Abstract Background Pulmonary arterial hypertension (PAH)-targeted therapies exert significant hemodynamic changes. We aimed to systematically synthesize these effects and explore the pulmonary pressure and flow changes in relation to the resistance changes. Methods We systematically searched PubMed, CENTRAL, and Web of Science for studies evaluating the hemodynamic effects (mean pulmonary artery pressure [mPAP], cardiac index/output [CI/CO], pulmonary vascular resistance [PVR]) of PAH-targeted therapies (comprising endothelin receptor antagonists [ERA], phosphodiesterase type 5 inhibitors [PDE5i], prostanoids [either i.v./s.c. or p.o./inh], riociguat, and selexipag) either in monotherapy or combinations as assessed by right heart catheterization (RHC) in treatment-naïve PAH patients. We performed a random-effects meta-analysis and used meta-regression to evaluate the contribution of mPAP % reduction and CI/CO % increase on the PVR % reduction across different treatment groups. Results We included 68 studies comprising 90 treatment groups and 4276 patients (age 47.3±13.2, 74% women). PVR reduction as a percentage of the pre-treatment value was more pronounced in the oral + prostanoid i.v./s.c. combination therapy (mean difference [MD] -50.0%, 95% confidence interval [CI] -60.8%; -39.2%), compared to oral combination therapy (MD -41.7%, 95% CI -47.6%; -35.8%), prostanoid i.v./s.c. monotherapy (MD -31.8%, 95% CI -37.6%; -25.9%), and oral monotherapy (MD -21.6%, 95% CI -25.4%; -17.8%) (Figure 1). The contribution of mPAP % reduction and of CI/CO % increase to the PVR % reduction was equally significant in all treatment groups (Figure 2). In the oral combination therapy group CI/CO % increase had superior contribution over mPAP % reduction (R2 90% vs R2 0%), but this difference was driven by an outlier study with n = 8 patients and after the exclusion of the outlier, the contribution of mPAP % reduction and of CI/CO % increase to the PVR % reduction was equally significant also in the oral combination group. The same results applied in a sensitivity analysis including only studies with idiopathic/heritable/drugs-induced/connective tissue disease-associated PAH patients. Conclusion Combination therapies, especially with the inclusion of parenteral prostanoids, lead to remarkable hemodynamic improvement in treatment-naïve PAH patients. The contribution of mPAP and CI/CO % changes to the overall PVR % reduction is equally significant.Figure 1Figure 2