Hyperkalemia constitutes a constraint for implementing renin-angiotensin-aldosterone inhibition: the widening gap between mandated treatment guidelines and the real-world clinical arena

Abstract

Recent studies have reported a large gap between the forceful and assertive recommendations in the guidelines and real-world practice in the use of renin-angiotensin-aldosterone inhibitors (RAASi) therapies. A comprehensive, retrospective analysis of a large database of electronic medical records (>7 million patients) was undertaken to evaluate 3 pivotal concerns: (i) whether RAASi are being prescribed according to treatment guidelines, (ii) what happens to RAASi prescriptions after hyperkalemia events, and (iii) what the clinical outcomes are in patients whose RAASi are discontinued or who are prescribed at doses lower than the guidelines recommend. The results indicate that a substantial gap exists between guideline recommendations and real-world prescribing patterns for RAASi. Among patients with cardiorenal comorbidities for which RAASi are recommended by the guidelines, more than one-half were prescribed lower-than-recommended doses, and approximately 14% to 16% discontinued RAASi therapy. RAASi prescribing patterns may be altered by the development of hyperkalemia. Moderate-to-severe hyperkalemia events were followed by down-titration or discontinuation of RAASi therapy in nearly one-half of all patients on maximal dose and by discontinuation in nearly one-third of patients on submaximal dose. This analysis highlights the challenge behind RAASi prescribing decisions, balancing the risk of provoking hyperkalemia with the benefits to reducing cardiorenal morbidity and mortality. Patients who are known to derive the greatest benefit from these drugs (chronic kidney disease patients with concomitant diabetes mellitus or heart failure) are the same patients who are at highest risk of developing hyperkalemia. These observations constitute a "call to action" to develop newer treatment modalities to lower serum potassium and to achieve and sustain normokalemia long-term.

Keywords: MR antagonism; cardiorenal comorbidities; chronic kidney disease; guideline recommendations for RAASi treatment; hyperkalemia; prescribing patterns for RAASi; renin-angiotensin inhibition; “big-data analytics”.

Figure 1

A comparison of hyperkalemia rates in patients with CHF in clinical trials and in the real-world setting. The left bars in the 2 panels depict hyperkalemia rates in RALES (Randomized Aldactone Evaluation Study) and in a clinical study after the publication of RALES. The right bars in the two panels depict the hyperkalemia rates in the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) study and an analysis following the application of the RALES trial protocol to the care of 104 patients, who were identified as being started on spironolactone for HF after prerelease of the RALES trial. Clearly, hyperkalemia rates are higher in congestive heart failure patients on mineralocorticoid receptor antagonist therapy in a real-world clinical setting.

Figure 2

As CKD progresses, the prevalence of heart failure and diabetes increases. Longitudinal estimated glomerular filtration rate (eGFR) among 1,120,295 adults within a large integrated system between 1996 and 2000 who had not undergone dialysis or kidney transplantation. It is readily apparent that as chronic kidney disease (CKD) progresses, the prevalence of both heart failure and diabetes mellitus increases as baseline eGFR declines progressively. Consequently, the risk of hyperkalemia increases, because of both the underlying disease and concomitant therapies.

Figure 3

Changes in RAASi dose subsequent to hyperkalemia events. Among patients on renin-angiotensin-aldosterone system inhibitor (RAASi) at (a) maximum dose and (b) submaximum dose.

Figure 4

Percentage of patients who experienced adverse outcomes or mortality by prior RAASi dose. Patients on submaximum doses or who discontinued renin-angiotensin-aldosterone system inhibitor (RAASi) therapy demonstrated consistently worse outcomes compared with patients on maximum doses, irrespective of comorbidity status. CKD, chronic kidney disease.

Figure 5

Percentage of mortality by prior RAASi dose. Patients on submaximum dose or who discontinued renin-angiotensin-aldosterone system inhibitor (RAASi) died twice as frequently as patients on maximum dose irrespective of comorbidity status. CKD, chronic kidney disease.