Imatinib Mesylate as Add-on Therapy for Pulmonary Arterial Hypertension

Abstract

P ulmonary arterial hypertension (PAH) is characterized by progressive obliteration of the pulmonary vascular bed, eventually leading to right heart failure and death if not treated effectively.1,2 Although some forms of PAH are heritable or associated with other conditions such as scleroderma, many cases are idiopathic in origin. Editorial see p 1098 Clinical Perspective on p 1138The median survival of patients with idiopathic or heritable PAH was >3 years before the availability of targeted PAH drugs.4 Current treatment options consist of prostacyclin and Background-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 openlabel 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, betweengroup 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. Conclusions-Imatinib improved exercise capacity and hemodynamics in patients with advanced PAH, but serious adverse events and study drug discontinuations were common.

The challenge of managing pulmonary arterial hypertension in adults with congenital heart disease

“…Imatinib (a tyrosine kinase inhibitor used to treat chronic myeloid leukemia) has now been studied in experimental models of PAH with promising initial results [69]. A recent randomized controlled study of imatinib as an add-on therapy in iPAH patients showed some encouraging results but serious adverse effects and discontinuation were common [70]. In addition, experience with imatinib in the setting of CHD-PAH is limited.…”

Clinical features of pulmonary arterial hypertension in patients receiving dasatinib

“…While cases of PAH have been reported during dasatinib treatment in a small number of patients, imatinib and nilotinib have been clinically investigated as treatments for PAH [20,21]. Imatinib provided hemodynamic and clinical improvements for some patients with severe or refractory PAH but resulted in severe side effects, including edema, anemia, and unexplained subdural hematoma [20,22].…”

Imatinib is Partially Effective for the Treatment of Pulmonary Capillary Hemangiomatosis

“…In the International Multicentre PREvalence Study on Sepsis (IMPRESS) study, treatment with imatinib improved exercise capacity and hemodynamics in patients with advanced PAH already treated with two or more pulmonary vasodilators; however, serious adverse events and imatinib discontinuation were common (14). In particular, subdural hematomas developed in 4.2% of the patients treated with imatinib, all of which occurred in patients receiving concomitant anticoagulation.…”