Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol

BACKGROUND Inclisiran inhibits hepatic synthesis of proprotein convertase subtilisin-kexin type 9. Previous studies suggest that inclisiran might provide sustained reductions in low-density lipoprotein (LDL) cholesterol levels with infrequent dosing. METHODS We enrolled patients with atherosclerotic cardiovascular disease (ORION-10 trial) and patients with atherosclerotic cardiovascular disease or an atherosclerotic cardiovascular disease risk equivalent (ORION-11 trial) who had elevated LDL cholesterol levels despite receiving statin therapy at the maximum tolerated dose. Patients were randomly assigned in a 1:1 ratio to receive either inclisiran (284 mg) or placebo, administered by subcutaneous injection on day 1, day 90, and every 6 months thereafter over a period of 540 days. The coprimary end points in each trial were the placebo-corrected percentage change in LDL cholesterol level from baseline to day 510 and the time-adjusted percentage change in LDL cholesterol level from baseline after day 90 and up to day 540. RESULTS A total of 1561 and 1617 patients underwent randomization in the ORION-10 and ORION-11 trials, respectively. Mean (SD) LDL cholesterol levels at baseline were 104.738.3 mg per deciliter (2.710.99 mmol per liter) and 105.539.1 mg per deciliter (2.731.01 mmol per liter), respectively. At day 510, inclisiran reduced LDL cholesterol levels by 52.3% (95% confidence interval [CI], 48.8 to 55.7) in the ORION-10 trial and by 49.9% (95% CI, 46.6 to 53.1) in the ORION-11 trial, with corresponding time-adjusted reductions of 53.8% (95% CI, 51.3 to 56.2) and 49.2% (95% CI, 46.8 to 51.6) (P<0.001 for all comparisons vs. placebo). Adverse events were generally similar in the inclisiran and placebo groups in each trial, although injection-site adverse events were more frequent with inclisiran than with placebo (2.6% vs. 0.9% in the ORION-10 trial and 4.7% vs. 0.5% in the ORION-11 trial); such reactions were generally mild, and none were severe or persistent. CONCLUSIONS Reductions in LDL cholesterol levels of approximately 50% were obtained with inclisiran, administered subcutaneously every 6 months. More injection-site adverse events occurred with inclisiran than with placebo

Fabrication and texture characterization of bulk (Bi,Pb){sub 2}Sr{sub 2}Ca{sub 2}Cu{sub 3}O{sub x} and Bi{sub 2}Sr{sub 2}CaCu{sub 2}O{sub x} superconductors

Bulk (Bi,Pb){sub 2}Sr{sub 2}Ca{sub 2}Cu{sub 3}O{sub x} (Bi-2223) and Bi{sub 2}Sr{sub 2}CaCU{sub 2}0{sub x} (Bi-2212) superconductors were fabricated by sinter forging. Bi-2223 ({approx}90% Bi-2223, 10% (Bi,Pb){sub 2}Sr{sub 2}CaCU{sub 2}0. + other phases) and Bi-2212 (nearly phase pure) powders were first synthesized and then cold pressed into bars that were -50% dense. These bars were surrounded by Ag foil, heated in air to {approx}845{degrees}C, and compressed for 3--6 h. The resultant bars were dense and highly textured. At 77 K, the Bi-2223 exhibited transport critical current density (J{sub c}) values of 2000--8000 A/cm{sup 2}; the Bi-2212 exhibited very low J{sub c}. Extent of texture was evaluated by three X-ray diffraction methods: 2{theta} scans, rocking curves, and orientation distribution functions. It was found that J{sub c} correlated best with the orientation distribution functions

Association of lipoprotein(a) with risk of recurrent ischemic events following acute coronary syndrome: analysis of the dal-outcomes randomized clinical trial

IMPORTANCE: It is uncertain whether lipoprotein(a) [Lp(a)], which is associated with incident cardiovascular disease, is an independent risk factor for recurrent cardiovascular events after acute coronary syndrome (ACS). OBJECTIVE: To determine the association of Lp(a) concentration measured after ACS with the subsequent risk of ischemic cardiovascular events. DESIGN, SETTING, AND PARTICIPANTS: This nested case-cohort analysiswas performed as an ad hoc analysis of the dal-Outcomes randomized clinical trial. This trial compared dalcetrapib, the cholesteryl ester transfer protein inhibitor, with placebo in patients with recent ACS and was performed between April 2008 and September 2012 at 935 sites in 27 countries. There were 969 case patients who experienced a primary cardiovascular outcome, and there were 3170 control patients who were event free at the time of a case event and had the same type of index ACS (unstable angina ormyocardial infarction) as that of the respective case patients. Concentration of Lp(a) was measured by immunoturbidimetric assay. Data analysis for this present study was conducted from June 8, 2016, to April 21, 2017. INTERVENTIONS: Patients were randomly assigned to receive treatment with dalcetrapib, 600mg daily, or matching placebo, beginning 4 to 12 weeks after ACS. MAIN OUTCOMES AND MEASURES: Death due to coronary heart disease, a major nonfatal coronary event (myocardial infarction, hospitalization for unstable angina, or resuscitated cardiac arrest), or fatal or nonfatal ischemic stroke. RESULTS: The mean (SD) age was 63 (10) years for the 969 case patients and 60 (9) years for the 3170 control patients, and both cohorts were composed of predominantly male (770 case patients [79%] and 2558 control patients [81%]; P = .40) and white patients (858 case patients [89%] and 2825 control patients [89%]; P = .62). At baseline, the median (interquartile range) Lp(a) level was 12.3 (4.7-50.9)mg/dL. There was broad application of evidence-based secondary prevention strategies after ACS, including use of statins in 4030 patients (97%). The cumulative distribution of baseline Lp(a) levels did not differ between cases and controls at P = .16. Case-cohort regression analysis showed no association of baseline Lp(a) level with risk of cardiovascular events. For a doubling of Lp(a) concentration, the hazard ratio (case to control) was 1.01 (95%CI, 0.96-1.06; P = .66) after adjustment for 16 baseline variables, including assigned study treatment. CONCLUSIONS AND RELEVANCE: For patients with recent ACS who are treated with statins, Lp(a) concentration was not associated with adverse cardiovascular outcomes. These findings call into question whether treatment specifically targeted to reduce Lp(a) levels would thereby lower the risk for ischemic cardiovascular events after ACS. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00658515.3Gregory G. Schwartz, Christie M. Ballantyne, Philip J. Barter, David Kallend, Lawrence A. Leiter ... Stephen J. Nicholls ... et al

Safety and tolerability of dalcetrapib

Efficacy and safety data for dalcetrapib (RO4607381/JTT-705) are presented, following a report of increased mortality and cardiac events with another cholesteryl ester transfer protein inhibitor, torcetrapib, associated with off-target adverse effects (hypertension and the activation of the renin-angiotensin-aldosterone system). The efficacy and clinical safety of dalcetrapib 300, 600, and 900 mg or placebo were assessed (n = 838) in 4 pooled 4-week phase IIa trials (1 monotherapy, n = 193; 3 statin combination, n = 353) and 1 12-week phase IIb trial (with pravastatin, n = 292). Nonclinical safety, assessed by the induction of aldosterone production and aldosterone synthase (cytochrome P450 11B2) messenger ribonucleic acid, was measured in human adrenocarcinoma (H295R) cells exposed to dalcetrapib or torcetrapib. Dalcetrapib increased high-density lipoprotein cholesterol by up to 36% and apolipoprotein A-I by up to 16%. The incidence of adverse events (AEs) was similar between placebo (42%) and dalcetrapib 300 mg (50%) and 600 mg (42%), with more events with dalcetrapib 900 mg (58%) (p <0.05, pooled 4-week studies). Six serious AEs (3 with placebo, 1 with dalcetrapib 300 mg, and 2 with dalcetrapib 600 mg) were considered "unrelated" to treatment. Cardiovascular AEs were similar across treatment groups, with no dose-related trends and no clinically relevant changes in blood pressure or electrocardiographic results. Findings were similar in the 12-week study. In vitro, torcetrapib but not dalcetrapib increased aldosterone production and cytochrome P450 11B2 messenger ribonucleic acid levels. In conclusion, dalcetrapib alone or in combination with statins was effective at increasing high-density lipoprotein cholesterol and was well tolerated, without clinically relevant changes in blood pressure or cardiovascular AEs and no effects on aldosterone production as assessed nonclinicall

A review of EBSD: from rudimentary on line orientation measurements to high resolution elastic strain measurements over the past 30 years.

Considering that the Electron Back Scatter Diffraction technique, EBSD, features in more than 60% of the papers published in the current conference proceedings, this review concentrates on the most recent development in the last ten years, that is, High Resolution EBSD. An outline of the theory is presented and four-point bend test results are shown proving the sensitivity of the technique for measuring elastic strain is 1 part in 10000. Other examples of its use included here are strains surrounding indents in silicon, mapping the stress concentration at grain boundaries ahead of dislocation pile ups and dislocation generation at grain boundaries due to strain ahead of nano indentations. An application is presented to distinguish the c axis direction in slightly tetragonal PZT crystals and developments in obtaining absolute strain measurement as opposed to the relative strain measurement currently the norm are discussed.</p