Concomitant use of ARNI does not alter the efficacy of sGC stimulator in HFrEF

Introduction and methods

Background

Heart failure is related to impaired production of nitric oxide (NO) and decreased activity of its receptor, namely soluble guanylate cyclase (sGC). Deficiency of sGC-derived cyclic guanosine monophosphate (cGMP) contributes to myocardial and vascular dysfunction. Vericiguat is an sGC stimulator and restores cGMP deficiency through direct stimulation of sGC, independent of and synergistic with NO [1]. The placebo-controlled VICTORIA trial showed that vericiguat reduces the risk of cardiovascular death or first hospitalization for HF in patients with HFrEF [2]. However, the efficacy and safety of vericiguat in patients who received versus those who did not receive sacubitril/valsartan at randomization are unknown, as are the implications of follow-up (drop-in) use of sacubitril/valsartan.

Aim of the study

This secondary analysis of the VICTORIA trial compared the efficacy and safety of vericiguat between patients with HFrEF who were and were not treated concomitantly with sacubitril/valsartan.

Methods

The researchers used data from the VICTORIA trial, in which 5050 patients with HFrEF were randomized to treatment with vericiguat or placebo. They compared the efficacy and safety of vericiguat between patients with HFrEF who were and were not treated concomitantly with sacubitril/valsartan. The efficacy analyses first included only data from 677 patients who had been treated concomitantly with sacubitril/valsartan for at least 3 months from the time of randomization. Subsequently, analyses were performed based on data from 992 patients who had been treated concomitantly with sacubitril/valsartan for at least 3 months from the time of randomization or subsequently during follow-up (drop-ins). For the purpose of safety reporting, 164 patients who had been exposed to sacubitril/valsartan for less than 3 months were also considered.

Outcomes

The primary efficacy outcome was a composite of time to cardiovascular mortality or first hospitalization for HF. The secondary outcomes were the separate components of the composite primary outcome, time to total mortality or first hospitalization for HF, and time to total mortality. The safety outcomes were specific (serious) adverse events, namely symptomatic hypotension, syncope, worsening renal function (defined as increase in serum creatinine concentration ≥0.5 mg/dL or decrease in eGFR ≥25%, or both), and hyperkalemia (defined as increase in serum potassium concentration ≥1.0 mEq/L or serum potassium concentration >5.5 mmol/L).

Main results

General

• In the group of patients who did not use sacubitril/valsartan at randomization (n = 4309), post-randomization drop-in use of sacubitril/valsartan was lower in the vericiguat group than in the placebo group (n = 187/2161 [8.7%] vs. n = 238/2148 [11.7%]; P =0.007)

Efficacy

• In the group of patients who used sacubitril/valsartan concomitantly for at least 3 months from the time of randomization, patients treated with vericiguat had an equally high risk of cardiovascular death or first hospitalization for HF as patients who received placebo (HR: 0.92; 95%CI: 0.71-1.19).
• In the group of patients not using sacubitril/valsartan, patients treated with vericiguat had a lower risk of cardiovascular death or first hospitalization for HF than patients receiving placebo (HR: 0.89; 95%CI: 0.80-0.98), but there was no statistically significant interaction between the use of sacubitril/valsartan and the treatment effect of vericiguat (P for interaction =0.81).
• In the group of patients who used sacubitril/valsartan concomitantly for at least 3 months from the time of randomization, patients treated with vericiguat had a similarly high risk of cardiovascular death (HR: 0.71; 95%CI: 0.45-1.12), first hospitalization for HF (HR: 0.98; 95%CI: 0.74-1.29), total mortality or first hospitalization for HF (HR: 0.90; 95%CI: 0.70-1.17), and total mortality (HR: 0.77; 95%CI: 0.50-1.19) as patients receiving placebo.
• In the group of patients not using sacubitril/valsartan, patients treated with vericiguat had an equally high risk of cardiovascular death (HR: 0.95; 95%CI: 0.82-1.11) and total mortality (HR: 0.95; 95%CI: 0.83-1.09) and a lower risk of first hospitalization for HF (HR: 0.87; 95%CI: 0.78-0.98) and total mortality or first hospitalization for HF (HR: 0.89; 95%CI: 0.80-0.98) than patients receiving placebo, but there was no statistically significant interaction between the use of sacubitril/valsartan and the treatment effect of vericiguat (all P for interaction >0.2).
• Similarly, in the group of patients who used sacubitril/valsartan concomitantly for at least 3 months at any time after randomization, no statistically significant interaction was found between the use of sacubitril/valsartan and the treatment effect of vericiguat (all P for interaction >0.05).

Safety

• In the group of patients who used sacubitril/valsartan concomitantly for at least 3 months at any time after randomization, the number of patients with symptomatic hypotension (12.4 vs. 13.0%), syncope (4.5 vs. 4.6%), worsening renal function (31.9 vs. 29.9%), and hyperkalemia (7.9 vs. 10.3%) did not differ between the vericiguat and placebo groups (all P >0.05).
• When compared to patients without concomitant sacubitril/valsartan therapy, concomitant use of sacubitril/valsartan for at least 3 months was linked to a numerically higher incidence of hypotension and hyperkalemia and a trend towards worsening renal function.
• In the group of patients who used sacubitril/valsartan concomitantly at any time after randomization regardless of duration, a trend towards symptomatic hypotension and significantly more syncope was observed in the vericiguat group than in the placebo group.

Conclusion

References

Find this article online at Eur J Heart Fail.