Francesco Cavalli

Pirfenidone, nintedanib and N-acetylcysteine for the treatment of idiopathic pulmonary fibrosis: A systematic review and meta-analysis

BACKGROUND The prevalence of idiopathic pulmonary fibrosis (IPF) is increasing every year. Pirfenidone and nintedanib were approved for treatment of IPF in 2014, but they received only a conditional recommendation for use and, thus, to date no drugs are strongly recommended for IPF. The aim of this study was to assess the effectiveness and safety of the currently approved drugs for IPF and N-acetylcysteine (NAC), the most debated drug in the last update of guidelines for IPF treatment. METHODS RCTs in IPF were identified searching from databases of published and unpublished studies. The influence of pirfenidone, nintedanib and NAC on clinical outcomes, safety, and mortality was assessed via pair-wise meta-analysis. RESULTS Ten papers (3847 IPF patients; 2254 treated; 1593 placebo) were included in this study. Our results showed that both pirfenidone and nintedanib, but not NAC, were significantly effective in reducing FVC decline and the risk of FVC ≥10% decline in percent predicted over 12 months. Nintenadib significantly protected against the risk of acute exacerbation and mortality. Pirfenidone and nintedanib showed a similar and good safety profile, whereas NAC provided a signal for increased adverse events. CONCLUSIONS The rank of effectiveness emerging from this meta-analysis represents an indirect indicator of potential differences between currently approved doses of pirfenidone and nintedanib. Direct comparisons are necessary to assess this matter, and well designed bench-to-bedside studies would permit to understand the potential of combined, sequential, or adjunctive treatment regimens in which perhaps NAC may have a role for specific clusters of IPF patients.

Optimizing drug delivery in COPD: The role of inhaler devices

BACKGROUND Inhaled medication is the cornerstone of the pharmacological treatment for patients with asthma and chronic obstructive pulmonary disease (COPD). Several inhaler devices exist, and each device has specific characteristics to achieve the optimal inhalation of drugs. The correct use of inhaler devices is not granted and patients may incur in mistakes when using pressurized metered-dose inhalers (pMDIs) or dry-powder inhaler (DPIs). The incorrect use of inhaler devices can lead to a poorly controlled disease status. Unfortunately, guidelines provide limited guidance regarding the choice of devices. This article presents a review of the literature on different inhaler device requirements. Data from literature (PubMed and Google Scholar) on the commercially available inhaler devices have been evaluated and the history of inhaler medicine described. Furthermore, advantages and disadvantages of each type of device have been analyzed. The evaluation of literature indicated the availability of robust data on the devices characteristics and factors influencing selection of delivery devices. Each type of device has its own pro and cons. The age, cognitive status, visual acuity, manual dexterity, manual strength and ability to coordinate the inhaler actuation with inhalation may be as important as the disease severity in determining the correct approach to delivery of respiratory medication. The administration of effective therapies via a device that is simple to use and accepted by patients may help to improve treatment outcomes in patients with COPD.

Effect of adding roflumilast or ciclesonide to glycopyrronium on lung volumes and exercise tolerance in patients with severe COPD: A pilot study

COPD is a chronic inflammatory disease characterized by partially reversible airflow limitation. Currently, phosphodiesterase4 inhibitors and inhaled corticosteroids are anti-inflammatory agents that can be used in patients with severe COPD, always added to at least one bronchodilator. In this prospective interventional pilot study, we investigated the effect of adding oral roflumilast 500 μg once-daily or inhaled ciclesonide 160 μg once-daily to glycopyrronium 44 μg once-daily on lung volumes and exercise tolerance in 16 patients with severe COPD, of which 8 received roflumilast and 8 ciclesonide for 8 weeks. Detailed pulmonary function and endurance shuttle tests were performed at time 0, after 2 weeks of glycopyrronium and after 8 weeks of add-on of either roflumilast or ciclesonide. Glycopyrronium increased significantly (p < .05) FEV1, and IC at rest and at the peak of exercise and improved the walking distance. In particular, it induced a bronchodilation similar to that elicited by salbutamol 800 μg. After 8 weeks of combination therapy, both the trough and the post bronchodilator FEV1 further improved but the increase was very small and not significant. Furthermore, adding either roflumilast or ciclesonide did not provide a further improvement in IC and walking distance. This study provides further evidence of the efficacy of glycopyrronium 44 μg once daily, confirming that improvements in airflow are associated with increases in IC and improvements in exercise tolerance. The addition of anti-inflammatory drugs, regardless of class used, does not seem to add benefits on lung function and exercise tolerance, likely because of the large effect induced by glycopyrronium.

Impact of pulmonary vascular volume on mortality in IPF: is it time to reconsider the role of vasculature in disease pathogenesis and progression?

The article by Jacob et al. [1], reporting a computer-based computed tomography (CT) approach able to provide a precise quantification of disease extension in idiopathic publmonary fibrosis (IPF) patients by means of specific computer algorithm, CALIPER, is very interesting. Vascular disarrangement as a possible central event in disease progression in idiopathic pulmonary fibrosis (IPF) http://ow.ly/hln3307TyBk

A six minute walking test (6MWT) derived index (O2-GAP) predicts mortality in IPF

Background: Although IPF mortality in clinical trials appears to be of 8-10% in the first year of observation, predicting progression remains a challenging task. Aim of the study: To build a mortality prediction model by means of a previously validated 6 MWT derived index, O2-Gap*, in a cohort of anti-fibrotic naive IPF patients and to test it on a population treated according to a fixed protocol. Methods: Clinical data and the O2-Gap calculated upon an equation incorporating 6MWT duration, O 2 saturation, distance walked as % predicted (age, gender, height, weight) and SpO 2 recovery time, were retrospectively analyzed in a group of 52 patients with an 18 months follow up to build a mortality prediction model using Cox survival analysis and ROC analysis. The model was then applied to a group of pirfenidone (PF)-treated patients (n=49, mean follow up 14,7 months). Results: Observed mortality was 40.4% in the derivation population, with a death RR of 1.4 (CL95% 1.1-1.8) per unit of O2-Gap. With a O2-Gap threshold of 3.2 the test showed sensitivity and specificity values of 62% and 77.4% (area under the ROC curve: 77.5 CI95% 64.5-90.4). Consistent with the model, IPF treated patients with O2-GAP >3 showed an increased mortality rate (n=15, 9 deaths=60%,) compared to those with a Conclusions: Even with the limitation of the small population, this study indicates the O2-Gap, a simple index that can be automatically calculated on an electronic pulse-oxymeter, as a strong mortality predictor and a potentially useful clinical tool, once validated in larger cohort studies. *Patent # PCT/IT2010/000361.