Imatinib in pulmonary arterial hypertension patients with inadequate response to established therapy.
BACKGROUND
Pulmonary arterial hypertension (PAH) is a progressive condition with a poor prognosis. Platelet-derived growth factor receptor (PDGFR) signaling plays an important role in its pathobiology.


OBJECTIVE
To assess safety, tolerability, and efficacy of the PDGFR inhibitor imatinib in patients with PAH.


METHODS
Patients with PAH in functional classes II-IV were enrolled in a 24-week randomized, double-blind, placebo-controlled pilot study. Patients received imatinib (an inhibitor of PDGFR activity) 200 mg orally once daily (or placebo), which was increased to 400 mg if the initial dose was well tolerated. The primary endpoints were safety and change from baseline in the 6-minute-walk distance (6MWD). Secondary endpoints included hemodynamics and functional classification.


RESULTS
Fifty-nine patients enrolled (imatinib [n = 28]; placebo [n = 31]); 42 completed the study. Dropouts were equally matched between the two groups. In the intention-to-treat (ITT) population there was no significant change in the 6MWD (mean ± SD) in the imatinib versus placebo group (+22 ± 63 versus -1.0 ± 53 m). There was a significant decrease in pulmonary vascular resistance (imatinib -300 ± 347 versus placebo -78 ± 269 dynes · s · cm⁻⁵, P < 0.01) and increase in cardiac output (imatinib +0.6 ± 1.2 versus placebo -0.1 ± 0.9 L/min, P = 0.02). Serious adverse events occurred in 11 imatinib recipients (39%) and 7 placebo recipients (23%). Three deaths occurred in each group. Post hoc subgroup analyses suggest that patients with greater hemodynamic impairment may respond better than patients with less impairment.


CONCLUSIONS
These data from a Phase II study are consistent with imatinib being well tolerated in patients with PAH, and provide proof of concept for further studies evaluating its safety, tolerability, and efficacy in PAH. Clinical trial registered with www.clinicaltrials.gov (NCT00477269).
Ghofrani
Hossein A
HA
Pulmonary Hypertension Division, Medical Clinic II/V, University Hospital Giessen und Marburg GmbH, Giessen, Germany. ardeschir.ghofrani@innere.med.uni-giessen.de
Morrell
Nicholas W
NW
Hoeper
Marius M
MM
Olschewski
Horst
H
Peacock
Andrew J
AJ
Barst
Robyn J
RJ
Shapiro
Shelley
S
Golpon
Heiko
H
Toshner
Mark
M
Grimminger
Friedrich
F
Pascoe
Steve
S
D000328:Adult; D001549:Benzamides; D004311:Double-Blind Method; D005080:Exercise Test; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000503:physiopathology; D000068877:Imatinib Mesylate; D057194:Intention to Treat Analysis; D008168:Lung / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D017479:Receptors, Platelet-Derived Growth Factor / Q000187:drug effects; D012129:Respiratory Function Tests; D016896:Treatment Outcome
D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D017479:Receptors, Platelet-Derived Growth Factor