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

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. FelserDeborah A. Quinn, Hossein Ardeschir Ghofrani

Research output: Contribution to journalArticlepeer-review

62 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1366-1375
Number of pages10
JournalJournal of Heart and Lung Transplantation
Volume34
Issue number11
DOIs
Publication statusPublished - 2015 Nov

Bibliographical note

Funding Information:
A.E.F. has received honoraria for consultations and/or speaking about a product or about pulmonary hypertension from Actelion, United Therapeutics/Lung LLC, Gilead, Novartis, Bayer and Pfizer; and grant support from Actelion, United Therapeutics/Lung LLC, Gilead, Novartis, Bayer and Pfizer. R.J.B. (deceased) received honoraria for consultations/scientific advisory board activity from Actelion, Bayer, Lilly, Gilead, GlaxoSmithKline, Ikaria, Merck, Novartis, Pfizer, and VentriPoint Diagnostics. M.M.H. received honoraria for consultations and/or speaking at conferences from Actelion, Bayer, GlaxoSmithKline, Novartis, and Pfizer. R.P.F. has received research funding from United Therapeutics, served on advisory boards for United Therapeutics and Actelion, and has had a consultancy agreement with Pfizer. Y.F. has received lecturer fees from Bayer, Daiichi Sankyo, Pfizer, GlaxoSmithKline, Novartis, and Nippon Shinyaku. N.G. has been involved with Steering Committee activities for Lilly, Actelion, Pfizer, Bayer-Schering, GlaxoSmithKline, and Novartis, has received payment for lecturer fees from Actelion, Lilly, Pfizer, Bayer-Schering, and GlaxoSmithKline, and has also conducted contract research for Actelion, Pfizer, United Therapeutics, Bayer-Schering, and GlaxoSmithKline. P.M.H. has received honoraria for consultations and/or scientific advisory board activities from Gilead, Novartis, and Merck. H.K. has received fees from Actelion, Bayer, GlaxoSmithKline, Novartis, United Therapeutics, and Pfizer, and grant support from Actelion. H.M. has received lecturer fees from GlaxoSmithKline, Actelion Pharmaceuticals Japan, and Nippon Shinyaku. N.W.M. has received a research grant from Novartis. A.J.P. received personal fees from BMS during the conduct of the study and has received honoraria for advisory boards from Actelion, Bayer, GlaxoSmithKline, and United Therapeutics. V.F.T. has received research funds and consulting fees from Actelion, Bayer, Gilead, Lung LLC, United Therapeutics, and research funds only from Novartis. F.T. has received personal fees from Actelion, Gilead, Pfizer, and United Therapeutics, and grant support from Actelion, Gilead, Ikaria, Medtronic, Novartis, Pfizer, and United Therapeutics. C.D.V. has received fees for serving as a speaker, consultant, and an advisory board member from Actelion, Dompè, GlaxoSmithKline, Italfarmaco, Lilly, and Pfizer. W.Y., J.M.F., and D.A.Q. are employees of Novartis and all hold shares with Novartis. D.L. was a Novartis employee at the time the study was conducted. H.A.G. has received grants from Actelion, Bayer, Ergonex, and Pfizer during the conduct of the study; has received personal fees (outside of the submitted work) for board membership from Actelion, Bayer, Ergonex, GlaxoSmithKline, Novartis, and Pfizer, consultancy fees from Actelion, Bayer, Ergonex, Gilead, GlaxoSmithKline, Merck, Novartis, and Pfizer, payment for lectures (including speakers’ bureaus) from Actelion, Bayer, Ergonex, Gilead, GlaxoSmithKline, Novartis, and Pfizer, and travel/accommodation/meeting expenses from Actelion, Bayer, Ergonex, GlaxoSmithKline, Merck, Novartis, and Pfizer. H-J.C., M.P. and G.S. do not have a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.

Publisher Copyright:
© 2015 International Society for Heart and Lung Transplantation.

All Science Journal Classification (ASJC) codes

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine
  • Transplantation

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