Interpretation of time-to-event outcomes in randomized trials: an online randomized experiment.

Background: Multiple features in the presentation of randomized controlled trial (RCT) results are known to influence comprehension and interpretation. We aimed to compare interpretation of cancer RCTs with time-to-event outcomes when the reported treatment effect measure is the hazard ratio (HR), difference in restricted mean survival times (RMSTD), or both (HR+RMSTD). We also assessed the prevalence of misinterpretation of the HR. Methods: We carried out a randomized experiment. We selected 15 cancer RCTs with statistically significant treatment effects for the primary outcome. We masked each abstract and created three versions reporting either the HR, RMSTD, or HR+RMSTD. We randomized corresponding authors of RCTs and medical residents and fellows to one of 15 abstracts and one of 3 versions. We asked how beneficial the experimental treatment was (0-10 Likert scale). All participants answered a multiple-choice question about interpretation of the HR. Participants were unaware of the study purpose. Results: We randomly allocated 160 participants to evaluate an abstract reporting the HR, 154 to the RMSTD, and 155 to both HR+RMSTD. The mean Likert score was statistically significantly lower in the RMSTD group when compared with the HR group (mean difference -0.8, 95% confidence interval, -1.3 to -0.4, P < 0.01) and when compared with the HR+RMSTD group (difference -0.6, -1.1 to -0.1, P = 0.05). In all, 47.2% (42.7%-51.8%) of participants misinterpreted the HR, with 40% equating it with a reduction in absolute risk. Conclusion: Misinterpretation of the HR is common. Participants judged experimental treatments to be less beneficial when presented with RMSTD when compared with HR. We recommend that authors present RMST-based measures alongside the HR in reports of RCT results.

Representation of obese participants in obesity-related cancer randomized trials.

Background: Obesity is a risk factor for numerous cancer types, and may influence cancer treatment outcomes. Underrepresentation of obese patients in obesity-related cancer randomized controlled trials (RCTs) may affect generalizability of results. We aimed to assess the reporting of information about eligibility and enrollment of obese participants in obesity-related cancer RCTs. Methods: We conducted a systematic review of RCTs of 10 obesity-related cancer types (esophagus, colon/rectum, liver, gallbladder, pancreas, postmenopausal breast, endometrium, ovary, kidney, and thyroid cancer). We selected RCTs published between 2013 and 2016 in five major journals. For each trial, we examined the article, the protocol, and the registration record. We assessed if eligibility criteria limiting the enrollment of obese participants were reported, the proportion of obese participants that were enrolled, and if a subgroup analysis according to obesity status was reported. We systematically contacted corresponding authors and asked for information about eligibility of obese participants and the proportion of obese participants. Results: We included 76 RCTs. Colon/rectum (n = 20), postmenopausal breast (n = 11), and kidney (n = 11) cancers were the most frequent types. Based on publicly available sources, information on the eligibility of obese participants was available in 5 (7%) trials. The proportion of obese participants could be estimated in 9 (12%) trials only. We found a subgroup analysis in only one RCT. When considering unpublished information, the eligibility of obese participants was explicitly stated in 31 (41%) trials but it was unclear if the remaining 59% trials considered obese participants as eligible and what proportion of obese participants was included. Across 22 trials, the median proportion of obese participants included was 18% (Q1-Q3 11-23). Conclusion: Information on the eligibility and enrollment of obese participants in cancer RCTs is dramatically underreported. More transparency is needed to understand the applicability of obesity-related cancer RCT results to obese patients with cancer.

Non-opioid analgesics in adults after major surgery: systematic review with network meta-analysis of randomized trials.

BACKGROUND: Morphine, and analgesics other than morphine (AOM), are commonly used to treat postoperative pain after major surgery. However, which AOM provides the best efficacy-safety profile remains unclear. METHODS: Randomized trials of any AOM alone or any combination of AOM compared with placebo or another AOM in adults undergoing major surgery and receiving morphine patient-controlled analgesia were included in a network meta-analysis. The outcomes were morphine consumption, pain, incidence of nausea, vomiting at 24 h and severe adverse effects. RESULTS: 135 trials (13,287 patients) assessing 14 AOM alone or in combination were included. For all outcomes, comparisons with placebo were over-represented. Few trials assessed combinations of two AOM and none the combination of three or more. Network meta-analysis found morphine consumption reduction was greatest with the combination of two AOM (acetaminophen + nefopam, acetaminophen + NSAID, and tramadol + metamizol): -23.9 (95% CI -40;-7.7), -22.8 (-31.5;-14) and -19.8 (35.4;-4.2) mg per 24 h, respectively. For AOM used alone, morphine consumption reduction was greatest with α-2 agonists, NSAIDs, and COX-2 inhibitors. When considering the risk of nausea, NSAIDs, corticosteroids and α-2 agonists used alone were the most efficacious (OR 0.7 [95% CI: 0.6-0.8], 0.36 [0.18-0.79], 0.41 [0.15-.64], respectively). The paucity of severe adverse effects data did not allow assessment of efficacy-safety balance. CONCLUSIONS: A combination of aetaminophen with either an NSAID or nefopam was superior to most AOM used alone, in reducing morphine consumption. Efficacy was best with three AOM used alone (α-2 agonists, NSAIDs and COX-2 inhibitors) and least with tramadol and acetaminophen. There is insufficient trial data reporting adverse events. CLINICAL TRIAL REGISTRATION: PROSPERO: CRD42013003912.

Accuracy of multi-detector computed tomographic angiography assisted by post-processing software for diagnosis atheromatous renal artery stenosis.

PURPOSE: To compare the diagnostic performance of MDCTA versus renal angiography in the detection of>50% renal artery stenosis in patients suspected of reno-vascular hypertension. MATERIALS AND METHODS: Between January 2005 and January 2010, 92 MDCTA and renal arteriographies were retrospectively analysed. Renal angiographies were read by one interventional radiologist. Three blinded independent readers (two senior radiologists and one technician) scored MDCTA images using three different approaches. Reader 1 scored stenosis using only MPR and MIP. Reader 2 (technician) used only proprietary automatic arterial segmentation software. Reader 3 used the cited software, using manual diameter measurements. RESULTS: A total of 92 patients, (235 renal arteries) were assessed in which 48 significant stenosis were found by arteriography. Sensitivity, specificity, of MDCTA compared to renal arteriography were respectively per patient for reader 1: (88%; 80%); for reader 2: (58%; 80%); for reader 3: (96%; 90%) (P<.02). CONCLUSION: When using automated vessel analysis software edited by a radiologist, MDCTA studies had a Sensibility/Specificity of 96%/90% to detect>50% renal artery stenosis.

[Drug-eluting stents: do we respect the on-label use in our daily practice?]. / Endoprothèses coronaires actives: respectons-nous les recommandations de la Société française de cardiologie et de la Haute Autorité de santé dans notre pratique quotidienne ?

Drug-eluting stents (DES) are known to dramatically reduce restenosis. However, they are more expansive than bare-metal stents (BMS) and they require prolonged dual antiplatelet therapy. In France, the French Society of Cardiology and the "Haute Autorité de santé" have defined recommendations for the use of DES (restricted to patients in high-risk group). The aim of this work was to evaluate our practice (whether these recommendations were well respected or not in our center). Between November 2007 and January 2008 then November 2008 and January 2009 we evaluated all Percutaneous Coronary Interventions (PCI). Two hundred and sixteen (216) patients (mean age 65 ± 13 years, 164 (76 %) were males and, 41 (19 %) were diabetics) had a PCI for stable angina or silent ischemia (47 %), unstable angina or acute coronary syndrome (ACS) ST- (26 %), ACS ST+<48 hours (24 %) or ACS ST+>48 hours-1 month (3 %). Two hundred and seventy six (276) stents were used, including 35 % of DES. The recommendations were well respected in 82 % of cases. However, 27 % of BMS were implanted in patients in whom DES were indicated. The French recommendations for DES are a reference to help practitioners, but they require to be adapted to each patient, depending on clinical state and their ability to be treated with prolonged dual antiplatelet therapy.

Perfusion defects after pulmonary embolism: risk factors and clinical significance.

BACKGROUND: Little is known about residual abnormalities after pulmonary embolism (PE). OBJECTIVES: To assess risk factors and the clinical significance of perfusion defects in patients with PE. PATIENTS/METHODS: Consecutive patients receiving at least 3 months of anticoagulant for an acute PE were included in a prospective cohort study. Ventilation/perfusion lung scan, echocardiography, 6-min walk test, thrombophilia and hemostatic variables were performed 6-12 months after PE. Perfusion defect was defined as a perfusion defect in at least two segments. RESULTS: Seventy-three out of 254 patients (29%) had perfusion defects during follow-up (median 12 months) and were more likely to have dyspnea, had a higher systolic pulmonary arterial pressure [39 mmHg (SD) (12) vs. 31 mmHg (8); P < 0.001] and walked a shorter distance during the 6-min walk test [374 m (122) vs. 427 m (99); P = 0.004]. Age [odds ratio (OR) 1.35; 95% confidence interval (CI), 1.11-1.63], the time interval between symptom onset and diagnosis (OR, 1.17; 95% CI, 1.04-1.31), pulmonary vascular obstruction at the onset of PE (OR, 1.34; 95% CI, 1.16-1.55) and previous venous thromboembolism (OR 2.06; 95% CI, 1.03-4.11) were independent predictors of perfusion defect after treatment of acute PE. Total tissue factor pathway inhibitor concentration was associated with perfusion defects. CONCLUSIONS: Perfusion defects are associated with an increase in pulmonary artery pressure (PAP) and functional limitation. Age, longer times between symptom onset and diagnosis, initial pulmonary vascular obstruction and previous venous thromboembolism were associated with perfusion defects.

Multicentre trial evaluating alveolar NO fraction as a marker of asthma control and severity.

BACKGROUND: Exhaled NO can be partitioned in its bronchial and alveolar sources, and the latter may increase in the presence of recent asthmatic symptoms and in refractory asthma. The aim of this multicentre prospective study was to assess whether alveolar NO fraction and FE(NO) could be associated with the level of asthma control and severity both at the time of measurement and in the subsequent 3 months. METHODS: Asthma patients older than 10 years, nonsmokers, without recent exacerbation and under regular treatment, underwent exhaled NO measurement at multiple constant flows allowing its partition in alveolar (with correction for back-diffusion) and bronchial origins based on a two-compartment model of NO exchange; exhaled NO fraction at 50 ml/s (FE(NO,0.05)) was also recorded. On inclusion, severity was assessed using the four Global initiative for asthma (GINA) classes and control using Asthma Control Questionnaire (ACQ). Participants were followed-up for 12 weeks, control being assessed by short-ACQ on 1st, 4th, 8th and 12th week. RESULTS: Two-hundred patients [107 children and 93 adults, median age (25th; 75th percentile) 16 years (12; 38)], 165 receiving inhaled corticosteroid, were included in five centres. The two-compartment model was valid in 175/200 patients (87.5%). Alveolar NO and FE(NO,0.05) did not correlate to control on inclusion or follow-up (either with ACQ /short-ACQ values or their changes), nor was influenced by severity classes. Alveolar NO negatively correlated to MEF(25-75%) (rho = -0.22, P < 0.01). CONCLUSION: Alveolar and exhaled NO fractions are not indexes of control or severity in asthmatic children and adults under treatment.

Optimizing the size variation threshold for the CT evaluation of response in metastatic renal cell carcinoma treated with sunitinib.

BACKGROUND: In metastatic renal cell carcinoma (mRCC), antiangiogenic treatments rarely achieve a reduction of -30% in the sum of longest diameters (SLD) of target lesions required by RECIST for an 'objective response', although they objectively improve progression-free survival (PFS). We sought to determine a threshold for the computed tomography evaluation of these patients' best reflecting patient outcome. PATIENTS AND METHODS: In 334 mRCC patients treated with sunitinib, we tested thresholds from -45% to +10%. We classified patients as 'responders' when the best relative variation of the sum of longest diameters (DeltaSLD) reached the tested threshold and as 'nonresponders' otherwise. For each tested threshold, the median PFS of the two groups were compared. Receiver operating characteristic (ROC) analysis was also carried out among the 103 patients that progressed during follow-up. Finally, the 'optimal' threshold was retested on an independent cohort of 39 patients. RESULTS: The DeltaSLD threshold of -10% gave the most significant difference. It divided patients into 256 responders and 78 nonresponders (median PFS 11.1 and 5.6 months). The same -10% threshold was found using the ROC analysis. Results were confirmed on the external validation cohort. CONCLUSION: A variation of -10% in the SLD accurately and rapidly identifies mRCC patients benefiting from sunitinib.

[Hospital LOS, medical complexity and deprivation indicators]. / Lien précarité - durée et complexité des séjours hospitaliers en secteur de court séjour.

BACKGROUND: Several studies have shown that socioeconomic deprivation is associated with increased hospitalization lengths of stay (LOS) and costs. Yet, the French DRG-based information system (PMSI) does not take deprived situations into account. Hence, we aimed at extracting routinely available variables measuring deprivation from the Hospital Information System and at assessing their association with severity of illness and hospital LOS. METHODS: We performed record linkage between the PMSI database concerning stays of patients aged more than 16years in the short-stay sector of Assistance publique-Hôpitaux de Paris in 2007 and an administrative database which provided the following deprivation measures: recipients of Couverture Médicale Universelle (basic or complementary health insurances adapted for underprivileged French citizens) or Aide Médicale d'Etat (health and medical emergency insurances adapted for underprivileged non French citizens living in France) and homeless patients. We compared length of stays showing a deprivation measure to others after adjustment on morbidity, age and sex. RESULTS: Among 352,721 stays, the prevalence of the deprivation measures ranged from 0.71% for "homelessness" to 6.24% for complementary Couverture Médicale Universelle. Stays showing a deprivation measure had specific illnesses and had more frequently associated comorbidities or complications than others. After adjustment, deprivation measures were associated with significantly increased LOS (by 5% for Couverture Médicale Universelle to 48% for emergency Aide Médicale d'Etat. CONCLUSION: Routine extraction of deprivation measures from Hospital Information Systems is feasible. Age, sex and illness being equal, these deprivation measures were associated with more complicated cases and increased LOS. We recommend that case mix-based hospital prospective payment systems take socioeconomic deprivation into account.

Exhaled nitric oxide in cystic fibrosis: relationships with airway and lung vascular impairments.

A reduction of exhaled nitric oxide (NO) fraction and endothelial-mediated dysfunction have been reported in cystic fibrosis (CF). The aims of the present study were to search for relationships between flow-independent NO exchange parameters (bronchial NO flux (J'(aw,NO)) and alveolar NO concentration (C(A,NO))) and lung function tests characterising airflow limitation and pulmonary vascular bed (capillary blood volume and physiological dead space/tidal volume (V(D)/V(T)) ratio on exercise). In total, 34 patients (16 children, 18 adults) with CF, without resting pulmonary hypertension, underwent spirometry, exhaled NO measurement (multiple constant flow analytical method), gas transfer assessment (carbon monoxide and NO, allowing the calculation of capillary volume and membrane conductance) and a graded exercise test with oxygen uptake (V'(O(2))), carbon dioxide production (V'(CO(2))) and arterial blood gas evaluations. Both J'(aw,NO) and C(A,NO )correlated positively with airflow limitation. C(A,NO) correlated positively with capillary/alveolar volume. During exercise, criteria of mild pulmonary vascular disease were evidenced in some patients that participated in exercise limitation (negative correlation between physiological V(D)/V(T) and peak V'(O(2))). C(A,NO )at rest correlated positively with these parameters of wasted ventilation during exercise (physiological V(D)/V(T), minute ventilation (V'(E))/V'(CO(2)) at ventilatory threshold and V'(E)/V'(CO(2)) slope). Flow-independent exhaled NO parameters are linked to airway and early vascular diseases in patients with CF.