PCSK9R46L, Low-Density Lipoprotein Cholesterol Levels, and Risk of Ischemic Heart Disease 3 Independent Studies and Meta-Analyses

ObjectivesThe aim of this study was to examine the effect of PCSK9R46L on low-density lipoprotein cholesterol (LDL-C), risk of ischemic heart disease (IHD), and mortality.BackgroundThe 46L allele has been associated with reductions in LDL-C and risk of IHD, but results vary between studies.MethodsWe determined the association of R46L genotype with LDL-C, risk of IHD, myocardial infarction (MI), and mortality in the prospective CCHS (Copenhagen City Heart Study) (n = 10,032) and validated the results in: 1) the cross-sectional CGPS (Copenhagen General Population Study) (n = 26,013); and 2) the case-control CIHDS (Copenhagen Ischemic Heart Disease Study) (n = 9,654). We also performed meta-analyses of present and previous studies (n = 66,698).ResultsIn carriers (2.6%) versus noncarriers, the 46L allele was associated with reductions in LDL-C of 0.35 to 0.55 mmol/l (11% to 16%) from 20 to 80+ years in the general population (CCHS and CGPS; p values <0.0001). Observed risk reductions for IHD in 46L allele carriers were: 6% in the CCHS study (hazard ratio [HR]: 0.94; 95% confidence interval [CI]: 0.68 to 1.31), 46% in the CGPS study (odds ratio [OR]: 0.54; 95% CI: 0.39 to 0.77), 18% in the CIHDS study (OR: 0.82; 95% CI: 0.55 to 1.21), and 30% in the studies combined (OR: 0.70; 95% CI: 0.58 to 0.86). In the CCHS study, HR for mortality was 1.18 (95% CI: 0.93 to 1.50). In meta-analyses, 46L allele carriers had a 12% (0.43 mmol/l) reduction in LDL-C and a 28% reduction in risk of IHD (HR: 0.72; 95% CI: 0.62 to 0.84), similar to results in the CCHS, CGPS, and CIHDS studies combined. However, the observed 12% (0.43 mmol/l) reduction in LDL-C theoretically predicted an only 5% reduction in risk of IHD (HR: 0.95; 95% CI: 0.92 to 0.97).ConclusionsThe PCSK946L allele was associated with reductions in LDL-C from 20 to 80+ years in the general population. The reduction in risk of IHD was larger than predicted by the observed reduction in LDL-C alone. This could be because genotype is a better predictor of lifelong exposure to LDL-C than LDL-C measured in adult life

Thrombin-receptor antagonist vorapaxar in acute coronary syndromes

Background: Vorapaxar is a new oral protease-activated-receptor 1 (PAR-1) antagonist that inhibits thrombin-induced platelet activation. Methods: In this multinational, double-blind, randomized trial, we compared vorapaxar with placebo in 12,944 patients who had acute coronary syndromes without ST-segment elevation. The primary end point was a composite of death from cardiovascular causes, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization. RESULTS: Follow-up in the trial was terminated early after a safety review. After a median follow-up of 502 days (interquartile range, 349 to 667), the primary end point occurred in 1031 of 6473 patients receiving vorapaxar versus 1102 of 6471 patients receiving placebo (Kaplan-Meier 2-year rate, 18.5% vs. 19.9%; hazard ratio, 0.92; 95% confidence interval [CI], 0.85 to 1.01; P = 0.07). A composite of death from cardiovascular causes, myocardial infarction, or stroke occurred in 822 patients in the vorapaxar group versus 910 in the placebo group (14.7% and 16.4%, respectively; hazard ratio, 0.89; 95% CI, 0.81 to 0.98; P = 0.02). Rates of moderate and severe bleeding were 7.2% in the vorapaxar group and 5.2% in the placebo group (hazard ratio, 1.35; 95% CI, 1.16 to 1.58; P<0.001). Intracranial hemorrhage rates were 1.1% and 0.2%, respectively (hazard ratio, 3.39; 95% CI, 1.78 to 6.45; P<0.001). Rates of nonhemorrhagic adverse events were similar in the two groups. Conclusions: In patients with acute coronary syndromes, the addition of vorapaxar to standard therapy did not significantly reduce the primary composite end point but significantly increased the risk of major bleeding, including intracranial hemorrhage. (Funded by Merck; TRACER ClinicalTrials.gov number, NCT00527943.

Optimal Data Partitioning and a Test Case for Ray-Finned Fishes (Actinopterygii) Based on Ten Nuclear Loci

Data partitioning, the combined phylogenetic analysis of homogeneous blocks of data, is a common strategy used to accommodate heterogeneities in complex multilocus data sets. Variation in evolutionary rates and substitution patterns among sites are typically addressed by partitioning data by gene, codon position, or both. Excessive partitioning of the data, however, could lead to overparameterization; therefore, it seems critical to define the minimum numbers of partitions necessary to improve the overall fit of the model. We propose a new method, based on cluster analysis, to find an optimal partitioning strategy for multilocus protein-coding data sets. A heuristic exploration of alternative partitioning schemes, based on Bayesian and maximum likelihood (ML) criteria, is shown here to produce an optimal number of partitions. We tested this method using sequence data of 10 nuclear genes collected from 52 ray-finned fish (Actinopterygii) and four tetrapods. The concatenated sequences included 7995 nucleotide sites maximally split into 30 partitions defined a priori based on gene and codon position. Our results show that a model based on only 10 partitions defined by cluster analysis performed better than partitioning by both gene and codon position. Alternative data partitioning schemes also are shown to affect the topologies resulting from phylogenetic analysis, especially when Bayesian methods are used, suggesting that overpartitioning may be of major concern. The phylogenetic relationships among the major clades of ray-finned fish were assessed using the best data-partitioning schemes under ML and Bayesian methods. Some significant results include the monophyly of “Holostei” (Amia and Lepisosteus), the sister-group relationships between (1) esociforms and salmoniforms and (2) osmeriforms and stomiiforms, the polyphyly of Perciformes, and a close relationship of cichlids and atherinomorphs

Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial

Few treatments with a distinct mechanism of action are available for patients with platinum-refractory advanced or metastatic urothelial carcinoma. We assessed the efficacy and safety of treatment with docetaxel plus either ramucirumab-a human IgG1 VEGFR-2 antagonist-or placebo in this patient population