Adeline Paris

Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomised crossover ex vivo study in healthy volunteers.

The new anticoagulants dabigatran and rivaroxaban can be responsible for haemorrhagic complications. As for any anticoagulant, bleeding management is challenging. We aimed to test the effect of all putative haemostatic agents on the anticoagulant activity of these new drugs using thrombin generation tests. In an ex vivo study, 10 healthy white male subjects were randomised to receive rivaroxaban (20 mg) or dabigatran (150 mg) in one oral administration. After a two weeks washout period, they received the other anticoagulant. Venous blood samples were collected just before drug administration (H0) and 2 hours thereafter. Reversal of anticoagulation was tested in vitro using prothrombin complex concentrate (PCC), rFVIIa or FEIBA® at various concentrations. Rivaroxaban affects quantitative and kinetic parameters, including the endogenous thrombin potential (ETP-AUC and more pronouncedly the thrombin peak), the lag-time and time to peak. PCC strongly corrected ETP-AUC, whereas rFVIIa only modified the kinetic parameters. FEIBA corrected all parameters. Dabigatran specially affects the kinetics of thrombin generation with prolonged lag-time and time to peak. Although PCC increased ETP-AUC, only rFVIIa and FEIBA corrected the altered lag-time. For both anticoagulants, lower doses of FEIBA, corresponding to a quarter to half the dose usually used, have potential reversal profile of interest. In conclusion, some non-specific reversal agents appear to be able to reverse the anticoagulant activity of rivaroxaban or dabigatran. However, clinical evaluation is needed regarding haemorrhagic situations, and a meticulous risk-benefit evaluation regarding their use in this context is required.

Comparison of nine blood tests and transient elastography for liver fibrosis in chronic hepatitis C: the ANRS HCEP-23 study.

BACKGROUND & AIMS Blood tests and transient elastography (Fibroscan™) have been developed as alternatives to liver biopsy. This ANRS HCEP-23 study compared the diagnostic accuracy of nine blood tests and transient elastography (Fibroscan™) to assess liver fibrosis, vs. liver biopsy, in untreated patients with chronic hepatitis C (CHC). METHODS This was a multicentre prospective independent study in 19 French University hospitals of consecutive adult patients having simultaneous liver biopsy, biochemical blood tests (performed in a centralized laboratory) and Fibroscan™. Two experienced pathologists independently reviewed the liver biopsies (mean length=25±8.4 mm). Performance was assessed using ROC curves corrected by Obuchowskis method. RESULTS Fibroscan™ was not interpretable in 113 (22%) patients. In the 382 patients having both blood tests and interpretable Fibroscan™, Fibroscan™ performed similarly to the best blood tests for the diagnosis of significant fibrosis and cirrhosis. Obuchowskis measure showed Fibrometer® (0.86), Fibrotest® (0.84), Hepascore® (0.84), and interpretable Fibroscan™ (0.84) to be the most accurate tests. The combination of Fibrotest®, Fibrometer®, or Hepascore® with Fibroscan™ or Apri increases the percentage of well classified patients from 70-73% to 80-83% for significant fibrosis, but for cirrhosis a combination offers no improvement. For the 436 patients having all the blood tests, AUROCs ranged from 0.82 (Fibrometer®) to 0.75 (Hyaluronate) for significant fibrosis, and from 0.89 (Fibrometer® and Hepascore®) to 0.83 (FIB-4) for cirrhosis. CONCLUSIONS Contrarily to blood tests, performance of Fibroscan™ was reduced due to uninterpretable results. Fibrotest®, interpretable Fibroscan™, Fibrometer®, and Hepascore® perform best and similarly for diagnosis of significant fibrosis and cirrhosis.

Improvement of the comprehension of written information given to healthy volunteers in biomedical research: a single-blind randomized controlled study.

Writing an informed consent form (ICF) for biomedical research is a difficult task. We conducted a multicenter single‐blind randomized controlled trial to identify whether a working group or the systematic improvement in lexico‐syntactic readability or an association of the two could increase the comprehension of the written information given to healthy volunteers enrolled in biomedical research. Participants were randomized to read one of four versions of the ICF: unchanged ICF (A), ICF with systematic lexico‐syntactic readability improvement (B), ICF modified by a working group (C), and ICF modified by the working group followed by systematic lexico‐syntactic improvement (D). The primary end‐point was the objective comprehension score at day 0 for each study group. The scores of objective comprehension at day 0 were statistically different between the four study groups (anovaP = 0.020). The pairwise analysis showed an improvement in the working group vs. the unchanged group (P = 0.003), and a tendency to improvement in the group who read the ICF modified using lexico‐syntactic readability and in the group who read the ICF modified using the two methods (P = 0.020 and 0.027 respectively). We conducted a two‐way anova to identify some characteristics of the population which could explain this score. There was a significant interaction between the type of informed consent document (ICD) and the gender. Improving the ICD in phase I biomedical research leads to better comprehension, whether the method used is systematic lexico‐syntactic improvement or a review by a working group. The improvement is specifically observed in men compared with women. Conversely, while both methods diverge in their effect on lexico‐syntactic readability, their association is not mandatory. We suggest that in all phase I clinical trials, the ICF be improved by either method.

Effect of homeopathy on analgesic intake following knee ligament reconstruction: a phase III monocentre randomized placebo controlled study

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT The efficacy of homeopathy is still under debate and a recent meta-analysis recommended further randomized double-blind clinical trials to identify any clinical situation in which homeopathy might be effective. WHAT THIS STUDY ADDS The complex of homeopathy tested in this study (Arnica montana 5 CH, Bryonia alba 5 CH, Hypericum perforatum 5 CH and Ruta graveolens 3 DH) is not superior to placebo in reducing 24 h morphine consumption after knee ligament reconstruction. AIMS The efficacy of homeopathy is still under debate. The objective of this study was to assess the efficacy of homeopathic treatment (Arnica montana 5 CH, Bryonia alba 5 CH, Hypericum perforatum 5 CH and Ruta graveolens 3 DH) on cumulated morphine intake delivered by PCA over 24 h after knee ligament reconstruction. METHODS This was an add-on randomized controlled study with three parallel groups: a double-blind homeopathic or placebo arm and an open-label noninterventional control arm. Eligible patients were 18-60 years old candidates for surgery of the anterior cruciate ligament. Treatment was administered the evening before surgery and continued for 3 days. The primary end-point was cumulated morphine intake delivered by PCA during the first 24 h inferior or superior/equal to 10 mg day(-1). RESULTS One hundred and fifty-eight patients were randomized (66 in the placebo arm, 67 in the homeopathic arm and 25 in the noninterventional group). There was no difference between the treated and the placebo group for primary end-point (mean (95% CI) 48% (35.8, 56.3), and 56% (43.7, 68.3), required less than 10 mg day(-1) of morphine in each group, respectively). The homeopathy treatment had no effect on morphine intake between 24 and 72 h or on the visual analogue pain scale, or on quality of life assessed by the SF-36 questionnaire. In addition, these parameters were not different in patients enrolled in the open-label noninterventional control arm. CONCLUSIONS The complex of homeopathy tested in this study was not superior to placebo in reducing 24 h morphine consumption after knee ligament reconstruction.

Nitrous Oxide-Oxygen Mixture During Care of Bedsores and Painful Ulcers in the Elderly : A Randomized, Crossover, Open-Label Pilot Study

Bedsore and ulcer care can often be painful and no standardized analgesic method exists today for pain relief during treatment in adults and the elderly. To evaluate the analgesic efficacy of a nitrous oxide-oxygen mixture vs. morphine during painful bedsore and ulcer care in adult and elderly patients, we conducted a randomized, crossover, multicenter, prospective, open-label, pilot study. Thirty-four inpatients, aged 53-96 years (median 84 years), were recruited in Grenoble University Hospital, Annecy Hospital and Chambéry Hospital, France, from January to June 2001. Each of the 34 patients received morphine (M), nitrous oxide-oxygen mixture (E), or morphine+nitrous oxide-oxygen mixture (ME) during painful care in a crossover protocol. Treatments were changed every two days and the study duration was six days. Analgesia was evaluated before and after each care session using a behavioral scale to evaluate pain in noncommunicating adults (ECPA), a visual analog scale (VAS), a global hetero-evaluation scale (GHES), and the DOLOPLUS-2 scale. There was a significant overall difference (P<0.01) among the three treatments. On the ECPA, the average difference after and before care was +5.2+/-8.6 (M), -0.3+/-8 (E), and -0.6+/-7.4 (ME), respectively. There was a significant difference between M and E, and M and ME (each P<0.01). No difference was found between E and ME (P=0.97). There were similar significant differences in the GHES and DOLOPLUS-2 scales (all tests P<0.01). Post hoc comparisons showed a significant difference (P<0.01) between M and E, and between M and ME without any additional effect for M+E. No differences were found with regard to safety or tolerability. This pilot study demonstrates the superiority of nitrous oxide-oxygen mixture over morphine for analgesia. This experience suggests that this mixture has ease of use, rapid effect, and limited contraindications when used during painful bedsore and ulcer care in elderly patients. Furthermore, it is well accepted by these patients and by nursing staff.

Automation of the Hepascore and validation as a biochemical index of liver fibrosis in patients with chronic hepatitis C from the ANRS HC EP 23 Fibrostar cohort.

BACKGROUND Hepascore combining serum bilirubin, gamma glutamyl transpeptidase, hyaluronic acid (HA) and alpha2-macroglobulin with age and sex, was reported as relevant in predicting liver fibrosis in patients with chronic HCV infection and was proposed as an alternative to liver biopsy. METHODS Since an automated HA assay (Latex method, Wako, Japan) became available, we investigated to automate Hepascore by simultaneous measurements of components using an OLYMPUS AU640 analyzer (Tokyo, Japan). For its clinical evaluation, we considered a cohort of chronic HCV patients included in a multicenter prospective study (ANRS HC EP 23 Fibrostar). RESULTS Automated Hepascore was not significantly different than assayed as previously described. An improvement in HA variability was evidenced. In 512 chronic HCV patients, automated Hepascore, using ROC curves analysis, showed good predictive performances for significant fibrosis (AUROC=0.81), severe fibrosis (AUROC=0.82), and cirrhosis (AUROC=0.88). For significant fibrosis, Hepascore (cut-off=0.5) had a sensitivity of 0.77, a specificity of 0.70, a positive predictive value of 0.71 and a negative predictive value (NPV) of 0.77. Hepascore <0.25 could exclude significant fibrosis with a sensitivity of 0.95 and a NPV of 0.90 and Hepascore <0.75 could exclude cirrhosis with a sensitivity of 0.86 and a NPV of 0.97. CONCLUSIONS This study shows that Hepascore, a non-invasive index of liver fibrosis, necessitating only one serum sample, can be totally automated using a single analyzer and confirms that Hepascore accurately predicts liver fibrosis in chronic HCV. Hepascore might be largely used in assessing liver fibrosis as surrogate to the liver biopsy.

Effect of Gelsemium 5CH and 15CH on anticipatory anxiety: a phase III, single-centre, randomized, placebo-controlled study

Therapeutics to treat or prevent anxiety are numerous but many people choose to try non‐conventional medicine such as homeopathy. This study aimed at evaluating the effectiveness of Gelsemium 5CH and 15CH on provoked anxiety in healthy volunteers, in comparison with placebo. This was a double‐blind, single‐centre, randomized, placebo‐controlled study. Eligible healthy men or women aged from 18 to 40 years without a history of psychiatric disorders were randomly allocated to receive Gelsemium 5 or 15CH or placebo. Anxiety was proved by performance of the Stroop colour word test (SCWT). The primary end‐point was anxiety assessed by the State measure of the State‐Trait Anxiety Inventory (STAI‐S) as the absolute value and difference with baseline, according to the treatment received. We included 180 healthy volunteers. The distribution into each treatment group was homogenous. There was no statistical difference between groups for the values of STAI‐S at baseline, just before the SCWT and the difference between these times (1.8 [0.20 to 3.4], 1.0 [−0.6 to 2.6] and 1.4 [−0.3 to 3.0] for Gelsemium 15CH, 5CH and placebo respectively). Likewise, no statistical difference was observed between groups in anxiety as measured by a Visual Analogue Scale and the Competitive State Anxiety Inventory. Mean arterial pressure and heart rate significantly increased (P < 0.001) but no interaction between time prior to provoked anxiety and treatment was shown (P = 0.59 and P = 0.46, respectively). Gelsemium 5CH and 15CH do not prevent anticipatory anxiety in the conditions used in this study.

Evaluation of the effect of one large dose of erythropoietin against cardiac and cerebral ischemic injury occurring during cardiac surgery with cardiopulmonary bypass: a randomized double-blind placebo-controlled pilot study

Cardiac surgery and cardiopulmonary bypass (CPB) induce ischemia–reperfusion and subsequent cellular injury with inflammatory reaction. Clinical and experimental studies suggest that recombinant human erythropoietin (EPO) independently of its erythropoietic effect may be used as a cytoprotective agent against ischemic injury. We tested the hypothesis that one large dose of EPO administered shortly before CPB prevents the elevation of cardiac and cerebral ischemic blood markers as well as the systemic inflammatory response induced by cardiac surgery with CBP through this randomized double‐blind placebo‐controlled pilot trial. Fifty patients scheduled for coronary artery bypass graft (CABG) surgery with CPB were randomly allocated to EPO or control groups. EPO (800 IU/kg intravenously) or placebo (saline) was administered before CPB. The primary end point was to study the effect of EPO administration on several blood markers of myocardial and cerebral ischemia in relation to CABG with CPB. In both groups, surgery increased plasma concentrations of cardiac (troponin T, NT‐proBNP, and creatine kinase MB) and cerebral (S100β protein) markers ischemic as well as the pro‐inflammatory marker interleukin‐6. Compared with the placebo, EPO administration before CPB did not prevent an increase of all these markers following CPB. In conclusion, one large dose of EPO, given shortly before CPB, did not protect against cardiac and cerebral ischemia and inflammatory response occurring during CABG surgery with CPB. Although the long‐term clinical implications remain unknown, the findings do not support use of EPO at this dose as a cytoprotective agent in patients undergoing cardiac surgery.

338 STEATO-HEPATITIS HAS A STRONG IMPACT ON LIVER STIFFNESS MEASURED BY TRANSIENT ELASTOGRAPHY IN CHRONIC HEPATITIS C PATIENTS

pregnancy. LS was measured by Fibroscan either using the M or XL probe. Besides basic gynecological data, BMI and transaminases were obtained. Results: LS could be measured in all 103 women using the M probe except one case where the XL probe was required for reliable interquartile range. 17 women (16.5%) had a pathological LS higher than 8 kPa, four of them higher than 12.5 kPa which is regarded as cut-off value for F4 fibrosis. All women with increased LS were in the third trimester starting with week 31 while all women within the second trimester had normal LS 20% of pregnant women in the third trimester probably due to hemodynamic reasons. Increased LS generally normalizes after delivery. Our data suggest that LS could be an important non-invasive predictor of hepatic complications during pregnancy.

Continuous assessment of volunteers’ satisfaction in clinical research through simplified questionnaires

OBJECTIVES In our clinical research center, a 27 multiple-choice and 3 verbatim questions satisfaction questionnaire has been used since 2008 in order to assess the satisfaction of the volunteers participating in our studies. In this work, we aimed at reducing the number of questions of this cumbersome questionnaire while exploring the same dimensions. MATERIALS AND METHODS We used k-mean and hierarchical clustering to determine which questions provided the same information or, on the contrary, which questions were able to discriminate a satisfied volunteer from an unsatisfied volunteer. RESULTS We were able to reduce our satisfaction questionnaire from 30 questions to 6 closed-ended and 2 open-ended questions, which will allow to save volunteers time while increasing their participation rate. CONCLUSION This questionnaire could be used in other structures practicing clinical research, as part of their quality process.