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Saint-Prex, Switzerland

Albertsen P.C.,University of Connecticut Health Center | Klotz L.,University of Toronto | Tombal B.,Catholic University of Leuven | Grady J.,University of Connecticut Health Center | And 2 more authors.
European Urology | Year: 2014

Background Androgen deprivation therapy (ADT) is associated with increased cardiovascular morbidity. Objective To determine whether cardiovascular morbidity differs following initiation of gonadotropin-releasing hormone (GnRH) agonists compared with an antagonist. Design, setting, and participants Pooled data from six phase 3 prospective randomized trials that recruited 2328 men between 2005 and 2012 to compare the efficacy of GnRH agonists against an antagonist. Men recruited had pathologically confirmed prostate cancer, an Eastern Cooperative Oncology Group score <2, a minimum life expectancy of 12 mo, and were naïve to ADT. Men were excluded if they had a prolonged baseline QT/corrected QT interval, other risk factors for heart failure, hypokalemia or a family history of long QT syndrome, or had another cancer diagnosed within 5 yr. Intervention Men were randomized to receive a GnRH agonist or an antagonist for either 3-7 mo (n = 642) or 12 mo (n = 1686). Treatment groups were balanced for common baseline characteristics. Outcome measurements and statistical analysis Event analysis was based on death from any cause or cardiac events. Data documenting adverse experiences were classified based on the Medical Dictionary for Regulatory Activities. The following conditions defined a cardiac event: arterial embolic or thrombotic events, hemorrhagic or ischemic cerebrovascular conditions, myocardial infarction, and other ischemic heart disease. Kaplan-Meier curves and log-rank tests were used to compare time to a cardiovascular event or death. Results and limitations Among men with preexisting cardiovascular disease, the risk of cardiac events within 1 yr of initiating therapy was significantly lower among men treated with a GnRH antagonist compared with GnRH agonists (hazard ratio: 0.44; 95% confidence interval, 0.26-0.74; p = 0.002). Since our analysis is post hoc, our findings should only be interpreted as hypothesis generating. Conclusions GnRH antagonists appear to halve the number of cardiac events experienced by men with preexisting cardiovascular disease during the first year of ADT when compared to GnRH agonists. © 2013 European Association of Urology.

Bosch E.,University of Valencia | Labarta E.,University of Valencia | Crespo J.,University of Valencia | Simon C.,University of Valencia | And 3 more authors.
Human Reproduction | Year: 2010

Background: The influence of elevated serum progesterone levels during in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles on pregnancy rates is a matter of continued debate among fertility clinicians. Efforts to resolve this question have been impeded by the various assays used to measure progesterone and the different, arbitrary threshold values for defining 'high' progesterone levels. Methods: A non-interventional, retrospective, observational, single-centre cohort study evaluated the relationship between serum progesterone levels on the day of human chorionic gonadotrophin (hCG) administration and the ongoing pregnancy rate in 4032 patients undergoing IVF/ICSI cycles using gonadotrophin-releasing hormone (GnRH) analogues for pituitary down-regulation. Results: Ongoing pregnancy rates were inversely associated with serum progesterone levels on the day of hCG (P < 0.001 for overall trend), irrespective of the GnRH analogue used for pituitary down-regulation. Patients with serum progesterone levels ≤1.5 ng/ml had significantly higher ongoing pregnancy rates than those with progesterone levels >1.5 ng/ml (31.0 versus 19.1; P = 0.00006); odds ratio, 0.53 (95 confidence interval, 0.38-0.72). Multivariate regression analysis showed that daily follicle-stimulating hormone dose, number of oocytes and estradiol values on the day of hCG administration were positively associated with progesterone levels (P < 0.0001 for all). Serum progesterone levels were significantly greater in women treated with GnRH agonists (n = 1177) versus antagonists (n = 2855; 0.84 ± 0.67 versus 0.75 ± 0.66 ng/ml; P = 0.0003). Conclusion: SElevated serum progesterone levels on the day of hCG administration is associated with reduced ongoing pregnancy rates. In particular, serum progesterone levels of >1.5 ng/ml were associated with lower ongoing pregnancy rates following IVF/ICSI cycles irrespective of the GnRH analogue used for pituitary down-regulation. © 2010 The Author.

Travis S.P.L.,Translational Gastroenterology Unit | Danese S.,Istituto Clinico Humanitas | Kupcinskas L.,Lithuanian University of Health Sciences | Alexeeva O.,Regional Clinical Hospital Named after N.A. Semachko | And 7 more authors.
Gut | Year: 2014

Objective Budesonide MMX is a novel oral formulation of budesonide that uses Multi-Matrix System (MMX) technology to extend release to the colon. This study compared the efficacy of budesonide MMX with placebo in patients with active, mild-to-moderate ulcerative colitis (UC). Design Patients were randomised 1:1:1:1 to receive budesonide MMX 9 mg or 6 mg, or Entocort EC 9 mg (budesonide controlled ileal-release capsules; reference arm) or placebo once daily for 8 weeks. The primary endpoint was combined clinical and endoscopic remission, defined as UC Disease Activity Index score ≤1 with a score of 0 for rectal bleeding and stool frequency, no mucosal friability on colonoscopy, and a ≤1-point reduction in endoscopic index score from baseline. Results 410 patients were evaluated for efficacy. Combined clinical and endoscopic remission rates with budesonide MMX 9 mg or 6 mg, Entocort EC and placebo were 17.4%, 8.3%, 12.6% and 4.5%, respectively. The difference between budesonide MMX 9 mg and placebo was significant (OR 4.49; 95% CI 1.47 to 13.72; p=0.0047). Budesonide MMX 9 mg was associated with numerically higher rates of clinical (42.2% vs 33.7%) and endoscopic improvement (42.2% vs 31.5%) versus placebo. The rate of histological healing (16.5% vs 6.7%; p=0.0361) and proportion of patients with symptom resolution (23.9% vs 11.2%; p=0.0220) were significantly higher for budesonide MMX 9 mg than placebo. Adverse event profiles were similar across groups. Conclusion Budesonide MMX 9 mg was safe and more effective than placebo at inducing combined clinical and endoscopic remission in patients with active, mild-to-moderate UC.

Smith M.R.,Massachusetts General Hospital | Klotz L.,University of Toronto | Persson B.-E.,Ferring Pharmaceuticals | Olesen T.K.,Clinical Research and Development Urology | Wilde A.A.M.,Heart Failure Research Center
Journal of Urology | Year: 2010

Purpose We assessed the cardiovascular safety profile of degarelix, a new gonadotropin-releasing hormone antagonist. Materials and Methods This is the first report to our knowledge on cardiovascular safety data from a completed 1-year randomized controlled trial of leuprolide acetate vs degarelix. Outcomes considered in these analyses included the QT interval by central reading and analysis, and cardiovascular adverse events. On multivariate analyses relationships between selected baseline factors and cardiovascular events were evaluated. Results There were no significant differences between treatment groups for mean change in Fridericia's correction of QT during the trial. Markedly abnormal Fridericia's correction of QT values (500 milliseconds or greater) were observed in only a small number of subjects by treatment group, that is 2 (less than 1%) in the pooled degarelix group and 2 (1%) in the leuprolide group. Supraventricular arrhythmias were the most common type of arrhythmias, affecting 2% of subjects in the pooled degarelix group and 4% in the leuprolide group. Other arrhythmias occurred in 1% or less of subjects by treatment group. The most frequently reported cardiac disorder was ischemic heart disease, which occurred in 4% of subjects treated with degarelix and 10% of those on leuprolide. Cox proportional hazard ratio estimates for selected baseline covariates showed a significantly increased risk of cardiovascular events by age (p = 0.0459) and systolic blood pressure (p = 0.0061). Conclusions In men with prostate cancer degarelix and leuprolide have similar cardiovascular safety profiles. These observations suggest that the cardiovascular events associated with both agents result from hypogonadism rather than a direct drug effect. © 2010 American Urological Association Education and Research, Inc.

Klotz L.,University of Toronto | Miller K.,Charite - Medical University of Berlin | Crawford E.D.,University of Colorado at Denver | Shore N.,Urologic | And 4 more authors.
European Urology | Year: 2014

Background Studies comparing the gonadotropin-releasing hormone antagonist, degarelix, with luteinising hormone-releasing hormone (LHRH) agonists indicate differences in outcomes.Design, setting, and participants Data were pooled from five prospective, phase 3 or 3b randomised trials (n = 1925) of degarelix and leuprolide or goserelin in men requiring androgen deprivation therapy for the treatment of prostate cancer. Patients received either 3 mo (n = 467) or 12 mo (n = 1458) of treatment. Intervention Men were randomised to receive degarelix (n = 1266), leuprolide (n = 201), or goserelin (n = 458).Outcome measurements and statistical analysis Unadjusted Kaplan-Meier analyses were supported by the Cox proportional hazards model, adjusted for disease-related baseline factors, to estimate hazard ratios (HRs) of efficacy and safety outcomes. The Fisher exact test compared crude incidences of adverse events.Results and limitations Prostate-specific antigen (PSA) progression-free survival (PFS) was improved in the degarelix group (HR: 0.71; p = 0.017). For patients with baseline PSA levels >20 ng/ml, the HR for PSA PFS was 0.74 (p = 0.052). Overall survival (OS) was higher in the degarelix group (HR: 0.47; p = 0.023). OS was particularly improved with degarelix in patients with baseline testosterone levels >2 ng/ml (HR: 0.36; p = 0.006). In terms of disease-related adverse events, there were, overall, fewer joint-related signs and symptoms, musculoskeletal events, and urinary tract events in the degarelix group.Conclusions These data indicate clinical benefits with degarelix, including a significant improvement in PSA PFS and OS, as well as reduced incidence of joint, musculoskeletal, and urinary tract adverse events, compared with LHRH agonists. © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved. -absp. Objective To assess differences in efficacy and safety outcomes in a pooled analysis of trials comparing degarelix with LHRH agonists.

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