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

Study Questions:

Imatinib, the anti-proliferative agent that targets tyrosine kinase inhibitors (TKI), is a platelet-derived growth factor inhibitor. Is imatinib efficacious in treating patients with pulmonary arterial hypertension (PAH)?

Methods:

IMPRES (Imatinib in Pulmonary Arterial Hypertension, a Randomized, Efficacy Study), is a randomized, double-blind, placebo-controlled 24-week trial that evaluated imatinib in patients with pulmonary vascular resistance (PVR) ≥800 dynes • sec • cm–5 symptomatic on ≥2 PAH therapies. The primary outcome was change in 6-minute walk distance (6MWD). Secondary outcomes included changes in hemodynamics, functional class, N-terminal B-type natriuretic peptide (NT-proBNP), and time to clinical worsening (TTCW). After completion of the core study, patients could enter an open-label long-term extension study.

Results:

Of 202 patients enrolled, 41% patients received three PAH therapies, with the remainder on two therapies. Median age was 48 years, 81% were female, >90% were World Health Organization functional class II or III, and 75% had idiopathic or heritable PAH. After 24 weeks, the mean placebo-corrected treatment-effect on 6MWD was 32 m (95% confidence interval, 12-52; p = 0.002), an effect maintained in the extension study in patients remaining on imatinib. PVR decreased by 379 dynes • sec • cm–5 (p < 0.001). Functional class, TTCW, and mortality did not differ between treatments. Serious adverse events and discontinuations were more frequent with imatinib than placebo (44% vs. 30%, 33% vs. 18%, respectively). Subdural hematoma occurred in eight patients (two in the core study, six in the extension) receiving imatinib and anticoagulation.

Conclusions:

The investigators concluded that 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.

Perspective:

Despite the major advances in improving quality of life and survival with PAH-specific therapies, mortality remains high, particularly in patients with connective tissue disease. Among the newer agents with promise includes the family of TKIs, each of which has unique characteristics that need to be assessed in well-designed trials.

Clinical Topics: Anticoagulation Management, Heart Failure and Cardiomyopathies, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Statins, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Pulmonary Hypertension

Keywords: Hematoma, Subdural, Connective Tissue Diseases, Pyrimidines, Piperazines, Hemodynamics, Platelet-Derived Growth Factor, Protein-Tyrosine Kinases, Heart Failure, Hypertension, Pulmonary, Peptide Fragments, Vascular Resistance, Benzamides, Natriuretic Peptide, Brain


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