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Evaluation of the Treatment Gap Between Clinical Guidelines and the Utilization of Renin-Angiotensin-Aldosterone System Inhibitors
Murray Epstein, MD; Nancy L. Reaven, MA; Susan E. Funk, MBA; Karen J. McGaughey, PhD; Nina Oestreicher, PhD; John Knispel, MD
Participating Faculty: Evaluation of the Treatment Gap Between Clinical Guidelines and the Utilization of Renin-Angiotensin-Aldosterone System Inhibitors

Evaluation of the Treatment Gap Between Clinical Guidelines and the Utilization of Renin-Angiotensin-Aldosterone System Inhibitors

Murray Epstein, MD; Nancy L. Reaven, MA; Susan E. Funk, MBA; Karen J. McGaughey, PhD; Nina Oestreicher, PhD; John Knispel, MD
Objectives: This study examined renin-angiotensin-aldosterone system (RAAS) inhibitor dose levels in a US patient population and investigated the impact of hyperkalemia on RAAS inhibitor dose and the association between dose levels and clinical outcomes.
Study Design: De-identified medical records from a large database of electronic health records (Humedica) for patients 5 years of age or older with at least 2 serum potassium readings were analyzed (N = 205,108 patients; 1.7 million records).
Methods: Inclusion criteria required 1 RAAS inhibitor prescription and 12 months’ data prior to July 1, 2009 (index date). Patients were classified by comorbidities (chronic kidney disease, heart failure, or diabetes) and RAAS inhibitor dose level at index date, as determined by prescription information. Additional analyses examined RAAS inhibitor dose changes following hyperkalemia and the frequency of cardiorenal adverse outcome/mortality or mortality alone by post index dose level.
Results: Dose level was similarly distributed irrespective of patient comorbidity status, with RAAS inhibitors prescribed at maximum dose in 19% to 26% of patients and submaximum dose in 58% to 65% of patients; RAAS inhibitors were discontinued in 14% to 16% of patients. RAAS inhibitor dose was down-titrated after 16% to 21% of hyperkalemia events and discontinued after 22% to 27% of hyperkalemia events. Cardiorenal adverse event/mortality and mortality occurred in 34.3% and 11.0% of patients who discontinued RAAS inhibitors, 24.9% and 8.2% of patients on submaximum doses, and 24.9% and 4.1% of patients on maximum doses, respectively.
Conclusions: Relatively few patients were prescribed maximum doses of RAAS inhibitors, and dose and usage declined following hyperkalemia. Patients on submaximum doses or who discontinued RAAS inhibitors had worse outcomes than patients on maximum doses.
Am J Manag Care. 2015;21:S212-S220

For author information and disclosures, see end of text.

Renin-angiotensin-aldosterone system (RAAS) inhibitors comprise a large class of drugs, which includes angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARBs), direct renin inhibitors, and mineralocorticoid receptor antagonists (MRAs). Numerous randomized clinical trials have clearly demonstrated that RAAS inhibitors can reduce the risk of death and slow disease progression in patients with heart failure (HF), chronic kidney disease (CKD), and diabetes (DM).1-7 Based on these results, evidence-based treatment guidelines recommend the use of RAAS inhibitors for patients with HF8,9 or CKD10,11, and for DM patients with hypertension and/ or renal insufficiency.12 The guidelines specifically recommend that RAAS inhibitors be titrated up to moderate to high doses, as used in clinical trials, in order for patients to derive optimal treatment benefits.8-12 However, the use of these drugs may be limited by their potential to cause hyperkalemia.

Although usually asymptomatic, clinical manifestations of hyperkalemia include muscle fatigue, paralysis, and the more serious manifestations of cardiac arrhythmia and cardiac arrest.13,14 Treatment guidelines provide several recommendations for minimizing the risk of hyperkalemia, including: avoiding RAAS inhibitor therapy in patients who may be at risk of developing hyperkalemia, performing regular potassium monitoring, titrating the dose of the RAAS inhibitor, and discontinuing drugs that can interfere with renal potassium excretion prior to initiating RAAS inhibitors.8-12 Discontinuing or lowering the dose of the RAAS inhibitor is recommended if hyperkalemia develops after initiating therapy.8-12

Several observational and retrospective studies have reported a large gap between recommendations in guidelines and real-world practice in the use of RAAS inhibitor therapies.15-18 A retrospective analysis of data from the American Heart Association’s Get With the Guidelines– Coronary Artery Disease database showed that less than 10% of eligible HF patients hospitalized for myocardial infarction were prescribed an aldosterone agonist at discharge, 17 and a large European registry has reported that while 67% to 92% of hospitalized HF patients were prescribed the recommended RAAS inhibitor therapy, less than 30% were up-titrated to the recommended target dose.18 In order to better elucidate this apparent treatment gap, this study undertook a comprehensive analysis of a large database of electronic medical records (>7 million patients) to evaluate: (1) whether RAAS inhibitors are being prescribed according to treatment guidelines, (2) what happens to RAAS inhibitor prescriptions after hyperkalemia events, and (3) what the clinical outcomes are in patients whose RAAS inhibitors are discontinued or prescribed at doses lower than recommended in guidelines.


Data Source and Patient Selection

De-identified medical records (2007-2012) for patients 5 years of age or older with at least 2 potassium readings were obtained from Humedica, a large US database of electronic health records ( A total of 1.7 million patient records met these criteria. Study patients were individuals receiving care from providers in integrated health delivery networks across the United States, including those insured by commercial insurance, Medicare, Medicaid, other health insurance, or no insurance. For all study patients, the data include any services provided in hospitals as well as office and outpatient care. Medication data include written prescriptions and medication administrations that occurred in-clinic and/ or in-hospital. Results were available for a limited number of lab tests.

Inclusion criteria required at least 1 outpatient RAAS inhibitor prescription and 12 months of data prior to July 1, 2009 (index date). RAAS inhibitors included ACE inhibitors, ARBs, direct renin inhibitors, and select MRAs. To ensure continuity, evidence that patient engagement with the healthcare provider began at least 12 months prior to the index date and continued up to the index date was required. This requirement is analogous to requiring continuous enrollment in a claims data study.

Patients with end-stage renal disease (ESRD) at the index date were excluded from the analysis of dose distribution and outcomes. The dose distribution analysis further excluded patients with CKD stage 5 and acute kidney injury. Response to hyperkalemia events was evaluated for each hyperkalemia event in the data (2007- 2012) without restriction by patient comorbidity status.

Classification of Patient Comorbidity and RAAS Inhibitor Dose Category

Patients were classified by disease comorbidity (CKD stages 3-4 and/or HF or DM [types 1 and 2]) and age (<65 vs ≥65 years) prior to the index date using International Classification of Diseases, Ninth Edition (ICD-9) diagnosis codes; results of testing for estimated glomerular filtration rate (eGFR), left ventricular ejection fraction, and glycated hemoglobin (if available); and prescriptions for anti-DM medications. If multiple values were available for a particular biomarker, the value indicating greatest severity was utilized. A condition was deemed present if identified by 1 or more indicators in the medical record, irrespective of setting of care. Diagnosis codes used in defining comorbidities generally reflect definitions used by the US Renal Data System (USRDS) and are listed in eAppendix 1 (available online at

RAAS inhibitor prescriptions were classified by dose level using the following dose categories: “supramaximum,” defined as any RAAS inhibitor dose above the labeled dose; “maximum,” defined as the labeled dose; “submaximum,” defined as any RAAS inhibitor dose lower than the labeled dose; or “discontinued,” defined as the absence of RAAS inhibitor prescriptions for a period of more than 390 days subsequent to prior prescription. The 390-day period allows 360 days (longest common prescription length in the database) plus 30 additional days for patients to see or contact their healthcare provider for a refill. Specific medications and their dose levels included in each dose category are listed in eAppendix 2 (available online at Results are not reported for the small group of patients on supramaximum doses.

Dose Distribution Study

A patient-level analysis was performed to examine RAAS inhibitor dose distribution as of the index date. The distribution (number and percent) of patients by dose category was assessed for the total study population and for each of 10 comorbidity groups as listed in Figure 1.

Determining RAAS Inhibitor Dose Subsequent to Hyperkalemia Event

An event-level analysis was used to examine RAAS inhibitor dose changes following hyperkalemia. Hyperkalemia was defined as any serum potassium measurement above 5.0 mEq/L. All laboratory-reported events of serum potassium of 5.1 mEq/L or higher were classified by severity (mild, 5.1-5.4 mEq/L; moderateto- severe, ≥5.5 mEq/L). RAAS inhibitor prescription status was assessed before and after each hyperkalemia event, with a 390-day follow-up period for assessing RAAS inhibitor dose following hyperkalemia. (The 390 days corresponds to the time period required to identify discontinued RAAS inhibitor prescriptions.) Post hyperkalemia event dosing was compared with the last prehyperkalemia dose (or prescription expiration) before the hyperkalemia event. Outcomes were described as the percent of hyperkalemia events for which the next RAAS inhibitor dose represented maintenance of dose, down titration, or discontinuation. Results were segmented by RAAS inhibitor dose category (submaximum or maximum) at the time of the hyperkalemia event and severity of the hyperkalemia event (mild or moderate-to-severe).

Outcomes Study

In this patient-level analysis, differences in clinical outcomes between patients with submaximum or discontinued RAAS inhibitor versus those remaining on maximum doses were evaluated in the total study population and within disease categories (CKD 3-5, HF, or DM). Adverse outcomes evaluated were CKD progression and progression to ESRD (by eGFR laboratory value, diagnosis code, or chronic dialysis by procedure code); stroke and acute myocardial infarction (by diagnosis code during inpatient hospitalization); and coronary artery bypass and percutaneous coronary intervention (by procedure code); or all-cause mortality (from Social Security or hospital records). Code sets were consistent with USRDS methodology and are supplied in eAppendix 1 and eAppendix 3 (availble online at

End points included a composite measure of any adverse outcome or mortality and mortality alone and were assessed from July 1, 2009, until the patient’s last interaction or December 31, 2012 (post index period; median follow-up 3.4 years). Date of death was not available; therefore, it was not possible to ascertain time frames from last prescription/expiration to death.

For the composite end point, the most frequently prescribed dose level of RAAS inhibitor was identified for each patient during the post index period. RAAS inhibitor dose category was reevaluated and adjusted for patients who experienced an adverse outcome to ensure that the dominant dose category did not reflect data occurring after the adverse outcome; this adjustment resulted in a higher or lower RAAS inhibitor dose category for 1.6% and 3.5% of patients, respectively. For the end point of mortality alone, all patients were classified according to their last RAAS inhibitor dose level in the data.

Chi-square tests were carried out to compare differences in the proportion of adverse outcomes or death between the various RAAS inhibitor dose groups. P values for the 3 contrast comparisons were adjusted using the step-down Bonferroni procedure of Holm to protect the family-wise error rate at 0.05.20


Study Population Characteristics

Table 1 shows the age, gender, and comorbidity classifications for the patient populations included in each analysis. A total of 205,108 patients met the inclusion criteria; of these, 66,862 (32.8%) experienced 1 or more hyperkalemia events. Of the patients who experienced hyperkalemia events, 58,520 (28.5%) experienced 1 or more mild hyperkalemia events and 30,912 (15.1%) experienced 1 or more moderate-to-severe hyperkalemia events. After excluding patients with ESRD, 201,655 patients were included in the outcomes analyses. After further excluding patients with CKD stage 5 and acute kidney injury, 195,327 patients were included in the dose distribution study.

RAAS Inhibitor Dose Distribution

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