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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">IPF pharmacological treatment algorithm&#46; FVC&#58; forced vital capacity&#59; DL<span class="elsevierStyleInf">CO</span>&#58; carbon monoxide diffusing capacity&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">In 2013&#44; we published the Idiopathic Pulmonary Fibrosis &#40;IPF&#41; Treatment Guidelines&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">1</span></a> Since then&#44; results have emerged from clinical trials with pirfenidone&#44; nintedanib and N-acetylcysteine &#40;NAC&#41;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">2&#8211;4</span></a> that have led to changes in the therapeutic management of this disease&#46; In 2015&#44; the 2011 International Consensus on IPF was updated&#44; and new recommendations on the use of these drugs in the treatment of this disease were incorporated&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">5</span></a> These changes have prompted us to update our IPF Treatment Guidelines&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Pharmacological Treatment</span><p id="par0010" class="elsevierStylePara elsevierViewall">In 2015&#44; recommendations for the treatment of IPF were updated on the basis of new scientific evidence that emerged after the first diagnostic-therapeutic guidelines were published in 2011&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">5&#44;6</span></a> This was a major milestone in the treatment of IPF&#44; as for the first time a Grade A therapeutic recommendation was established for 2 antifibrotic drugs&#44; pirfenidone and nintedanib&#44; on the basis of Level 1 scientific evidence &#40;clinical trials with reproducible results and meta-analyses&#41; according to the GRADE system&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">7</span></a> In 2011&#44; only grade C or D recommendations had been established for treatment &#40;based on expert opinions&#44; retrospective or unvalidated prospective studies or clinical case series&#41;&#46; By 2014&#44; the new drugs were providing benefits in terms of a significant reduction in mortality&#44; positioning IPF as one of the few areas in respiratory medicine in which treatment could provide such clinically significant improvements&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Antifibrotic Drugs Showing Therapeutic Benefit</span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Pirfenidone &#40;Esbriet<span class="elsevierStyleSup">&#174;</span>&#41;</span><p id="par0015" class="elsevierStylePara elsevierViewall">Pirfenidone is a pleiotropic drug with antifibrotic and antiinflammatory properties&#44; which inhibits the synthesis of profibrinogenic growth factors&#44; such as transforming growth factor-beta &#40;TGF-&#946;&#41; and platelet-derived growth factor &#40;PDGF&#41;&#44; fibroblast proliferation&#44; and formation of collagen&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">8</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Its clinical efficacy has been evaluated in several double-blind&#44; placebo-controlled randomized clinical trials&#58; 2 Asian studies&#44; 1 phase II and 1 phase III&#44;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">9&#44;10</span></a> and 3 phase III studies in the West &#40;CAPACITY-1&#44; CAPACITY-2&#44; and ASCEND&#41;&#46; The 3 Western studies were designed to evaluate the efficacy and safety of pirfenidone in patients with mild-moderate IPF&#46; <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> summarizes the main methodological features of the clinical trials&#46; The 2 CAPACITY studies were conducted simultaneously over a 72-week period&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">8</span></a> Meta-analysis of the pooled results of both studies showed less decline in FVC compared to placebo during the 72-week treatment period&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">8</span></a> A Cochrane analysis showed that pirfenidone increased progression-free survival by 30&#37; compared to placebo&#46; European health authorities granted marketing approval to the drug for use in mild-moderate IPF &#40;FVC&#62;50&#44; DLCO&#62;35&#37;&#41;&#44; although in the United States&#44; a new study with the same characteristics of the CAPACITY trials was requested to ensure reproducibility of the favorable effects&#46; Thus&#44; the ASCEND study was initiated in 2011&#44;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">2</span></a> in which patients received treatment for 52 weeks&#46; This study again showed a significant delay in functional decline compared to the placebo group&#44; with a relative reduction of 48&#37; in cases of progressive disease or death during the study period&#46; Similarly&#44; patients in the treatment group had significantly longer progression-free survival than patients in the placebo group&#46; Moreover&#44; fewer patients died in the treatment group&#44; and an overall analysis of the data from the CAPACITY-1 and -2 studies&#44; which included 1247 patients&#44; showed a significant reduction in mortality after 1 year of pirfenidone treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">2</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">A meta-analysis evaluating the results from the CAPACITY and ASCEND studies after 1 year of treatment with pirfenidone showed a reduction in the proportion of patients with a decline in FVC&#8805;10&#37; or death &#40;43&#46;8&#37;&#41; and an increase in the proportion of cases with stable FVC &#40;59&#46;3&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">11</span></a> Benefits in progression-free survival&#44; exercise capacity &#40;measured with the 6-min walk test&#41; and dyspnea were observed&#46; The analysis of these results by patient subgroups showed that the reduction in FVC decline occurs in patients with initial FVC values both above and below 80&#37; predicted value&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">11</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The recommended dose of pirfenidone is 2403<span class="elsevierStyleHsp" style=""></span>mg&#47;day divided in 3 doses to be taken with meals&#46; The maximum dose is reached after 3 weeks of progressive dose escalation&#58; in week 1&#44; one 267<span class="elsevierStyleHsp" style=""></span>mg tablet is administered every 8<span class="elsevierStyleHsp" style=""></span>h&#44; in week 2&#44; two 267<span class="elsevierStyleHsp" style=""></span>mg tablets every 8<span class="elsevierStyleHsp" style=""></span>h and in week 3&#44; three 267<span class="elsevierStyleHsp" style=""></span>mg tablets every 8<span class="elsevierStyleHsp" style=""></span>h&#46; The most significant adverse events are gastrointestinal &#40;nausea&#44; dyspepsia&#44; anorexia&#44; and weight loss&#41;&#44; followed by rash&#44; photosensitivity&#44; and to a lesser extent&#44; liver function changes &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; Taking the drug with meals reduces the maximum plasma peak and consequently the risk of adverse effects&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">12</span></a> When gastrointestinal symptoms are significant&#44; the dose may be reduced or even temporarily suspended until symptoms are controlled&#46; When control has been achieved&#44; escalation can be attempted again&#44; until the maximum dose is achieved&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">12</span></a> Prokinetics and proton pump inhibitors &#40;PPI&#41; are useful in the management of gastrointestinal symptoms&#46; However&#44; omprezazole can interact with pirfenidone&#44; so pantoprazole or esomeprazole are recommended if PPIs are required&#46; To minimize the possibility of skin reactions that occur as rash or photosensitivity&#44; patients are advised to avoid direct&#44; prolonged exposure to the sun&#44; to use sun protection cream &#40;PF &#43;50&#41;&#44; to wear a hat and sunglasses&#44; and to reduce the areas exposed with appropriate clothing&#44; particularly 1&#8211;2<span class="elsevierStyleHsp" style=""></span>h after administration&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">12</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">Accumulated experience after 5 years of use indicates that adverse events and drug withdrawal due to severe adverse effects occur in 3&#37;&#8211;4&#37; of cases &#8211; an incidence similar to that described in clinical trials&#46;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">13&#44;14</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">The main contraindications for the use of pirfenidone are drug hypersensitivity&#44; concomitant use of fluvoxamine&#44; and severe liver or kidney disease&#46; Consumption of grapefruit juice should be avoided during pirfenidone administration&#46; No data are available on its use in pregnancy &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a> shows pirfenidone drug interactions&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><elsevierMultimedia ident="tbl0020"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Nintedanib &#40;Ofev<span class="elsevierStyleSup">&#174;</span>&#41;</span><p id="par0045" class="elsevierStylePara elsevierViewall">Nintedanib is a triple tyrosine kinase receptor inhibitor that has anti-platelet-derived growth factor activity &#40;PDGF&#41;&#44; anti-fibroblast growth factor &#40;FGF&#41; activity&#44; and anti-vascular endothelial growth factor &#40;VEGF&#41; activity&#44; all associated with the pathogenic mechanisms of fibrosis&#46; The benefit of nintedanib in IPF is supported by 3 double-blind&#44; placebo-controlled randomized trials&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">In 2011&#44; the results of a phase II trial &#40;TOMORROW&#41; were published&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">15</span></a> These showed that&#44; compared to placebo&#44; nintedanib at a dose of 150<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h significantly delayed lung function decline over a 1-year period and reduced the rate of acute exacerbations&#46; This led to the performance of the phase III studies INPULSIS 1 and 2&#44; the results of which were published in 2014&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">3</span></a><a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a> summarizes the methodological features of these trials&#46;</p><elsevierMultimedia ident="tbl0025"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">In the INPULSIS studies&#44; patients were assigned to receive nintedanib &#40;150<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h&#41; or placebo for 52 weeks&#46; The results showed that FVC decline was significantly lower with nintedanib treatment&#46; The INPULSIS-2 trial found a lower percentage of patients with acute exacerbations in the treatment group&#44; and less loss of quality of life&#46; Mortality was lower in the treatment group&#44; but this difference was not statistically significant&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">3</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">An analysis of the combined evidence from the TOMORROW and INPULSIS trials showed that nintedanib significantly reduces lung function decline&#44; prolongs time to first acute exacerbation and improves quality of life&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">16</span></a> The subgroup analysis of the data obtained in the 2 INPULSIS studies in 1066 patients found that the delay in disease progression &#40;FVC decline&#41; was independent of age &#40;&#62;&#60;65 years&#41;&#44; FVC at the time of starting treatment &#40;&#60;&#62;70&#37;&#44; &#60;&#62;90&#37;&#41; and the existence or absence of associated emphysema&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">3&#44;17&#44;18</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">The most common adverse effect of nintedanib&#44; occurring in up to 60&#37; of cases&#44; is diarrhea&#44; generally mild-to-moderate in intensity&#46; In only about 4&#37;&#8211;5&#37; of patients is it sufficiently severe or recurrent to require definitive withdrawal of the drug&#46; Other less common effects are nausea and vomiting&#44; anorexia&#44; weight loss&#44; and changes in hepatic function &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">To minimize gastrointestinal side effects&#44; particularly diarrhea&#44; the daily dose can be reduced to 100<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h&#44; or administration can even be temporarily suspended until symptoms are controlled&#46; The medication can then be reintroduced and escalated up to the full dose&#46; A binding diet&#44; use of probiotics&#44; and loperamide&#44; combined or not combined with codeine&#44; can help manage the frequency and intensity of diarrhea&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">The main contraindications of nintedanib include hypersensitivity to the product&#44; a history of allergic reactions to peanuts or soya&#44; and severe hepatic insufficiency&#46; Caution should be used in patients with hemorrhagic diathesis&#44; dual antiplatelet or chronic anticoagulation&#44; ischemic heart disease&#44; or history of cerebrovascular stroke and recent abdominal surgery &#40;less than 4 weeks&#41;&#46; In the INPULSIS studies&#44; patients with cardiovascular risk were excluded&#44; so safety in this population could not be determined &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a> shows nintedanib drug interactions&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Pirfenidone and Nintedanib in Clinical Practice</span><p id="par0080" class="elsevierStylePara elsevierViewall">When a diagnosis of IPF has been established&#44; antifibrotic medication should begin as soon as possible in order to delay functional decline that would occur without treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">19</span></a> In asymptomatic patients with minimal functional or radiological impact&#44; a wait-and-see approach can be taken&#44; after the risks and benefits of such a strategy have been weighed up&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">20</span></a> Taking into account the inclusion criteria of the clinical trials with both drugs &#40;<a class="elsevierStyleCrossRefs" href="#tbl0005">Tables 1 and 2</a>&#41;&#44; clinical evidence suggests that pirfenidone and nintedanib can be recommended in IPF patients with mild to moderate functional decline &#40;FVC&#8805;50&#37; and DLCO&#8805;30&#37;&#41;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">1&#8211;3&#44;5&#44;8</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0030">Table 6</a> and <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Patients who present contraindications or intolerance to these drugs should be included in clinical trials&#46; Treatment should be administered for 12 months&#44; and should be continued if the disease improves or stabilizes&#46; If it worsens&#44; each patient should be evaluated to determine if continuing treatment is advisable or if other therapeutic strategies should be adopted&#46; Patients with poor prognosis on diagnosis or with rapidly progressing disease should be referred to lung transplantation units&#46; Patients on transplant waiting lists should continue their antifibrotic treatment&#44; since this has been shown to reduce disease progression and does not increase the incidence of post-transplantation complications&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">21</span></a> In severe disease &#40;FVC&#62;50&#37;&#44; DLCO&#60;30&#37;&#41;&#44; the treatment of choice is lung transplantation&#46; Patients who still fail to benefit from drug treatment should be included in clinical trials&#46; The need for palliative care must also be evaluated &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0030"></elsevierMultimedia><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Current Utility of Corticosteroids</span><p id="par0085" class="elsevierStylePara elsevierViewall">A Cochrane meta-analysis conducted in 2003 on the use of corticosteroids in IPF concluded that insufficient clinical evidence was available to justify their use&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">22</span></a> However&#44; until very recently&#44; oral corticosteroids were commonly used in clinical practice&#44; probably because until around 2000&#8211;2002&#44; other types of pulmonary fibrosis that respond partially to corticosteroid treatment&#44; such as non-specific interstitial pneumonia&#44; were indistinguishable from IPF&#46; Moreover&#44; the IFIGENIA clinical trial studied the effect of NAC and found that this compound in combination with corticosteroids and azathioprine reduced DLCO &#40;&#37;&#41; compared to the use of the latter 2 without NAC&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">23</span></a> This study led to the use of this triple therapy in IPF&#46; The PANTHER study&#44; initiated in 2011&#44; evaluated the effect of triple treatment compared to placebo and to NAC alone&#46; Less than 1 year after starting the study&#44; the triple therapy arm had to be suspended for safety reasons&#44; as mortality and hospital admission rates were higher than with placebo&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">24</span></a> The placebo and single-agent NAC arms continued until the study was completed&#46; No therapeutic benefit was found for NAC after a 60-week follow-up&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">4</span></a> Thus&#44; there is sufficient evidence to advise against the use of corticosteroids in combination with azathioprine in the treatment of IPF&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">5</span></a> Currently&#44; the use of corticosteroids in IPF is limited to &#40;1&#41; acute disease exacerbations &#40;see the specific section&#41;&#44; and &#40;2&#41; cases with difficult-to-manage symptoms&#44; such as refractory cough that does not improve with low dose antitussives &#40;5&#8211;10<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41;&#44; occasionally as part of palliative care&#46; In both cases&#44; the clinical evidence for benefit is low&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Antifibrotics in Clinical Trials</span><p id="par0090" class="elsevierStylePara elsevierViewall">Clinical trials are currently ongoing with antifibrotics in 2 settings&#58; &#40;1&#41; IPF disease phases that fail to show therapeutic benefit with marketed antifibrotics&#44; including subclinical or incipient disease or more advanced stages &#40;FVC&#60;50&#37;&#44; DLCO&#60;30&#37;&#41;&#46; Both marketed antifibrotics and new antifibrotics are being used in single-agent and combination therapy in this setting &#40;<a href="http://www.clinicaltrials.gov/">www&#46;clinicaltrials&#46;gov</a>&#41;&#46; &#40;2&#41; In mild-moderate IPF phases &#40;FVC&#62;50&#37;&#44; DLCO&#62;30&#37;&#41;&#44; new proposals for investigational antifibrotics always involve a combination with either of the 2 marketed products&#46; Given the complexity of the multiple pathogenic pathways of the disease&#44; the simultaneous use of different treatment lines may&#44; theoretically&#44; act synergically to generate greater clinical benefit&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">25&#44;26</span></a> The first combination to enter trials was pirfenidone plus NAC after preliminary studies suggested that the combination was potentially synergic&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">27</span></a> Initial safety data with both drugs are positive but no clinical benefit is obtained from combining NAC with pirfenidone&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">28</span></a> Another combination to enter trials is nintedanib&#43;pirfenidone&#46; A recent phase II clinical trial conducted in Asia to evaluate the safety&#44; tolerance and pharmacokinetics of the combination has shown short-term safety&#44; albeit with increased gastrointestinal side effects&#44; particularly nausea and vomiting&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">29</span></a> The phase IV COMBO clinical trial is currently being performed to evaluate 32-week safety&#46; Other combinations of pirfenidone or nintedanib with other new antifibrotics&#44; initiated before either drug received marketing approval&#44; are also ongoing &#40;<a href="http://www.clinicaltrials.gov/">www&#46;clinicaltrials&#46;gov</a>&#41;&#44; including pirfenidone&#177;lebrikizumab &#40;RIFF study&#41;&#44; pirfenidone or nintedanib&#177;PRM-151 &#40;PROMEDIOR study&#41;&#44; pirfenidone&#177;vismodegib &#40;GB29764 study&#41;&#44; pirfenidone&#177;sildenafil&#46;</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Treatment of Associated Comorbidities</span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Gastroesophageal Reflux</span><p id="par0095" class="elsevierStylePara elsevierViewall">Some studies have shown the benefit of medical and surgical treatment of gastroesophageal reflux &#40;GER&#41;&#46; In a small series of 4 patients with IPF and GER&#44; treating GER with proton pump inhibitors &#40;PPI&#41; or Nissen fundoplication helped stabilize FVC&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">30</span></a> In another retrospective study in 204 IPF patients&#44; Lee et al&#46; found an increase in survival in patients whose GER was treated&#44; primarily with PPIs&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">31</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">An analysis of data from 242 patients included in the placebo arms of 3 randomized clinical trials found that patients who had received PPIs or histamine-2 receptor &#40;H2R&#41; antagonists had less FVC decline and fewer acute exacerbations than those who did not receive antacids&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">32</span></a> In the 2011 ATS&#47;ERS&#47;JRS&#47;ALAT guidelines and the treatment update published in 2015&#44; regular use of PPIs in IPF patients was suggested&#44; although the recommendation was conditional&#44; due to the very low level of evidence for the effect estimates&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">5</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">In another study&#44; the effect of antacid treatment on disease progression was evaluated in patients assigned to the placebo arm in 3 phase III clinical trials with pirfenidone &#40;CAPACITY and ASCEND&#41;&#46; A total of 624 patients were included in the placebo group&#44; of whom only 291 received antacids&#46; No differences were found between treated and untreated patients in disease progression&#44; all-cause mortality&#44; or FVC decline &#62;10&#37;&#46; An insignificant increase was observed in pulmonary infections in patients receiving antacids&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">33</span></a> The effect of treating GER with laparoscopic Nissen fundoplication on disease progression was evaluated in IPF patients with clinical and functional worsening despite antacid therapy&#46; No significant differences were found between FVC decline before surgery and after a 1-year follow-up period&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">34</span></a> Randomized&#44; placebo-controlled studies are required to determine the benefit of antacid treatment in patients with IPF&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Pulmonary Emphysema</span><p id="par0110" class="elsevierStylePara elsevierViewall">No effective treatment is currently available for combined pulmonary fibrosis and emphysema &#40;CPFE&#41; syndrome&#44;<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">35&#44;36</span></a> so it seems logical to base therapeutic decisions on the separate recommendations for emphysema and IPF&#46; Smoking cessation is the main recommendation for the treatment of COPD and IPF&#46; If CFPE is associated with other environmental exposures&#44; these must be avoided&#46; Oxygen therapy is the most appropriate treatment for concomitant hypoxemia and pulmonary hypertension&#46; In order to reduce acute exacerbations and infections&#44; anti-influenza and anti-<span class="elsevierStyleItalic">Streptococcus pneumoniae</span> vaccination is recommended&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">For patients with obstructive or mixed functional limitations&#44; inhaled bronchodilators may be prescribed as for COPD&#46; The use of long-acting inhaled corticosteroids has been beneficial in some patients<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">37&#44;38</span></a> for improving lung function and reducing the severity of acute episodes&#46; However&#44; the benefit of bronchodilators in CFPE has not been adequately demonstrated&#46; Lung function decline may also differ in CFPE patients with or without airflow limitation&#44; and as such&#44; the efficacy of one or another bronchodilator may differ&#46; Although the evidence is still unclear&#44; inhaled bronchodilators are prescribed in less than 50&#37; of cases&#44;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">39</span></a> but as no definitive treatment is available for IPF&#44; management of comorbidities may be a good therapeutic strategy for improving the course of the disease&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">39</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">Although the CAPACITY &#40;pirfenidone&#41; and INPULSIS &#40;nintedanib&#41; studies included patients with CFPE&#44; evidence for the efficacy of the new antifibrotics is limited and insufficient to draw any conclusions in this respect&#46; A recent study found that in most IPF patients&#44; including those with cardiovascular diseases and emphysema&#44; pirfenidone was well tolerated&#44; and a stable disease course could be maintained&#46; However&#44; specific efficacy in CFPE with either pirfenidone or nintedanib has not been proven&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">11&#44;17</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Specific clinical and diagnostic criteria must be established for CPFE&#44; and there is an urgent need to improve understanding of the pathogenesis&#44; pathophysiology and prognostic factors of the CFPE syndrome&#44; to design prospective cohort studies&#44; and to explore new and effective therapeutic strategies&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">39</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Pulmonary Hypertension</span><p id="par0130" class="elsevierStylePara elsevierViewall">PH generally appears when IPF is advanced&#59; it is usually mild&#44; but has a negative impact on disease prognosis&#46; Patients with PH and IPF who have chronic hypoxemia must receive home oxygen therapy &#40;strong recommendation&#44; low level of evidence&#41;&#44; and lung transplantation must be considered&#44; if this procedure is not contraindicated by age or comorbidities&#46; In 2015&#44; 2 guidelines were published that mention the treatment of IPF-associated PH&#58; the ATS&#47;ERS&#47;JRS&#47;ALAT IPF guidelines&#44;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">5</span></a> in which the recommendation regarding treatment was deferred&#44; and the ESC&#47;ERS guidelines on the diagnosis and treatment of PH&#44;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">40</span></a> in which the use of drugs approved for PH caused by lung disease is not recommended &#40;strong recommendation&#44; low level of evidence&#41;&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Dual endothelin receptor antagonists &#40;bosentan&#44; macitentan&#41; have been ineffective in the treatment of PH associated with IPF&#46; The selective antagonist ambrisentan&#44; evaluated in the ARTEMIS-IPF clinical trial&#44;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">41</span></a> is contraindicated due to lack of efficacy and increased disease progression and hospitalization for respiratory complications &#40;strong recommendation&#44; level of evidence low&#41;&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">The phase II study RISE-IIP &#40;<a href="ctgov:NCT02138825">NCT02138825</a>&#41; designed to study the efficacy and safety of riociguat&#44; a soluble guanylate cyclase stimulator of the nitric oxide pathway&#44; in symptomatic PH associated with idiopathic interstitial pneumonias&#44; was suspended after increased mortality and serious adverse events were observed in the riociguat-treated patient group&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Sildenafil&#44; a phosphodiesterase-5 inhibitor&#44; was evaluated in the STEP-IPF study in patients with advanced IPF &#40;DLCO&#60;35&#37;&#41;&#59; the subgroup of patients with right ventricular systolic dysfunction showed improvements in the 6-min walk test and quality of life&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">42</span></a> Patients with PH or severe right ventricular dysfunction may be considered for personalized treatment &#40;weak recommendation&#44; low level of evidence&#41;&#46; Ongoing clinical trials combining pulmonary vasodilators with antifibrotics will show if this approach is beneficial&#46;</p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Treatment of Exacerbations</span><p id="par0150" class="elsevierStylePara elsevierViewall">To date&#44; no randomized clinical trial specifically designed to study the treatment of IPF exacerbations has been conducted&#46; Current recommendations&#44; then&#44; are based on results from the few published case series&#46; The only recommendation given on the basis of these studies is to optimize life support &#40;weak recommendation&#44; very low quality of evidence&#41;&#44; although several studies have shown that mechanical ventilation in patients with IPF and respiratory failure is ineffective in the majority of cases&#46; The administration of high doses of corticosteroids should be evaluated in the initial days after the event &#40;methylprednisolone in boluses of 500&#8211;1000<span class="elsevierStyleHsp" style=""></span>mg&#47;day for 3 days&#44; followed by high doses of prednisone &#91;0&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day&#93;&#41; &#40;weak recommendation&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">43</span></a> No randomized studies are available to support the addition of a second immunosuppressive drug &#40;azathioprine&#44; cyclophosphamide or cyclosporin&#41;&#46; No controlled studies are available to support the use of low-weight molecular heparin in the treatment of exacerbations&#44; unless concomitant venous thromboembolic disease is suspected&#46; The empirical use of wide-spectrum antibiotics is also accepted in clinical practice&#44; given the difficulty in many cases of ruling out an underlying infectious process&#46;<a class="elsevierStyleCrossRefs" href="#bib0445"><span class="elsevierStyleSup">43&#8211;46</span></a> No studies have been conducted to evaluate the effect of the new antifibrotic drugs in the treatment of IPF exacerbations&#44; but data are available that suggest a possible preventive effect&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">3</span></a> Thus&#44; prevention is perhaps the most important intervention in IPF exacerbations&#58; anti-influenza and anti-pneumococcal vaccination must be emphasized&#44; GER symptoms must be treated&#44; and surgical biopsies must be avoided in patients with deteriorated lung function and typical findings of usual interstitial pneumonia on high-resolution computed tomography&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Conflicts of Interest</span><p id="par0155" class="elsevierStylePara elsevierViewall">All the authors have participated in scientific activities organizad by Roche and Bohringher&#46; In addition all the authors are have been membres of the advisory committe for IPF from the same pharmaceuticals&#46;</p></span></span>"
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        1 => array:2 [
          "identificador" => "xpalclavsec830165"
          "titulo" => "Keywords"
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          "identificador" => "xres834128"
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          "titulo" => "Introduction"
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          "titulo" => "Pharmacological Treatment"
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            0 => array:3 [
              "identificador" => "sec0015"
              "titulo" => "Antifibrotic Drugs Showing Therapeutic Benefit"
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                  "titulo" => "Pirfenidone &#40;Esbriet&#41;"
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                  "identificador" => "sec0025"
                  "titulo" => "Nintedanib &#40;Ofev&#41;"
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                  "identificador" => "sec0030"
                  "titulo" => "Pirfenidone and Nintedanib in Clinical Practice"
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              "identificador" => "sec0035"
              "titulo" => "Current Utility of Corticosteroids"
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              "identificador" => "sec0040"
              "titulo" => "Antifibrotics in Clinical Trials"
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          "identificador" => "sec0045"
          "titulo" => "Treatment of Associated Comorbidities"
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              "identificador" => "sec0050"
              "titulo" => "Gastroesophageal Reflux"
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              "identificador" => "sec0055"
              "titulo" => "Pulmonary Emphysema"
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            2 => array:2 [
              "identificador" => "sec0060"
              "titulo" => "Pulmonary Hypertension"
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          "identificador" => "sec0065"
          "titulo" => "Treatment of Exacerbations"
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          "identificador" => "sec0070"
          "titulo" => "Conflicts of Interest"
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          "titulo" => "References"
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    "fechaRecibido" => "2016-11-11"
    "fechaAceptado" => "2016-12-19"
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec830165"
          "palabras" => array:4 [
            0 => "Idiopathic pulmonary fibrosis"
            1 => "Treatment"
            2 => "Pirfenidone"
            3 => "Nintedanib"
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        0 => array:4 [
          "clase" => "keyword"
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          "palabras" => array:4 [
            0 => "Fibrosis pulmonar idiop&#225;tica"
            1 => "Tratamiento"
            2 => "Pirfenidona"
            3 => "Nintedanib"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Idiopathic pulmonary fibrosis is defined as chronic fibrosing interstitial pneumonia limited to the lung&#44; with poor prognosis&#46; The incidence has been rising in recent years probably due to improved diagnostic methods and increased life expectancy&#46; In 2013&#44; the SEPAR guidelines for the diagnosis and treatment for idiopathic pulmonary fibrosis were published&#46; Since then&#44; clinical trials and meta-analyses have shown strong scientific evidence for the use of pirfenidone and nintedanib in the treatment of idiopathic pulmonary fibrosis&#46; In 2015&#44; the international consensus of 2011 was updated and new therapeutic recommendations were established&#44; prompting us to update our recommendation for the medical treatment of idiopathic pulmonary fibrosis accordingly&#46; Diagnostic aspects and non-pharmacological treatment will not be discussed as no relevant developments have emerged since the 2013 guidelines&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La fibrosis pulmonar idiop&#225;tica es una enfermedad intersticial fibrosante limitada al pulm&#243;n&#44; con mal pron&#243;stico&#46; Su incidencia ha aumentado en los &#250;ltimos a&#241;os&#44; probablemente por la optimizaci&#243;n de los m&#233;todos diagn&#243;sticos y el aumento en la esperanza de vida&#46; En 2013 se public&#243; la normativa SEPAR sobre el diagn&#243;stico y tratamiento de la fibrosis pulmonar idiop&#225;tica&#46; Desde entonces&#44; se han publicado los resultados de ensayos cl&#237;nicos y metaan&#225;lisis que han supuesto&#44; con base en la evidencia cient&#237;fica&#44; la introducci&#243;n de pirfenidona y nintedanib en el tratamiento de la enfermedad&#46; En 2015 se ha actualizado el consenso internacional de 2011&#44; en el que se describen los cambios en las recomendaciones terap&#233;uticas&#46; Debido a ello cab&#237;a actualizar el apartado de la normativa sobre el tratamiento farmacol&#243;gico de la fibrosis pulmonar idiop&#225;tica&#46; No se tratar&#225;n aspectos diagn&#243;sticos ni el tratamiento no farmacol&#243;gico&#44; ya que no se han producido cambios relevantes desde la normativa de 2013&#46;</p></span>"
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        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Xaubet A&#44; Molina-Molina M&#44; Acosta O&#44; Bollo E&#44; Castillo D&#44; Fern&#225;ndez-Fabrellas E&#44; et al&#46; Normativa sobre el tratamiento farmacol&#243;gico de la fibrosis pulmonar idiop&#225;tica&#46; Arch Bronconeumol&#46; 2017&#59;53&#58;263&#8211;269&#46;</p>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">IPF pharmacological treatment algorithm&#46; FVC&#58; forced vital capacity&#59; DL<span class="elsevierStyleInf">CO</span>&#58; carbon monoxide diffusing capacity&#46;</p>"
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          "leyenda" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">DLCO&#58; carbon monoxide diffusing capacity&#59; FVC&#58; forced vital capacity&#59; HRCT&#58; high-resolution computed tomography&#59; UIP&#58; usual interstitial pneumonia&#46;</p>"
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">CAPACITY -1 and -2<br>&#40;<span class="elsevierStyleItalic">n</span>&#61;779&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">ASCEND<br>&#40;<span class="elsevierStyleItalic">n</span>&#61;555&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Age &#40;years&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">40&#8211;80&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">40&#8211;80&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">FVC &#40;inclusion criterion&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8805;50&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">50&#37;&#8211;90&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">DLCO &#40;inclusion criterion&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8805;35&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8805;30&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Phase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">III&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">III&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Study duration &#40;weeks&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">72&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">52&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">UIP on HRCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">92&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">95&#46;7&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Initial FVC &#40;mean&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">74&#46;1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">67&#46;8&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Initial DLCO &#40;mean&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">47&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">43&#46;7&#37;&nbsp;\t\t\t\t\t\t\n
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">CAPACITY-1 and -2 and ASCEND Clinical Trials&#58; Methodology and Clinical Features of IPF Patients Included&#46;</p>"
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            "identificador" => "at2"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Drug&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Recommended Dose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Most Common Adverse Effects&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pirfenidone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2403<span class="elsevierStyleHsp" style=""></span>mg&#47;day &#40;801<span class="elsevierStyleHsp" style=""></span>mg with each meal&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nausea&#47;vomiting<br>Dyspepsia<br>Anorexia&#47;weight loss<br>Rash&#47;photosensitivity<br>Liver function changes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Nintedanib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">300<span class="elsevierStyleHsp" style=""></span>mg&#47;day &#40;150<span class="elsevierStyleHsp" style=""></span>mg with breakfast and evening meal&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Diarrhea<br>Nausea&#47;vomiting<br>Dyspepsia<br>Anorexia&#47;weight loss<br>Liver function changes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1406653.png"
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          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Doses and Main Adverse Effects of Recommended Antifibrotic Drugs&#46;</p>"
        ]
      ]
      3 => array:8 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at3"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Drug&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Absolute Contraindication&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Additional Suggestions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pirfenidone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hypersensitivity to the drug<br>Severe liver disease<br>Severe kidney disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Avoid use during pregnancy and breast-feeding&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Nintedanib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hypersensitivity to the drug<br>Peanut or soya allergy<br>Severe hepatic insufficiency&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Special precautions in case of&#58;<br><span class="elsevierStyleHsp" style=""></span>- Hemorrhagic diathesis<br><span class="elsevierStyleHsp" style=""></span>- Dual antiplatelets<br><span class="elsevierStyleHsp" style=""></span>- Chronic anticoagulation<br><span class="elsevierStyleHsp" style=""></span>- Ischemic heart disease<br><span class="elsevierStyleHsp" style=""></span>- Cerebrovascular stroke<br><span class="elsevierStyleHsp" style=""></span>- Abdominal surgery &#40;&#60;4 weeks&#41;<br>Avoid use during pregnancy and breast-feeding&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1406657.png"
              ]
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          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Contraindications and Suggestions for the Use of Recommended Antifibrotic Drugs&#46;</p>"
        ]
      ]
      4 => array:8 [
        "identificador" => "tbl0020"
        "etiqueta" => "Table 4"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at4"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Drug&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Increases Bioavailability&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Reduces Bioavailability&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pirfenidone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Grapefruit juice<br>Fluvoxamine<br>Ciprofloxacin<br>Amiodarone&#47;propafenone<br>Fluoxetine&#47;paroxetine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Smoking<br>Omeprazole<br>Rifampicin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Nintedanib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ketoconazole<br>Erythromycin<br>Cyclosporin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rifampicin<br>Carbamazepine<br>Phenytoin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab1406654.png"
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Main Drug Interactions With Recommended Antifibrotics&#46;</p>"
        ]
      ]
      5 => array:8 [
        "identificador" => "tbl0025"
        "etiqueta" => "Table 5"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at5"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">DLCO&#58; carbon monoxide diffusing capacity&#59; FVC&#58; forced vital capacity&#59; HRCT&#58; high-resolution computed tomography&#59; UIP&#58; usual interstitial pneumonia&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">TOMORROW<br>&#40;<span class="elsevierStyleItalic">n</span>&#61;422&#44; 85 at Doses of 150<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">INPULSIS-1 and -2<br>&#40;<span class="elsevierStyleItalic">n</span>&#61;1066&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Age &#40;years&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">40&#8211;80&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">40&#8211;80&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">FVC &#40;inclusion criterion&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8805;50&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8805;50&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">DLCO &#40;inclusion criterion&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">30&#37;&#8211;79&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">30&#37;&#8211;79&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Phase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">II&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">III&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Study duration &#40;weeks&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">52&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">52&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">UIP on HRCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">38&#46;8&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">76&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Initial FVC &#40;mean&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">78&#46;1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">79&#46;5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Initial DLCO &#40;mean&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">47&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1406655.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">TOMORROW and INPULSIS Clinical Trials&#58; Methodology and Clinical Features of IPF Patients Included&#46;</p>"
        ]
      ]
      6 => array:8 [
        "identificador" => "tbl0030"
        "etiqueta" => "Table 6"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at6"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">NAC&#58; N-acetylcysteine&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Antifibrotic Agent&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Mechanism of Action&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Recommendations&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">Recommended in selected patients</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Pirfenidone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Antifibrotic&#43;anti-inflammatory&#43;antioxidant&#43;ant TGF-&#946;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes&#46; Scientific evidence&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Nintedanib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tyrosine kinase inhibitor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes&#46; Scientific evidence&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">Not recommended</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Steroids&#43;azathioprine&#43;NAC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Immune suppressor&#43;antioxidant&#43;anti-inflammatory&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Do not use&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Anticoagulation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anticoagulant&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Do not use&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Bosentan&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Dual endothelin receptor antagonism&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Do not use&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Steroids in monotherapy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Immune suppressor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Do not use&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Steroids&#43;immune modulating therapy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Immune suppressor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Do not use&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Colchinine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Collagen proliferation&#47;synthesis inhibitor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Do not use&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Cyclosporine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Immune suppressor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Do not use&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Etanercept&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anti-TNF-&#945;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Do not use&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Interferon gamma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Antifibrotic and immune modulator&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Do not use&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Ambrisentan&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Selective endothelin A receptor antagonist&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Do not use&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>NAC in monotherapy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Antioxidant&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Do not use&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Recommendations for Antifibrotic Treatment in IPF&#46;</p>"
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