Imatinib in pulmonary arterial hypertension patients with inadequate response to established therapy.

Abstract

RATIONALE:

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.

OBJECTIVES:

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.

MEASUREMENTS AND MAIN 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).

• Authors: Hossein A Ghofrani, Nicholas W Morrell, Marius M Hoeper, Horst Olschewski, Andrew J Peacock, Robyn J Barst, Shelley Shapiro, Heiko Golpon, Mark Toshner, Friedrich Grimminger, Steve Pascoe
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 182 Issue 9 Pg. 1171-7 (Nov 01 2010) ISSN: 1535-4970 [Electronic] United States
• PMID: 20581169 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Benzamides
• Piperazines
• Protein Kinase Inhibitors
• Pyrimidines
• Imatinib Mesylate
• Receptors, Platelet-Derived Growth Factor

Topics

• Adult
• Benzamides
• Double-Blind Method
• Exercise Test
• Female
• Humans
• Hypertension, Pulmonary (drug therapy, physiopathology)
• Imatinib Mesylate
• Intention to Treat Analysis
• Lung (physiopathology)
• Male
• Middle Aged
• Piperazines (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Pyrimidines (pharmacology)
• Receptors, Platelet-Derived Growth Factor (drug effects)
• Respiratory Function Tests
• Treatment Outcome