Efficacy of intermittent inhaled iloprost in inoperable chronic thromboembolic pulmonary hypertension

Abstract

PH (pulmonary hypertension) targeted therapy may play an essential role in chronic thromboembolic pulmonary hypertension (CTEPH) patients considered inoperable. Given the limited number of PH-targeted drugs approved for CTEPH, reliable long-term data are necessary on the effects of PH-targeted drugs in patients with inoperable CTEPH. We aimed to evaluate the efficacy and safety of intermittent inhaled iloprost in inoperable CTEPH. Methods. The open randomized controlled trial included 22 inoperable CTEPH patients (aged (Me (25%; 75%)) 48,3 (38,4; 59,5) years; 63.6% females; 9.1% with WHO functional class (FC) IV, 72.7% with WHO-FC III, 18.2% with WHO-FC II; 6-minute walking test (6-MWT) distance of 348 (145; 443) m; mean pulmonary artery pressure (mPAP) of 41.8 (29.3; 52.8) mmHg; tricuspid annular plane systolic excursion (TAPSE) of 16.3 (14.5; 18.2) mm; plasma NT-proBNP of 853.8 (562.2; 1124.2) pg/mL). The patients were enrolled 3 – 6 months after acute pulmonary embolism and were randomized 1:1 to receive either standard therapy with vitamin K antagonists and, if indicated, oxygen and diuretics or inhaled iloprost 5.0 µg / inhalation 4 times a day for 2 weeks every 3 months for 2 years in addition to the standard of care. Efficacy endpoints included changes from baseline in 6-MWT, WHO-FC, echo-parameters, inflammatory markers, time to clinical worsening, and all-cause mortality. Results. At baseline (prior to therapy), there were no significant differences between iloprost and control groups. Levels of C-reactive protein and the interleukin (IL)-1b, IL-6, IL-8, γ-IF, and TNF-α cytokines were increased. At month 24, a mean 6-MWT distance increased by 215 m (p < 0.001) in the patients receiving inhaled iloprost and by 137 m in the control patients (p < 0.01). The control-adjusted difference was +78 m (p = 0.03). WHO-FC improved by two classes in 63.6% in iloprost group vs 0% in the control group (p = 0.028), by one class in 36.4% vs 30% (p = 0.091), and remained the same in 0% vs 70 % (p = 0.018), respectively. Inhaled iloprost delayed the time to clinical worsening (p = 0.0064). Improvements were noted in control-adjusted changes in ePASP (–18.6 mmHg; p = 0.0065), TAPSE (+2.4 mm; p = 0.028), and plasma NT-proBNP (–256.9 pg/mL; p < 0.01). The levels of inflammation decreased significantly in the iloprost group, while remained unchanged in the control group. Combination therapy with inhaled iloprost was tolerated well. One patient died in the control group (p = 0.093). Conclusion. Long-term intermittent inhaled iloprost for patients with inoperable CTEPH may improve their clinical status, hemodynamics, and anti-inflammatory status.