Comparative Efficacy and Safety of Soluble Guanylate Cyclase Stimulators in Heart Failure with Preserved Ejection Fraction: A Network Meta-Analysis

Background: Heart failure with preserved ejection fraction (HFpEF) makes up nearly half of all heart failure cases and remains a difficult condition to treat due to limited therapeutic options. Soluble guanylate cyclase (sGC) stimulators namely Riociguat, Vericiguat, and Praliciguat have shown potential in improving heart muscle relaxation and vascular function. However, their comparative effectiveness and safety are still uncertain. Methods: We conducted a Bayesian network meta analysis (NMA) that included eight randomized controlled trials encompassing 7,330 HFpEF patients, with an average age of 69.5 years. The outcomes evaluated included survival rates, left ventricular ejection fraction (LVEF), NT-proBNP levels, hospital readmissions, New York Heart Association (NYHA) functional class, and adverse events. Treatment outcomes were presented as odds ratios (OR) or mean differences (MD) along with 95% credible intervals (CI). Results: Riociguat indicated a potentially favourable survival benefit (OR 3.69, 95% CI: 0.53;29.2) and a reduced risk of hospital readmission (OR 0.40, 0.11;1.30), though these findings were not definitive. Praliciguat had neutral effects on survival (OR 1.05, 0.017;61.0). Vericiguat did not improve survival (OR 0.42, 0.12;1.16) but did offer a modest improvement in NYHA functional class (log RR 0.27, ;0.12 to 0.67). Changes in LVEF were unclear: Riociguat (MD 3.00, ;1.15 to 7.13), Vericiguat (MD 1.59, ;2.03 to 5.17), and Praliciguat (MD ;0.19, ;7.34 to 6.84). Riociguat was associated with a reduction in NT-proBNP levels (MD ;7.41, ;21.2 to 4.41), whereas Vericiguat (0.65, ;9.54 to 10.8) and Praliciguat (5.28, ;12.6 to 23.0) had neutral effects. Adverse events such as headache (log RR 0.21, ;0.35 to 0.78), low blood pressure (0.42, ;0.21 to 1.05), and neurological symptoms (;0.04, ;0.87 to 0.79) were not significantly increased. Conclusion: Among the agents studied, Riociguat showed the most promise in terms of survival and reducing hospital readmissions in HFpEF patients. Vericiguat offered modest improvements in patient functional status, while Praliciguat had minimal clinical impact. The findings suggest that more extensive, long-term clinical trials are needed to better establish the efficacy and safety of these therapies.