N Engl J Med 2014; 370:2142-2143May 29, 2014DOI: 10.1056/NEJMe1403448
I suspect that many of my patients have picked up on more than a hint of frustration in my voice when I tell them that the cause of their shortness of breath is idiopathic pulmonary fibrosis. This frustration stems from the fact that beyond providing information about prognosis or referral for lung transplantation or palliation, there has been little to offer in the way of treatment. Idiopathic pulmonary fibrosis is a chronic, progressive disorder of lung scarring that predominantly affects older patients and has a death rate worse than that of many cancers (3-year survival, 50%).1 However, in contrast to most cancers, there has been limited, and sometimes conflicting,2 evidence that any drug could alter the course of this disease.
The game has now changed. With the publication of the INPULSIS-1 and INPULSIS-2 trials3 and the ASCEND (Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis) trial4 in the Journal, we may soon have choices in the medical management of idiopathic pulmonary fibrosis.
The INPULSIS trials were two randomized, double-blind, placebo-controlled, phase 3 trials that were conducted simultaneously to evaluate the role of nintedanib, as compared with placebo, in patients with idiopathic pulmonary fibrosis. Nintedanib (formerly called BIBF-1120)5 is thought to have antifibrotic properties that are mediated through the inhibition of a variety of tyrosine kinase receptors (including platelet-derived growth factor, fibroblast growth factor, and vascular endothelial growth factor) that have been implicated in the pathogenesis of idiopathic pulmonary fibrosis.6Patients receiving nintedanib had significant reductions in the rate of decline in forced vital capacity (FVC) at 1 year, the primary end point of the two studies. The magnitude of the effect of nintedanib on preventing acute exacerbations varied between the two replicate trials, and there was no evidence of improvement in scores for respiratory symptoms. Although these trials were not powered to detect statistically significant differences in mortality, it is comforting that nintedanib resulted in a trend toward a reduced rate of death that mirrored the reduced rate of decline in lung function.
The ASCEND trial was the fourth in a series of randomized, double-blind, placebo-controlled, phase 3 trials that had been conducted in Japan and at multinational sites in which pirfenidone was compared with placebo in patients with idiopathic pulmonary fibrosis. The results of the first three trials were mixed,2 leading to approval of pirfenidone for idiopathic pulmonary fibrosis by many governing bodies worldwide but not by the Food and Drug Administration. Although the precise actions of pirfenidone are not clear, its primary antifibrotic mechanism is felt to be, at least in part, mediated through its inhibition of the expression of transforming growth factor β1.7 In the ASCEND trial, pirfenidone met the primary end point by showing significant reductions in the 1-year rate of decline in FVC. The use of pirfenidone also resulted in a reduced decline in distances on the 6-minute walk test, but no effect on respiratory symptoms was noted. In a prespecified mortality analysis combining the 1-year results from both the ASCEND trial and the previously reported Clinical Studies Assessing Pirfenidone in Idiopathic Pulmonary Fibrosis: Research of Efficacy and Safety Outcomes (CAPACITY 004 and 006 trials),2 there was evidence that pirfenidone may also reduce mortality in patients with idiopathic pulmonary fibrosis.
Although the two INPULSIS trials and the ASCEND trial showed that treatment resulted in relative reductions in the rate of decline in FVC, the pirfenidone group in the ASCEND study had a greater annual decline in the mean FVC (−235 ml) than did the placebo groups of both of the INPULSIS studies (−205 ml). The differences in the overall rate of decline in FVC between the INPULSIS and ASCEND studies may be explained by differences in recruitment criteria. The INPULSIS trials did not exclude patients with normal values for FVC, which is reflected in the fact that the mean baseline FVC was higher in the INPULSIS trials (approximately 80% of the predicted value) than in the ASCEND trial (approximately 68% of the predicted value). More simply, the average patient with idiopathic pulmonary fibrosis in the INPULSIS trials had less severe disease than the average patient in the ASCEND trial.
Although these results are a major breakthrough for patients with idiopathic pulmonary fibrosis, we should be cautious in extrapolating these findings to patients who fall outside the recruitment criteria for these trials. The studies provide little insight into the use of these drugs in patients with more severe disease (FVC <50% of the predicted value) or with an acute disease exacerbation. Are these effects durable beyond 1 year? How do these drugs work when used together or for pulmonary fibrosis in patients with other interstitial lung diseases? These are questions worth answering.
In addition, a small but growing body of literature suggests that we may be able to detect persons at increased risk for idiopathic pulmonary fibrosis at a stage before advanced fibrotic changes can be seen on imaging studies.8 Now that we have evidence that medical therapy can treat early stages of this disease, it is possible that effective medical therapy could also be used to prevent, rather than slow the progression of, end-stage fibrotic lung disease.
The publication of the results of Prednisone, Azathioprine, and N-acetylcysteine: A Study That Evaluates Response in Idiopathic Pulmonary Fibrosis (PANTHER-IPF) completes a separate trilogy of studies.9-11 However, unlike the results for the drugs evaluated in the INPULSIS and ASCEND trials, the initial promise of this three-drug regimen9 has now faded. As reported in the Journal, it appears that acetylcysteine does not slow the rate of decline in FVC,11 although it may reduce the toxicity of prednisone and azathioprine10 in patients with idiopathic pulmonary fibrosis. From these findings, it is reasonable to shift our understanding of the pathogenesis of this disease. It is now clear that idiopathic pulmonary fibrosis is a disease perpetuated by aberrant wound healing, rather than primarily by chronic inflammation.12 With new understanding comes new hope. As in the 1977 episode of the Star Wars series, the force is finally with us.13 May we learn to use it wisely.
Disclosure forms provided by the author are available with the full text of this article at NEJM.org.
This article was published on May 18, 2014, at NEJM.org.
From the Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston.
ver historia personal en: www.cerasale.com.ar [dado de baja por la Cancillería Argentina por temas políticos, propio de la censura que rige en nuestro medio]//
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