News - June 22, 2020

Effect of Vericiguat on Left Ventricular Function: The VICTORIA Echocardiographic Sub-Study

HFA Discoveries 2020 webinar presented by Prof. dr. Burkert Pieske (Berlin, Germany)

Heart failure with reduced ejection fraction (HFrEF) is characterized by decreased activity of soluble guanylate cyclase (sGC). This results in a decreased availability of cyclic GMP (cGMP). The sGC stimulator vericiguat restores cGMP levels. The VICTORIA trial recently demonstrated a clinical benefit of vericiguat in HFrEF after a worsening HF event, in comparison with placebo.

The VICTORIA echocardiographic sub-study aimed to describe the cardiac functional and structural features of patients included in the VICTORIA trial and assessed the natural course of cardiac function and structure after a worsening HF event. Furthermore, this sub-study aimed to characterize the effects of vericiguat vs. placebo on cardiac function and structure over 8 months of therapy.

Patients who enrolled in the VICTORIA trial were recruited to participate in the VICTORIA Echocardiography sub-study. An echocardiogram was made at baseline and after 8 months of therapy. A total of 419 paired echos at baseline and after 8 months of therapy were evaluable (n=208 in vericiguat arm, n=211 in placebo arm). The primary readout was change in left ventricular ejection fraction (LVEF) and left ventricular end-systolic volume index (LVESVI) from baseline to 8 months follow-up.

Main results

• Baseline echocardiographic measurements were balanced between groups for LVEF (31.8±8.2% in placebo arm, 33.0±9.4% in vericiguat arm, mean±SD, P=0.172). However, baseline measurements were not balanced for LVESVI between treatment arms (68.2±31.0 mL/m² in the placebo arm vs. 60.7±26.8 mL/m² in the vericiguat arm, P=0.009).
• LVEF improved significantly from baseline to 8 months follow-up in both the placebo arm (31.8±8.2% to 34.2±9.5% [mean ±SD], P<0.001) and the vericiguat arm (33.0±9.4 to 36.1±10.2%, P<0.001). The difference between the two groups was not significant (ΔP=0.14).
• LVESVI significantly decreased in the placebo arm (68.2±31.0 to 61.1±29.9 ml/m², P<0.001) and vericiguat arm (60.7±26.8 to 56.8±30.4 ml/m², P<0.001). There was no significant difference between the two arms (ΔP=0.21).
• Relative change of LVEF was 13.5±31.4% in the vericiguat arm vs. 10.4±27.6% in the placebo arm (Δ:3.1%, P=0.29). Relative change of LVESVI was -6.2±25.9% in the vericiguat arm vs. -8.5±28.0% in the placebo arm (Δ2.3%, P=0.39).

Conclusion

The VICTORIA echocardiographic sub-study showed that LVEF and LVESVI significantly improved from baseline to 8 months follow-up irrespective of treatment assignment. Treatment with vericiguat had no additional significant effect on LVEF or LVESVI compared to placebo. Further studies are necessary to understand the mechanism behind the clinical benefits of vericiguat in HFrEF.

Discussion

Discussant prof. dr. Rudolf de Boer (Groningen, The Netherlands) pointed out that the absence of an additional effect of sGC stimulator on LVEF or LVESVI compared to placebo may be explained by the fact that patients -also those dosed on placebo- tend to be treated very well in randomized clinical trials. In real world patients, less reverse remodelling may be expected. Furthermore, mean LVESVI was smaller in the vericiguat group at baseline. This created less of an opportunity of vericiguat to make a difference. Most strikingly, the absence of effect of vericiguat on echo-parameters contrasts with the positive clinical benefits of vericiguat in HFrEF. It could be imagined that the crude echo-parameters (LVEF and LVESVI) miss a more subtle effect of vericiguat. Vericiguat may potentially affect peripheral and pulmonary vasculature. Future evaluations of RV pressure, RV function and arterial-ventricular coupling might provide insights into how vericiguat exerts its function.

-Our reporting is based on the information provided by the HFA Discoveries webinar -