Many patients with acromegaly do not achieve biochemical control despite receiving high doses of the first-generation somatostatin analogues octreotide or lanreotide. In the PAOLA trial, we aimed to ...assess the efficacy and safety of two different doses of the somatostatin analogue pasireotide long-acting release compared with active control (octreotide or lanreotide) in patients with inadequately controlled acromegaly.
In a multicentre, randomised, phase 3 trial, we enrolled eligible patients aged 18 years or older with acromegaly who were inadequately controlled (5-point, 2 h mean growth hormone concentration >2·5 μg/L and insulin-like growth factor 1 IGF-1 concentration >1·3 times the upper normal limit) and had received 30 mg octreotide long-acting repeatable or 120 mg lanreotide (Somatuline Autogel; Ipsen, UK) as monotherapy for 6 months or longer. We randomly assigned patients in a 1:1:1 ratio with an interactive voice-web response system to receive 40 mg pasireotide long-acting release once every 28 days for 24 weeks, 60 mg pasireotide long-acting release once every 28 days for 24 weeks, or continued treatment with octreotide or lanreotide (active control). Patients were stratified according to previous treatment (octreotide or lanreotide) and growth hormone concentrations at screening (2·5-10 μg/L and >10 μg/L). Patients and study investigators were not masked to study drug assignment but were masked to pasireotide dose allocation. The primary endpoint was number of patients achieving biochemical control, defined as mean growth hormone concentration less than 2·5 μg/L and normalised IGF-1 concentration. Efficacy analyses were based on intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01137682.
Between Dec 17, 2010, and Aug 6, 2012, 198 patients were enrolled and randomly assigned to pasireotide 40 mg (n=65), pasireotide 60 mg (n=65), or active control (n=68) groups. At 24 weeks, ten (15%) patients in the pasireotide 40 mg group and 13 (20%) patients in the pasireotide 60 mg group achieved biochemical control, compared with no patients in the active control group (absolute difference from control group 15·4%, 95% CI 7·6-26·5, p=0·0006 for pasireotide 40 mg group, 20·0%, 11·1-31·8, p<0·0001 for pasireotide 60 mg group). The most common adverse events were hyperglycaemia (21 33% for treatment with 40 mg pasireotide, 19 31% with 60 mg pasireotide, and nine 14% with active control), diabetes (13 21%, 16 26%, and five 8%), and diarrhoea (ten 16%, 12 19%, and three 5%); most were grade 1 or 2 in severity. Serious adverse events were reported in six (10%) patients in the pasireotide 40 mg group, two (3%) in the pasireotide 60 mg group, and three (5%) in the active control group.
Pasireotide provides superior efficacy compared with continued treatment with octreotide or lanreotide, and could become the new standard pituitary-directed treatment in patients with acromegaly who are inadequately controlled using first-generation somatostatin analogues.
Novartis Pharma AG. Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation.
Summary Background Primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction has traditionally been supported by unfractionated heparin, which has never been directly ...compared with a new anticoagulant using consistent anticoagulation and similar antiplatelet strategies in both groups. We compared traditional heparin treatment with intravenous enoxaparin in primary PCI. Methods In a randomised open-label trial, patients presenting with ST-elevation myocardial infarction were randomly assigned (1:1) to receive an intravenous bolus of 0·5 mg/kg of enoxaparin or unfractionated heparin before primary PCI. Wherever possible, medical teams travelling in mobile intensive care units (ambulances) selected, randomly assigned (using an interactive voice response system at the central randomisation centre), and treated patients. Patients who had received any anticoagulant before randomisation were excluded. Patients and caregivers were not masked to treatment allocation. The primary endpoint was 30-day incidence of death, complication of myocardial infarction, procedure failure, or major bleeding. The main secondary endpoint was the composite of death, recurrent acute coronary syndrome, or urgent revascularisation. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov , number NCT00718471. Findings 910 patients were assigned to treatment with enoxaparin (n=450) or unfractionated heparin (n=460). The primary endpoint occurred in 126 (28%) patients after anticoagulation with enoxaparin versus 155 (34%) patients on unfractionated heparin (relative risk RR 0·83, 95% CI 0·68–1·01, p=0·06). The incidence of death (enoxaparin, 17 4% vs heparin, 29 6% patients; p=0·08), complication of myocardial infarction (20 4% vs 29 6%; p=0·21), procedure failure (100 26% vs 109 28%; p=0·61), and major bleeding (20 5% vs 22 5%; p=0·79) did not differ between groups. Enoxaparin resulted in a significantly reduced rate of the main secondary endpoint (30 7% vs 52 11% patients; RR 0·59, 95% CI 0·38–0·91, p=0·015). Death, complication of myocardial infarction, or major bleeding (46 10% vs 69 15% patients; p=0·03), death or complication of myocardial infarction (35 8% vs 57 12%; p=0·02), and death, recurrent myocardial infarction, or urgent revascularisation (23 5% vs 39 8%; p=0·04) were all reduced with enoxaparin. Interpretation Intravenous enoxaparin compared with unfractionated heparin significantly reduced clinical ischaemic outcomes without differences in bleeding and procedural success. Therefore, enoxaparin provided an improvement in net clinical benefit in patients undergoing primary PCI. Funding Direction de la Recherche Clinique, Assistance Publique-Hôpitaux de Paris; Sanofi-Aventis.
To establish whether the success rate of surgery for small idiopathic macular holes (diameter, ≤ 400 μm) is significantly reduced if facedown positioning is replaced by simply taking care to avoid ...the supine position.
Randomized, controlled, parallel-assignment, open-label, interventional, multicenter clinical trial.
Sixty-nine patients from 6 specialized vitreoretinal units, randomized into 2 parallel groups and followed up after surgery for 3 months.
All patients underwent pars plana vitrectomy, peeling of any epiretinal membrane, and 17% C₂F₆ gas filling. Patients then were advised randomly to observe either strict facedown positioning for 22 of 24 hours or simply to avoid the supine position for 10 days.
The primary outcome measure was the rate of anatomic closure 3 months after surgery. Main secondary measurements included Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity, progression of cataract, and frequency of complications.
The mean size of macular holes was approximately 300 μm in both groups. Closure rates were more than 90% in both groups: 32 (91.4%) of 34 eyes in the alleviated positioning group versus 32 (94.1%) of 35 eyes in the facedown positioning group (lower margin of 95% confidence interval of difference, -14.88%). The ETDRS scores at 3 months increased in both groups by 10.23 ± 14.64 and 10.52 ± 14.54 letters, respectively. Progression of cataract and the rate of other complications were not significantly different in the 2 groups.
The success rate of surgery for idiopathic macular holes of 400 μm or smaller is not significantly reduced if facedown positioning is replaced by simply taking care to avoid the supine position. These macular holes can be treated by streamlined surgery, that is, with no internal limiting membrane peeling and no facedown positioning (only avoidance of the supine position) with a closure rate of more than 90% and a mean gain in visual acuity of more than 2 ETDRS lines at 3 months.
Abstract Background Diagnosis of acute myocardial infarction (AMI) in out-of-hospital cardiac arrest (OHCA) patients is important because immediate coronary angiography with coronary angioplasty ...could improve outcome in this setting. However, the value of acute post-resuscitation electrocardiographic (ECG) data for the detection of AMI is debatable. Methods We assessed the diagnostic characteristics of post-resuscitation ECG changes in a retrospective single centre study evaluating several ECG criteria of selection of patients undergoing AMI, in order to improve sensitivity, even at the expense of specificity. Immediate post resuscitation coronary angiogram was performed in all patients. AMI was defined angiographically using coronary flow and plaque morphology criteria. Results We included 165 consecutive patients aged 56 (IQR 48–67) with sustained return of spontaneous circulation after OHCA between 2002 and 2008. 84 patients had shockable, 73 non-shockable and 8 unknown initial rhythm; 36% of the patients had an AMI. ST-segment elevation predicted AMI with 88% sensitivity and 84% specificity. The criterion including ST-segment elevation and/or depression had 95% sensitivity and 62% specificity. The combined criterion including ST-segment elevation and/or depression, and/or non-specific wide QRS complex and/or left bundle branch block provided a sensitivity and negative predictive value of 100%, a specificity of 46% and a positive predictive value of 52%. Conclusion In patients with OHCA without obvious non-cardiac causes, selection for coronary angiogram based on the combined criterion would detect all AMI and avoid the performance of the procedure in 30% of the patients, in whom coronary angiogram did not have a therapeutic role.
Background & Aims Mechanisms linking obesity and unfavourable outcomes in patients with viral hepatitis C (HCV) cirrhosis are not well understood. Obesity is associated with insulin resistance, ...increased leptin, and decreased adiponectin serum levels. Methods We assessed the predictive value of those factors for the occurrence of hepatocellular carcinoma (HCC) and liver-related death or transplantation in a cohort of 248 patients (mean age 58 (12 years, BMI 25.4 ± 4.4 kg/m2 ) with compensated HCV cirrhosis and persistent infection prospectively followed and screened for HCC. Results The mean baseline serum levels of adiponectin and leptin were 16.8 ± 15 mg/L and 16.8 ± 19 ng/ml, respectively. The mean homeostasis model assessment of insulin resistance (HOMA) index was 3.8 ± 3; median 2.9. After a median follow-up of 72 months, 61 patients developed HCC, 58 died of liver causes, and 17 were transplanted. The incidences (Kaplan Meier) of HCC were 7%, 18%, and 27% at 5 years ( p = 0.017) and of liver-related death or transplantation 15%, 15% and 29% ( p = 0.002) according to the lowest, middle and highest tertile of HOMA, respectively. In multivariate analysis, the HOMA index was associated with HCC occurrence (HR = 1.10, 1.01–1.21 p = 0.026) and was a strong predictor of liver-related death or transplantation (HR = 1.13, 1.07–1.21 p <0.0001). Serum levels of adiponectin and leptin were not associated with the outcome. Conclusions In patients with compensated HCV cirrhosis, insulin resistance but not serum levels of adiponectin and leptin predicted the occurrence of HCC and of liver-related death or transplantation.
Background & Aims The prognosis of hepatocellular carcinoma (HCC) treated by radiofrequency ablation (RFA) is mainly linked to tumor recurrence. So far, no tissue biomarker of recurrence has been ...validated in biopsy samples. We aimed at investigating the prognostic value of tissue biomarkers in HCC biopsy samples of patients treated with RFA. Methods All consecutive naive patients from 3 university hospitals, with compensated cirrhosis, early-stage (BCLC 0/A) uninodular HCC treated with RFA, and available tumor biopsy, were included. Edmondson’s grade, and the expression of cytokeratin 19, glutamine synthase, beta-catenin, epithelial cell adhesion molecule (EpCAM), and endothelial cell-specific molecule 1 (ESM-1) were assessed. Main clinical end points were overall and early recurrence. Statistical analyses were performed using Kaplan Meier, Log-rank test, and Cox models. Results 150 patients were included. Recurrence, death or liver transplantation occurred in 85, 51, and 12 patients, respectively. Median follow-up was 27 months. ESM-1 expression by HCC stromal endothelial cells was observed in 58 patients (40%) and was associated with higher serum AFP levels, larger tumor, and more frequent expression of EpCAM and surrogate markers of activation of the Wnt-ß-catenin pathway. The 2 independent predictive factors of overall recurrence were serum AFP (HR 1.11 1.002; 1.22, p = 0.045) and ESM-1 expression (HR 1.56 1.004; 2.43, p = 0.048). ESM-1 expression was also an independent predictive factor of early recurrence (HR 1.81 1.02; 3.21, p = 0.042). Conclusions ESM-1 expression by stromal endothelial cells, in tumor biopsy samples, has an independent predictive value of early recurrence after RFA.
Intravenous enoxaparin did not reduce significantly the primary end point (p = 0.06) compared with unfractionated heparin (UFH) in the randomized Acute Myocardial Infarction Treated with primary ...angioplasty and intravenous enoxaparin Or unfractionated heparin to Lower ischemic and bleeding events at short- and Long-term follow-up (ATOLL) trial. We present the results of the prespecified per-protocol analysis excluding patients who did not receive the treatment allocated by randomization or received both enoxaparin and UFH. We evaluated all-cause mortality, complication of myocardial infarction, procedural failure, or major bleeding (primary end point) and all-cause mortality, recurrent acute coronary syndrome, or urgent revascularization (main secondary end point). Baseline and procedural characteristics were well balanced between the 2 treatment groups. Of 910 randomized patients, 795 patients (87.4%) were treated according to the protocol with consistent anticoagulation using intravenous enoxaparin (n = 400) or UFH (n = 395). Enoxaparin reduced significantly the rates of the primary end point (relative risk RR 0.76, 95% confidence interval CI 0.62 to 0.94, p = 0.012) and the main secondary end point (RR 0.37, 95% CI 0.22 to 0.63, p <0.0001). There was less major bleeding with enoxaparin (RR 0.46, 95% CI 0.21 to 1.01, p = 0.050) contributing to the significant improvement of the net clinical benefit (RR 0.46, 95% CI 0.3 to 0.74, p = 0.0002). All-cause mortality was also reduced with enoxaparin (RR 0.36, 95% CI 0.18 to 0.74, p = 0.003). In conclusion, in the per-protocol analysis of the ATOLL trial, pertinent to >87% of the study population, enoxaparin was superior to UFH in reducing ischemic end points and mortality.
Study objective The quality of endoscopy depends on the quality of upper gastrointestinal tract preparation. We determine whether in acute upper gastrointestinal bleeding the frequency of ...satisfactory stomach visualization was different after intravenous erythromycin, a nasogastric tube with gastric lavage, or both. Methods We performed a prospective, randomized, multicenter (6 emergency departments) study in patients with acute upper gastrointestinal bleeding presenting with hematemesis or melena. The patients were randomized into 3 groups: (1) intravenous erythromycin infusion without nasogastric tube placement (erythromycin group), (2) nasogastric tube placement without erythromycin (nasogastric group), and (3) intravenous erythromycin infusion combined with nasogastric tube placement (nasogastric-erythromycin group). The main outcome measure was the proportion of satisfactory stomach visualization. Results Two hundred fifty-three patients (181 men, mean age 61 years SD 15 years, 84 with cirrhosis) were randomized: 84 (erythromycin group), 85 (nasogastric group), and 84 (nasogastric-erythromycin group). Overall, there was 85% satisfactory stomach visualization; between-group differences were not significant: −4% (95% confidence interval CI −15% to 6%) for the erythromycin group and nasogastric-erythromycin group, 2% (95% CI −14% to 9%) for the erythromycin group and nasogastric group, and −6.5% (95% CI −17% to 4%) for the nasogastric group and nasogastric-erythromycin group. The duration of the endoscopic procedure, rebleeding frequency, the need for a second endoscopy, the number of transfused blood units, and mortality at days 2, 7, and 30 did not differ significantly between groups. Conclusion In acute upper gastrointestinal bleeding, administration of intravenous erythromycin provides satisfactory endoscopic conditions, without the need for a nasogastric tube and gastric lavage.
The use of glycoprotein IIb/IIIa receptor inhibitors (GPIs) in high-risk patients with acute coronary syndromes has been associated with reductions in ischemic events but increases in bleeding ...complications. The role of GPIs in patients who undergo primary percutaneous coronary intervention (PCI) by the transradial approach (TRA) is not well studied. The aim of this post hoc analysis from the randomized prospective Acute Myocardial Infarction Treated With Primary Angioplasty and Intravenous Enoxaparin or Unfractionated Heparin to Lower Ischemic and Bleeding Events at Short- and Long-Term Follow-Up (ATOLL) trial was to assess the safety and efficacy of GPIs in primary PCI performed using the TRA. A total of 910 patients were enrolled in ATOLL; 522 patients (67%) underwent PCI using the TRA. Two comparative analyses were performed. First, patients who underwent PCI using the TRA who received GPIs were compared with those who did not receive GPIs. Second, patients who underwent PCI using the TRA who received GPIs were compared with those who underwent PCI using a nonradial route and received GPIs. Composite end points of net clinical benefit, ischemic outcomes, and safety consisting of bleeding and transfusion at 1 month were analyzed. A propensity score was constructed, and weight adjustment were made for variables, including but not limited to age, weight, gender, renal function, concomitant use of other medications, Killip class, and medical history, when analyzing the end points. There was no significant difference in net clinical benefit or ischemic outcomes between either TRA patients with versus without GPIs or TRA patients with GPIs versus non-TRA patients with GPIs. Additionally, there were significantly fewer major bleeding events and blood transfusions in TRA patients with GPIs compared with non-TRA patients with GPIs. In conclusion, the addition of GPIs in the setting of primary PCI using the TRA was not associated with bleeding liability. The use of GPIs with TRA was associated with safer outcomes than using GPIs with a nontransradial approach. This study was limited in that it was a nonrandomized retrospective analysis.
PDF
