Drugs and Toxic-Associated Pulmonary Arterial Hypertension, Prognosis, and Management in the Current Era of Treatment: Results from the REHAP Registry

Abstract RATIONALE Pulmonary Arterial Hypertension (PAH) is a progressive disease that leads to high pulmonary artery pressure and often results in heart failure. Drug and toxin-induced PAH (D&TPAH) is a notable PAH subgroup, with certain drugs historically linked to PAH outbreaks. Interferon therapies for hepatitis C and multiple sclerosis, as well as cancer treatments like tyrosine kinase inhibitors, have also been associated with PAH. This study describes the characteristics, treatment patterns, and survival of patients with D&TPAH in Spain's REHAP registry, comparing them to idiopathic (IPAH) and hereditary PAH (HPAH) cases. METHODS The REHAP registry in Spain gathers data on patients aged ≥14 with group 1 or group 4 pulmonary hypertension (PH) from 62 hospitals since 1998. Patients diagnosed with D&TPAH or IPAH/HPAH between January 1998 and November 2023 were included. Analyzed variables include demographics, clinical indicators, biomarkers, hemodynamics, echocardiographic data, and toxic exposure types. Survival estimates were calculated using Kaplan-Meier analysis, while Cox regression identified mortality risk factors. Statistical analysis was performed using SPSS version 29, with significance set at P<0.05. RESULTS Demographics were similar across D&TPAH and IPAH/HPAH groups, with a comparable proportion of female patients. D&TPAH patients, however, were diagnosed more quickly (0.9 years vs. 2.0 years), suggesting faster progression or heightened clinical suspicion for drug-induced cases. Dyspnea was more common in D&TPAH (94% vs. 90%), and 57% of D&TPAH patients were classified as NYHA III-IV, indicating higher functional impairment. Functional assessments, hemodynamics, and echocardiographic findings, including mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR), were generally similar between groups, though D&TPAH patients had slightly lower values.Both groups primarily received monotherapy or dual therapy, with PDE5 inhibitors and endothelin receptor antagonists (ERAs) as the main drugs. Initial survival analysis indicated variations based on toxic exposure type, with chemotherapy exposure showing the best cumulative survival early on, though five-year outcomes were comparable across groups. Kaplan-Meier analysis showed an early survival advantage for IPAH/HPAH patients, but this trend reversed after two years, favoring D&TPAH patients by five years. The log-rank test found no statistically significant survival difference between groups (p = 0.697) (figure 1), suggesting similar long-term outcomes. CONCLUSIONS While D&TPAH patients initially showed lower survival rates, their long-term outcomes were comparable to those of IPAH/HPAH, indicating a similar response to current therapies.