Contribution of pressure and flow changes to resistance reduction after pulmonary arterial hypertension treatment: a meta-analysis of 3898 patients

Background Pulmonary arterial hypertension (PAH)-targeted therapies exert significant haemodynamic changes; however, systematic synthesis is currently lacking. Methods We searched PubMed, CENTRAL and Web of Science for studies evaluating mean pulmonary artery pressure (mPAP), cardiac index/cardiac output (CI/CO) and pulmonary vascular resistance (PVR) of PAH-targeted therapies either in monotherapy or combinations as assessed by right heart catheterisation in treatment-naive PAH patients. We performed a random-effects meta-analysis with meta-regression. Results We included 68 studies (90 treatment groups) with 3898 patients (age 47.4 +/- 13.2 years, 74% women). In studies with small PVR reduction (<4 WU), CI/CO increase (R2=62%) and not mPAP reduction (R2=24%) was decisive for the PVR reduction ( p<0.001 and p=0.36, respectively, in the multivariable meta-regression model); however, in studies with large PVR reduction (>4 WU), both CI/CO increase (R2=72%) and mPAP reduction (R2=35%) contributed significantly to the PVR reduction ( p<0.001 and p=0.01, respectively). PVR reduction as a percentage of the pre-treatment value was more pronounced in the oral+prostanoid intravenous/subcutaneous combination therapy (mean difference -50.0%, 95% CI -60.8- -39.2%), compared to oral combination therapy (-41.7%, -47.6- -35.8%), prostanoid i.v./s.c. monotherapy (-31.8%, -37.6- -25.9%) and oral monotherapy (-21.6%, -25.4- -17.8%). Changes in haemodynamic parameters were significantly associated with changes in functional capacity of patients with PAH as expressed by the 6-min walking distance. Conclusion Combination therapies, especially with the inclusion of parenteral prostanoids, lead to remarkable haemodynamic improvement in treatment-naive PAH patients and may unmask the contribution of mPAP reduction to the overall PVR reduction in addition to the increase in CO.