Idiopathic pulmonary fibrosis is a
chronic, progressive, and ultimately
fatal lung disease. After more than
a decade of clinical trials yielding
negative or inconsistent results,
two compounds, pirfenidone
and nintedanib, have finally been
proven to be effective in slowing
functional decline in idiopathic
pulmonary fibrosis and both have
now been approved in the USA,
Europe, and Japan.
Furthermore, the
previously widely used combination
of prednisone, azathioprine, and
N-acetylcysteine has been shown to
be harmful compared with placebo
for patients with the disease. Accordingly, an update of the 2011
American Thoracic Society–European
Respiratory Society– Japanese
Respiratory Society–Latin American
Thoracic Association clinical practice
guideline on idiopathic pulmonary
fibrosis treatment has been published
this year. In keeping with the 2011 document,
for the 2015 update, all available
evidence was assessed with the Grading of Recommendations,
Assessment, Development and
Evaluation (GRADE) method and
discussed at a multidisciplinary
level. Recommendations were
formulated and graded exclusively
by group members with no financial
or intellectual conflicts of interest.
By contrast with the 2011 guidelines,
the committee also included a patient
representative. According to the
GRADE system, recommendations
are presented as either “strong” or
“conditional” (the 2011 guidelines
used the term “weak” rather than
“conditional”). For a treatment with
a conditional recommendation,
it is judged that “the majority of
individuals in this situation would
want the suggested course of action
but many would not”. The table shows
a comparison of the 2011 and 2015
recommendations.
The major change in the 2015
recommendations is the introduction
of a conditional recommendation for
the use of pirfenidone (which received
a weak recommendation against its
use in 2011), and of nintedanib, a
multitarget tyrosine kinase inhibitor
that was not included in the previous
guideline. Because of the absence
of a head-to-head comparison, the guideline does not provide
recommendations for one treatment
regimen over the other. The three-drug
regimen, prednisone–azathioprine–
N-acetylcysteine, received a strong
recommendation against its use,
whereas recommendations for
N-acetylcysteine monotherapy
(conditional recommendation against
use) and for anti-acid treatment
(conditional recommendation for use)
remain unchanged.
The new guideline document
represents the recent substantial
advances in the pharmacological
treatment of idiopathic pulmonary
fi brosis. A weakness of the document
is the fact that decisions were made
within a month of publication of
key phase 3 trial data and before
information provided as part
of regulatory submissions had
become available (data that have
had important consequences in
changing the US Food and Drug
Administration’s opinion of forced
vital capacity [FVC] as a clinically
relevant effi cacy measure in idiopathic
pulmonary fibrosis).
Furthermore,
the guideline committee factored
drug cost into their decisionmaking
process without doing a
detailed health economic analysis This approach has resulted in the
apparent incongruity of drugs, with
high-quality clinical trial data being
given the same conditional level
of recommendation as anti-acid
therapy (which has never been tested
in a randomised controlled trial).4
Importantly, the guidelines emphasise
several major issues that need further
research: first, existing anti-fibrotic
therapy slows disease decline, but
neither halts nor cures idiopathic
pulmonary fibrosis, and thus the
need for new pharmacotherapies
persists; second, the effectiveness
of anti-fibrotic therapy beyond the
52–72-week duration of clinical trials
remains to be fully defined; third,
whether or not treatment is benefi cial
in more advanced disease (eg, FVC
<50%) is unknown; and fourth,
combination anti-fibrotic therapy
might provide synergistic eff ects with
larger functional benefit, although
trial data showing both safety and
efficacy are needed before such an
approach can be considered.
In summary, the updated
guidelines represent the important
developments that have occurred in
the pharmacological treatment of
idiopathic pulmonary fibrosis, while
simultaneously drawing attention to
the continued large unmet clinical
need of individuals afflicted by this
terrible disease.This approach has resulted in the
apparent incongruity of drugs, with
high-quality clinical trial data being
given the same conditional level
of recommendation as anti-acid
therapy (which has never been tested
in a randomised controlled trial). Importantly, the guidelines emphasise
several major issues that need further
research: first, existing anti-fibrotic
therapy slows disease decline, but
neither halts nor cures idiopathic
pulmonary fibrosis, and thus the
need for new pharmacotherapies
persists; second, the effectiveness
of anti-fibrotic therapy beyond the
52–72-week duration of clinical trials
remains to be fully defined; third,
whether or not treatment is benefi cial
in more advanced disease (eg, FVC
<50%) is unknown; and fourth,
combination anti-fibrotic therapy
might provide synergistic eff ects with
larger functional benefit,6
although
trial data showing both safety and
efficacy are needed before such an
approach can be considered.
In summary, the updated
guidelines represent the important
developments that have occurred in
the pharmacological treatment of
idiopathic pulmonary fibrosis, while
simultaneously drawing attention to
the continued large unmet clinical
need of individuals afflicted by this
terrible disease.
Reference: www.thelancet.com/respiratory Vol 3 September 2015
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