Long-Term Outcomes in Pulmonary Arterial Hypertension by Functional Class: A Meta-Analysis of Randomized Controlled Trials and Observational Registries

Abstract

Purpose Patients with World Health Organization (WHO) functional class (FC) I/II pulmonary arterial hypertension (PAH) are often considered to be patients whose disease is controlled. However, little is known about their prognosis compared with patients with WHO FC III/IV disease. This meta-analysis evaluated survival outcomes in observational registries by FC, and compared treatment effects observed in randomized controlled trials (RCTs) by FC. Methods We searched the PubMed and EMBASE databases for English-only articles, with our search supplemented by annual registry reports. Inclusion criteria for observational (minimal or no intervention) registries included patients with WHO group 1 pulmonary hypertension (PAH), N>30, and survival data. RCT inclusion criteria included patients with WHO group 1 pulmonary hypertension (PAH); morbidity, mortality, or time to worsening as primary or secondary endpoints; and a mean duration of exposure to study treatment >6 months. The primary outcome was survival for registries and time to first clinical event for RCTs, both analyzed by FC. Separate random-effects models assuming inter-study heterogeneity were calculated for eligible registry studies and RCTs. Results Ten registry studies (n=6,578) and 4 RCTs (n=2,482) met inclusion criteria. Registries enrolled 9% to 47% FC I/II patients. Three-year survival rates were 78% (95% CI, 73-83%) and 55% (95% CI, 50-59%) for FC I/II and III/IV patients, respectively. Three RCTs had roughly equal numbers of FC I/II and III/IV patients while one enrolled 30% FC I/II and 70% III/IV. The hazard ratio for the overall treatment effect was 0.61 (95% CI, 0.51-0.74). It was 0.60 (95% CI, 0.44-0.82) for FC I/II patients, and 0.62 (95% CI, 0.49-0.80) for FC III/IV patients. Conclusion Even though FC I/II PAH is often considered controlled disease, registry data show a >20% risk of death within 3 years for patients with FC I/II disease. Analysis of RCT data demonstrates that PAH medications delay disease progression in both FC I/II and FC III/IV patients. The high mortality rate among FC I/II patients highlight both the severity of PAH and the limitations of relying on a single clinical parameter to assess disease status.