Effect of off‐label targeted drugs on long‐term survival in chronic thromboembolic pulmonary hypertension: Insights from a national multicentre prospective registry

Background and Objective Off‐label pulmonary arterial hypertension (PAH)‐targeted drugs are commonly prescribed for non‐operated chronic thromboembolic pulmonary hypertension (CTEPH), but their effect on the long‐term prognosis of CTEPH remains unknown. This study investigated the effect of off‐label PAH‐targeted drugs on the long‐term survival of CTEPH patients. Methods CTEPH patients were enrolled from a prospective multicentre national registry. Except for licensed riociguat and treprostinil, other PAH‐targeted drugs were off‐label. In the original and propensity score–matched (PSM) samples, five‐year survival was compared in two groups: (a) patients not receiving off‐label PAH‐targeted drugs (control) versus (b) patients receiving off‐label PAH‐targeted drugs (treatment). The latter group was investigated for the effect of started off‐label PAH‐targeted drugs at baselines (initial) or during follow‐up (subsequent). Results Of 347 enrolled patients, 212 were treated with off‐label PAH‐targeted drugs initially (n = 173) or subsequently (n = 39), and 135 were untreated. The 1‐, 2‐, 3‐ and 5‐year survival of the treatment group was significantly higher than that of the control group (97.1% vs. 89.4%, 92.3% vs. 82.1%, 83.2% vs. 75.1% and 71.1% vs. 55.3%, respectively, log‐rank test, p = 0.005). Initial treatment was correlated with better 5‐year survival after excluding patients with subsequent treatment to reduce the immortal‐time bias (hazard ratio: 0.611; 95% CI: 0.397–0.940; p = 0.025). In PSM samples, patients given initial treatment showed significantly better 5‐year survival than untreated patients (68.9% vs. 49.3%, log‐rank test, p = 0.008). Conclusion Off‐label targeted drugs contributed to improved long‐term survival in CTEPH patients receiving pharmacotherapies. The study demonstrates that off‐label use of pulmonary arterial hypertension medication improves long‐term survival in patients with chronic thromboembolic pulmonary hypertension. This is a national, multicentre, prospective registry with a large sample size and low rate of loss to follow‐up. The efficacy is more transparent after rigorously reducing bias.