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 journalArticle

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 (US)
Pages (from-to)1366-1375
Number of pages10
JournalJournal of Heart and Lung Transplantation
Volume34
Issue number11
DOIs
StatePublished - Nov 1 2015

Fingerprint

Pulmonary Hypertension
Safety
Hemodynamics
Off-Label Use
Subdural Hematoma
Protein Kinase Inhibitors
Imatinib Mesylate
Pharmaceutical Preparations
Therapeutics
Placebos
Exercise

Keywords

  • efficacy
  • imatinib
  • long-term
  • pulmonary arterial hypertension
  • safety

ASJC Scopus subject areas

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

Cite this

Frost, A. E., Barst, R. J., Hoeper, M. M., Chang, H. J., Frantz, R. P., Fukumoto, Y., ... Ghofrani, H. A. (2015). Long-term safety and efficacy of imatinib in pulmonary arterial hypertension. Journal of Heart and Lung Transplantation, 34(11), 1366-1375. https://doi.org/10.1016/j.healun.2015.05.025

Long-term safety and efficacy of imatinib in pulmonary arterial hypertension. / Frost, Adaani E.; Barst, Robyn J.; Hoeper, Marius M.; Chang, Hyuk Jae; Frantz, Robert P.; Fukumoto, Yoshihiro; Galié, Nazzareno; Hassoun, Paul M; Klose, Hans; Matsubara, Hiromi; Morrell, Nicholas W.; Peacock, Andrew J.; Pfeifer, Michael; Simonneau, Gérald; Tapson, Victor F.; Torres, Fernando; Dario Vizza, Carmine; Lawrence, David; Yang, Wei; Felser, James M.; Quinn, Deborah A.; Ghofrani, Hossein Ardeschir.

In: Journal of Heart and Lung Transplantation, Vol. 34, No. 11, 01.11.2015, p. 1366-1375.

Research output: Contribution to journalArticle

Frost, AE, Barst, RJ, Hoeper, MM, Chang, HJ, Frantz, RP, Fukumoto, Y, Galié, N, Hassoun, PM, Klose, H, Matsubara, H, Morrell, NW, Peacock, AJ, Pfeifer, M, Simonneau, G, Tapson, VF, Torres, F, Dario Vizza, C, Lawrence, D, Yang, W, Felser, JM, Quinn, DA & Ghofrani, HA 2015, 'Long-term safety and efficacy of imatinib in pulmonary arterial hypertension', Journal of Heart and Lung Transplantation, vol. 34, no. 11, pp. 1366-1375. https://doi.org/10.1016/j.healun.2015.05.025
Frost, Adaani E. ; Barst, Robyn J. ; Hoeper, Marius M. ; Chang, Hyuk Jae ; Frantz, Robert P. ; Fukumoto, Yoshihiro ; Galié, Nazzareno ; Hassoun, Paul M ; Klose, Hans ; Matsubara, Hiromi ; Morrell, Nicholas W. ; Peacock, Andrew J. ; Pfeifer, Michael ; Simonneau, Gérald ; Tapson, Victor F. ; Torres, Fernando ; Dario Vizza, Carmine ; Lawrence, David ; Yang, Wei ; Felser, James M. ; Quinn, Deborah A. ; Ghofrani, Hossein Ardeschir. / Long-term safety and efficacy of imatinib in pulmonary arterial hypertension. In: Journal of Heart and Lung Transplantation. 2015 ; Vol. 34, No. 11. pp. 1366-1375.
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T1 - Long-term safety and efficacy of imatinib in pulmonary arterial hypertension

AU - Frost, Adaani E.

AU - Barst, Robyn J.

AU - Hoeper, Marius M.

AU - Chang, Hyuk Jae

AU - Frantz, Robert P.

AU - Fukumoto, Yoshihiro

AU - Galié, Nazzareno

AU - Hassoun, Paul M

AU - Klose, Hans

AU - Matsubara, Hiromi

AU - Morrell, Nicholas W.

AU - Peacock, Andrew J.

AU - Pfeifer, Michael

AU - Simonneau, Gérald

AU - Tapson, Victor F.

AU - Torres, Fernando

AU - Dario Vizza, Carmine

AU - Lawrence, David

AU - Yang, Wei

AU - Felser, James M.

AU - Quinn, Deborah A.

AU - Ghofrani, Hossein Ardeschir

PY - 2015/11/1

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N2 - 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.

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