Tyrosine kinase inhibitors 
One of the most promising targets in PAH is platelet-derived growth factor (PDGF). PDGF has been implicated in endothelial cell dysfunction and proliferation and migration of smooth muscle cells. It has been suggested that PDGF may play a role in PAH [263-265]. Pulmonary vascular remodelling in different animal models of PAH was shown to regress with the administration of imatinib mesylate (Gleevec®), a PDGF receptors antagonist approved for the treatment of chronic myeloid leukaemia [266]. Moreover, case reports suggest a beneficial effect of imatinib among severe PAH patients and a first randomized (imatinib vs placebo), double-blind, 24 weeks Phase II study was performed in 59 PAH patients in NYHA functional class II to IV receiving specific PAH therapies [267]. The primary endpoint (6-MWD after 24 weeks) was not different between 2 groups (+22 m in imatinib group as compared to placebo) even if a significant improvement of hemodynamic parameters was observed, especially among the patients with the most severe hemodynamic compromise [267]. This preliminary study does not allow concluding on the potential benefits of imatinib in PAH, but led to development of a phase III clinical trial (IMPRES) evaluating imatinib in a randomized controlled double-blind trial of 24-week, in 202 severe PAH patients treated with at least two PAH specific drugs. After 24 weeks, a significant improvement in the primary endpoint, 6MWD, was observed (+32 m in imatinib group vs. placebo) as well as an improvement of secondary endpoints including hemodynamic parameters [268]. However, several cases of subdural hematoma were reported in patients treated with imatinib: 2 cases in the double-blind period of 24 weeks and 7 supplemental cases in an open-label extension phase of the study. The mechanism of these subdural hematomas is not elucidated and the high incidence observed may be partly favored by anticoagulation recommended for PAH patients. Subdural hematoma is a complication of imatinib previously reported in other settings where it has been used, including oncology or pulmonary fibrosis. Netherless, this complication has rarely been reported in previous clinical trials in PAH or in registries. In addition, it has been demonstrated that tyrosine kinase inhibitors, including imatinib, may have possible cardiac adverse effects on long term use that might limit its benefice in PAH [269]. According to these results, the benefit/risk ratio of imatinib in PAH was not considered to be sufficient and to date, the use imatinib was not recommended in PAH.