Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials

Background Idiopathic pulmonary fibrosis is a progressive and fatal lung disease with inevitable loss of lung function. The CAPACITY programme (studies 004 and 006) was designed to confirm the results of a phase 2 study that suggested that pirfenidone, a novel antifibrotic and anti-inflammatory drug, reduces deterioration in lung function in patients with idiopathic pulmonary fibrosis. Methods In two concurrent trials (004 and 006), patients (aged 40–80 years) with idiopathic pulmonary fibrosis were randomly assigned to oral pirfenidone or placebo for a minimum of 72 weeks in 110 centres in Australia, Europe, and North America. In study 004, patients were assigned in a 2:1:2 ratio to pirfenidone 2403 mg/day, pirfenidone 1197 mg/day, or placebo; in study 006, patients were assigned in a 1:1 ratio to pirfenidone 2403 mg/day or placebo. The randomisation code (permuted block design) was computer generated and stratified by region. All study personnel were masked to treatment group assignment until after final database lock. Treatments were administered orally, 801 mg or 399 mg three times a day. The primary endpoint was change in percentage predicted forced vital capacity (FVC) at week 72. Analysis was by intention to treat. The studies are registered with ClinicalTrials.gov, numbers NCT00287729 and NCT00287716. Findings In study 004, 174 of 435 patients were assigned to pirfenidone 2403 mg/day, 87 to pirfenidone 1197 mg/day, and 174 to placebo. In study 006, 171 of 344 patients were assigned to pirfenidone 2403 mg/day, and 173 to placebo. All patients in both studies were analysed. In study 004, pirfenidone reduced decline in FVC (p=0·001). Mean FVC change at week 72 was −8·0% (SD 16·5) in the pirfenidone 2403 mg/day group and −12·4% (18·5) in the placebo group (difference 4·4%, 95% CI 0·7 to 9·1); 35 (20%) of 174 versus 60 (35%) of 174 patients, respectively, had a decline of at least 10%. A significant treatment effect was noted at all timepoints from week 24 and in an analysis over all study timepoints (p=0·0007). Mean change in percentage FVC in the pirfenidone 1197 mg/day group was intermediate to that in the pirfenidone 2403 mg/day and placebo groups. In study 006, the difference between groups in FVC change at week 72 was not significant (p=0·501). Mean change in FVC at week 72 was −9·0% (SD 19·6) in the pirfenidone group and −9·6% (19·1) in the placebo group, and the difference between groups in predicted FVC change at week 72 was not significant (0·6%, −3·5 to 4·7); however, a consistent pirfenidone effect was apparent until week 48 (p=0·005) and in an analysis of all study timepoints (p=0·007). Patients in the pirfenidone 2403 mg/day group had higher incidences of nausea (125 [36%] of 345 vs 60 [17%] of 347), dyspepsia (66 [19%] vs 26 [7%]), vomiting (47 [14%] vs 15 [4%]), anorexia (37 [11%] vs 13 [4%]), photosensitivity (42 [12%] vs 6 [2%]), rash (111 [32%] vs 40 [12%]), and dizziness (63 [18%] vs 35 [10%]) than did those in the placebo group. Fewer overall deaths (19 [6%] vs 29 [8%]) and fewer deaths related to idiopathic pulmonary fibrosis (12 [3%] vs 25 [7%]) occurred in the pirfenidone 2403 mg/day groups than in the placebo groups. Interpretation The data show pirfenidone has a favourable benefit risk profile and represents an appropriate treatment option for patients with idiopathic pulmonary fibrosis.

Prospective comparison of clinical prognostic scores in elderly patients with pulmonary embolism

Background: The Geneva Prognostic Score (GPS), the Pulmonary Embolism Severity Index (PESI), and its simplified version (sPESI) are well known clinical prognostic scores for pulmonary embolism (PE).Objectives: To compare the prognostic performance of these scores in elderly patients with PE. Patients/Methods: In a multicenter Swiss cohort of elderly patients with venous thromboembolism, we prospectively studied 449 patients aged ≥65 years with symptomatic PE. The outcome was 30-day overall mortality. We dichotomized patients as low- vs. higher-risk in all three scores using the following thresholds: GPS scores ≤2 vs. >2, PESI risk classes I-II vs. III-V, and sPESI scores 0 vs. ≥1. We compared 30-day mortality in low- vs. higher-risk patients and the areas under the receiver operating characteristic curve (ROC). Results: Overall, 3.8% of patients (17/449) died within 30 days. The GPS classified a greater proportion of patients as low risk (92% [413/449]) than the PESI (36.3% [163/449]) and the sPESI (39.6% [178/449]) (P<0.001 for each comparison). Low-risk patients based on the sPESI had a mortality of 0% (95% confidence interval [CI] 0-2.1%) compared to 0.6% (95% CI 0-3.4%) for low-risk patients based on the PESI and 3.4% (95% CI 1.9-5.6%) for low-risk patients based on the GPS. The areas under the ROC curves were 0.77 (95%CI 0.72-0.81), 0.76 (95% CI 0.72-0.80), and 0.71 (95% CI 0.66-0.75), respectively (P=0.47). Conclusions: In this cohort of elderly patients with PE, the GPS identified a higher proportion of patients as low-risk but the PESI and sPESI were more accurate in predicting mortality.

Distribution pattern of infrageniculate arterial obstructions in patients with diabetes mellitus and renal insufficiency - implications for revascularization

BACKGROUND: Diabetes mellitus (DM) and renal insufficiency (RI) were shown to be associated with an obstructive lesion pattern favouring distal lower limb arterial segments in patients with peripheral arterial disease (PAD). We hypothesized that presence of DM is associated with pronounced involvement of the tibioperoneal arteries, whereas RI predominantly affects the pedal arch. PATIENTS AND METHODS: A consecutive series of PAD patients (mean age 75 +/- 10 years, 40 women) with RI alone (n = 15), RI and DM (n = 25), DM alone (n = 25) and without RI or DM (n = 25) underwent diagnostic angiography. We analyzed the obstructive burden of different segments of the infrageniculate arterial tree using the Bollinger score as well as accessibility of pedal arteries for bypass surgery. RESULTS: In patients with DM and in patients with RI the mean total obstructive burden was higher in pedal as compared to tibioperoneal arteries (9.79 +/- 4.60 vs. 6.99 +/- 3.45, p = 0.03;10.50 +/- 5.53 vs. 6.88 +/- 4.12, p = 0.05, respectively). However, rates of patency of at least one pedal artery were significantly lower in patients with RI and RI/DM as compared to controls (47% and 48% vs. 80%, respectively; p = 0.007), whereas patency was comparable between patients with diabetes alone and controls (72% vs. 80%, ns). Rates of viability of pedal arteries as an attachment site for distal bypass was 80%, 68%, 47% and 44% in controls, patients with DM alone, RI alone and RI/DM, respectively (p = 0.0042). CONCLUSIONS: In contrast to previous anecdotal observations, both DM and RI are associated with a high atherosclerotic burden of the pedal arch in the present angiographic series. The presence of RI, however, is associated with a lower patency of the pedal arch as compared to the presence of DM alone, and more than fifty percent patients are unsuitable for distal bypass grafting.

Markers for silent atrial fibrillation in esophageal long-term electrocardiography.

PURPOSE Paroxysmal atrial fibrillation (PAF) often remains undiagnosed. Long-term surface ECG is used for screening, but has limitations. Esophageal ECG (eECG) allows recording high quality atrial signals, which were used to identify markers for PAF. METHODS In 50 patients (25 patients with PAF; 25 controls) an eECG and surface ECG was recorded simultaneously. Partially A-V blocked atrial runs (PBARs) were quantified, atrial signal duration in eECG was measured. RESULTS eECG revealed 1.8‰ of atrial premature beats in patients with known PAF to be PBARs with a median duration of 853ms (interquartile range (IQR) 813-1836ms) and a median atrial cycle length of 366ms (IQR 282-432ms). Even during a short recording duration of 2.1h (IQR 1.2-17.2h), PBARs occurred in 20% of PAF patients but not in controls (p=0.05). Left atrial signal duration was predictive for PAF (72% sensitivity, 80% specificity). CONCLUSIONS eECG reveals partially blocked atrial runs and prolonged left atrial signal duration - two novel surrogate markers for PAF.