sGC stimulators have emerged as a potential treatment for HF due to their ability to stimulate the production of cyclic guanosine monophosphate, which is an impaired pathway in those patients [17, 18]. Despite being tested for safety and efficacy in several clinical trials, only a few studies have reviewed and analyzed the reported data. In this systematic review and meta-analysis, we synthesized evidence from eight RCTs conducted between 2013 and 2022 with a total of 7307 HF patients. Our analysis shows that only vericiguat at a dose of 10 mg significantly reduced the risk of composite cardiovascular mortality and HF hospitalization in patients with HF, which was only sustained in the HFrEF subgroup, with no effect in HFpEF patients. Vericiguat also showed to be relatively safe, with only an increased risk of all-cause mortality in HFpEF patients at 5 mg. However, riociguat and praliciguat did not show different effects from placebo on the composite cardiovascular mortality and HF hospitalization, but an increased risk of hypotension in general HF and HFpEF patients was observed in the praliciguat group at the dose of 40 mg.

Vericiguat showed to have the best outcomes despite the variations in the follow-up duration and HF type between the included trials. Among the tested range of doses (1.25–15 mg), 10 mg was only effective when administered once per day. Furthermore, our subgroup analysis showed that vericiguat 10 mg had positive outcomes mainly in HFrEF, a type of HF that represents approximately 50% of all HF cases and has a high mortality rate of approximately 75% [19, 20]. Conversely, HFpEF patients did not seem to benefit from vericiguat. Our findings may have been influenced by the large subgroup population of HFrEF patients included in the VICTORIA trial [2]. Therefore, further research with a larger population of HFpEF patients is recommended to confirm our findings. However, a recent network meta-analysis showed that other pharmacotherapies such as sodium-glucose transporter sodium-glucose cotransporter-2 (SGLT2) inhibitors, angiotensin receptor-neprilysin inhibitors (ARNIs), and mineralocorticoid receptor antagonists (MRAs) significantly reduced HF hospitalization in HFpEF, which could help this particular patient population unlike sGC stimulators [21].

In HF, N-terminal pro-B-type natriuretic peptide (NT-proBNB) is released from the cardiac myocytes in response to the increased stretching/stress of the cardiac wall, and therefore it is considered a gold standard biomarker of HF [22,23,24]. NT-proBNB levels in the blood are also used to monitor the effectiveness of certain HF medications such as beta-blockers, ACE inhibitors, and diuretics [23, 25]. Pieske et al. in the SOCRATES-PRESERVED trial and Gheorghiade et al. in the SOCRATES-REDUCED trial [6, 12] investigated the effect of vericiguat on the baseline change of log-transformed NT-proBNB and found no statistically significant reduction (improvement) in the log-transformed NT-proBNB levels at 12 weeks post-treatment. Dachs et al. [9] also reported no improvement in NT-proBNB levels in HFpEF patients 26 weeks after treatment with riociguat. Left atrial volume (LAV) was another outcome measured by Pieske et al. [12] through echocardiography as an indicator of left ventricular filling pressure (LVFP). Vericiguat did not show a significant effect on LAV compared with placebo.

Moreover, Udelson et al., Dachs et al., Bonderman et al., and Armstrong et al. [7,8,9, 11] utilized the 6-min-walk test (6MWT) to assess the HF patients’ exercise tolerance and monitor their response to sGC stimulators treatment. They reported no statistically significant change in 6MWT from baseline after treatment with praliciguat (40 mg), riociguat (0.5 mg (up-titrated to 1.0 or 1.5 mg)), riociguat (0.5, 1 and 2 mg), and vericiguat (10 or 15 mg), respectively. Additionally, Pieske et al. and Bonderman et al. [7, 12] evaluated the effects of vericiguat and riociguat, respectively, on the quality of life of HF patients using the 5-dimension EuroQol questionnaire (EQ-5D) and the scores did not show significant improvement compared with placebo.

Regarding the safety of sGC stimulators use in HF patients, when compared with a placebo, sGC stimulators were safe and well-tolerable with no reported serious adverse events, adverse events leading to drug discontinuation, or any adverse events, including syncope and AKI. However, hypotension was a common adverse event with praliciguat use in HFpEF patients. Also, while all sGC stimulators did not show an increase in the incidence of all-cause mortality, vericiguat 5 mg showed a higher risk than placebo in HFpEF patients. Similarly, BBs, MRAs, ACEIs, angiotensin receptor blockers (ARBs), ARNIs, and SGLT2 inhibitors were not effective on all-cause mortality in a recent network meta-analysis evaluating pharmacotherapies in HFpEF patients [21]. Conversely, in another recent meta-analysis, vericiguat showed to significantly reduce all-cause-mortality in HFrEF patients when combined with ARNIs, BBs, and MRAs, despite being not significantly different from SGLT2 inhibitors and omecamtiv-mecarbil [26].

Moreover, The PARADIGM-HF and DAPA-HF trials; on the other hand, have neprilysin inhibition (sacubitril/valsartan) and SGLT2 inhibition (Dapagliflozin), respectively [27, 28]. These trials have shown significant benefits in reducing mortality, hospitalizations, and improving symptoms in patients with HF, providing additional therapeutic options beyond traditional therapies. The differential outcomes between trials of sGC stimulators and those like PARADIGM-HF and DAPA-HF underscore the complex pathophysiology of HF and the need for a multifaceted approach to its management [27, 28].

Therefore, further research to investigate the effect of sGC stimulators on both HFrEF and HFpEF outcomes when combined with other HF medications is still warranted, which may allow for a more reliable conclusion regarding the position of sGC stimulators in HF management guidelines.

This a network meta-analysis of double-blinded, multinational/centric RCTs, which strengthens the quality of our evidence and increases the generalizability of our study, with no identified heterogeneity of the data. However, our analysis has a few limitations. First, the population size of HFpEF patients, was small, which made it challenging to draw strong conclusions. Second, only one trial in our analysis evaluated the safety and efficacy of praliciguat in HF patients limiting the power of our data regarding its true effect. Third, we could not include some efficacy outcomes, such as NT-proBNB, 6MWT, LAV, and EQ-5D questionnaire in our analysis due to the lack of or the significant variation in the reported data. Finally, the follow-up duration among the included trials was not long enough to determine the long-term safety and efficacy of sGC stimulators in HF patients.