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Medwave2017;17(Suppl2):e6918 doi: 10.5867/medwave.2017.6918

�Es efectivo el nintedanib para la fibrosis pulmonar idiop�tica?

Is nintedanib effective for idiopathic pulmonary fibrosis?

Alejandro Jeldres, Gonzalo Labarca

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Abstract

Idiopathic pulmonary fibrosis has poor prognosis and effective therapies are scarce. In the search for treatments that can modify the course of the disease, nintedanib (BIBF 1120), a tyrosine kinase inhibitor, has emerged as an alternative. However, its role is still unclear. To answer this question, we searched in Epistemonikos database, which is maintained by screening multiple sources of information. We identified seven systematic reviews including seven randomized trials overall. We extracted data, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. We concluded nintedanib probably decreases the risk of acute exacerbations, and might reduce mortality in idiopathic pulmonary fibrosis. On the other hand, it is probably not associated with serious adverse events.

Problem

Idiopathic pulmonary fibrosis is a rare condition of unknown etiology [1]. The prognosis of this disease is poor and until the last decade, there were no interventions with a proven benefit on survival [2]. After diagnosis, survival decreases rapidly and factors such as acute exacerbations, time to disease progression and deterioration in respiratory functions are associated with a poorer prognosis [3],[4].

Nintedanib (BIBF 1120) is an inhibitor of multiple tyrosine kinase related signals through its binding to growth factor receptors. Among the most important are vascular endothelial growth factor receptor, fibroblast growth factor receptor and platelet-derived growth factor receptor [5]. An initial trial reported efficacy of this drug [6], which was later replicated, so the FDA approved this drug for idiopathic pulmonary fibrosis in 2015 [7],[8].

Methods

We used Epistemonikos database, which is maintained by screening multiple databases, to identify systematic reviews and their included primary studies. With this information, we generated a structured summary using a pre-established format, which includes key messages, a summary of the body of evidence (presented as an evidence matrix in Epistemonikos), meta-analysis of the total of studies, a summary of findings table following the GRADE approach and a table of other considerations for decision-making.

Key messages

Nintedanib probably decreases the risk of acute exacerbations, and might reduce mortality in idiopathic pulmonary fibrosis.
Nintedanib is probably not associated with serious adverse events.

About the body of evidence for this question

What is the evidence. See evidence matrix in Epistemonikos later	We found seven systematic reviews, reported in eight references [9],[10],[11],[12],[13],[14],[15],[16] including seven randomized controlled trials reported in 10 references [6],[7],[17],[18],[19],[20],[21],[22],[23],[24].
What types of patients were included	Three trials included patients diagnosed with idiopathic pulmonary fibrosis according to ATS / ERS 2011 criteria [6],[18],[19]. All of the trials included patients over 40 years of age. One trial included patients with PaO2 ≥55 mmHg at rest and room air, patients diagnosed with idiopathic pulmonary fibrosis within 5 years prior to enrollment and patients with high resolution computed tomography performed less than 1 year prior to enrollment [6]. Four trials included patients with functional vital capacity greater than or equal to 50% [6],[18],[19],[20]. Three trials included patients with a test of carbon monoxide diffusion capacity between 30% and 79% [6],[18],[19].
What types of interventions were included	All of the trials used nintedanib as monotherapy at a dose of 300 mg daily. Three trials used an increasing dose of nintedanib until reaching the target dose of 300 mg daily [6],[20],[21]. All trials compared against placebo or standard treatment.
What types of outcomes were measured	The different systematic reviews identified grouped the outcomes as follows: Mortality from any cause and related to idiopathic pulmonary fibrosis Acute exacerbations Non-serious and severe adverse events (mainly gastrointestinal) Functional vital capacity drop > o = 10% Change in predicted functional vital capacity Change in walking test in 6 minutes Quality of life Scale of dyspnea

Summary of findings

The information on the effects of nintedanib is based on three randomized trials [6],[18],[19] which included 1231 patients. The other four trials were not used in this analysis because they did not report enough data to be incorporated into a meta-analysis. All trials measured mortality, acute exacerbations, and serious adverse events. The summary of findings is as follows:

Nintedanib might reduce mortality in idiopathic pulmonary fibrosis. The certainty of the evidence is low.
Nintedanib probably decreases the risk of acute exacerbations in idiopathic pulmonary fibrosis. The certainty of the evidence is moderate.
Nintedanib is probably not associated with serious adverse events. The certainty of the evidence is moderate.

Other considerations for decision-making

To whom this evidence does and does not apply

This evidence applies to adult patients diagnosed with idiopathic pulmonary fibrosis. Overall, the trials evaluated patients with a disease classified as mild to moderate, so it is not possible to extrapolate the findings to patients with more severe forms of disease, in whom the main benefit would be achieved through lung transplantation.

About the outcomes included in this summary

The outcomes that were included in this summary are those considered critical for decision-making by the authors of this article.
No results were included for pulmonary function tests, since these are surrogate outcomes. However, their inclusion would not have changed the conclusions. For example, RR for the fall in FVC> o = 10% was 0.72 (95% CI 0.62 to 0.85; high certainty).

Balance between benefits and risks, and certainty of the evidence

Nintedanib shows a clear benefit on the outcomes we consider relevant, and in addition, probably has no serious adverse effects.
The balance between benefits and risks is favorable to this intervention.

What would patients and their doctors think about this intervention

According to the evidence presented in this summary, both patients and clinicians should be inclined to use nintedanib.
However, considering the costs and the uncertainty about mortality, it is expected that the decision-making will vary in a case-by-case basis.

Resource considerations

It is a high-cost therapy that is not widely available. It is difficult to estimate the cost benefit due to the existing uncertainty about the effect on mortality. If only the effect on exacerbations, and not mortality, were real, it is possible that in most scenarios it would not be a cost-effective intervention.
It is reasonable to carry out a formal economic evaluation in the scenarios in which this intervention is intended to be incorporated.

Differences between this summary and other sources

The conclusions of this summary are consistent with those of the systematic reviews that were analyzed.
The conclusions of this summary are also consistent with the main guideline in the treatment of idiopathic pulmonary fibrosis [25] which recommends nintedanib, but warns about the limitations of existing evidence.

Could this evidence change in the future?

The likelihood that future evidence changes the conclusions of this summary is moderate, especially in terms of mortality, and also in terms of the magnitude of benefits, which may be important to balance with the cost of the intervention.

How we conducted this summary

Using automated and collaborative means, we compiled all the relevant evidence for the question of interest and we present it as a matrix of evidence.

Follow the link to access the interactive version: Nintedanib for idiopathic pulmonary fibrosis

Notes

The upper portion of the matrix of evidence will display a warning of “new evidence” if new systematic reviews are published after the publication of this summary. Even though the project considers the periodical update of these summaries, users are invited to comment in Medwave or to contact the authors through email if they find new evidence and the summary should be updated earlier. After creating an account in Epistemonikos, users will be able to save the matrixes and to receive automated notifications any time new evidence potentially relevant for the question appears.

The details about the methods used to produce these summaries are described here http://dx.doi.org/10.5867/medwave.2014.06.5997.

Epistemonikos foundation is a non-for-profit organization aiming to bring information closer to health decision-makers with technology. Its main development is Epistemonikos database (www.epistemonikos.org).

These summaries follow a rigorous process of internal peer review.

Conflicts of interest
The authors do not have relevant interests to declare.

Licencia Creative Commons

Esta obra de Medwave est� bajo una licencia Creative Commons Atribuci�n-NoComercial 3.0 Unported. Esta licencia permite el uso, distribuci�n y reproducci�n del art�culo en cualquier medio, siempre y cuando se otorgue el cr�dito correspondiente al autor del art�culo y al medio en que se publica, en este caso, Medwave.

Edici�n Julio 2022

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