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Clinical Trial
. 2013 Aug;34(31):2453-63.
doi: 10.1093/eurheartj/eht187. Epub 2013 May 27.

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

Bertram Pitt  1 , Lars Kober, Piotr Ponikowski, Mihai Gheorghiade, Gerasimos Filippatos, Henry Krum, Christina Nowack, Peter Kolkhof, So-Young Kim, Faiez Zannad
Affiliations
Clinical Trial

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

Bertram Pitt et al. Eur Heart J. 2013 Aug.

Abstract

Aims: Mineralocorticoid receptor antagonists (MRAs) improve outcomes in patients with heart failure and reduced left ventricular ejection fraction (HFrEF), but their use is limited by hyperkalaemia and/or worsening renal function (WRF). BAY 94-8862 is a highly selective and strongly potent non-steroidal MRA. We investigated its safety and tolerability in patients with HFrEF associated with mild or moderate chronic kidney disease (CKD).

Methods and results: This randomized, controlled, phase II trial consisted of two parts. In part A, the safety and tolerability of oral BAY 94-8862 [2.5, 5, or 10 mg once daily (q.d.)] was assessed in 65 patients with HFrEF and mild CKD. In part B, BAY 94-8862 (2.5, 5, or 10 mg q.d., or 5 mg twice daily) was compared with placebo and open-label spironolactone (25 or 50 mg/day) in 392 patients with HFrEF and moderate CKD. BAY 94-8862 was associated with significantly smaller mean increases in serum potassium concentration than spironolactone (0.04-0.30 and 0.45 mmol/L, respectively, P < 0.0001-0.0107) and lower incidences of hyperkalaemia (5.3 and 12.7%, respectively, P = 0.048) and WRF. BAY 94-8862 decreased the levels of B-type natriuretic peptide (BNP), amino-terminal proBNP, and albuminuria at least as much as spironolactone. Adverse events related to BAY 94-8862 were infrequent and mostly mild.

Conclusion: In patients with HFrEF and moderate CKD, BAY 94-8862 5-10 mg/day was at least as effective as spironolactone 25 or 50 mg/day in decreasing biomarkers of haemodynamic stress, but it was associated with lower incidences of hyperkalaemia and WRF.

Keywords: Aldosterone; Antagonist; Chronic kidney disease; Heart failure; Mineralocorticoid receptor.

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Figures

Figure 1
Figure 1
Disposition of patients in part A (A) and part B (B) of ARTS. b.i.d., twice daily; q.d., once daily.
Figure 2
Figure 2
Mean change from baseline to visit 4 (day 15 ± 1) and the mean of visit 6 (day 22) and visit 7 (day 29 ± 2) in serum potassium concentration in patients receiving BAY 94-8862, placebo, or spironolactone in the full analysis set of part B of ARTS. *P < 0.05 between the BAY 94-8862 dose group and the placebo group at visit 6/7; †P < 0.05 between the BAY 94-8862 dose group and the spironolactone group at visit 6/7. Significance of visit 4 data was not analysed. b.i.d., twice daily; q.d., once daily.
Figure 3
Figure 3
Mean change from baseline to visit 4 (day 15 ± 1) and visit 7 (day 29 ± 2) in the estimated glomerular filtration rate (eGFR), as calculated using the modification of diet in renal disease formula, in patients receiving BAY 94-8862, placebo, or spironolactone in the safety analysis set of part B of ARTS. *P < 0.05 compared with the placebo group at visit 6/7; †P < 0.05 compared with the spironolactone group at visit 6/7. Significance of visit 4 data was not analysed. b.i.d., twice daily; q.d., once daily; SD, standard deviation.
Figure 4
Figure 4
Mean change from baseline to visits 4 (day 15 ± 1) and 7 (day 29 ± 2) in systolic blood pressure in the safety analysis set of part B of ARTS. *P < 0.05 compared with the placebo group at visit 6/7; †P < 0.05 compared with the spironolactone group at visit 6/7. Significance of visit 4 data was not analysed. b.i.d., twice daily; q.d., once daily; SD, standard deviation.
Figure 5
Figure 5
Change from baseline to visits 4 (day 15 ± 1) and 7 (day 29 ± 2) in serum BNP (A: median change), NT-proBNP (B: median change), and UACR (C: geometric mean change) in the safety analysis set of part B of ARTS. b.i.d., twice daily; BNP, B-type natriuretic peptide; IQR, inter-quartile range; NT-proBNP, amino-terminal pro-B-type natriuretic peptide; q.d., once daily; SD, standard deviation; UACR, urinary albumin:creatinine ratio.
Figure 6
Figure 6
Mean change from baseline to visit 4 (day 15 ± 1) and visit 7 (day 29 ± 2) in serum aldosterone levels in the safety analysis set of part B of ARTS. *P < 0.05 compared with the placebo group at visit 6/7; †P < 0.05 compared with the spironolactone group at visit 6/7. Significance of visit 4 data was not analysed. b.i.d., twice daily; q.d., once daily; SD, standard deviation.
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References

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