Imatinib Mesylate as Add-On Therapy for Pulmonary Arterial Hypertension: Results of the Randomized IMPRES Study.

1Medizinische Hochschule, Hannover, Germany.
Circulation (Impact Factor: 14.43). 02/2013; 127(10). DOI: 10.1161/CIRCULATIONAHA.112.000765
Source: PubMed


By its inhibitory effect on platelet-derived growth factor signaling, imatinib could be efficacious in treating patients with pulmonary arterial hypertension (PAH).

Methods and results:
Imatinib in Pulmonary Arterial Hypertension, a Randomized, Efficacy Study (IMPRES), a randomized, double-blind, placebo-controlled 24-week trial, evaluated imatinib in patients with pulmonary vascular resistance ≥ 800 dyne·s·cm(-5) symptomatic on ≥ 2 PAH therapies. The primary outcome was change in 6-minute walk distance. Secondary outcomes included changes in hemodynamics, functional class, serum levels of N-terminal brain natriuretic peptide, and time to clinical worsening. After completion of the core study, patients could enter an open-label long-term extension study. Of 202 patients enrolled, 41% patients received 3 PAH therapies, with the remainder on 2 therapies. After 24 weeks, the mean placebo-corrected treatment effect on 6-minute walk distance was 32 m (95% confidence interval, 12-52; P=0.002), an effect maintained in the extension study in patients remaining on imatinib. Pulmonary vascular resistance decreased by 379 dyne·s·cm(-5) (95% confidence interval, -502 to - 255; P<0.001, between-group difference). Functional class, time to clinical worsening, and mortality did not differ between treatments. Serious adverse events and discontinuations were more frequent with imatinib than placebo (44% versus 30% and 33% versus 18%, respectively). Subdural hematoma occurred in 8 patients (2 in the core study, 6 in the extension) receiving imatinib and anticoagulation.

Imatinib improved exercise capacity and hemodynamics in patients with advanced PAH, but serious adverse events and study drug discontinuations were common. Further studies are needed to investigate the long-term safety and efficacy of imatinib in patients with PAH.

Clinical trial registration:
URL: Unique identifier: NCT00902174 (core study); NCT01392495 (extension).

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    • "hemodynamics and exercise capacity, even in patients with 35 advanced PAH, but serious adverse events leading to the 36 discontinuation of the trial were common [7] [8]. This unsatisfactory 37 safety profile has demonstrated the necessity for further studies to 38 assess, inter alia, the risk-benefit profile or optimal dosage of 39 imatinib in PAH. "
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    ABSTRACT: Background Co-administration of statin with imatinib is thought to result in greater improvement in pulmonary arterial hypertension (PAH) than imatinib treatment alone, and hence may allow greater effectiveness of imatinib therapy at lower doses. Methods The effects of imanitib at dose of 20 and 50 mg/kg bw given together with rosuvastatin or simvastatin were investigated with respect to right ventricle pressure (RVP), arterial blood pressure and right ventricle hypertrophy (RVH) in experimental monocrotaline (MCT)-induced pulmonary hypertension. Fourteen days after MCT injection, male rats were treated orally for another 14 days with imatinib, statin or a combination of the two. Results Concurrent administration of statin (lipophilic simvastatin, hydrophilic rosuvastatin) and higher dose imatinib reversed the MCT-induced increase in RVP more than each drug alone and decreased RV hypertrophy (RV/LV + S ratio), significantly. The increased RVP and RV hypertrophy was found to be reversed when a lower dose of imatinib was co-administered with rosuvastatin or simvastatin. Conclusions Statins may intensify the beneficial effects of imatinib in PAH, which may be due to the additional influence of statin on the decrease of platelet-derived growth factor (PDGF)-induced effects. These properties allow the dose of imatinib used in PAH treatment to be reduced and thereby might improve its safety profile.
    Pharmacological reports: PR 08/2014; 67(1). DOI:10.1016/j.pharep.2014.07.011 · 1.93 Impact Factor
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    • "In that study, a post hoc subgroup analysis suggested that patients with greater hemodynamic impairment might respond better to imatinib than patients with less advanced disease. This preliminary study led to the development of IMPRES (IMatinib in Pulmonary arterial hypertension, a Randomized Efficacy Study), a randomized, double-blind, placebo-controlled 24-week trial [71]. This study evaluated imatinib in patients with pulmonary vascular resistance ≥800 dynes·sec·cm−5 symptomatic on ≥2 PAH therapies. "
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    ABSTRACT: This systematic review aims to provide an update on pharmacological and interventional strategies for the treatment of pulmonary arterial hypertension in adults. Currently US Food and Drug Administration approved drugs including prostanoids, endothelin-receptor antagonists, phosphodiesterase type-5 inhibitors, and soluble guanylate-cyclase stimulators. These agents have transformed the prognosis for pulmonary arterial hypertension patients from symptomatic improvements in exercise tolerance ten years ago to delayed disease progression today. On the other hand, percutaneous balloon atrioseptostomy by using radiofrequency perforation, cutting balloon dilatation, or insertion of butterfly stents and pulmonary artery catheter-based denervation, both associated with very low rate of major complications and death, should be considered in combination with specific drugs at an earlier stage rather than late in the progression of pulmonary arterial hypertension and before the occurrence of overt right-sided heart failure.
    BioMed Research International 06/2014; 2014(2):743868. DOI:10.1155/2014/743868 · 2.71 Impact Factor
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    • "However, induction of apoptosis by imatinb is controversial. Furthermore, two randomized controlled trials in PAH patients treated with imatinib have shown positive results on exercise capacity and hemodynamics, in association with increased incidence of subdural hematoma in the patients treated with both imatinib and oral anticoagulants [14]. "
    Journal of Cardiology Cases 05/2014; 9(5). DOI:10.1016/j.jccase.2014.02.004
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