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

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• 作者：Adaani E. Frost ; MD^a ; ^{afrost@houstonmethodist.org" class="auth_mail" title="E-mail the corresponding author} ; Robyn J. Barst ; MD^b ; ¹ ; Marius M. Hoeper ; MD^c ; Hyuk-Jae Chang ; MD^d ; Robert P. Frantz ; MD^e ; Yoshihiro Fukumoto ; MD^f ; Nazzareno Galié ; MD^g ; Paul M. Hassoun ; MD^h ; Hans Klose ; MDⁱ ; Hiromi Matsubara ; MD^j ; Nicholas W. Morrell ; MD^k ; Andrew J. Peacock ; MD¹ ; Michael Pfeifer ; MD^m ; Gé ; rald Simonneau ; MDⁿ ; Victor F. Tapson ; MD^o ; Fernando Torres ; MD^p ; Carmine Dario Vizza ; MD^q ; David Lawrence ; PhD^r ; Wei Yang ; MD^r ; James M. Felser ; MD^r ; Deborah A. Quinn ; MD^r ; Hossein-Ardeschir Ghofrani ; MD^s
• 关键词：pulmonary arterial hypertension ; imatinib ; safety ; long-term ; efficacy
• 刊名：Journal of Heart and Lung Transplantation
• 出版年：2015
• 出版时间：November 2015
• 年：2015
• 卷：34
• 期：11
• 页码：1366-1375
• 全文大小：1001 K

文摘

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.