Long-term safety and efficacy of imatinib in pulmonary arterial hypertension.

Abstract

BACKGROUND:

Imatinib is an oral inhibitor of several protein kinases implicated in the pathophysiology of pulmonary hypertension. Treatment with imatinib resulted in improved hemodynamics and exercise capacity in a controlled trial (Imatinib [QTI571] in Pulmonary Arterial Hypertension, a Randomized Efficacy Study [IMPRES]), among pulmonary arterial hypertension (PAH) patients inadequately responsive to 2 to 3 PAH-specific therapies.

METHODS:

The long-term (up to 204 weeks) safety and efficacy of imatinib in this open-label extension study were reviewed until early study termination on April 16, 2014. Of 202 IMPRES-enrolled patients, 66 imatinib and 78 placebo recipients entered the extension.

RESULTS:

Overall, 93.8% (135 of 144) of patients discontinued the extension study; administrative issues (i.e., sponsor termination; 32.6%) and adverse events (31.3%) were the primary reasons for discontinuation. Nine patients completed the extension study before it was terminated. Serious and unexpected adverse events were frequent. These included 6 subdural hematomas in the extension study and 17 deaths during or within 30 days of study end. Although the patients who tolerated imatinib and remained in the extension for a longer duration did experience an improvement in functional class and walk distance, most discontinued the drug and the study.

CONCLUSIONS:

Severe adverse events, significant side effects, and a high discontinuation rate limit the utility of imatinib in the treatment of PAH. These risks outweigh any possible improvements in hemodynamics and walk distance seen in those patients able to remain on drug. The off-label use of this compound in PAH is discouraged.

• Authors: Adaani E Frost, Robyn J Barst, Marius M Hoeper, Hyuk-Jae Chang, Robert P Frantz, Yoshihiro Fukumoto, Nazzareno Galié, Paul M Hassoun, Hans Klose, Hiromi Matsubara, Nicholas W Morrell, Andrew J Peacock, Michael Pfeifer, Gérald Simonneau, Victor F Tapson, Fernando Torres, Carmine Dario Vizza, David Lawrence, Wei Yang, James M Felser, Deborah A Quinn, Hossein-Ardeschir Ghofrani
• Journal: The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation (J Heart Lung Transplant) Vol. 34 Issue 11 Pg. 1366-75 (Nov 2015) ISSN: 1557-3117 [Electronic] United States
• PMID: 26210752 (Publication Type: Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Chemical References

• Protein Kinase Inhibitors
• Imatinib Mesylate

Topics

• Adolescent
• Adult
• Aged
• Dose-Response Relationship, Drug
• Double-Blind Method
• Exercise Tolerance (physiology)
• Female
• Follow-Up Studies
• Hemodynamics (drug effects)
• Humans
• Hypertension, Pulmonary (drug therapy, physiopathology)
• Imatinib Mesylate (administration & dosage)
• Male
• Middle Aged
• Protein Kinase Inhibitors (administration & dosage)
• Retrospective Studies
• Time Factors
• Treatment Outcome
• Young Adult