Renal function and vericiguat in heart failure patients: light at the end of the tunnel!

This article refers to ‘Renal function and the effects of vericiguat in patients with worsening heart failure with reduced ejection fraction: insights from the VICTORIA (Vericiguat Global Study in Subjects with HFrEF) trial’ by A.A. Voors et al., published in this issue on pages 1313–1321. The optimization of guideline-directed heart failure (HF) therapy remains the mainstay to further improve outcomes for patients with HF with reduced ejection fraction (HFrEF).1 New HF drugs have been shown to target various pathways, such as the sodium–glucose co-transporter 2 (SGLT2) inhibitors (dapagliflozin, empagliflozin), the guanylate cyclase stimulator (vericiguat) and the cardiac myosin activator (omecamtiv mecarbil), and have been shown to improve prognosis.2 Renal dysfunction is common in patients with HF, with a greater prevalence in those with more advanced symptoms and associated with a worse outcome.3 Nonetheless, HF patients with severe renal dysfunction have usually been excluded from the major HF randomized trials, making it difficult to be certain of the benefit of HF drugs in this group of patients.3 In HF, the impaired formation of cyclic guanosine monophosphate (cGMP) contributes to endothelial dysfunction and possibly causes myocardial relaxation impairment.4 Vericiguat is an orally available soluble guanylate cyclase (sGC) stimulator that activates the formation of cGMP.4 Based on this concept, the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial was designed and randomized 5050 patients to vericiguat vs. placebo. The trial included patients with more severe HF and reduced ejection fraction (<45%), some of whom were randomized immediately after recovery from acute decompensation. The VICTORIA trial showed a significant 10% reduction in the combined endpoint of cardiovascular death and HF hospitalizations, although the individual components of the primary endpoint were not significantly reduced.5 However, given the high incidence of events in the placebo arm, which was up to 50% over 20 months, the absolute risk reduction was about 4.2%, which is comparable with the absolute risk reduction observed in other HF trials [e.g. PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure): 2.7% und DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure): 4%].6 Interestingly, in contrast to all HF trials with inhibitors of the renin–angiotensin–aldosterone system (RAAS),3 the VICTORIA trial included patients with severe renal dysfunction and estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2. In chronic kidney disease (CKD), cGMP deficiency is suspected to be involved in the pathogenesis of renal dysfunction.7 Direct stimulation of sGC might be a new approach for the treatment of renal disorders based on its potential to increase glomerular cGMP, dilate glomerular arterioles and consequently improve endothelial and myocardial function.7 In this issue of the Journal, Voors et al.8 evaluated the relationship between the efficacy of vericiguat and baseline and subsequent changes in renal function as pre-specified analysis from the VICTORIA trial. Voors et al.8 showed that in patients with severe HFrEF and a high risk of cardiovascular events, renal function trajectories were similar between vericiguat- and placebo-treated patients. In addition, vericiguat reduced the primary composite endpoint of cardiovascular death or HF hospitalization across the full range of baseline eGFR, from 15 to >60 mL/min/1.73 m2. The beneficial effects of vericiguat on the primary endpoint were similar in patients eGFR <30 mL/min/1.73 m2 and those eGFR >60 mL/min/1.73 m2. These data revealed a similar effect of vericiguat across the full range of eGFR, with no additional benefits in those with low or high eGFR. Notably, this study indicates that vericiguat can be safely prescribed to patients with high serum potassium concentrations, including those with hyperkalaemia in whom RAAS inhibitors (RAASi) are contraindicated. Voors et al. are to be congratulated on an important contribution to the evolving literature on the safety and efficacy of HF drugs in CKD. Data from this study support the use of vericiguat on top of evidence-based HF therapies regardless of baseline eGFR. Notable strengths of the current analysis include using a relatively contemporary patient population ranging from very low to normal eGFR with sample collections for analyses across multiple time points of the study. However, the cardiac benefit of vericiguat was unfortunately not similar for the kidney! Vericiguat did not show an improvement in renal outcomes or reduce the slope of eGFR decline compared to placebo. This might be due to short follow-up period and the post-hoc nature of the study. Renal dysfunction is one of the most important reasons for under-dosing or discontinuation of guideline-directed HF therapy and particularly RAASi.9 The benefit observed in most of RAAS trials was also similar if not greater in patients with reduced eGFR.10 In stable symptomatic HFrEF patients, a beneficial effect of angiotensin-converting enzyme (ACE) inhibition has been illustrated even in patients with baseline CKD and in those who experienced a drop in eGFR after initiation of ACE inhibitors (ACEi).11 Additionally, a propensity adjusted analysis showed a similar benefit of angiotensin receptor blockers (ARBs) on outcome despite presence of CKD.12 Despite this proved benefits of ACEi/ARBs, there is still lack of data whether ACEi/ARBs have a protective effect in HFrEF patients and can reduce the slope of eGFR decline in comparison to placebo. Contrary to ACEi/ARBs, a significant reduction in the slope of eGFR decline was revealed in patients assigned to sacubitril/valsartan in comparison to enalapril.13 The beneficial effects of angiotensin receptor–neprilysin inhibitors (ARNIs) on the primary endpoint were similar in patients with more advanced CKD. Moreover, the incidence of hyperkalaemia was lower in the sacubitril/valsartan group compared to enalapril.13 However, hyperkalaemia remains a major problem in patients treated with RAASi and should be assessed on regular basis.14 Furthermore, regarding SGLT2 inhibitors, a recent meta-analysis of data from the DAPA-HF and EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction) trials consistently showed favourable outcomes and safety across a wide range of HFrEF severity.15 Pooled results from these two trials showed a significant reduction of a combined renal endpoint (chronic dialysis, renal transplant, or a ≥ 50% sustained reduction in eGFR): 38% relative risk reduction (hazard ratio 0.62; 95% confidence interval 0.43–0.90). Furthermore, it is important to note that these cardio-renal benefits were achieved despite high utilization rates of standard HF therapy (∼92% treated with ACEi/ARNIs, ∼95% with a beta-blocker, and ∼71% with mineralocorticoid receptor antagonists) and were sustained regardless of background HFrEF therapy.15, 16 Despite available data, a consensus is required, in acute and chronic HF, to investigate on evidence-based treatments or strategies that are specifically designed and executed in HF patients with low eGFR. Nonetheless, based on the available literature, the effect of evidence-based treatments on the slope of eGFR was reported for most evidence-based therapies. Understanding the benefits of evidence-based HF therapies even in case of a small decline in eGFR, particularly in patients with co-existent CKD, is therefore crucial (Figure 1).3, 10, 17 M.B. is supported by the Deutsche Forschungsgemeinschaft (German Research Foundation; TTR 219, project number 322900939). Conflict of interest: M.B. reports personal fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Medtronic, Novartis, Servier, and Vifor. A.A. has nothing to disclose.