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The current standard of care for patients after an acute coronary syndrome includes dual antiplatelet therapy, typically with aspirin and clopidogrel. Despite aggressive use of dual antiplatelet therapy, however, patients frequently have recurrent ischemic events. Newer, more potent P2Y12-receptor antagonists provide additional reductions in ischemic events and mortality but at the cost of an increase in bleeding. Thus, patients with a substantial risk of recurrent events have an important unmet need for better secondary prevention. A combination of antiplatelet and anticoagulant agents seems to be an attractive approach. However, such broad antithrombotic therapy may also pose an unacceptable risk of bleeding. In this trial, we enrolled a high-risk patient population, with large proportions of patients who had diabetes, heart failure, or renal insufficiency, as well as a large proportion of patients who did not undergo revascularization for the index event. We hypothesized that this population was most likely to benefit from the addition of an oral anticoagulant agent in addition to standard antiplatelet and other evidencebased therapies. Further investigation is required to determine whether there are other patient populations for which the results may be different or concomitant interventions that might change the risk–benefit profile of the combination of anticoagulation plus antiplatelet therapy in this population.

Three phase 2 clinical trials have investigated the use of new oral anticoagulant drugs in addition to contemporary antiplatelet therapy in patients who have had a recent acute coronary syndrome. When added to antiplatelet therapy, both apixaban and rivaroxaban resulted in doserelated increases in bleeding but also appeared to result in larger absolute reductions in ischemic events than those seen with placebo. The increases in bleeding were smaller and the reductions in ischemic events were more pronounced among patients taking aspirin alone than among those taking aspirin plus clopidogrel. The findings from the APPRAISE-2 trial definitively confirm the increases in bleeding observed in the phase 2 trials of factor Xa inhibitors administered in addition to antiplatelet therapy. Unfortunately, the reductions in ischemic events suggested in the phase 2 trial were not observed in this larger phase 3 trial. Because this trial was stopped early owing to the increase in bleeding events, with fewer events having occurred than the number planned, uncertainty remains regarding the effect of apixaban on ischemic events. The ATLAS-ACS 2 TIMI 51 trial (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction 51; ClinicalTrials.gov number NCT00402597), which includes a lower-risk population than that in the APPRAISE-2 trial and is evaluating two different doses of another factor Xa inhibitor, is currently ongoing. Whether this trial will have similar results remains to be seen. Meta-analyses of earlier studies with oral vitamin K antagonists combined with aspirin, as compared with aspirin alone, showed that there were reductions in recurrent ischemic events in patients after acute coronary syndromes. In a large, observational analysis that included more than 40,000 patients with myocardial infarction, the use of triple therapy (aspirin, clopidogrel, and a vitamin K antagonist), as compared with aspirin alone, was associated with a rate of bleeding that was increased by a factor of 4, with no significant difference in the rate of survival. Similar increases in bleeding events have been seen in other studies and other clinical settings in which the use of combined antiplatelet and anticoagulant therapy may be considered. The results of the current trial raise doubt about whether meaningful incremental efficacy can be achieved with an acceptable risk of bleeding by combining a long-term oral anticoagulant with both aspirin and a P2Y12-receptor antagonist in patients with coronary disease. In summary, we evaluated the addition of apixaban, at a dose of 5 mg twice daily, to standard antiplatelet therapy in patients with an acute coronary syndrome. Treatment with apixaban, as compared with placebo, was associated with a significant increase in the risk of bleeding, without a significant effect on the incidence of recurrent ischemic events.

In the on-treatment analysis, the primary safety outcome of TIMI major bleeding occurred in 46 of the 3673 patients (1.3%) who received at least one dose of apixaban (2.4 events per 100 patientyears), as compared with 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). Among the patients receiving apixaban, as compared with those receiving placebo, there were more events of fatal bleeding (5 vs. 0), intracranial bleeding (12 vs. 3), ISTH major or clinically relevant nonmajor bleeding (117 vs. 45), and total bleeding (679 vs. 305). Patients receiving apixaban received more transfusions than did patients receiving placebo (144 [3.9%] vs. 73 [2.0%]). The findings with respect to the primary safety outcome were consistent among all key subgroups. The increase in bleeding events with apixaban, as compared with placebo, was seen both in patients taking combination antiplatelet therapy (1.3% vs. 0.6%; hazard ratio, 2.27; 95% CI, 1.28 to 4.02) and in patients taking aspirin alone (1.1% vs. 0.1%), although there was only a small number of major bleeding events in the aspirin-only subgroup. The frequencies of serious adverse events and overall adverse events were similar in the apixaban group and the placebo group (24.3% and 59.0%, respectively, in the apixaban group and 24.3% and 57.7%, respectively, in the placebo group). The frequencies of events other than ischemic events and bleeding were either similar in the two groups or lower in the apixaban group than in the placebo group. There were no significant between-group differences in the rates of adverse events related to hepatotoxicity.

In this randomized clinical trial, the oral factor Xa inhibitor apixaban, administered at a dose of 5 mg twice daily in high-risk patients who were taking either aspirin or aspirin plus clopidogrel after an acute coronary syndrome, resulted in a significant increase in bleeding events, including increases in events of fatal and intracranial bleeding, without a significant reduction in recurrent ischemic events. These findings were consistent in all subgroups, including subgroups defined according to antiplatelet therapy (aspirin plus clopidogrel vs. aspirin alone) and according to management of the acute coronary syndrome (revascularization vs. noninvasive management). The increase in bleeding with apixaban led more frequently to discontinuation of the study drug and resulted in the premature termination of the trial — both of which limit the certainty of the conclusions that can be drawn about efficacy.

A total of 7315 of the 7392 patients who underwent randomization (99.0%) received at least one dose of the assigned study drug; 8.5% of the patients were assigned to the reduced dose of apixaban or matching placebo. Of these 7315 patients, 863 of the 3673 patients who received at least one dose of apixaban (23.5%) and 746 of the 3642 who received at least one dose of placebo (20.5%) stopped taking the study drug before the end of the trial (P = 0.002). The median exposure to the study drug was 175 days (interquartile range, 66 to 293) among patients receiving apixaban and 185 days (interquartile range, 75 to 298) among patients receiving placebo. The most common reasons for discontinuation of the study drug were adverse events (8.5% in the apixaban group vs. 6.5% in the placebo group) and withdrawal of consent (5.3% vs. 4.2%). A total of 1310 (21.5%) of the patients who were taking aspirin plus a P2Y12-receptor antagonist at the time of randomization stopped taking the P2Y12-receptor antagonist during the course of the trial, at a median of 39 days (interquartile range, 13 to 108) after randomization; 135 (11.1%) of the patients receiving aspirin alone at randomization started taking a P2Y12-receptor antagonist during the trial, at a median of 14 days (interquartile range, 4 to 93) after randomization.

Efficacy Outcomes
The final number of primary efficacy events was 572, or 61.0% of the initially planned number. In the intention-to-treat analysis, the primary efficacy outcome of cardiovascular death, myocardial infarction, or ischemic stroke occurred in 279 patients (7.5%) assigned to apixaban (13.2 events per 100 patient-years) and in 293 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). Similar results were seen in an on-treatment analysis (218 vs. 249 events; hazard ratio, 0.89; 95% CI, 0.74 to 1.06; P = 0.19). There were also no significant differences between the apixaban and placebo groups with respect to any of the secondary efficacy outcomes. The effect of apixaban as compared with placebo was similar among patients receiving combination antiplatelet therapy and among those receiving aspirin alone. The rates of the primary efficacy outcome among patients who were receiving combination antiplatelet therapy were 7.2% in the apixaban group and 7.5% in the placebo group (hazard ratio with apixaban, 0.95; 95% CI, 0.79 to 1.15), and the corresponding rates among those receiving aspirin alone were 9.0% and 9.8% (hazard ratio, 0.92; 95% CI, 0.66 to 1.29) (P = 0.87 for interaction). Similar findings with respect to the primary efficacy outcome were seen in all key subgroups.

A total of 7315 of the 7392 patients who underwent randomization (99.0%) received at least one dose of the assigned study drug; 8.5% of the patients were assigned to the reduced dose of apixaban or matching placebo. Of these 7315 patients, 863 of the 3673 patients who received at least one dose of apixaban (23.5%) and 746 of the 3642 who received at least one dose of placebo (20.5%) stopped taking the study drug before the end of the trial (P = 0.002). The median exposure to the study drug was 175 days (interquartile range, 66 to 293) among patients receiving apixaban and 185 days (interquartile range, 75 to 298) among patients receiving placebo. The most common reasons for discontinuation of the study drug were adverse events (8.5% in the apixaban group vs. 6.5% in the placebo group) and withdrawal of consent (5.3% vs. 4.2%). A total of 1310 (21.5%) of the patients who were taking aspirin plus a P2Y12-receptor antagonist at the time of randomization stopped taking the P2Y12-receptor antagonist during the course of the trial, at a median of 39 days (interquartile range, 13 to 108) after randomization; 135 (11.1%) of the patients receiving aspirin alone at randomization started taking a P2Y12-receptor antagonist during the trial, at a median of 14 days (interquartile range, 4 to 93) after randomization.

Efficacy Outcomes
The final number of primary efficacy events was 572, or 61.0% of the initially planned number. In the intention-to-treat analysis, the primary efficacy outcome of cardiovascular death, myocardial infarction, or ischemic stroke occurred in 279 patients (7.5%) assigned to apixaban (13.2 events per 100 patient-years) and in 293 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). Similar results were seen in an on-treatment analysis (218 vs. 249 events; hazard ratio, 0.89; 95% CI, 0.74 to 1.06; P = 0.19). There were also no significant differences between the apixaban and placebo groups with respect to any of the secondary efficacy outcomes. The effect of apixaban as compared with placebo was similar among patients receiving combination antiplatelet therapy and among those receiving aspirin alone. The rates of the primary efficacy outcome among patients who were receiving combination antiplatelet therapy were 7.2% in the apixaban group and 7.5% in the placebo group (hazard ratio with apixaban, 0.95; 95% CI, 0.79 to 1.15), and the corresponding rates among those receiving aspirin alone were 9.0% and 9.8% (hazard ratio, 0.92; 95% CI, 0.66

Efficacy and bleeding outcomes were analyzed with the use of a Cox proportional-hazards model that included the assigned study group as a covariate and that was stratified according to antiplatelet therapy (single or dual) at baseline. Data on patients who died of noncardiovascular causes were censored at the time of death. A point estimate and two-sided 95% confidence interval for the hazard ratio were calculated for each outcome. Prespecified efficacy and safety analyses were performed in subgroups according to baseline antiplatelet therapy, type of acute coronary syndrome, treatment for acute coronary syndrome, dose of apixaban, region, age, sex, race, body-mass index, degree of renal impairment, number of risk factors, presence or absence of diabetes mellitus, and presence or absence of heart failure. The rates of efficacy and bleeding events are reported as percentages and as events per 100 patient-years. Other categorical variables are reported as percentages. All P values are two-sided. All analyses were per formed with the use of SAS software, version 9.0 (SAS Institute).

Study Participants
A total of 7392 patients underwent randomization between March 17, 2009, and November 18, 2010 (Fig. 1 in the Supplementary Appendix). Patients underwent randomization a median of 6 days (interquartile range, 4 to 7) after the index event of acute coronary syndrome and 2 days (interquartile range, 2 to 4) after discontinuation of parenteral antithrombotic therapy. Among the patients who underwent randomization, 81 (1.1%) withdrew consent and 50 (0.7%) were lost to follow-up for the primary end point during the intended treatment period. The median duration of follow-up from the time of randomization through the last date of contact in the study was 240 days (interquartile range, 132 to 352) among patients assigned to apixaban and 242 days (interquartile range, 131 to 352) among patients assigned to placebo. By design, the trial population had high rates of diabetes, prior myocardial infarction, cerebrovascular and peripheral vascular disease, heart failure or left ventricular dysfunction, and impaired renal function, and a large proportion of the patients had not undergone revascularization for the index event. More than half the patients had three or more protocol-defined high-risk characteristics at the time of enrollment. The index event was a myocardial infarction with ST-segment elevation in approximately 40% of patients, a myocardial infarction without STsegment elevation in 42%, and unstable angina in 18%. More than 52% of the patients underwent coronary angiography, 44% underwent a percutaneous coronary intervention, and 55% had their condition managed medically. At the time of randomization, nearly all the patients (97%) were taking aspirin. The majority of the patients (81%) were receiving aspirin plus a P2Y12-receptor antagonist, predominantly clopidogrel. Most patients were receiving other evidence- based therapies as well, and the rates of these therapies were similar in the apixaban and placebo groups.

At 84 hours after transfection, apoptotic morphological changes, such as cell rounding, cytoplasmic blebbing, and irregularities of shape, were observed in NB-39-nu cells treated with ALK-siRNAs, whereas no significant changes were seen in the mock-transfected cells or in the luc-siRNA and the s-siRNA treated cells.

These morphological changes were not observed in SK-N-MC cells treated with ALK-siRNAs (data not shown). At 90 hours after transfection, NB-39-nu cells treated with ALK-siRNAs started to detach from the dish due to cell death.

To examine the localization of expression of ALK kinase, we performed double staining by anti-ALK antibody and TOTO-3, which stains the nucleus, in several neuroblastic cell lines. ALK protein overexpressed in NB-39-nu cells is localized in both membrane and cytoplasm. ALK staining was very weak in cell lines such as YT-nu and SK-N-MC with one copy of the ALK gene, however, its localization appeared to be the same as in NB-39-nu (data not shown). It was observed that the expression of ALK was completely lost after the RNAi-induced suppression of ALK. To confirm whether the cell death resulted from apoptosis, cells were also analyzed by immunofluorescent TUNEL staining in NB-39-nu cells. TUNEL staining was clearly positive in these cells at 84 hours after transfection, indicating that apoptosis was induced in NB-39-nu cells treated with ALK-siRNAs. No significant TUNEL staining was observed in the mock-transfected cells or the luc-siRNA treated cells. Finally, DNA fragmentation assay was performed to measure the endonuclease activity accompanied by apoptosis. The formation of significant DNA fragmentation was observed in the NB-39-nucells but not in SK-N-MC cells treated with ALK-siRNAs, indicating that cell apoptosis was induced through the suppression of ALK only in the NB-39-nu cells. This suggests that signaling pathways downstream of activated ALK dominantly regulate the survival of neuroblastoma cells with amplified ALK; therefore, the loss of ALK protein results in apoptotic changes to these cells.

Expression of ALK in Primary Neuroblastoma Tissues
Immunohistochemically, ALK was positively detected both in the cytoplasm of the neuroblastic cells and in the fine meshwork of neuropil of seven of nine tumors with favorable histology cases with nonamplified N-myc (FH&NA). All seven unfavorable histology tumors (two UH&A tumors and five UH&NA tumors) were positive in the cytoplasm and/or in the fine meshwork of neuropil for ALK. There was no correlation between the frequency or intensity of ALK-staining and histology of neuroblastoma tissues, showing majority of neuroblastoma samples showed a detectable amount of ALK. There was no significant staining using preimmune serum from the same rabbit as that for anti-ALK antibody (data not shown). Essentially the same results were obtained using a mouse monoclonal antibody against human ALK (ALK1: DAKO) (data not shown).

Article written by Canadian Pharmacy.

A targeted national scan of processed foods sold primarily in grocery stores, conducted by Health Canada and Food & Consumer Products of Canada in June 2005, confirmed the Task Force’s assumption that the use of alternatives to trans fats was increasing rapidly, although more so in some food categories than in others.

Almost all bread products and salad dressings were free of trans fats. Significant progress had also been achieved in certain food categories such as french fries and chips. However, some varieties of baked goods, oriental noodles, snack puddings, liquid coffee whiteners, microwave popcorn, toaster pastries, hard margarines and shortenings still contained high amounts of trans fats. It was also noted that new and reformulated products with minimal amounts of trans fat were appearing on the market on a regular basis.

In many instances, partially hydrogenated oils had been replaced by oils rich in monounsaturated and polyunsaturated fatty acids – fats that have been identified as healthier alternatives to oils and fats rich in saturated fatty acids. However, alternatives rich in polyunsaturated fatty acids are more prone to lipid oxidation and do not possess the functional characteristics (e.g. an appropriate melting point) needed in processing certain food products. In fact, it was noted that in some food categories (e.g. cookies, snack puddings, crackers, granola bars, oriental noodles and liquid coffee whiteners), partially hydrogenated oils had sometimes been replaced by oils in which 50-100% of total fat was saturated fat.

While these high saturated fat alternatives are still less harmful to health than oils containing high amounts of trans fatty acids, they do not contribute to the goal of reducing coronary heart disease risk and achieving the Task Force’s objective of “significant net health benefit.” That said, even in some of the more problematic food categories (e.g. crackers and other snack foods), the Task Force noted innovative products that have incorporated more healthful alternative oils. This finding can be attributed to targeted research and development efforts by industry – efforts that should be encouraged.

The Task Force’s consultations revealed some concerns regarding the use of trans fats in baby and toddler foods (i.e. foods for children under two years of age). It seems that increased awareness has already sparked actions by industry, and the Task Force did not devote time to discussing this issue.In summary, there is good evidence that growing consumer awareness and mandatory nutrition labeling have motivated industry to reduce or eliminate trans fat from many processed foods sold in grocery stores.

However, there is also evidence that these factors alone will not result in reformulation of all processed foods, and that some products with higher trans fat content are likely to remain unchanged in the absence of a regulated limit. These include products where it is more difficult for manufacturers to generate an adequate return on the investment required for reformulation. Examples of such products are low-cost foods (oriental noodles), foods consumed for reasons other than nutritional value (cakes and pastries) and foods for which nutrient information is not easily accessible (nachos sold in movie theatres).