title: 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.affiliation: Baylor College of Medicine and The Lung Center at Houston Methodist Hospital, Houston, Texas. Electronic address: afrost@houstonmethodist.org.
authors.forename: Adaani E
authors.initials: AE
authors.lastname: Frost
authors.affiliation: College of Physicians and Surgeons, Columbia University, New York, New York.
authors.forename: Robyn J
authors.initials: RJ
authors.lastname: Barst
authors.affiliation: Department of Respiratory Medicine, Medizinische Hochschule, and German Centre of Lung Research (DZL), Hannover, Germany.
authors.forename: Marius M
authors.initials: MM
authors.lastname: Hoeper
authors.affiliation: Cardiology Division, Severance Cardiovascular Hospital, Yonsei University Health System, Seoul, South Korea.
authors.forename: Hyuk-Jae
authors.initials: HJ
authors.lastname: Chang
authors.affiliation: Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Frantz
authors.affiliation: Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Fukumoto
authors.affiliation: Department of Specialised, Experimental, and Diagnostic Medicine, Università di Bologna, Bologna, Italy.
authors.forename: Nazzareno
authors.initials: N
authors.lastname: Galié
authors.affiliation: John Hopkins Bayview Medical Center, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Hassoun
authors.affiliation: Department of Pulmonology, University Medical Centre Hamburg, Hamburg, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Klose
authors.affiliation: Division of Cardiology, National Hospital Organization Okayama Medical Center, Okayama, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Matsubara
authors.affiliation: Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrookes and Papworth Hospitals, Cambridge, United Kingdom.
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Morrell
authors.affiliation: Scottish Pulmonary Vascular Unit, Golden Jubilee National Hospital, Glasgow, United Kingdom.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Peacock
authors.affiliation: Clinic for Internal Medicine, University of Regensburg, Regensburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Pfeifer
authors.affiliation: Department of Pneumology and ICU, Hopital Bicetre, Paris, France.
authors.forename: Gérald
authors.initials: G
authors.lastname: Simonneau
authors.affiliation: Duke Pulmonary Vascular Disease Center, Duke University Medical Center, Durham, North Carolina.
authors.forename: Victor F
authors.initials: VF
authors.lastname: Tapson
authors.affiliation: University of Texas Southwestern Advanced Lung Disease & Lung Transplant Clinic, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Fernando
authors.initials: F
authors.lastname: Torres
authors.affiliation: Department of Cardiovascular and Respiratory Disease, La Sapienza University, Rome, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Dario Vizza
authors.affiliation: Department of Global Clinical Development, Novartis Pharmaceuticals, East Hanover, NJ.
authors.forename: David
authors.initials: D
authors.lastname: Lawrence
authors.affiliation: Department of Global Clinical Development, Novartis Pharmaceuticals, East Hanover, NJ.
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Global Clinical Development, Novartis Pharmaceuticals, East Hanover, NJ.
authors.forename: James M
authors.initials: JM
authors.lastname: Felser
authors.affiliation: Department of Global Clinical Development, Novartis Pharmaceuticals, East Hanover, NJ.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Quinn
authors.affiliation: University of Giessen and Marburg Lung Center, University Hospital Giessen and Marburg GmbH, Giessen, Germany.
authors.forename: Hossein-Ardeschir
authors.initials: HA
authors.lastname: Ghofrani
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D017079:Exercise Tolerance / Q000502:physiology; D005260:Female; D005500:Follow-Up Studies; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000503:physiopathology; D000068877:Imatinib Mesylate / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D047428:Protein Kinase Inhibitors; D000068877:Imatinib Mesylate
keywords: efficacy; imatinib; long-term; pulmonary arterial hypertension; safety