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The ARTS of third-generation mineralocorticoid receptor antagonists: achieving cardiovascular benefit with minimized renal side effects?

Johann Bauersachs
DOI: http://dx.doi.org/10.1093/eurheartj/eht235 2426-2428 First published online: 3 July 2013

This editorial refers to ‘Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: a randomized, double-blind trial,’ by B. Pitt et al., on page 2453

The mineralocorticoid receptor antagonists (MRAs) spironolactone and eplerenone have been proven to reduce total mortality and hospitalization in three large randomized controlled trials in patients with symptomatic chronic heart failure and patients with left ventricular dysfunction and heart failure symptoms early after myocardial infarction. This marked and sustained evidence-proven benefit led to the class I recommendation for MRAs in the treatment of all patients with symptomatic systolic heart failure already treated with angiotensin-converting enzyme (ACE) inhibitors and beta-blockers.13

Despite considerable efforts to enable the broad application of these life-saving medications in all patients with systolic heart failure,4 many clinicians are still reluctant to employ MRAs in their clinical practice.5 While these restraints are hard to understand in heart failure patients with normal kidney function, worsening renal function and hyperkalaemia are significant clinical problems in patients with mild to moderate, and especially with severe, renal dysfunction. However, when contraindications such as co-medication with potassium-sparing diuretics are respected and renal function and potassium levels are closely followed, patients with mild to moderate renal insufficiency appear to gain similar reductions in mortality and hospitalization by MRA treatment as heart failure patients with normal renal function.6 Although patients with severe renal dysfunction had been excluded from the mortality studies investigating MRAs in heart failure, there is growing interest not only from heart failure specialists, but also from nephrologists to treat these patients too with low dose MRAs to obtain cardiovascular but also potential renal benefits.

How will it be possible for broad patient populations including the elderly and those with chronic kidney disease to profit from the clear-cut cardiovascular benefits of MRAs without suffering from risks such as worsening renal function and hyperkalaemia? Can we separate the renal and cardiovascular actions of MRAs?

Experimental evidence suggests that depending on their cell-specific activation, mineralocorticoid receptors (MRs) precipitate a plethora of different adverse cardiac and vascular effects.7 In addition to the MRs in epithelial cells of the distal colon and renal nephron whose activation mediates the classical actions of aldosterone, i.e. sodium reabsorption and potassium excretion, MRs have been identified in vascular endothelial and smooth muscle cells as well as in cardiomyocytes, endothelial cells, fibroblasts, and macrophages in the heart.7,8 Recently, investigations in mice with cell-specific overexpression or deletion of the MR in cardiomyocytes or vascular smooth muscle cells provided evidence that activation of the cardiovascular MR is a main driver for the development and progression of hypertension and heart failure.7,9,10 Thus, treatment of cardiovascular disease with MRAs may prove to be feasible using novel MR blockers with enhanced tissue selectivity compared with spironolactone and eplerenone. The advantage of eplerenone as a so-called ‘second-generation MRA’ compared with spironolactone is mainly the higher selectivity for MRs to avoid hormonal side effects such as gynaecomastia; however, eplerenone displays only low MR blocking potency (Figure 1). Several pharmaceutical companies have developed novel MR-antagonizing compounds.11,12 These so-called ‘third-generation MRAs’ are non-steroidal compounds with both high selectivity and high potency to inhibit the MR. The first compound of these novel MRAs undergoing clinical evaluation, BAY 94-8862, appears, furthermore, to display a distinct tissue distribution different from that of first- and second-generation MRAs: while spironolactone and—to a somewhat lesser extent—eplerenone are enriched in the kidneys as compared with the heart, BAY 94-8862 appears to have an equal tissue distribution. Will BAY 94-8862 fulfil the hope of achieving cardiovascular benefit without or at least with fewer renal side effects than spironolactone and eplerenone?

Figure 1

Characteristics of three generations of mineralocorticoid receptor antagonists (MRAs) are shown (see also Kolkhof and Borden11). The novel non-steroidal third-generation MRA, BAY 94-8862, was associated with significantly less hyperkalaemia and worsening renal function than spironolactone in the ARTS study (right; see Pitt et al.13). Although BAY 94-8862 did reduce the heart failure biomarkers BNP and NT-proBNP at least as much as spironolactone (left), it remains to be clarified whether the novel MRA displays similar effectiveness in reducing mortality and cardiovascular events as compared with eplerenone and spironolactone. (C)HF, (chronic) heart failure; MI, myocardial infarction.

The first phase II clinical trial with this promising compound has now been published.13 The minerAlocorticoid-Receptor Antagonist Tolerability Study (ARTS) is a 4-week randomized, double-blind trial investigating increasing dosages of the novel non-steroidal MRA BAY 94-8862 compared with placebo or open-label spironolactone in patients with systolic heart failure [New York Heart Association (NYHA) class II/III] and mild to moderate chronic kidney disease. In the main part B of the study, the novel MRA was given at several dosages to heart failure patients with moderate renal insufficiency [estimated glomerular filtration rate (eGFR) 30–60 mL/min/1.73 m2]. The main results are very encouraging, as BAY 94-8662 was associated with significantly less hyperkalaemia, worsening renal function, and blood pressure decrease in comparison with spironolactone (25–50 mg). Although the average age of the patients in the main study was 72 years, it is of special importance that in a subanalysis of patients aged >75 years the advantage of BAY 94-8862 regarding increases in potassium concentration and eGFR decrease over the spironolactone group was maintained.

Clearly, it remains to be proven that the novel compound is at least as effective as spironolactone in the prevention of major cardiovascular events. Although this question could not be addressed in the 4-week ARTS study, several surrogate parameters point to a maintained effect of BAY 94-8862 in this regard: the biomarkers brain natriuretic peptide (BNP) and N-terminal pro brain natriuretic peptide (NT-proBNP), as well as albuminuria were reduced by the novel MRA at least as much as with spironolactone, thus providing reassurance that the lower incidence of side effects most probably does not come at the expense of lower efficacy.

Given the class I recommendation for an MRA in all patients with symptomatic systolic heart failure, the results of the ARTS trial are of utmost importance as the risk of hyperkalaemia and worsening renal function is the main obstacle of an even broader utilization of MRAs in clinical practice. Further assessment of BAY 94-8862 is mandatory. An important question in this regard is the adequate comparator. As eplerenone was very successful in the EMPHASIS trial,14 and, despite the lack of direct comparative data, the assumption that it may be associated with less severe hyperkalaemia than spironolactone,4 it appears to be a wise choice to compare BAY 94-8862 with eplerenone in the 90-day phase IIb ARTS-HF study in patients hospitalized with worsening chronic heart failure (ClinicalTrials.gov identifier: NCT01807221).

In summary, in patients with systolic heart failure and chronic kidney disease, the ARTS trial demonstrates a remarkable reduction of hyperkalaemia and worsening renal function with the novel non-steroidal MRA BAY 94-8862 as compared with spironolactone. These exciting results suggest that novel MRAs with improved tissue selectivity and fewer side effects are on the horizon, enabling even broader applications of MRAs in cardiovascular and other diseases.

Conflict of interest: J.B. reports grants and personal fees from Pfizer, personal fees from Novartis, personal fees from Medtronic, grants from Sanofi Aventis, and grants from Bayer, outside the submitted work.


  • The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.

  • doi:10.1093/eurheartj/eht187.