The “wonder drugs” Gleevec (imatinib) and Viagra (sildenafil) make strange bedfellows, but they both appear to improve pulmonary function in patients with pulmonary arterial hypertension (PAH), report researchers here.
They described the Gleevec case in a letter published in the Sept. 29 New England Journal of Medicine.
In a last-ditch attempt to save a 61 year-old man with severe, familial idiopathic PAH that was rapidly progressing despite other therapies, Friedrich Grimminger, M.D., Ph.D., and colleagues at the University Hospital Giessen here gave him oral Gleevec (imatinib) 200 mg daily on a compassionate basis.
Gleevec, which is approved for chronic myeloid leukemia, has potent antiproliferative properties that the researchers hypothesized might be able to reverse the lung vascular remodeling - uncontrolled proliferation of the vascular wall - that is the underlying pathogenic mechanism of PAH.
The use of Gleevec in this situation was motivated in part by experimental studies in animals performed by the authors. “We have 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” they said. These studies are in press in the Journal of Clinical Investigation.
In contrast, Viagra (sildenafil), which has also been shown in randomized placebo-controlled trials to improve function in patients with PAH, works by prolonged vasodilation, allowing better oxygenation.
In addition to taking Gleevec, the patient described in the case report continued on his other medications, including Tracleer (bosentan), Ventavis (iloprost), Viagra, oral anticoagulants and diuretics.
After three months of Gleevec, the patient’s condition “improved impressively,” as indicated by improved exercise capacity, hemodynamics, mean pulmonary artery pressure, cardiac index, and New York Heart Association (NYHA) functional class.
Although this was only a single case report, Dr. Grimminger and colleagues had previously demonstrated in a randomized placebo controlled trial (SUPER-1) that patients who received 80 mg of Viagra three times daily increased six-minute walk results by 50 meters after 12 weeks. Patients on 40 mg Viagra t.i.d. increased their six-minute distance by 46 meters, and those at a 20 mg three times daily dose increased by 45 meters. The difference were significant at P < .001.
Among all patients on Viagra in that study, 35% had a functional class improvement, compared with 7% of patients in the placebo group, and there was a non-significant trend toward reduction in mean pulmonary arterial pressure.
The results of the SUPER-1 study were first reported at CHEST 2004, the 70th annual meeting of the American College of Chest Physicians.
In the current case report letter, Dr. Grimminger and colleagues report that five years prior to starting their patient on Gleevec, he presented at their PAH referral center with signs of right-sided heart failure. During the previous year, his condition had progressively worsened, despite advanced combination therapy with oral bosentan (125 mg b.i.d), inhaled iloprost (nine inhalations/day), and Viagra 50 mg t.i.d., plus anticoagulants and diuretics.
The patient’s six-minute walking distance had progressively declined during the previous nine months, from 323 m to 260 m, and pulmonary vascular resistance increased from 1056 dyn/sec/cm-5 (mean pulmonary-artery pressure 59 mm Hg and a cardiac index of 2.08 liters/min/m2) to 1,538 dyn/sec/cm-5 (mean pulmonary-artery pressure 58 mm Hg and a cardiac index of 1.36 liters/min/m2).
At the time of the case report, the patient was in NYHA functional class IV. Other causes of his deterioration, including occult neoplasms, were ruled out, and the patient was then offered Gleevec on a compassionate basis.
“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; 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),” Dr. Grimminger and colleagues wrote.
After six months, his walking distance improved to 395 m, his NYHA status remained at class II; and he had improved right ventricular performance as assessed by echocardiography. There were no apparent adverse responses to Viagra, the investigators reported.
“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,” they write.
The authors are currently planning a controlled clinical trial with Gleevec in patients with PAH.
Revision date: June 22, 2011
Last revised: by Janet A. Staessen, MD, PhD