Correspondence
Imatinib for the Treatment of Pulmonary Arterial Hypertension
N Engl J Med 2005; 353:1412-1413September 29, 2005
- Article
To the Editor:
We report on a 61-year-old man with a rapidly progressing form of familial idiopathic pulmonary arterial hypertension. Five years earlier, the patient had presented with signs of right-sided heart failure in our pulmonary-hypertension referral center. During the previous year, his condition had progressively deteriorated, despite advanced combination therapy with oral bosentan (125 mg twice daily),1 inhaled iloprost (nine inhalations per day),2 and oral sildenafil (50 mg three times a day).3,4 The patient's six-minute walking distance had progressively declined during the previous nine months, from 323 m to 260 m, and the pulmonary vascular resistance increased from 1056 dyn · sec · cm–5 (with a mean pulmonary-artery pressure of 59 mm Hg and a cardiac index of 2.08 liters per minute per square meter) to 1538 dyn · sec · cm–5 (with a mean pulmonary-artery pressure of 58 mm Hg and a cardiac index of 1.36 liters per minute per square meter). At this point, the patient was in New York Heart Association (NYHA) functional class IV (Figure 1Figure 1
Time Course of Clinical Status, Exercise Capacity, and Hemodynamics before and after Initiation of Imatinib Treatment.). During preparations for lung transplantation, the patient refused intravenous prostanoid treatment for bridging to this procedure. Other causes of deterioration (including occult neoplasms) were ruled out by diagnostic measures (e.g., whole-body computed tomography, bone marrow aspiration, and assessment of serum tumor markers).In this desperate situation, we decided to initiate compassionate treatment with daily administration of 200 mg of oral imatinib mesylate (Gleevec), a selective antagonist of the platelet-derived growth factor receptor, which is approved for the treatment of chronic myeloid leukemia. The patient continued to receive his previous medications (including bosentan, iloprost, sildenafil, oral anticoagulants, and diuretics) and was monitored closely. After three months of imatinib treatment, the patient's condition had improved impressively, as indicated by improved exercise capacity (six-minute walking distance, 383 m), improved hemodynamics (pulmonary vascular resistance, 815 dyn · sec · cm–5; mean pulmonary-artery pressure, 56 mm Hg; and cardiac index of 2.33 liters per minute per square meter), and an improved functional class (NYHA class II). Noninvasive follow-up after six months of treatment revealed sustained clinical efficacy (six-minute walking distance, 395 m; NYHA class II; and improved right ventricular performance as assessed by echocardiography). No side effects of the treatment were apparent.
This report describes our first experience with the use of a specific antagonist to the platelet-derived growth factor receptor for the treatment of pulmonary arterial hypertension. The rationale for such treatment derives from the potent antiproliferative potency of this class of drugs. We recently described the successful use of imatinib in two well-established experimental models of progressive pulmonary arterial hypertension; this treatment resulted in virtually complete reversal of lung vascular remodeling, pulmonary hypertension, and right-sided heart hypertrophy.5
We recognize the limitations of a single case report, but we believe that antiproliferative treatment with an antagonist to the platelet-derived growth factor receptor may be a promising new targeted therapy for pulmonary hypertension. Reversal of lung vascular remodeling rather than prolonged vasodilation is the concept underlying the use of imatinib in pulmonary hypertension. (A controlled clinical trial addressing this issue is currently in preparation.)
5 ReferencesHossein A. Ghofrani, M.D.
Werner Seeger, M.D.
Friedrich Grimminger, M.D., Ph.D.
University Hospital Giessen, 35392 Giessen, Germany
ardeschir.ghofrani@inner. med. uni-giessen. de 1
Rubin LJ ,Badesch DB ,Barst RJ , et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002;346:896-903[Erratum, N Engl J Med 2002;346:1258.]
Full Text | Web of Science | Medline2
Olschewski H ,Simonneau G ,Galie N , et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 2002;347:322-329
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Ghofrani HA ,Wiedemann R ,Rose F , et al. Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial. Lancet 2002;360:895-900
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Ghofrani HA ,Wiedemann R ,Rose F , et al. Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension. Ann Intern Med 2002;136:515-522
Web of Science | Medline5
Schermuly RT, Dony E, Ghofrani HA, et al. Reversal of experimental pulmonary hypertension by platelet derived growth factor inhibition. J Clin Invest (in press).
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