Objectives

The STEP-IPF study sought to evaluate if treatment with sildenafil would improve walk distance, dyspnea, and quality of life in patients with advanced idiopathic pulmonary fibrosis (IPF).

Background

IPF is a chronic, progressive lung disease of unknown cause that is characterized by the histopathologic pattern of usual interstitial pneumonia. Progression to end-stage respiratory insufficiency and death within 5 years after the onset of symptoms is characteristic. To date, no pharmacologic therapies have definitively been shown to improve survival or quality of life in patients with this disease.

Patients with severe IPF have abnormalities of the pulmonary vasculature leading to decreased levels of resting and exercise-induced production of nitric oxide. Since nitric oxide is a potent pulmonary vasodilator, reduced levels are associated with pulmonary vasoconstriction and impaired gas exchange.

Sildenafil (Revatio, Pfizer) is a phosphodiesterase-5 inhibitor that stabilizes the second messenger of nitric oxide, cyclic guanosine monophosphate, which leads to pulmonary vasodilatation. Such vasodilatation could improve ventilation–perfusion matching and thus gas exchange in patients with IPF.

Participants

A total of 180 patients were enrolled in the study: 89 in the sildenafil group and 91 in the placebo group. The mean age of the patients was 69 years, 17% were women, and 91% were white. Eligibility criteria included a diagnosis of idiopathic pulmonary fibrosis, as defined by consensus criteria, in an advanced stage, which was defined as a diffusing capacity for carbon monoxide of less than 35% of the predicted value.

Design

STEP-IPF was a double-blind, randomized, placebo-controlled trial of oral sildenafil (20 mg three times daily). Patients meeting eligibility criteria were randomly assigned in a 1:1 ratio to receive sildenafil or matched placebo with the use of a permuted-block design, with stratification according to clinical center. The primary outcome was the presence or absence of an improvement of at least 20% in the 6-minute walk distance at 12 weeks, as compared with baseline. Key secondary outcomes included changes in the 6-minute walk distance, degree of dyspnea, and quality of life.

Screening procedures included the taking of a detailed history, a physical examination, spirometry, echocardiography, CT imaging, and measurements of lung volume on plethysmography, carbon monoxide diffusion capacity, and arterial blood gases. Eligible patients returned for an enrollment visit within 6 weeks after screening. All patients received an initial dose of a study drug at this visit and were monitored for 60 minutes for adverse effects. Follow-up visits were scheduled at 1, 6, and 12 weeks. After completion of the 12-week visit, all patients were started on treatment with open-label sildenafil. Visits were scheduled at 13, 18, and 24 weeks; at 28 weeks, serious adverse events and vital status were documented. Testing of the 6-minute walk distance was performed with the use of a standardized protocol at the time of screening and enrollment and at study visits at 6, 12, 18, and 24 weeks. Patients with pulse oxygen saturation below 88% received supplemental oxygen.

Conclusions

This study did not show a benefit for sildenafil for the primary outcome. The presence of some positive secondary outcomes creates clinical equipoise for further research. There were small but significant differences in arterial oxygenation, carbon monoxide diffusion capacity, degree of dyspnea, and quality of life favoring the sildenafil group.
(N Engl J Med. Aug 12, 2010; 363(7): 620–628.)

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