Klaus-Uwe Kirchgaessler

Antacid therapy and disease outcomes in idiopathic pulmonary fibrosis: a pooled analysis

BACKGROUND Gastro-oesophageal reflux disease is a potential risk factor for the development and progression of idiopathic pulmonary fibrosis (IPF). We aimed to investigate the effect of antacid therapy on disease progression in patients randomly assigned to placebo through analysis of three large, phase 3 trials of pirfenidone in IPF. METHODS Patients with IPF from the placebo groups of three trials of pirfenidone (CAPACITY 004, CAPACITY 006, and ASCEND) were included in this post-hoc analysis. We analysed effects of antacid therapy use from baseline for pulmonary function, exercise tolerance, survival, hospital admission, and adverse events for 52 weeks with and without adjustment for potential confounders. The primary endpoint, disease progression by 1 year, was defined as a decrease in predicted forced vital capacity (FVC) by 10% or more, a decrease in 6 min walk distance (6MWD) by 50 m or more, or death. We did survival analyses with the Kaplan-Meier estimator and evaluated using the log-rank test. FINDINGS Of 624 patients, 291 (47%) received antacid therapy and 333 (53%) did not. At 52 weeks, we noted no significant difference between groups for disease progression (114 [39%] for antacid therapy vs 141 [42%] for no antacid therapy, p=0·4844). Rates also did not differ for all-cause mortality (20 [7%] vs 22 [7%], p=0·8947), IPF-related mortality (11 [4%] vs 17 [5%]; p=0·4251), absolute FVC decrease by 10% or more (49 [17%] vs 64 [19%]; p=0·4411), or mean observed change in FVC (% predicted -4·9% [SD 6·4] vs -5·5% [7·2], p=0·3355; observed volume -0·2 L [0·3] vs -0·2 L [0·3], p=0·4238). The rate of hospital admission was non-significantly higher in the antacid therapy group (65 [22%] vs 54 [16%]; p=0·0522). When stratified by baseline FVC (<70% or ≥70%), disease progression, mortality, FVC, 6MWD, and hospital admission did not differ between groups. Adverse events were similar between treatment and no treatment groups; however, overall infections (107 [74%] vs 101 [62%]; p=0·0174) and pulmonary infections (20 [14%] vs 10 [6%]; p=0·0214) were higher in patients with advanced IPF (ie, FVC <70%) who were treated with antacids than not treated with antacids. INTERPRETATION Antacid therapy did not improve outcomes in patients with IPF and might potentially be associated with an increased risk of infection in those with advanced disease. FUNDING F Hoffmann-La Roche.

Unfavourable effects of medically indicated oral anticoagulants on survival in idiopathic pulmonary fibrosis

Procoagulant and antifibrinolytic activity has been associated with idiopathic pulmonary fibrosis (IPF); however, investigation of anticoagulant therapy in IPF has suggested deleterious effects. This post hoc analysis evaluated the effect of medically indicated anticoagulation on mortality and other clinical outcomes in IPF. Patients randomised to placebo (n=624) from three controlled trials in IPF were analysed by oral anticoagulant use. End-points included all-cause and IPF-related mortality, disease progression, hospitalisation, and adverse events, over 1 year. At baseline, 32 (5.1%) patients randomised to placebo were prescribed anticoagulants for non-IPF indications, 29 (90.6%) of whom received warfarin. Unadjusted analyses demonstrated significantly higher all-cause and IPF-related mortality at 1 year in baseline anticoagulant users versus nonusers (15.6% versus 6.3%, p=0.039 and 15.6% versus 3.9%, p=0.002, respectively). In multivariate analyses, baseline use of anticoagulants was an independent predictor of IPF-related mortality (hazard ratio 4.7, p=0.034), but not other end-points. Rates of bleeding and cardiac events did not differ significantly between groups. In an exploratory analysis, anticoagulant use at any time during the study was an independent predictor of all end-points. This post hoc analysis suggests that anticoagulants used for non-IPF indications may have unfavourable effects in IPF patients. Future studies are needed to explore this relationship further. Anticoagulant use for medically indicated comorbidities may have unfavourable effects in IPF http://ow.ly/XZC9j

Effect of statins on disease-related outcomes in patients with idiopathic pulmonary fibrosis

Background Data are conflicting regarding the possible effects of statins in patients with idiopathic pulmonary fibrosis (IPF). This post hoc analysis assessed the effects of statin therapy on disease-related outcomes in IPF. Methods Patients randomised to placebo (n=624) in three controlled trials of pirfenidone in IPF (CAPACITY 004 and 006, ASCEND) were categorised by baseline statin use. Outcomes assessed during the 1-year follow-up included disease progression, mortality, hospitalisation and composite outcomes of death or ≥10% absolute decline in FVC and death or ≥50 m decline in 6-minute walk distance (6MWD). Results At baseline, 276 (44%) patients were statin users versus 348 (56%) non-users. Baseline characteristics were similar between groups, except statin users were older and had higher prevalence of cardiovascular disease and risk factors. In multivariate analyses adjusting for differences in baseline characteristics, statin users had lower risks of death or 6MWD decline (HR 0.69; 95% CI 0.48 to 0.99, p=0.0465), all-cause hospitalisation (HR 0.58; 95% CI 0.35 to 0.94, p=0.0289), respiratory-related hospitalisation (HR 0.44; 95% CI 0.25 to 0.80, p=0.0063) and IPF-related mortality (HR 0.36; 95% CI 0.14 to 0.95, p=0.0393) versus non-users. Non-significant treatment effects favouring statin use were observed for disease progression (HR 0.75; 95% CI 0.52 to 1.07, p=0.1135), all-cause mortality (HR 0.54; 95% CI 0.24 to 1.21, p=0.1369) and death or FVC decline (HR 0.71; 95% CI 0.48 to 1.07, p=0.1032). Conclusions This post hoc analysis supports the hypothesis that statins may have a beneficial effect on clinical outcomes in IPF. Prospective clinical trials are required to validate these observations. Trial registration numbers NCT01366209, NCT00287729 and NCT00287716.

Effect of Emphysema Extent on Serial Lung Function in Patients with Idiopathic Pulmonary Fibrosis

Rationale: Patients with idiopathic pulmonary fibrosis and emphysema may have artificially preserved lung volumes. Objectives: In this post hoc analysis, we investigated the relationship between baseline emphysema and fibrosis extents, as well as pulmonary function changes, over 48 weeks. Methods: Data were pooled from two phase III, randomized, double‐blind, placebo‐controlled trials of IFN‐&ggr;‐1b in idiopathic pulmonary fibrosis (GIPF‐001 [NCT00047645] and GIPF‐007 [NCT00075998]). Patients with Week 48 data, baseline high‐resolution computed tomographic images, and FEV1/FVC ratios less than 0.8 or greater than 0.9 (<0.7 or >0.9 in GIPF‐007), as well as randomly selected patients with ratios of 0.8‐0.9 and 0.7‐0.8, were included. Changes from baseline in pulmonary function at Week 48 were analyzed by emphysema extent. The relationship between emphysema and fibrosis extents and change in pulmonary function was assessed using multivariate linear regression. Measurements and Main Results: Emphysema was identified in 38% of patients. A negative correlation was observed between fibrosis and emphysema extents (r = −0.232; P < 0.001). In quartile analysis, patients with the greatest emphysema extent (28 to 65%) showed the smallest FVC decline, with a difference of 3.32% at Week 48 versus patients with no emphysema (P = 0.047). In multivariate analyses, emphysema extent greater than or equal to 15% was associated with significantly reduced FVC decline over 48 weeks versus no emphysema or emphysema less than 15%. No such association was observed for diffusing capacity of the lung for carbon monoxide or composite physiologic index. Conclusions: FVC measurements may not be appropriate for monitoring disease progression in patients with idiopathic pulmonary fibrosis and emphysema extent greater than or equal to 15%.

Pirfenidone safety and adverse event management in idiopathic pulmonary fibrosis

Pirfenidone is one of two approved therapies for the treatment of idiopathic pulmonary fibrosis (IPF). Randomised controlled clinical trials and subsequent post hoc analyses have demonstrated that pirfenidone reduces lung function decline, decreases mortality and improves progression-free survival. Long-term extension trials, registries and real-world studies have also shown similar treatment effects with pirfenidone. However, for patients with IPF to obtain the maximum benefits of pirfenidone treatment, the potential adverse events (AEs) associated with pirfenidone need to be managed. This review highlights the well-known and established safety profile of pirfenidone based on randomised controlled clinical trials and real-world data. Key strategies for preventing and managing the most common pirfenidone-related AEs are described, with the goal of maximising adherence to pirfenidone with minimal AEs. Using key strategies to prevent and manage pirfenidone-related AEs can help maximise adherence to pirfenidone http://ow.ly/Veyk30gsFTs

Metformin Does Not Affect Clinically Relevant Outcomes in Patients with Idiopathic Pulmonary Fibrosis

Background: Diabetes mellitus is a possible risk factor for the development of idiopathic pulmonary fibrosis (IPF), yet the effect of antidiabetic therapy on the course of IPF is unknown. Objectives: This post hoc analysis assessed the effect of metformin on clinically relevant outcomes in patients with IPF. Methods: For the primary analysis, patients randomized to placebo (n = 624) in 3 phase 3, double-blind, controlled trials of pirfenidone (CAPACITY [NCT00287716 and NCT00287729]; ASCEND [NCT01366209]) were categorized by baseline metformin use. The primary outcome was disease progression (forced vital capacity [FVC] decline ≥10%, 6-min walking distance [6MWD] decline ≥50 m, or death). Other outcomes included mortality, hospitalization, FVC decline (≥10 and ≥5%), and 6MWD decline. Outcomes were also assessed in patients with diabetes and/or hyperglycemia (impaired glucose tolerance [IGT] and diabetes population [IGT-diabetes population]) and all patients included in the 3 studies (intention-to-treat [ITT] population). Results: Overall, 71 (11.4%) patients were metformin users and 553 (88.6%) were nonmetformin users. Baseline data were similar between groups, except for a higher percentage of males (84.5 vs. 73.2%) and a history of diabetes (98.6 vs. 11.6%) in metformin users versus nonmetformin users. The unadjusted 1-year analyses demonstrated no significant differences in disease progression or other outcomes. A higher proportion of metformin users compared with nonmetformin users had a relative FVC decline of ≥5% (63.4 vs. 50.6%, p = 0.043). Results were similar for the IGT-diabetes population and for the ITT population. Multivariable analyses yielded similar results. Conclusions: Metformin has no effect on clinically relevant outcomes in patients with IPF.

Unfavourable effects of medically indicated oral anticoagulants on survival in idiopathic pulmonary fibrosis: methodological concerns

We read the correspondence of L. Kawano-Dourado and colleagues related to our article “Unfavourable effects of medically indicated oral anticoagulants on survival in idiopathic pulmonary fibrosis” with great interest [1]. There is compelling evidence of an association between disturbances in the coagulation system and idiopathic pulmonary fibrosis (IPF); however, results from the ACE-IPF (anticoagulant effectiveness in idiopathic pulmonary fibrosis) randomised controlled trial of the vitamin K antagonist warfarin demonstrated deleterious effects of anticoagulation in IPF [2]. Based on these data, the recent update of the international guideline on IPF gave a strong recommendation against the use of anticoagulants [3]. Yet, the potential risks of medically indicated anticoagulation on mortality and other clinical outcomes in IPF remain unexplored. This is an important clinical question as almost one in every five patients with IPF receives anticoagulants for different indications [4]. In this regard, our post hoc analysis, which describes that patients in the placebo groups treated with anticoagulants in the CAPACITY and ASCEND trials had a higher rate of all-cause and IPF-related mortality compared with non-users, adds further insights in to the potential hazard of anticoagulant use in IPF [1]. We agree with Kawano-Dourado and colleagues that these data should be interpreted in light of the inherent limitations of a post hoc analysis based on a small number of events. However, these data represent, to our knowledge, the largest cohort of IPF subjects in whom this question has been addressed. Furthermore, our data are in line with two retrospective studies in IPF populations that also report a significantly higher risk of mortality in association with the use of anticoagulants for medical indications [5, 6] and this important clinical problem has recently also been highlighted by others [7]. Comorbidities requiring anticoagulants may not explain unfavourable effects of these drugs on survival in IPF http://ow.ly/tmgm302VEXz

Sildenafil added to pirfenidone in patients with advanced idiopathic pulmonary fibrosis and risk of pulmonary hypertension: A Phase IIb, randomised, double-blind, placebo-controlled study – Rationale and study design

BACKGROUND Pulmonary hypertension (PH) is commonly observed in patients with advanced idiopathic pulmonary fibrosis (IPF). Despite the availability of therapies for both IPF and PH, none are approved for PH treatment in the context of significant pulmonary disease. This study will investigate the use of sildenafil added to pirfenidone in patients with advanced IPF and risk of PH, who represent a group with a high unmet medical need. METHODS This Phase IIb, randomised, double-blind, placebo-controlled trial is actively enrolling patients and will study the efficacy, safety and tolerability of sildenafil or placebo in patients with advanced IPF and intermediate or high probability of Group 3 PH who are receiving a stable dose of pirfenidone. Patients with advanced IPF (diffusing capacity for carbon monoxide ≤40% predicted) and risk of Group 3 PH (defined as mean pulmonary arterial pressure ≥20 mm Hg with pulmonary arterial wedge pressure ≤15 mm Hg on a previous right-heart catheterisation [RHC], or intermediate/high probability of Group 3 PH as defined by the 2015 European Society of Cardiology/European Respiratory Society guidelines) are eligible. In the absence of a previous RHC, patients with an echocardiogram showing a peak tricuspid valve regurgitation velocity ≥2.9 m/s can enrol if all other criteria are met. The primary efficacy endpoint is the proportion of patients with disease progression over a 52-week treatment period. Safety will be evaluated descriptively. DISCUSSION Combination treatment with sildenafil and pirfenidone may warrant investigation of the treatment of patients with advanced IPF and pulmonary vascular involvement leading to PH.

Long-term safety of pirfenidone: results of the prospective, observational PASSPORT study

Real-world studies include a broader patient population for a longer duration than randomised controlled trials (RCTs) and can provide relevant insights for clinical practice. PASSPORT was a multicentre, prospective, post-authorisation study of patients who were newly prescribed pirfenidone and followed for 2 years after initiating treatment. Physicians collected data on adverse drug reactions (ADRs), serious ADRs (SADRs) and ADRs of special interest (ADRSI) at baseline and then every 3 months. Post hoc stepwise logistic regression models were used to identify baseline characteristics associated with discontinuing treatment due to an ADR. Patients (n=1009, 99.7% with idiopathic pulmonary fibrosis) had a median pirfenidone exposure of 442.0 days. Overall, 741 (73.4%) patients experienced ADRs, most commonly nausea (20.6%) and fatigue (18.5%). ADRs led to treatment discontinuation in 290 (28.7%) patients after a median of 99.5 days. Overall, 55 (5.5%) patients experienced SADRs, with a fatal outcome in six patients. ADRSI were reported in 693 patients, most commonly gastrointestinal symptoms (38.3%) and photosensitivity reactions/skin rashes (29.0%). Older age and female sex were associated with early treatment discontinuation due to an ADR. Findings were consistent with the known safety profile of pirfenidone, based on RCT data and other post-marketing experience, with no new safety signals observed. Real-world safety results from 1009 patients in PASSPORT were consistent with the known pirfenidone safety profile http://ow.ly/oXjv30lrzAf

Dose modification and dose intensity during treatment with pirfenidone: analysis of pooled data from three multinational phase III trials

Introduction Temporary dose modifications, such as reductions or interruptions, may allow patients to better manage adverse events (AEs) associated with pirfenidone use and continue treatment for idiopathic pulmonary fibrosis (IPF). However, the impact of such dosing adjustments on efficacy and safety is uncertain. Methods Patients randomised to receive treatment with pirfenidone 2403 mg/day or placebo in the Clinical Studies Assessing Pirfenidone in Idiopathic Pulmonary Fibrosis: Research of Efficacy and Safety Outcomes (CAPACITY (Study 004 (NCT00287716)) and Study 006 (NCT00287729))) and Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND (Study 016 (NCT01366209)) trials were included in the analysis (n=1247). Descriptive statistics and a linear mixed-effects model (slope analysis) for annual rate of decline in forced vital capacity (FVC) by dose intensity were performed. Treatment-emergent AEs (TEAEs) were summarised and grouped by dose intensity or body size. Results Dose reductions and interruptions occurred in 76.9% (95% CI 73.4% to 80.1%) and 46.5% (95% CI 42.6% to 50.6%) of patients receiving pirfenidone vs 72.0% (95% CI 68.3% to 75.4%) and 31.1% (95% CI 27.5% to 34.9%) of patients receiving placebo, respectively. Dose interruptions tended to occur during the first 6 months of treatment, whereas dose reductions exhibited more variability. Less FVC decline from baseline was observed in patients receiving pirfenidone versus placebo at >90% dose intensity (p<0.001) or ≤90% dose intensity (p=0.0191), showing treatment benefit in both subgroups of dose intensity. No meaningful relationship between weight and TEAEs was observed. Conclusion Dose interruptions, which may be required to manage TEAEs, mostly occurred during the first 6 months of treatment. Despite dose reductions and interruptions, most patients with IPF maintained relatively high dose intensity on pirfenidone, without compromising its treatment effect compared with placebo. Trial registration numbers NCT00287729, NCT00287716, NCT01366209.