Long‐Term Outcomes in Patients with Connective Tissue Disease‐Associated Pulmonary Arterial Hypertension in the Modern Treatment Era: Meta‐Analyses of Randomized, Controlled Trials and Observational Registries

OBJECTIVE Data on the magnitude of benefit of modern pulmonary arterial hypertension (PAH) therapies in connective tissue disease-associated PAH (CTD-PAH) are limited. We performed meta-analyses of randomized, controlled trials (RCTs) and registries to quantify this benefit (PROSPERO# CRD42020167119). METHODS PubMed and EMBASE were searched for articles reporting data from RCTs or registries published 1/1/2000-11/25/2019. Eligibility criteria included multicenter studies with ≥30 CTD-PAH patients. RCTs had to evaluate approved PAH therapy and report long-term clinical morbidity/mortality or 6-minute walk distance. Registries had to report survival. Random effects models were used to pool data. RESULTS Eleven RCTs (N=4329 n=1267 CTD-PAH) and 19 registries (N=9739; n=4008 CTD-PAH) were included. Investigational therapy produced a 36% reduction in risk of clinical morbidity/mortality events versus control (HR=0.64; 95%CI: 0.54-0.75; P<0.001) in all patients and a 36% reduction (HR=0.64; 95% CI: 0.51-0.81; P<0.001) in CTD-PAH patients. Survival was lower in CTD-PAH versus all patients (62%, 95% CI: 57%-67% versus 72%, 95% CI: 69%-75% at 3 years). Survival in CTD-PAH patients treated primarily after 2010 was higher than in those treated before (73%, 95% CI: 62%-81% versus 65%, 95% CI: 59%-71% at 3 years). CONCLUSIONS Modern therapy provides a similar reduction in morbidity/mortality risk in CTD-PAH and the overall PAH population. Risk of death is higher in CTD-PAH than in PAH overall, but survival has improved in the last 10 years, which may be related to increased screening and/or new treatment approaches. Early detection of PAH in patients with CTD and upfront intensive treatment are warranted.