Apixaban with antiplatelet therapy after acute coronary syndrome.

BACKGROUND: Apixaban, an oral, direct factor Xa inhibitor, may reduce the risk of recurrent ischemic events when added to antiplatelet therapy after an acute coronary syndrome. METHODS: We conducted a randomized, double-blind, placebo-controlled clinical trial comparing apixaban, at a dose of 5 mg twice daily, with placebo, in addition to standard antiplatelet therapy, in patients with a recent acute coronary syndrome and at least two additional risk factors for recurrent ischemic events. RESULTS: The trial was terminated prematurely after recruitment of 7392 patients because of an increase in major bleeding events with apixaban in the absence of a counterbalancing reduction in recurrent ischemic events. With a median follow-up of 241 days, the primary outcome of cardiovascular death, myocardial infarction, or ischemic stroke occurred in 279 of the 3705 patients (7.5%) assigned to apixaban (13.2 events per 100 patient-years) and in 293 of the 3687 patients (7.9%) assigned to placebo (14.0 events per 100 patient-years) (hazard ratio with apixaban, 0.95; 95% confidence interval [CI], 0.80 to 1.11; P=0.51). The primary safety outcome of major bleeding according to the Thrombolysis in Myocardial Infarction (TIMI) definition occurred in 46 of the 3673 patients (1.3%) who received at least one dose of apixaban (2.4 events per 100 patient-years) and in 18 of the 3642 patients (0.5%) who received at least one dose of placebo (0.9 events per 100 patient-years) (hazard ratio with apixaban, 2.59; 95% CI, 1.50 to 4.46; P=0.001). A greater number of intracranial and fatal bleeding events occurred with apixaban than with placebo. CONCLUSIONS: The addition of apixaban, at a dose of 5 mg twice daily, to antiplatelet therapy in high-risk patients after an acute coronary syndrome increased the number of major bleeding events without a significant reduction in recurrent ischemic events. (Funded by Bristol-Myers Squibb and Pfizer; APPRAISE-2 ClinicalTrials.gov number, NCT00831441.).

Apixaban versus warfarin in patients with atrial fibrillation.

BACKGROUND: Vitamin K antagonists are highly effective in preventing stroke in patients with atrial fibrillation but have several limitations. Apixaban is a novel oral direct factor Xa inhibitor that has been shown to reduce the risk of stroke in a similar population in comparison with aspirin. METHODS: In this randomized, double-blind trial, we compared apixaban (at a dose of 5 mg twice daily) with warfarin (target international normalized ratio, 2.0 to 3.0) in 18,201 patients with atrial fibrillation and at least one additional risk factor for stroke. The primary outcome was ischemic or hemorrhagic stroke or systemic embolism. The trial was designed to test for noninferiority, with key secondary objectives of testing for superiority with respect to the primary outcome and to the rates of major bleeding and death from any cause. RESULTS: The median duration of follow-up was 1.8 years. The rate of the primary outcome was 1.27% per year in the apixaban group, as compared with 1.60% per year in the warfarin group (hazard ratio with apixaban, 0.79; 95% confidence interval [CI], 0.66 to 0.95; P<0.001 for noninferiority; P=0.01 for superiority). The rate of major bleeding was 2.13% per year in the apixaban group, as compared with 3.09% per year in the warfarin group (hazard ratio, 0.69; 95% CI, 0.60 to 0.80; P<0.001), and the rates of death from any cause were 3.52% and 3.94%, respectively (hazard ratio, 0.89; 95% CI, 0.80 to 0.99; P=0.047). The rate of hemorrhagic stroke was 0.24% per year in the apixaban group, as compared with 0.47% per year in the warfarin group (hazard ratio, 0.51; 95% CI, 0.35 to 0.75; P<0.001), and the rate of ischemic or uncertain type of stroke was 0.97% per year in the apixaban group and 1.05% per year in the warfarin group (hazard ratio, 0.92; 95% CI, 0.74 to 1.13; P=0.42). CONCLUSIONS: In patients with atrial fibrillation, apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality. (Funded by Bristol-Myers Squibb and Pfizer; ARISTOTLE ClinicalTrials.gov number, NCT00412984.).

QT/QTc prolongation in placebo-treated subjects: a PhRMA collaborative data analysis.

In an ongoing effort to try to understand the variability of QT/QTc data and determine how that variability would affect the design, analysis, and conclusions drawn from data collected in thorough QT/QTc studies, five Pharmaceutical Research and Manufacturers Association (PhRMA) companies recently performed retrospective analyses of placebo and nondrug 12-lead resting electrocardiogram (ECG) data. The data were obtained from five rigorously conducted studies in which the collection and analysis of QT/QTc intervals was a primary objective. Variables that are known to affect variability of QT/QTc intervals, such as adequate resting time before recording the ECGs, food, and consistency of lead placement, had been well controlled in each of the studies. Single ECGs were recorded at each time point, and the QT intervals were measured by ECG laboratories.

Antimicrobial susceptibility and oxymino-ß-lactam resistance mechanisms in Salmonella enterica and Escherichia coli isolates from different animal sources.

The impact of extended-spectrum ß-lactamases (ESBLs) and plasmid-mediated AmpC ß-lactamases (PMAßs) of animal origin has been a public health concern. In this study, 562 Salmonella enterica and 598 Escherichia coli isolates recovered from different animal species and food products were tested for antimicrobial resistance. Detection of ESBL-, PMAß-, plasmid-mediated quinolone resistance (PMQR)-encoding genes and integrons was performed in isolates showing non-wild-type phenotypes. Susceptibility profiles of Salmonella spp. isolates differed according to serotype and origin of the isolates. The occurrence of cefotaxime non-wild-type isolates was higher in pets than in other groups. In nine Salmonella isolates, blaCTX-M (n = 4), blaSHV-12 (n = 1), blaTEM-1 (n = 2) and blaCMY-2 (n = 2) were identified. No PMQR-encoding genes were found. In 47 E. coli isolates, blaCTX-M (n = 15), blaSHV-12 (n = 2), blaCMY-2 (n = 6), blaTEM-type (n = 28) and PMQR-encoding genes qnrB (n = 2), qnrS (n = 1) and aac(6')-Ib-cr (n = 6) were detected. To the best of our knowledge, this study is the first to describe the presence of blaCMY-2 (n = 2) and blaSHV-12 (n = 1) genes among S. enterica from broilers in Portugal. This study highlights the fact that animals may act as important reservoirs of isolates carrying ESBL-, PMAß- and PMQR-encoding genes that might be transferred to humans through direct contact or via the food chain.

Comparative genotypic and antimicrobial susceptibility analysis of zoonotic Campylobacter species isolated from broilers in a nationwide survey, Portugal.

Campylobacter is a major cause of human foodborne disease worldwide and has been associated with the consumption of contaminated poultry. The prevalence of Campylobacter species in broiler flocks from more than 200 producers widespread in mainland Portugal was assessed in 2008 in response to Commission Decision 2007/516/EC. Campylobacter isolates were obtained from 83.3% of 424 pooled cecal samples, with a higher prevalence of Campylobacter coli (61.2%) than Campylobacter jejuni (38.8%). Restriction fragment length polymorphism analysis of the flaA gene (flaA-RFLP) of 112 C. coli isolates and 67 C. jejuni isolates yielded 11 flaA-RFLP patterns with HinfI (Hunter Gaston diversity index [HGDI] = 0.62) and 48 flaA-RFLP patterns with DdeI (HGDI = 0.89), indicating a high level of genetic diversity. A wide geographic distribution of the most frequent restriction pattern was observed. MICs of five antimicrobials (ciprofloxacin, gentamicin, streptomycin, erythromycin, and tetracycline) were determined for 215 C. coli isolates and 136 C. jejuni isolates. The occurrence of non-wild-type isolates, exhibiting an acquired resistance phenotype, was higher for C. coli than C. jejuni for all antimicrobials tested. Sixty-three percent of C. jejuni and C. coli isolates were considered non-wild type based on their response to both ciprofloxacin and erythromycin, which are frequently used in the treatment of human infections. The high prevalence of antimicrobial-resistant Campylobacter strains detected supports the need for increased epidemiological surveillance and prevention in a country where large amounts of poultry meat are consumed.

Diagnosis of tuberculosis in the wild boar (Sus scrofa): a comparison of methods applicable to hunter-harvested animals.

BACKGROUND: To obtain robust epidemiological information regarding tuberculosis (TB) in wildlife species, appropriate diagnostic methods need to be used. Wild boar (Sus scrofa) recently emerged as a major maintenance host for TB in some European countries. Nevertheless, no data is available to evaluate TB post-mortem diagnostic methods in hunter-harvested wild boar. METHODOLOGY/PRINCIPAL FINDINGS: Six different diagnostic methods for TB were evaluated in parallel in 167 hunter-harvested wild boar. Compared to bacteriological culture, estimates of sensitivity of histopathology was 77.8%, gross pathology 72.2%, PCR for the MPB70 gene 66.7%, detection of acid-fast bacilli (AFB) in tissue contact smears 55.6% and in histopathology slides 16.7% (estimated specificity was 96.7%, 100%, 100%, 94.4% and 100%, respectively). Combining gross pathology with stained smears in parallel increased estimated sensitivity to 94.4% (94.4% specificity). Four probable bacteriological culture false-negative animals were identified by Discriminant Function Analysis. Recalculating the parameters considering these animals as infected generated estimated values for sensitivity of bacteriology and histopathology of 81.8%, gross pathology 72.7%, PCR for the MPB70 gene 63.6%, detection of AFB in tissue contact smears 54.5% and in histopathology slides 13.6% (estimated specificity was 100% for gross pathology, PCR, bacteriology and detection of AFB in histopathology slides, 96.7% for histopathology and 94.4% for stained smears). CONCLUSIONS/SIGNIFICANCE: These results show that surveys for TB in wild boar based exclusively on gross pathology considerably underestimate prevalence, while combination of tests in parallel much improves sensitivity and negative predictive values. This finding should thus be considered when planning future surveys and game meat inspection schemes. Although bacteriological culture is the reference test for TB diagnosis, it can generate false-negative results and this should be considered when interpreting data.