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Search results for
A total of 2,074 articles were found as a result of the database search. After excluding irrelevant and duplicate papers, 10 of his RCTs (12 papers) published from 2012 to 2022 finally met the inclusion criteria.16,17,18,19,20,21,22,23,24,25,26,27. Online access to the full journal text and supplementary materials is now available. Figure 1 shows the PRISMA flow diagram, literature search methodology, and explanation of exclusion criteria.

PRISMA flow diagram showing search strategy and inclusion/exclusion study.
Characteristics of RCTs included in the meta-analysis
The 10 RCTs (resulting in 12 articles) included a total of 7,526 heart failure patients, of whom 4,253 were in the sGC modulator group and 3,273 in the placebo group. Baseline characteristics of the studies included in the meta-analysis can be found in Table 1. The mean age of patients ranged from 61 to 75 years, and mean follow-up ranged from 4 weeks (for safety in the DILATE trial) to 47 weeks (for efficacy of 10.8 months in the VICTORIA trial). Patients have preserved ejection fraction (HFpEF, EF > 50%), mildly reduced ejection fraction (HFmrEF, EF = 41-49%), or reduced ejection fraction. (HFrEF, EF≦40%). Vericiguat doses ranged from 1.25 to 15 mg/day, riociguat doses ranged from 0.5 to 2.5 mg three times daily, pralisiguat doses ranged from 40 mg/day, and siniciguat doses ranged from 50 to 100 to 150 ug/h .
Demographics and medication characteristics at study entry were reported in Table 2 . Complications such as atrial fibrillation, diabetes mellitus (DM), and decreased renal function were observed in some patients.Control and treatment groups received conventional HF therapy [diuretics, angiotensin- converting-enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), beta-blockers, mineralocorticoid receptor antagonist (MRA)]. The Cochrane risk of bias tool was used to determine the risk of bias in the 10 included trials, with the majority showing low risk.Ten. A detailed methodological quality assessment of the included RCTs is also shown in Figure 2 .

From overview and methodological quality assessment of included RCTs to details.
Results of efficacy and safety analyzes for the entire study
Included studies reported the efficacy of sGC modulators (riociguat, vericiguat, pralisiguat as stimulants, and sinasiguat as activator) in HF patients. A total of 10 RCTs were evaluated for the association between sGC regulation and all-cause mortality. Analysis of RCTs with a fixed effects model showed that the use of sGC modulators in HF patients did not confer a significant benefit on the risk of all-cause mortality (RR = 0.97, 95% CI 0.88). 1.08, p≦=≦0.62) (Figure 3).There was no significant heterogeneity (I2±0.0%, pOf the included trials ≧=≦0.71), the analysis was performed via a fixed effects model. No significant publication bias was detected according to Egger’s linear regression test and his Begg and Mazumdar rank correlation test (Egger’s test: p==0.38; Begg’s test: p≦=≦0.62) (Supplementary Figure S1).

Forest plot of the effect of soluble guanylyl cyclase modulators on all-cause mortality in heart failure patients compared to placebo. CI = confidence interval.
In three trials, health-related quality of life was measured using the “EuroQol Group 5-Dimensional Self-report Questionnaire (EQ-5D) US Index” score. As a subgroup analysis, one study looked at the health status of patients who participated in the SOCRATES-PRESERVED RCT.twenty one. According to the results of the study using a fixed effects model, sGC modulators significantly improved her EQ-5D-based quality of life in HF patients (MD = ≤0.03, 95% CI 0.02–0.04, p≦0.001), and there was no significant heterogeneity among the three trials (I2±42%, p±0.18) (Figure 4).

Forest plots of changes in EuroQol Group 5-dimensional self-report questionnaire US index in heart failure participants: a randomized controlled trial (RCT) comparing soluble guanylyl cyclase modulator with placebo. CI = confidence interval.
Of note, based on the results of the study utilizing a fixed effects model, sGC modulators did not show significant changes in KCCQ scores (±0.20, 95% CI ±1.28 to 0.87, p) “=” ‘0.71) (Fig. 5), which was observed without significant heterogeneity (I2±57.0%, p±0.07).

Forest plot of changes in KCCQ in heart failure participants: a randomized controlled trial (RCT) comparing a soluble guanylyl cyclase modulator to a placebo. CI = confidence interval.
The effects of sGC modulators on 6MWD were also evaluated. Meta-analysis revealed that sGC modulators had no significant effect on her 6-MWD in his HF patients (≤1.41, 95% CI ≤11.87–9.05, p≧0.79). There was no significant heterogeneity between studies (I2±0%, p≦=≦0.51) (Figure 6). Therefore, we performed the analysis using a fixed effects model.

Forest plots of changes in 6-MWD in heart failure participants: a randomized controlled trial (RCT) comparing soluble guanylyl cyclase stimulators to placebo. CI = confidence interval.
The effect of sGC modulators on change from baseline in NT-proBNP was examined in five trials. log (NTproBNP) was included in the vericiguat group, indicating that vericiguat overall did not significantly reduce log (NTproBNP) values compared to the control group (±0.06, 95% CI ±0.23 to 0.12 , p±0.53), however, a single large study of vericiguat in HFrEF produced insignificant changes in NT-proBNP levels in relation to outcome (Figure 7). Riociguat treatment had a similar overall trend (±0.55; 95% CI ±1.14 to 0.04; p±0.07). There was no significant heterogeneity in the vericiguat group (I2±58%, p≧0.09). Significant heterogeneity was observed in the riociguat group (I2±82%, p±0.02). (Figure 7).

Forest plot for log (NT-proBNP) and change in NT-proBNP in heart failure participants: a randomized controlled trial (RCT) comparing soluble guanylyl cyclase modulators to placebo. CI = confidence interval.
The rate of therapeutically important drug-related serious adverse events was calculated using 10 RCTs with 7526 participants (4253 sGC modulators and 3273 placebo). This RCT included ventricular tachycardia, heart failure, syncope, peripheral edema, pulmonary edema, hypotension, decreased cardiac output, headache, and pulmonary hemorrhage. The use of sGC modulators in HF was associated with a trend toward a significant difference in the incidence of SAEs compared with placebo (RR = 1.10, 95% CI 0.99 to 1.22, p≦=≦0.07) (Figure 8).

Forest plot for the occurrence of SAEs in heart failure participants: a randomized controlled trial (RCT) comparing soluble guanylyl cyclase modulators to placebo. CI = confidence interval.
It should also be emphasized that the incidence of hypotension was significantly increased (RR = 1.22, 95% CI 1.03 to 1.43, p≦=≦0.02) (Figure 9). There was no significant heterogeneity in SAE and hypotension, respectively (I2±0.0%, p==0.47; me2±0.0%, p≧0.47). Based on a fixed effects model, the four RCTs of vericiguat had an RR of SAE of 1.08 (95% CI 0.96 to 1.21; p±0.20) There is no sign of heterogeneity (I2±29%, p≧0.24). Three other of his studies analyzed the results of riociguat and found an RR of 1.13 (95% CI 0.92 to 1.39, p≦=≦0.25) No significant heterogeneity (I2±7%, p≧0.34). The RR for participants using prariciguat and sinasiguat was 1.10 (95% CI 0.47 to 2.58; p±0.83) and 2.31 (95% CI 0.84 to 6.33, p≦=≦0.11), respectively. Pralisiguat was tested in only one of his studies, so heterogeneity was not calculated. There was no significant heterogeneity in sinasiguat (I2±0.0%, p≧0.34).

Forest plot for the occurrence of hypotension in heart failure participants: Effects of an RCT comparing soluble guanylyl cyclase modulators with placebo. CI = confidence interval.
The use of sGC modulators (vericiguat and riociguat) and risk of anemia in HF was evaluated using data from two eligible studies18,22. Use of sGC modulators in HF was associated with a significantly increased risk of anemia compared to placebo (RR = 1.35, 95% CI 1.10 to 1.66, p≦=≦0.005) (Figure 10). There was no significant heterogeneity between studies and the analysis was performed using a fixed effects model (I2±0.0%, p≧0.70).

Forest plot for the incidence of anemia in heart failure participants: Effects of an RCT comparing soluble guanylyl cyclase modulators with placebo. CI = confidence interval.
publication bias
SAE, hypotension, 6MWD, funnel plot, Egger test, and Begg test were used to assess possible publication bias in mortality (Figures S1–S4). We found no evidence of potential publication bias in the evaluation. Meanwhile, publication bias regarding the improvement of EQ-5D US index score, NT-proBNP, anemia, and KCCQ was not checked due to insufficient number of studies.
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