardial infarction, percutaneous coronary intervention, coronary artery bypass grafting, CKD progression, or progression to ESRD. Death was documented according to the Social Security Death Register or from the EHR. RAAS inhibitor prescriptions were classified by dose level as “maximum” (the recommended labeled dose), “submaximum” (any lesser amount), or “discontinued” (>390 days elapsed since the most recent prescription, with this time period allowing 30 days past the longest common prescription length for patients to seek prescription renewal). RAAS inhibitor dose level was classified as of the patient’s first adverse outcome or death (if applicable) or the dominant dose level of RAAS inhibitor prescriptions during the postindex period (in the absence of adverse outcomes or death), as defined in published supplemental data.22 Hyperkalemia was defined as a serum potassium level between 5.1 and 10.0 mEq/L (mild, 5.1 to 5.4 mEq/L; moderate-to-severe, ≥5.5 mEq/L).
Classification of Services and Medications
In the EHR data, healthcare services were grouped by calendar day and classified as inpatient (IP) admissions or emergency department (ED) visits or by type of outpatient (OP) services (inclusive of OP hospital surgeries, diagnostics, or visits, along with office, laboratory, or home visits). Medications prescribed in the OP setting were identified by generic name of the primary ingredient, irrespective of dose, brand, or formulation.
Cost of Services in Claims Data
Average health plan–allowed cost was obtained from 2013 commercial insurance and Medicare claims data (OptumInsight, Minneapolis, MN) as follows: per IP day, for multiple categories of surgical and nonsurgical admissions; per visit, for multiple categories of hospital/facility OP visits; and per calendar day for physician services in office, hospital OP, and hospital IP settings. Costs were normalized to 2016 US dollars at 3% per annum.
All-Cause Costs: Application of Cost of Services in Claims Data to Services Identified in Medical Records Data
The relevant cost per service derived from commercial and Medicare insurance claims was applied to each service event among patients in the commercial and Medicare groups, respectively. For IP costs, the average allowed cost per day of hospital plus IP physician care was applied to each hospitalization day using length-of-stay information and whether the claims were for medical or surgical admissions. The length of time in the intensive care unit was accounted for. Base costs were adjusted depending upon patient comorbidities (HF, diabetes, CKD stages 3/4). For OP/ED costs, the relevant average allowed cost per hospital visit plus the average allowed cost per day of physician services in the hospital OP setting was applied to each ED visit and other hospital OP visits. Relevant costs per visit were applied to each office visit (average allowed cost per day of physician services in the office setting), home health visit, and laboratory visit.
Cost of OP Medications
Data on the average cost per filled prescription and percent refills were obtained from 2013 commercial insurance and Medicare claims (OptumInsight) for 120 medications, which, together, made up 75% of all postindex OP prescriptions. The average cost per prescription (original + average refills) was calculated and applied to written OP prescriptions for each evaluated medication. The average cost per prescription for all evaluated medications combined was assigned for all other prescriptions.

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