Patient characteristics and initiation of mineralocorticoid receptor antagonists in patients with chronic kidney disease in routine clinical practice in the US: a retrospective cohort study

This retrospective, non-interventional cohort study examined patient characteristics and steroidal MRA use over a five-year observation period (October 2009–September 2014). The data source for this analysis was the PharMetrics Plus United States (US) claims database (PMTX+). PMTX+ comprises the adjudicated claims of more than 150 million patients. Diagnoses and procedures were coded to US claims standards (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] at the time of the study), Current Procedural Terminology and Healthcare Common Procedure Coding System. Drug treatment was captured using records of filled prescriptions (National Drug Code and Generic Product Identification) and recorded utilization in medical settings. Healthcare costs included amounts allowed by health plans. Patient records were anonymized in compliance with the Health Insurance Portability and Accountability Act 1996.

The primary objective of the study was to describe the clinical characteristics of patients with CKD with and without HF and/or T2D, and the real-world treatment patterns, including steroidal MRA initiation, in these patient cohorts. The secondary objective was to evaluate clinical predictors of steroidal MRA initiation.

Baseline variables (present at inclusion data or up to 12 months before) assessed in both populations included demographics, CKD stage (ICD-9-CM), comorbidities (based on ICD-9-CM codes), concomitant medication use and healthcare costs. It should be noted that ICD-9-CM codes differentiate between stage 5 CKD and ESRD based on a requirement for chronic dialysis. Follow-up variables included concomitant medication, clinical events use and healthcare costs.

The following variables were only assessed in the CKD population: previous steroidal MRA use, proportion of patients initiating steroidal MRAs and time to initiation of steroidal MRA treatment. The following variables were only assessed in the MRA population: dosing of steroidal MRAs and persistence on steroidal MRA therapy.

Descriptive analyses were performed for all baseline variables. For categorical measures, numbers of cases and percentages are reported. For continuous variables, the mean value with 95% confidence interval, standard deviation and median are reported.

Statistical comparisons across groups are reported at baseline only. Χ² tests were used for categorical variables and Wilcoxon rank-sum tests were used for continuous variables.

Clinical events, based on ICD-9-CM codes (Additional file 1: Table S2), and medication use during follow-up, based on GPI codes, are reported by diagnostic group and MRA treatment condition (no MRAs, < 6 and ≥ 6 months’ treatment) to capture characteristics by treatment duration.

The analysis of predictors of steroidal MRA treatment and clinical outcomes was conducted by means of logistic regression, overall and within each cohort. Given the exploratory nature of the study, all potential predictors of interest were initially included in the model, with final reported predictors selected by running step-wise logistic regression. Age and sex were always included. All statistical analyses were performed using SAS 9.1.3 (SAS Institute, Cary, NC, USA).

In total, 229,004 patients had a diagnosis of CKD during the study period and were eligible for inclusion. Of these, 114,080 patients had CKD only, 76,976 patients had DKD, 15,538 patients had CKD with HF and 22,410 patients had DKD with HF (Fig. 2a).

Table 1 shows baseline characteristics for each disease cohort stratified by MRA initiation. Median age increased, from 59 years in the CKD cohort of MRA non-users to 64 years in the DKD + HF MRA non-users. In each cohort, the median age was lower in MRA users than in MRA non-users.

Data on CKD stage was not available for approximately one-third of patients across all cohorts. For patients for whom information on CKD stage was available (N = 153,407/229,004), stage 3 CKD was the most common stage identified at baseline, irrespective of disease cohort or MRA use (45.5–50.1% for MRA non-users and 47.5–53.8% for MRA users). Patients with HF were more likely to be at a higher stage of CKD than those without HF (Fig. 2b). The proportion of patients with ESRD was higher in the cohorts with HF than in those without HF (Fig. 2b); it was also higher in the patients who received steroidal MRA treatment for up to six months than who received steroidal MRA treatment for at least six months (Table 1).

Previous use (more than 12 months before inclusion date) of spironolactone across the disease cohorts was low but increased along the disease cohorts from CKD to DKD + HF: CKD, 2.6%; DKD, 3.8%; CKD + HF, 12.1%; and DKD + HF, 14.6%. Thus, steroidal MRA use appeared to associate with disease burden. Previous use of eplerenone was very low across all cohorts (574/224,143 of MRA non-users). Owing to the low number of patients receiving eplerenone, only data from patients receiving spironolactone are reported as MRA users.

While concomitant medication use increased across the disease cohorts in line with the presence of T2D and HF, there were some differences in the pattern of use. For example, use of angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors appeared to be driven by the presence of T2D but not of HF. In contrast, the use of β-blockers, vasodilators, diuretics, renin inhibitors, and calcium-channel blockers appeared to be driven by the presence of both T2D and HF (Table 1). The proportion of patients who were using sodium polystyrene sulfonate, a potassium binder prescribed for the treatment of hyperkalemia, was low irrespective of cohort, ranging from 0.7–1.3% for non-users of MRAs and from 0.0–7.1% of MRA users; the highest use was observed in patients with DKD without HF who had used MRAs for less than 6 months.

For the comorbidities of hypertension, CVD, IHD, LVH and anemia, there was a trend for the presence of increasing number of comorbidities along the disease cohorts CKD, DKD, CKD + HF, and DKD + HF.

The number of patients in the CKD population who were initiated on spironolactone during the study period was low for all cohorts but was higher for patients with HF than for those without HF: CKD 1350/114,080 (1.2%); DKD 1360/76,976 (1.8%); CKD + HF 885/15,538 (5.7%); and DKD + HF 1266/22,410 (5.6%). Across the cohorts, the mean time to steroidal MRA initiation following CKD diagnosis ranged from 52.7 to 55.2 days in those receiving treatment for at least six months and from 139.1 to 177.8 days for those receiving treatment for less than six months (Table 1).

Steroidal MRA therapy was most commonly initiated by specialists, with nephrologists being the most common prescribers in those with CKD or DKD and without HF (Table 1).

The logistic regression analysis of predictors of steroidal MRA use is summarized in Table 2. The following predictors were consistently associated with steroidal MRA initiation across all cohorts: previous medication with ARBs or ACE inhibitors and presence of comorbid edema. Prescription by a specialist clinician at inclusion rather than a primary care physician was also associated with steroidal MRA initiation; however, the type of specialty that showed a significant association varied depending on the cohort.

The presence of hyperkalemia or left ventricular hypertrophy (both determined by ICD-9-CM codes; Additional file 1: Table S2) was significantly associated with lower odds of steroidal MRA initiation for all cohorts except the CKD cohort. Being a woman was predictive of steroidal MRA use in all cohorts except the DKD cohort. The associations between age and steroidal MRA use differed across the disease cohorts. Being middle aged (35–44 years or 45–54 years) rather than younger (18–34 years) was significantly associated with higher odds of steroidal MRA use in the CKD cohort; an age of 65+ years versus 18–34 years was significantly associated with higher odds of steroidal MRA use in the DKD and CKD + HF cohorts. Age was unrelated to the odds of steroidal MRA use in the DKD + HF cohort. The concordance statistics for the full model across the four cohorts are reported in Table 2.

In total, 5899 patients were included in the MRA population. The respective breakdown across the disease cohorts is shown in Fig. 3a. When compared to the distribution of patients in the CKD population (Fig. 2a), there was a more even distribution of patients across the four disease cohorts in the MRA population, reflecting increased steroidal MRA use driven by HF. Table 4 shows the baseline characteristics for each disease cohort in the MRA population. Median age increased with presence of T2D and/or HF, ranging from 57.0 years to 63.0 years. The proportion of males ranged from 47.5 to 66.8% across the disease cohorts. The proportion of patients with ESRD at baseline ranged from 8.8 to 15.7%, despite steroidal MRAs being contraindicated in this population (Fig. 3b and Table 4).

Similar patterns in concomitant medication use at baseline were observed in the MRA population (Table 4) when compared with the CKD population (Table 1).

The most common comorbidity at inclusion in the MRA population was hypertension (88.4–97.1%) (Table 4). The incidence of comorbidities (e.g. CVD, IHD, LVH, anemia, edema) in the MRA population was predominantly higher in the presence of HF (Table 4).

Patients in the MRA population were almost exclusively treated with spironolactone (≥ 96%); the median dose of spironolactone prescribed was 25 mg (Additional file 1: Table S4). Of those few patients (2.6–4.0%) who were prescribed eplerenone the median dose was 50 mg in the non-HF cohorts and 25 mg in the cohorts with HF. One-year persistence with spironolactone ranged from 36 to 43%. Only 1% of patients across all cohorts switched from spironolactone to eplerenone (Fig. 4).

At least 70% of patients in the CKD population and at least 88% of patients in the MRA population reported hypertension. Steroidal MRA use was at least threefold higher in patients with HF than in those without HF, suggesting that most prescribing of steroidal MRAs was in line with current guidelines recommending their use in patients with hypertension or heart failure (New York Heart Association [NYHA] Class 3–4 and left ventricular ejection fraction ≤35%) [15, 16, 19, 20]. However, given the relatively low proportions of patients in the CKD population that were subsequently prescribed steroidal MRAs (less than 6%), our results suggest that steroidal MRA use is rare in clinical practice and are in line with other reports showing that steroidal MRA use is low even in guideline-eligible patients [21, 22]. Reassuringly, given the guideline recommendations for steroidal MRA use, fewer than 5% of patients in the MRA population lacked a recorded code for either hypertension or HF; this may reflect missing data rather than the absence of the condition.

Of the available steroidal MRAs, patients predominantly received spironolactone, which could be either due to lower costs or its greater effectiveness compared with eplerenone [23‐26]. However, fewer than half of the patients were still receiving steroidal MRA treatment one year post-initiation; it is possible that this is be linked to the incidence of adverse events such as hyperkalemia, but the exact reasons for discontinuation were not available in the database.

As might be predicted, steroidal MRA therapy was most commonly initiated by specialists, particularly nephrologists, cardiologists and other hospital specialists, irrespective of the population studied, suggesting its use often occurs later in the development of disease. This most likely reflects the recommendation of steroidal MRAs as fourth-line therapy for hypertension in the guidelines [27, 28]. Indeed, patients who received steroidal MRAs were more likely to be multimorbid and more advanced in chronic kidney disease, as well as having higher medication loads and healthcare costs than the overall CKD population. Interestingly, steroidal MRAs were also prescribed to a proportion of patients with stage 4 and 5 CKD, or ESRD, for which they are contra-indicated. [19, 20]

Being seen by a specialist, previous treatment with ARBs or ACE inhibitors, previous steroidal MRA use, and multimorbid conditions were all significant predictors of steroidal MRA initiation in the CKD population. This reflects an increased prescription of steroidal MRAs in those patients with higher disease severity, particularly those with hypertension or HF. Moreover, there were differences between disease cohorts in the type of specialist that was predictive of steroidal MRA prescription. As might be expected, nephrologists were predictive for steroidal MRA initiation in CKD and DKD cohorts, but not for those with HF; internal medicine specialists were only predictive for steroidal MRA intiation in patients with DKD, while cardiologists were associated with an increased likelihood to prescribe steroidal MRAs in the most complex patient cohort (DKD + HF).

In general, steroidal MRA prescription was associated with the presence of more comorbid conditions and with higher rates of clinical events. Steroidal MRA use for less than six months was associated with a higher prevalence of all clinical events, including hyperkalemia, stroke, and myocardial infarction, when compared with steroidal MRA use for more than six months, suggesting that these events manifest early and may contribute to the decision to discontinue treatment. While the current study does not indicate any association between steroidal MRA use and the incidence of any of the clinical events reported, previous research assessing hyperkalemia risk observed higher risk estimates for short-term usage of steroidal MRAs compared with long-term usage [29].

As would be expected, given that steroidal MRA use is associated with more complex disease status, healthcare costs were higher for MRA users than for MRA non-users, and higher for MRA users with shorter rather than longer treatment durations. These observations reflect the inherent characteristics of the treatment groups, with patients with a more complex morbidity status requiring more care in terms of medication, hospitalization and outpatient visits. Systematic, longitudinal research will be necessary to investigate to what extent steroidal MRAs can influence healthcare utilization and costs.

The main strength of this longitudinal study is the inclusion of real-world clinical practice data covering a large number of patients who were eligible for inclusion across all four disease cohorts of interest. Moreover, records in the PMTX+ database are representative of the national, commercially insured, real-world population in terms of age and sex. In addition, the use of a large claims database removes the potential for selection or physician bias. However, the results from this study do need to be viewed in light of several limitations of using a claims database. For example, the geographic coverage of the PTMX+ database does not fully reflect the US census population; older patients are underrepresented in the data set and the use of a US data source may not allow for generalization to other countries. Moreover, because patients’ complete medical history is not available, it is possible that the date of first CKD diagnosis, or of first MRA use, could include repeated as well as new diagnoses. Also, the disease cohort “DKD” was built by combining CKD and T2D codes, which is an approximation that falls short of a true diagnosis of DKD. Similarly, because the full treatment history could not be assessed, certain values may be missing and the reason for a given prescription cannot always be directly ascertained. Moreover, due to the nature of the database, information on patient mortality was not collected in this study; therefore, potential immortality bias could not be considered in the analysis. Finally, the exclusion of previous users of MRAs and use of just one year of follow-up to assess MRA treatment persistence precludes conclusions about potential differences between long-term and newly initiated users of MRAs.