Cardiac Reverse Remodelling with Vericiguat: Victory or no Victory?

This article refers to ‘Effect of vericiguat on left ventricular structure and function in patients with heart failure with reduced ejection fraction: The VICTORIA echocardiographic substudy’ by B. Pieske et al., published in this issue on pages 1012–1021. Left ventricular (LV) remodelling refers to changes in LV architecture, volume, and function in response to pathophysiological stimuli. Several studies have shown that serial changes in LV end-systolic (LVESVI) and end-diastolic volume index (LVEDVI) are strongly associated with development and progression of heart failure (HF).1, 2 In a meta-analysis of 88 studies including 25 drug or device interventions, there was a significant correlation between longer term trial-level therapeutic effects on mortality and short-term trial-level therapeutic effects of a drug or device on LV ejection fraction (LVEF) (r = −0.51, p <0.001), LV end-diastolic volume (r = 0.44, p = 0.002), and LV end-systolic volume (r = 0.48, p = 0.002).1, 2 A decrease of 10 ml in mean change of LV end-diastolic volume was associated with an almost two-fold increased odds of an intervention favourably impacting mortality.2 While studies have shown that drugs that exert favourable LV remodelling improve HF outcomes, this concordance between favourable LV remodelling effect and HF outcomes has not always been present, such as in the case of mineralocorticoid receptor antagonists (MRA). Vericiguat, a novel soluble guanylate cyclase (sGC) stimulator, was recently approved for use in patients with symptomatic HF with reduced ejection fraction (HFrEF) who were recently hospitalized or required an intravenous diuretic therapy based on the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial.3 Pre-clinical studies have suggested that sGC stimulation may improve cardiomyocyte stiffness and adverse cardiac remodelling.4 A post-hoc analysis of the VICTORIA trial showed that vericiguat significantly decreased N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and this was related to improvement in outcomes observed.5 The association between the beneficial effects of vericiguat and improvement in LVEF and reduction in LV volumes, however, remains unclear. In this context, Pieske et al.6 conducted a pre-specified echocardiographic substudy of the VICTORIA trial to assess the effects of vericiguat versus placebo on LV structure and function in patients with HFrEF. Transthoracic echocardiograms were performed at baseline and after 8 months of randomization. The co-primary endpoints were change in LVESVI and LVEF. The original sample size was estimated to be ∼900 patients, however, this was later recalculated to be 419 patients due to logistic considerations during the trial. The authors found that there was a significant reduction in LVESVI in the vericiguat (from 60.7 ± 26.8 ml/m2 to 56.8 ± 30.4 ml/m2; p < 0.001) and the placebo (from 68.2 ± 31.0 ml/m2 to 61.1 ± 29.9 ml/m2; p < 0.001) groups, from baseline to after 8 months of follow-up. The absolute change in LVESVI were not significantly different between the vericiguat and placebo groups (−3.8 ± 15.4 ml/m2 vs. −7.1 ± 20.5 ml/m2; p = 0.07). LVEF also significantly increased in both, the vericiguat (from 33.0 ± 9.4% to 36.1 ± 10.2%; p < 0.001) and placebo (from 31.8 ± 8.2% to 34.2 ± 9.5%; p < 0.001) groups with no significant difference between the two (3.2 ± 8.0% vs. 2.4 ± 7.6%; p = 0.31). Similarly, no differences in LV global longitudinal strain, left atrial, and right ventricular structural and functional parameters were observed between the two groups. A reduction in HF hospitalization or cardiovascular death, from 33.2 to 12.2 events per 100 patient-years was observed when LVESVI improved (adjusted hazard ratio 2.46, 95% confidence interval 1.41–4.31; p = 0.002). No correlation was seen between clinical events and changes in LVEF. These results contrast with the dose finding phase 2 study, SOCRATES-REDUCED (Soluble Guanylate Cyclase Stimulator in Heart Failure with Reduced Ejection Fraction Study), where higher vericiguat doses were associated with greater reductions in levels of NT-proBNP.7 Patients receiving 10 mg vericiguat also had a significantly higher increase in LVEF at 12 weeks compared with placebo (+3.7% vs. +1.5%; p = 0.02) while there were no significant differences in LV end-diastolic volume (−7.32 ml vs. −7.26 ml; p = 0.99) or LV end-systolic volume (−11.0 ml vs. −6.83 ml; p = 0.40) between the placebo and 10 mg vericiguat dose group. The neutral results observed in the echocardiographic substudy of the VICTORIA trial can be in part explained by the improvement in the placebo arm. The VICTORIA trial enrolled a high-risk HFrEF population with more than two-thirds of the patients having an index HF hospitalization within 3 months of randomization. One potential explanation is that these patients had a room for improvement in LV volume with diuretics based on higher filling pressures with standard diuretic therapy alone, leading to an overall diminished relative treatment effect with vericiguat. Other potential reasons for the neutral results could be that the study was underpowered, with less than 10% of the patients enrolled in the main VICTORIA trial included in this substudy, which was resized in the middle of the trial. Loss to follow-up was also high (25%). This may have limited the ability to detect any significant differences between the vericiguat and placebo groups. Moreover, in the context of patients having worsening HF, the follow-up time of 8 months may have been relatively insufficient to detect any significant beneficial effects of vericiguat on LV structure and function. Nonetheless, it is important to note that HF is a complex, multifactorial, and a heterogeneous syndrome involving many different pathophysiological pathways, and drugs may have favourable effect through a variety of different pathways.8 For instance, MRAs have shown minimal beneficial effect on LV reverse remodelling despite their favourable impact on mortality in patients with HFrEF.9 The effect of other foundational HF therapies on cardiac reverse remodelling has been more evident. Beta-blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers have all shown significant correlation between the level of LV reverse remodelling and effect on mortality.1, 2 There have been three trials evaluating the effect of sodium–glucose cotransporter 2 (SGLT2) inhibitors on LV remodelling. In the EMPIRE-HF (Empagliflozin in Heart Failure Patients with Reduced Ejection Fraction),10 while there was no significant difference in the change in LVEF among the empagliflozin versus the placebo groups, empagliflozin did significantly improve LVESVI and LVEDVI. In the SUGAR-DM-HF (Studies of Empagliflozin and Its Cardiovascular, Renal and Metabolic Effects in Patients With Diabetes Mellitus, or Prediabetes, and Heart Failure) trial,11 SGLT2 inhibitors were shown to have favourable reverse remodelling effects with reductions in LVESVI over 36 weeks. Similarly, EMPA-TROPISM (Are the “Cardiac Benefits” of Empagliflozin Independent of Its Hypoglycemic Activity) showed that empagliflozin improved LVEF (+6.05%, p < 0.001), LV end-diastolic volume (−25.1 ml, p < 0.001), LV end-systolic volume (−26.6 ml, p < 0.001), and LV mass (−17.8 g, p < 0.001) after 6 months of treatment.12 The beneficial effect of angiotensin receptor–neprilysin inhibitor (ARNI) on reverse cardiac remodelling has been shown in the EVALUATE-HF (Study of Effects of Sacubitril/Valsartan vs. Enalapril on Aortic Stiffness in Patients with Mild to Moderate HF With Reduced Ejection Fraction),13 and the PROVE-HF (Prospective Study of Biomarkers, Symptom Improvement, and Ventricular Remodeling During Sacubitril/Valsartan Therapy for Heart Failure)14 trials. The EVALUATE-HF trial showed that the benefits of ARNI on cardiac geometry can be seen as early as 12 weeks with reductions in both atrial and ventricular volumes, and improvement in diastolic function and reduction in cardiac biomarkers, however, there was no significant change in LVEF. The PROVE-HF trial showed that ARNI led to significant improvements in left atrial volume index, LVEF, LVEDVI and LVESVI from baseline to 6 months; these were sustained and amplified by 12 months (Figure 1). In summary, while the study did not show any significant improvements in LV structure and function over 8 months with vericiguat compared with placebo in a high-risk HFrEF population, larger studies in a more stable HFrEF population are needed before the final verdict can be given regarding the effect of vericiguat on reverse cardiac remodelling. VICTOR (A Study of Vericiguat in Participants With Chronic Heart Failure With Reduced Ejection Fraction, NCT05093933) is a large phase 3, randomized, placebo-controlled clinical trial of vericiguat in 6000 patients with chronic HFrEF which will provide further insights regarding the clinical benefits of vericiguat in these patients. Conflict of interest: M.S.K. has nothing to disclose. P.A.G. reports grant support from Abbott Vascular, Boston Scientific, Cardiovalve, Edwards Lifesciences, Medtronic, Neochord, Restore Medical, W.L. Gore and 4C Medical; he also is a consultant for Abbott Vascular, Cardiovalve, Edwards Lifesciences, Medtronic, W.L. Gore and 4C Medical. J.B. has served as a consultant to Abbott, American Regent, Amgen, Applied Therapeutic, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimension, Cardior, CVRx, Cytokinetics, Edwards, Element Science, Innolife, Impulse Dynamics, Imbria, Inventiva, Lexicon, Lilly, LivaNova, Janssen, Medtronics, Merck, Occlutech, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Roche, Sequana, SQ Innovation, 3live, and Vifor.