Evaluation of risk factors predictive of nausea and vomiting with current standard-of-care antiemetic treatment: analysis of phase 3 trial of aprepitant in patients receiving adriamycin-cyclophosphamide-based chemotherapy.

GOALS OF WORK: A number of prognostic factors have been identified as risk factors for chemotherapy-induced emesis. This post-hoc analysis addressed whether: (1) these prognostic factors can identify a low-risk group for whom ondansetron plus dexamethasone alone provide a high level of protection (≥80% no emesis); (2) the NK1 receptor antagonist aprepitant improves antiemetic outcome regardless of emetic risk. PATIENTS AND METHODS: Breast cancer patients in a phase III double-blind, placebo-controlled trial were randomized to antiemetic regimens including ondansetron and dexamethasone, or aprepitant, ondansetron, and dexamethasone. Multivariate logistic regression models were used to assess the impact on emesis (but not nausea) of the regimen with aprepitant, and previously reported risk factors, including age (<55 and ≥55 years), ethanol use (0-4 or ≥5 drinks/week), history of pregnancy-related morning sickness, and history of motion sickness, using a modified intent-to-treat approach. RESULTS: Treatment with aprepitant (P < 0.0001), older age (P = 0.006), ethanol use (P = 0.0048), and no history of morning sickness (P = 0.0007) were all significantly associated with reduced likelihood of emesis. The proportion of patients with one, two, or three risk factors who remained emesis free was significantly higher with the aprepitant-containing regimen than with the active control (70.2-82.8% vs. 38.6-66.4%, respectively). CONCLUSIONS: Aprepitant markedly improved control of emesis in patients with one or more risk factors. This analysis did not support using risk factors for modifying the antiemetic approach. A low-risk group with zero risk factors for whom aprepitant provided little benefit was of questionable clinical utility, since they comprised less than 3% of patients.

Differential time course of action of 5-HT3 and NK1 receptor antagonists when used with highly and moderately emetogenic chemotherapy (HEC and MEC).

BACKGROUND: Cisplatin-based highly emetogenic chemotherapy (HEC) displays a biphasic pattern of emesis with both an early and delayed period. In contrast, moderately emetogenic chemotherapy (MEC) has a monophasic pattern. The objective of this analysis was to further investigate the impact of the NK1-receptor antagonist aprepitant on these patterns. METHODS: Three phase III HEC (patients scheduled to receive cisplatin-based chemotherapy) and one phase III MEC (breast cancer patients scheduled to receive anthracycline plus cyclophosphamide (AC)) trials of aprepitant were included. In all studies, patients were randomized in a 1:1 ratio to an aprepitant regimen (aprepitant plus ondansetron plus dexamethasone) or the standard regimen (ondansetron plus dexamethasone). The exact dosing regimen for ondansetron and dexamethasone was different in each study. In a post hoc analysis, multivariate logistic regression models were used to assess the impact on first emesis at different time intervals after chemotherapy. RESULTS: One thousand five hundred twenty-seven patients and 856 patients were randomized and assessed for efficacy in the HEC and MEC trials, respectively. For HEC, aprepitant reduced the risk of first emesis by 38-77% vs. standard regimen, beginning 15-18 h after cisplatin and extending to 60 h. For MEC, aprepitant reduced the risk of first emesis by 38-61% vs. active control, beginning 3 h after AC and for up to 12 h. CONCLUSIONS: Time of onset and duration of enhanced control of emesis with the addition of aprepitant differed between HEC and MEC. This suggests that the pattern of NK1-sensitive mechanisms may vary for different chemotherapy regimens.

Evaluation of risk factors predictive of nausea and vomiting with current standard-of-care antiemetic treatment: analysis of two phase III trials of aprepitant in patients receiving cisplatin-based chemotherapy.

GOALS OF WORK: Certain patient and treatment characteristics are predictive of chemotherapy-induced nausea and vomiting (CINV). Objectives of this analysis were: (1) confirm the importance of several previously reported adverse risk factors for CINV in patients receiving chemotherapy, (2) assess the impact of the NK(1) receptor antagonist aprepitant according to these risk factors, and (3) assess the impact of age on antiemetic outcome. PATIENTS AND METHODS: Patients from two double-blind, placebo-controlled trials were randomized to an active-control group (ondansetron 32 mg IV, dexamethasone 20 mg PO day 1; dexamethasone 8 mg bid days 2-4) or an aprepitant group (aprepitant 125 mg PO, ondansetron 32 mg IV, dexamethasone 12 mg day 1; aprepitant 80 mg days 2-3; dexamethasone 8 mg qd days 2-4). The primary endpoint was complete response (no emesis or rescue therapy use). In a post-hoc analysis, multivariate logistic regression models were used to assess the impact of treatment with aprepitant and previously reported risk factors, using a modified intent-to-treat approach. MAIN RESULTS: Treatment with aprepitant (p < 0.0001), male gender (p = 0.023), cisplatin dose <80 mg/m(2) (p = 0.001), age >or=65 years (p = 0.021), and five or more alcoholic drinks per week (p = 0.027) were all significantly associated with improved complete response. Aprepitant improved complete response regardless of risk for all factors and neutralized the risk associated with female gender. CONCLUSIONS: This analysis confirmed the relevance of several previously reported risk factors for CINV in patients receiving chemotherapy. Aprepitant improved complete response regardless of risk and eliminated the increased risk of CINV associated with the female gender.

Trans fats in America: a review of their use, consumption, health implications, and regulation.

Trans fatty acids have long been used in food manufacturing due in part to their melting point at room temperature between saturated and unsaturated fats. However, increasing epidemiologic and biochemical evidence suggest that excessive trans fats in the diet are a significant risk factor for cardiovascular events. A 2% absolute increase in energy intake from trans fat has been associated with a 23% increase in cardiovascular risk. Although Denmark has shown it is possible to all but eliminate commercial sources of trans fats from the diet, total elimination is not possible in a balanced diet due to their natural presence in dairy and meat products. Thus, the American Heart Association recommends limiting trans fats to <1% energy, and the American Dietetic Association, the Institute of Medicine, US Dietary Guidelines, and the National Cholesterol Education Project all recommend limiting dietary trans-fat intake from industrial sources as much as possible. The presence of small amounts of trans fat in hydrogenated or partially hydrogenated oils/food products will likely cause many Americans to exceed their recommended maximum. This likelihood is exacerbated by the Food and Drug Administration labeling rules, which allow products containing <0.5 g trans fat per serving to claim 0 g trans fat. Many products with almost 0.5 g trans fat, if consumed over the course of a day, may approximate or exceed the 2 g maximum as recommended by American Heart Association, all while claiming to be trans-fat free. Accordingly, greater transparency in labeling and/or active consumer education is needed to reduce the cardiovascular risks associated with trans fats.