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

Abstract

Objective. Data on the magnitude of benefit of modern therapies for pulmonary arterial hypertension (PAH) in connective tissue disease (CTD)-associated PAH are limited. In this study, we performed meta-analyses of randomized, controlled trials (RCTs) and registries to quantify the benefit of these modern therapies in patients with CTD-PAH.Methods. The PubMed and Embase databases were searched for articles reporting data from RCTs or registries published between January 1, 2000 and November 25, 2019. Eligibility criteria included multicenter studies with ≥30 CTD-PAH patients. For an RCT to be included, the trial had to evaluate an approved PAH therapy, and long-term risks of clinical morbidity and mortality or 6-minute walk distance had to be reported. For a registry to be included, survival rates had to be reported. Random-effects models were used to pool the data.Results. Eleven RCTs (total of 4,329 patients; 1,267 with CTD-PAH) and 19 registries (total of 9,739 patients; 4,008 with CTD-PAH) were included. Investigational therapy resulted in a 36% reduction in the risk of clinical morbidity/ mortality events both in the overall PAH population (hazard ratio [HR] 0.64, 95% confidence interval [95% CI] 0.54, 0.75; P < 0.001) and in CTD-PAH patients (HR 0.64, 95% CI 0.51, 0.81; P < 0.001) as compared to control subjects. The survival rate was lower in CTD-PAH patients compared to all PAH patients (survival rate 62%, 95% CI 57, 67% versus 72%, 95% CI 69, 75% at 3 years). The survival rate in CTD-PAH patients treated primarily after 2010 was higher than that in CTD-PAH patients treated before 2010 (survival rate 73%, 95% CI 62, 81% versus 65%, 95% CI 59, 71% at 3 years).Conclusion. Modern therapy provides a similar reduction in morbidity/mortality risk in patients with CTD-PAH when compared to the PAH population overall. Risk of death is higher in CTD-PAH patients than in those with 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 up-front intensive treatment are warranted.

Performance of the DETECT Algorithm for Pulmonary Hypertension Screening in a Systemic Sclerosis Cohort

“…High sensitivity is preferred in a screening tool, but the tradeoffs include an increased number of RHCs to exclude PAH, as seen in the original DETECT cohort (7). Since PAH is the leading cause of mortality in SSc and a recent meta‐analysis suggests better outcomes with utilization of screening algorithms and early initiation of combination therapy (2), we believe a higher rate of RHC to rule out PAH is justified. In patients who do not meet the criteria for RHC at a single time point according to the DETECT algorithm (i.e., the DETECT score does not indicate that the patient should be referred for RHC), we continue to incorporate the DETECT algorithm on an annual basis during clinic visits, with spirometry with DL co to assess the FVC:DL co ratio and with measurement of serum uric acid and NT‐proBNP levels.…”

“…Systemic sclerosis (SSc) is an autoimmune disease affecting multiple organ systems and characterized by fibrosis, inflammation, and vascular damage (1,2). Pulmonary arterial hypertension (PAH) is one of the leading causes of mortality in SSc, and in the past, SSc‐associated PAH (SSc‐PAH) had a significantly worse prognosis compared to other forms of PAH.…”

“…PAH is present in 10–12% of patients with SSc and in 19% of those with a diffusing capacity for carbon monoxide (DL co ) of <60% predicted (1,2). Over the last decade, treatment for PAH has evolved dramatically due to the addition of new therapies and the transition from sequential to initial combination therapy.…”

An expert opinion of the Polish Cardiac Society Working Group on Pulmonary Circulation and the Polish Society for Rheumatology on the diagnosis and treatment of pulmonary hypertension in patients with connective tissue disease

“…The 3-year survival was lower in patients with CTD-PAH vs all patients: 62% vs 72%, respectively. The 3-year survival of patients with CTD-PAH after 2010 was better than before 2010 at 73% vs 65%, respectively [50].…”

Pulmonary hypertension phenotypes in patients with systemic sclerosis

“…Medical therapy in SSc-PAH Current therapies for PAH target three main pathways: nitric oxide, endothelin-1 and prostacyclin [45,46]. A number of randomised controlled trials (RCTs) have published data on outcomes in patients with connective tissue disease (CTD), the majority of whom had SSc (table 3) [63]. With the exception of an unblinded RCT of epoprostenol, short-term monotherapy RCTs have tended to report lower response to therapy in patients with CTD associated PAH (CTD-PAH) [64,65].…”