Ambrisentan found ineffective against idiopathic pulmonary fibrosis

Image: PD/ Fibrotic lung

1. Ambrisentan is ineffective in delaying disease progression in idiopathic pulmonary fibrosis (IPF).

2. Compared to placebo, Ambrisentan is associated with increased risk of disease progression and respiratory hospitalization.

Evidence rating level: 1 (Excellent)

Study rundown: Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive form of fibrotic interstitial lung disease with unknown etiology. IPF is a diagnosis of exclusion, and has a median survival of 3 years after diagnosis. There are no approved drug therapies in the US that have been repeatedly proven efficacious. Therefore, there is a great deal of interest in potential therapies for IPF.

This trial is one of the few large, multicenter, placebo-controlled RCTs investigating new drug therapies for IPF. This study compared the effects of Ambrisentan, an endothelin receptor-A antagonist, against placebo on disease progression. However, the drug was found to not only not slow disease progression, but it was actually associated with accelerated decline in pulmonary function tests, increased respiratory hospitalizations, and higher mortality. The study authors concluded that Ambrisentan should not be used in the treatment of IPF. Nevertheless, it is unclear whether these results exclude further investigation into other endothelin receptor antagonists.

This study is particularly compelling, as it represents a large-scale, rigorously controlled investigation into novel drug treatments for IPF. However, it should be noted that the authors did not include a no-treatment arm, and that the study was terminated early once analysis made it clear that therapy targets would not be reached by the trial’s scheduled conclusion.

Click to read the study in Ann Intern Med

Relevant Reading: BUILD-1: a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis

In-Depth [randomized controlled trial]: 494 patients from 136 clinical sites throughout the Americas, Europe, Asia, New Zealand and Australia were assigned to the drug or placebo treatment arm. All patients were between 40-80 years of age, were diagnosed with IPF for at least 3 months, and with less than 5% honeycombing on HRCT scans. Assignment was randomized, but stratified by whether patients had undergone prior surgical lung biopsy and based on the presence of pulmonary hypertension. Ambrisentan was administered at 10mg/d, and mean drug exposure was 34.7 weeks.

The primary end point was time to disease progression, defined as: death, respiratory hospitalization, or categorical decrease in lung function (greater than 10% decrease in FVC plus greater than 5% decrease in D_LCO, or greater than 5% decrease in FVC plus greater than 15% decrease in D_LCO).

Ambrisentan was associated with higher risk of disease progression, respiratory hospitalization, and mortality. 27.4% and 17.2% of patients in the drug and placebo arms had disease progression (P = 0.010). 13.4% and 5.5% (P = 0.007), respectively, required respiratory hospitalizations. Finally, there was 7.9% and 2.7% mortality in the two arms (P = 0.100).

It should be noted that the study was terminated early, at 75% of expected enrollment, after early analysis found low probability of meeting the primary end point by scheduled end of the study.

By Monica Parks and Andrew Bishara

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