Experimental design issues in choice-based conjoint applied to patient choice in healthcare.

Choice-based conjoint (CBC) is used to understand how individuals develop preferences for decision alternatives. When decision alternatives can be described in terms of attributes, researchers want to determine the value respondents attach to various attribute levels. Popular in psychology, marketing, economics and other areas, CBC is now finding applications in healthcare to understand patient choice in healthcare policy, drug development, doctor-patient communications, etc. However, a lack of standard methodologies has served as a barrier to its use in healthcare. Therefore, there is a need to identify good research practices for CBC in healthcare. We review recent advances in CBC such as Pareto optimal choice sets, information per profile and reducing choice set sizes, as applied to patient choice.

Aprepitant and fosaprepitant: a 10-year review of efficacy and safety.

Chemotherapy-induced nausea and vomiting (CINV) is a common adverse event associated with anticancer treatment that can have a significant adverse impact on patient health-related quality of life and that can potentially undermine the effectiveness of chemotherapy. Traditional regimens to prevent CINV generally involved a combination of a corticosteroid plus a 5-hydroxytryptamine (5HT3) receptor antagonist (RA). In the past 10 years, antiemetic treatment has greatly advanced with the availability of the neurokinin-1 receptor antagonist (NK1 RA) aprepitant and its prodrug fosaprepitant. NK1 RAs have a different mechanism of action in CINV than corticosteroids and 5HT3 RAs, thus their use can complement traditional antiemetic drugs and can enhance control of CINV. This review examined accumulated data regarding the safety and efficacy of aprepitant and fosaprepitant over the decade since the first regulatory approval. Data from key studies of aprepitant and fosaprepitant in the prevention of CINV in patients receiving moderately and highly emetogenic chemotherapy were explored, as were recommendations in currently available guidelines for their use. In addition, their use as antiemetic therapy in special patient populations was highlighted. Future perspectives on potential uses of aprepitant and fosaprepitant for indications other than CINV are presented.

Changes in PINCH levels in the CSF of HIV+ individuals correlate with hpTau and CD4 count.

Several studies report associations between the particularly interesting new cysteine histidine-rich (PINCH) protein and HIV-associated CNS disease. PINCH is detected in the CSF of HIV patients, and changes in levels during disease may be indicative of changes in disease status over time. PINCH binds hyperphosphorylated Tau (hpTau) in the brain and CSF, but little is known about the relevance of these interactions to HIV CNS disease. In this study, PINCH and hpTau levels were assessed in three separate CSF samples collected longitudinally from 20 HIV+ participants before and after initiating antiretroviral therapy or before and after a change in the treatment regimen. The intervals were approximately 1 (T2) and 3-7 (T3) months from the initial visit (baseline, T1). Correlational analyses were conducted for CSF levels of PINCH and hpTau and other variables including blood CD4 T-cell count, plasma and CSF viral burden, CSF neopterin, white blood cell (WBC) count, and antiretroviral CNS penetration effectiveness (CPE). Values for PINCH and hpTau were determined for each patient by calculating the fold changes between the second (T2) and third measurements (T3) from the baseline measurement (T1). Statistical analyses showed that the fold changes in CSF PINCH protein from T1 to T2 were significantly higher in participants with CD4 counts >200 cells/mm(3) at T2 compared to those with CD4 counts <200 cells/mm(3) at T2. This trend persisted irrespective of plasma or CSF viral burden or antiretroviral therapy CPE scores. The fold changes in PINCH levels between T1 and T2, and T1 and T3 were highly correlated to the fold changes in hpTau at T2/T1 and T3/T1 (correlation coefficient = 0.69, p < 0.001; correlation coefficient = 0.83, p < 0.0001, respectively). In conclusion, in these HIV participants, changes in CSF levels of PINCH appear to correlate with changes in blood CD4 count and with changes in CSF hpTau levels, but not with plasma or CSF viral burden, neopterin, WBC, or antiretroviral regimen CPE.

Analysis of aprepitant for prevention of chemotherapy-induced nausea and vomiting with moderately and highly emetogenic chemotherapy.

AIM: This study aimed to determine how aprepitant affects the impact of chemotherapy-induced nausea and vomiting (CINV) on daily activities during highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC). PATIENTS & METHODS: Patients received aprepitant plus standard antiemetic therapy (ondansetron plus dexamethasone) or standard antiemetic therapy alone. Data were analyzed from pooled data of two Phase III randomized, double-blind HEC trials and one MEC trial. Patients completed the Functional Living Index-Emesis questionnaire. RESULTS: A significantly greater percentage of patients receiving aprepitant reported no or minimal CINV impact on daily life (overall total Functional Living Index-Emesis score >6) compared with those receiving standard therapy alone (HEC: 74.4 vs 63.9%, respectively; p < 0.01; MEC: 73.4 vs 66.3%; p < 0.05). In HEC, favorable responses to aprepitant treatment persisted in nausea (70.2 vs 60.9%) and vomiting domains (84.6 vs 68.7%; both p < 0.01). Similar results were seen in MEC. CONCLUSION: Addition of aprepitant reduced CINV impact on daily life compared with standard antiemetic therapy.

Review of the efficacy of aprepitant for the prevention of chemotherapy-induced nausea and vomiting in a range of tumor types.

Chemotherapy regimens differ according to the tumor type being treated and are associated with varying degrees of emetogenic potential. Since the distribution of risk factors for chemotherapy-induced nausea and vomiting differs across tumor types, it is important to understand the efficacy of antiemetic regimens in multiple patient populations. To characterize treatment response in patients with various malignancies (e.g., breast, gastrointestinal, genitourinary, and lung) treated with either highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC) regimens, a pooled analysis of patient-level data from 4 large randomized trials was performed (N=2813). Patients receiving an antiemetic regimen containing aprepitant, ondansetron, and dexamethasone were compared with patients receiving an active-control antiemetic regimen containing ondansetron plus dexamethasone. In all tumor types analyzed, complete responses were observed in a higher proportion of HEC-treated patients receiving aprepitant compared with active-control patients (genitourinary [61.5% vs 40.6%, P<0.001], gastrointestinal [68.2% vs 44.7%, P=0.013], and lung cancers [73.5% vs 52.8%, P<0.001]). For MEC-treated patients, complete response rates were also higher for aprepitant patients than active-control patients for all tumor types, with a significant difference noted among patients with breast cancer (54.9% vs 43.9%, P<0.0001). The proportion of patients with no vomiting was higher in both HEC- and MEC-treated patients. While results of previous studies provide support for the use of antiemetic regimens that include aprepitant, a selective 5-hydroxytryptamine-3 receptor antagonist, and dexamethasone, this analysis demonstrates the consistent efficacy of aprepitant as part of an antiemetic regimen across different tumor types and chemotherapy regimens.

Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized, double-blind study protocol--EASE.

PURPOSE: Addition of aprepitant, a neurokinin-1 receptor antagonist (NK1RA), to an ondansetron and dexamethasone regimen improves prevention of chemotherapy-induced nausea/vomiting (CINV), particularly during the delayed phase (DP; 25 to 120 hours). Therefore, recommended antiemetic regimens include multiple-day NK1RA administration. Preliminary data suggested that single-dose aprepitant before chemotherapy could provide CINV protection throughout the overall risk phase (OP; 0 to 120 hours). This study compared a 3-day oral aprepitant schedule to a regimen containing a single dose of the intravenous NK1RA fosaprepitant. PATIENTS AND METHODS: A randomized, double-blind, active-control design was used to test whether fosaprepitant is noninferior to aprepitant. Patients receiving cisplatin ≥ 70 mg/m(2) for the first time received ondansetron and dexamethasone with a standard aprepitant regimen (125 mg on day 1, 80 mg on day 2, 80 mg on day 3) or a single-dose fosaprepitant regimen (150 mg on day 1). The primary end point was complete response (CR; no vomiting, no rescue medication) during OP. Secondary end points were CR during DP and no vomiting during OP. Accrual of 1,113 evaluable patients per treatment arm was planned to confirm noninferiority with expected CR of 67.7% and noninferiority margin of minus 7 percentage points. RESULTS: A total of 2,322 patients were randomly assigned, and 2,247 were evaluable for efficacy. Antiemetic protection with aprepitant and fosaprepitant was equivalent within predefined bounds for noninferiority. Both regimens were well tolerated, although more frequent infusion site pain/erythema/thrombophlebitis was seen with fosaprepitant relative to aprepitant (2.7% v 0.3%, respectively). CONCLUSION: Given with ondansetron and dexamethasone, single-dose intravenous fosaprepitant (150 mg) was noninferior to standard 3-day oral aprepitant in preventing CINV during OP and DP.

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.

Aprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with a broad range of moderately emetogenic chemotherapies and tumor types: a randomized, double-blind study.

PURPOSE: Aprepitant was shown previously to be effective for prevention of chemotherapy-induced nausea and vomiting (CINV) with moderately emetogenic chemotherapy (MEC) in breast cancer patients receiving an anthracycline and cyclophosphamide (AC)-based regimen. This study assessed aprepitant in patients receiving a broad range of MEC regimens with a variety of tumor types. METHODS: This phase III, randomized, gender-stratified, double-blind trial enrolled patients with confirmed malignancies, naïve to MEC or highly emetogenic chemotherapy, who were scheduled to receive a single dose of at least one MEC agent. Patients received an aprepitant triple-therapy regimen (aprepitant, ondansetron, and dexamethasone) or a control regimen (ondansetron and dexamethasone) administered orally. Primary and key secondary efficacy endpoints were proportions of patients with no vomiting and complete response (no vomiting and no rescue medication), respectively, during the 120 h post-chemotherapy. RESULTS: Of 848 randomized patients, 77% were female, and 52% received non-AC-based antineoplastic regimens. Significantly, more patients in the aprepitant group achieved no vomiting and complete response, regardless of whether they received AC or non-AC regimens, in the 120 h after chemotherapy. Overall, the incidences of adverse events were generally similar in the aprepitant (62.8%) and control groups (67.2%). CONCLUSIONS: The aprepitant regimen provided superior efficacy in the treatment of CINV in a broad range of patients receiving MEC (non-AC or AC) in both no vomiting and complete response endpoints. Aprepitant was generally well tolerated. These results show the benefit of including aprepitant as part of the standard antiemetic regimen for cancer patients receiving MEC.

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.

PCPT: Evidence that finasteride reduces risk of most frequently detected intermediate- and high-grade (Gleason score 6 and 7) cancer.

OBJECTIVES: To determine the effect of finasteride relative to placebo on prostate cancer (PCa) risk at each individual Gleason score in the Prostate Cancer Prevention Trial using a post hoc generalization of a prespecified, exploratory, biopsy sampling density-adjusted analysis. METHODS: The Prostate Cancer Prevention Trial enrolled 18 882 men aged >or=55 years with a prostate-specific antigen level of <3.0 ng/mL and normal digital rectal examination findings, and randomized them to finasteride 5 mg daily or placebo. PCa data from evaluable biopsies obtained within 7 years plus

Aprepitant in adolescent patients for prevention of chemotherapy-induced nausea and vomiting: a randomized, double-blind, placebo-controlled study of efficacy and tolerability.

BACKGROUND: The neurokinin-1 receptor antagonist aprepitant, plus a 5HT3 antagonist and corticosteroid is well-tolerated and effective in preventing chemotherapy-induced nausea and vomiting in adults but has not been formally assessed in adolescents. PROCEDURE: Patients age 11-19 years old receiving emetogenic chemotherapy were randomized 2:1 to aprepitant triple therapy (aprepitant [A] 125 mg p.o., dexamethasone [D] 8 mg p.o., and ondansetron [O] 0.15 mg/kg i.v. t.i.d. day 1; A 80 mg, D 4 mg, and O 0.15 mg/kg t.i.d. day 2; A 80 mg and D 4 mg day 3; and D 4 mg day 4) or a control regimen (D 16 mg and O 0.15 mg/kg t.i.d. day 1; D 8 mg and O 0.15 mg/kg t.i.d. day 2; and D 8 mg days 3 and 4). The primary endpoint was the difference in drug-related adverse events during and for 14 days following treatment. Efficacy and aprepitant pharmacokinetics were assessed. RESULTS: Baseline characteristics were similar between aprepitant (N = 28) and control (N = 18) groups. Febrile neutropenia was more frequent in the aprepitant group (25% vs. 11.1%). Complete response (CR) rates were 35.7% for aprepitant triple therapy versus 5.6% for the control group. Mean plasma aprepitant AUC(0-24 hr) and C(max) on day 1 and mean trough concentrations on days 2 and 3 were consistently lower compared to historical data obtained from healthy adults; however, the differences were not clinically significant. CONCLUSION: Aprepitant triple therapy was generally well tolerated; CR were greater with aprepitant, although not statistically significant. Pharmacokinetics suggest that the adult dosing regimen is appropriate for adolescents.

Preventing postoperative nausea and vomiting: post hoc analysis of pooled data from two randomized active-controlled trials of aprepitant.

OBJECTIVE: Compared with the 5HT(3) antagonist ondansetron, the NK(1) antagonist aprepitant has been shown in two double-blind trials to provide greater protection against postoperative vomiting and comparable or greater control of nausea. Post hoc analyses of pooled data from these trials were performed to more fully characterize the efficacy profile of aprepitant in terms of nausea and use of rescue therapy. RESEARCH DESIGN AND METHODS: Patients (n = 1599) scheduled for major surgery under general anesthesia (primarily gynecological surgery) were assigned to receive a preoperative dose of aprepitant 40 mg PO, 125 mg PO, or ondansetron 4 mg IV. in two randomized, double-blind, clinical trials. MAIN OUTCOME MEASURES: Post-surgery vomiting episodes, use of rescue therapy, and nausea severity (verbal rating scale). RESULTS: In the 24 hours after surgery, aprepitant 40 mg was more effective than ondansetron for all five endpoints evaluated: (1) no significant nausea (56.4% vs. 48.1%); (2) no nausea (39.6% vs. 33.1%); (3) no vomiting (86.7% vs. 72.4%); (4) no nausea and no vomiting (38.3% vs. 31.4%); and (5) no nausea, no vomiting, and no use of rescue (37.9% vs. 31.2%) (p < 0.035 for the odds ratio for each comparison). Numerically more patients receiving aprepitant 125 mg also achieved these endpoints compared with ondansetron. CONCLUSIONS: These post hoc analyses confirm the favorable efficacy profile of aprepitant for the prevention of post operative nausea and vomiting.

Detection bias due to the effect of finasteride on prostate volume: a modeling approach for analysis of the Prostate Cancer Prevention Trial.

BACKGROUND: The Prostate Cancer Prevention Trial (PCPT) demonstrated a 24.8% reduction in the 7-year prevalence of prostate cancer among patients treated with finasteride (5 mg daily) compared with that among patients treated with placebo; however, a 25.5% increase in the prevalence of high-Gleason grade tumors was observed, the clinical significance of which is unknown. One hypothesized explanation for this increase is that finasteride reduced prostate volume, leading to detection of more high-grade tumors due to increased sampling density. This possibility was investigated in an observational reanalysis of the PCPT data, with adjustment for sampling density. METHODS: A logistic model for the association of high-grade (Gleason score 7-10) prostate cancer with baseline covariates and/or baseline covariates plus prostate volume and number of cores obtained at biopsy was developed using the placebo group (n = 4775) of the PCPT. This model was then applied to the finasteride group (n = 5123) to compare the predicted and observed numbers of high-grade tumors in that group. In a second approach, odds ratios (ORs) for prostate cancer in the finasteride versus placebo groups calculated from binary and polytomous logistic regression models that contained or excluded covariates for gland volume and number of needle cores were compared. RESULTS: Median prostate volume was 25% lower in the finasteride group (median = 25.1 cm3) than in the placebo group (median = 33.5 cm3). The logistic model developed in the placebo group showed that the likelihood of detection of high-grade prostate cancer decreased as volume increased (for each 10 cm3 increase in prostate volume, OR = 0.81, 95% confidence interval [CI] = 0.74 to 0.90). Based on this model, 239 high-grade prostate cancers were predicted in the finasteride group, whereas 243 were observed, a non-statistically significant difference. Among all participants, the odds ratios for high-grade cancer in the finasteride versus placebo groups decreased from 1.27 (95% CI = 1.05 to 1.54) with adjustment for baseline covariates to 1.03 (95% CI = 0.84 to 1.26) following additional adjustment for gland volume and number of biopsy cores in binary outcome models and from 1.14 (95% CI = 0.94 to 1.38) to 0.88 (95% CI = 0.72 to 1.09) following these adjustments in the polytomous models. CONCLUSIONS: Although analyses using postrandomization data require cautious interpretation, these results suggest that sampling density bias alone could explain the excess of high-grade cancers among the finasteride-assigned participants in the PCPT.

A randomized, double-blind comparison of the NK1 antagonist, aprepitant, versus ondansetron for the prevention of postoperative nausea and vomiting.

BACKGROUND: Antiemetics currently in use are not totally effective. Neurokinin-1 receptor antagonists are a new class of antiemetic that have shown promise for chemotherapy-induced nausea and vomiting. This is the first study evaluating the efficacy and tolerability of the neurokinin-1 receptor antagonist, aprepitant, for the prevention of postoperative nausea and vomiting. METHODS: In this multicenter, double-blind trial, we randomly assigned 805 patients receiving general anesthesia for open abdominal surgery to a preoperative dose of aprepitant 40 mg orally, aprepitant 125 mg orally, or ondansetron 4 mg IV. Vomiting, nausea, and use of rescue therapy were assessed over 48 h after surgery. Treatments were compared using logistic regression. RESULTS: Incidence rates for the primary end point (complete response [no vomiting and no use of rescue] over 0-24 h after surgery, tested for superiority of aprepitant) were not different across groups (45% with aprepitant 40 mg, 43% with aprepitant 125 mg, and 42% with ondansetron). The incidence of no vomiting (0-24 h) was higher with aprepitant 40 mg (90%) and aprepitant 125 mg (95%) versus ondansetron (74%) (P < 0.001 for both comparisons), although between-treatment use of rescue and nausea control was not different. Both aprepitant doses also had higher incidences of no vomiting over 0-48 h (P < 0.001). No statistically significant differences were seen among the side effect profiles of the treatments. CONCLUSIONS: Aprepitant was superior to ondansetron for prevention of vomiting in the first 24 and 48 h, but no significant differences were observed between aprepitant and ondansetron for nausea control, use of rescue, or complete response.

Antiemetic efficacy of the neurokinin-1 antagonist, aprepitant, plus a 5HT3 antagonist and a corticosteroid in patients receiving anthracyclines or cyclophosphamide in addition to high-dose cisplatin: analysis of combined data from two Phase III randomized clinical trials.

BACKGROUND: The tendency of chemotherapeutic regimens to cause vomiting is dependent on the individual drugs in the regimen. The authors analyzed data combined from 2 Phase III trials to assess the effect of the neurokinin-1 (NK(1)) antagonist aprepitant combined with a 5HT(3) antagonist plus a corticosteroid in a subpopulation receiving > 1 emetogenic chemotherapeutic agent. METHODS: In the current study, 1043 cisplatin-naive patients (42% were women) receiving cisplatin-based (> or = 70 mg/m(2)) chemotherapy were assigned randomly to a control regimen (ondansetron [O] 32 mg intravenously and dexamethasone [D] 20 mg orally on Day 1; D 8 mg twice daily on Days 2-4) or an aprepitant (A) regimen (A 125 mg orally plus O 32 mg and D 12 mg on Day 1; A 80 mg and D 8 mg once daily on Days 2-3; and D 8 mg on Day 4). Randomization was stratified for use of concomitant chemotherapy and female gender. The primary end point was complete response (no vomiting and no rescue therapy) on Days 1-5 (0-120 hours). Data were analyzed by a modified intent-to-treat approach, and logistic regression was used to make treatment comparisons among patients receiving the most frequently coadministered emetogenic concomitant chemotherapy (Hesketh level > or = 3). RESULTS: Among the approximately 13% of patients (n = 81 for A; n = 80 for control) who received additional emetogenic chemotherapy (doxorubicin or cyclophosphamide), the aprepitant regimen provided a 33 percentage-point improvement in the complete response rate compared with the control regimen. Among the general population, the advantage with aprepitant was 20 percentage points. CONCLUSIONS: The current analysis of > 1000 patients from 2 large randomized trials showed that in the subpopulation at increased risk of chemotherapy-induced nausea and vomiting due to concomitant emetogenic chemotherapy, the addition of aprepitant to standard antiemetics improved protection to an even greater extent than in the general study population.

The oral NK(1) antagonist aprepitant for the prevention of acute and delayed chemotherapy-induced nausea and vomiting: Pooled data from 2 randomised, double-blind, placebo controlled trials.

In this work, data from two phase III studies were pooled to further evaluate the NK(1) antagonist aprepitant for prevention of cisplatin induced nausea and vomiting. One thousand and forty three patients receiving cisplatin (> or = 70 mg/m2) were randomised to receive either a control regimen (32 mg intravenous ondansetron [O] and 20 mg oral dexamethasone [D] on day 1; 8 mg D twice daily on days 2-4) or an aprepitant (A) regimen (125 mg A plus 32 mg O and 12 mg D on day 1, 80 mg A and 8 mg D once daily on days 2-3, and 8 mg D on day 4). The primary endpoint was no emesis and no rescue therapy. Potential correlations between acute and delayed emesis were assessed, as were frequency of emetic episodes by time interval and effects on nausea and quality of life as measured by the functional living index emesis (FLIE) questionnaire. In the aprepitant group, there was statistically significantly less nausea over the study period as well as higher functioning on the FLIE questionnaire in both the nausea and vomiting domains. Patients without acute emesis were more likely to have no emesis in the delayed phase. Compared with control, the aprepitant regimen improved prevention of delayed emesis by 16% points in patients without acute emesis, and by 17% points in patients with acute emesis. Among patients who did not have complete response, the frequency of emesis at various intervals over 5 days was consistently lower in patients receiving aprepitant. Analyses of this combined Phase III population further characterized the clinical profile of the aprepitant regimen, showing that delayed emesis is correlated with, but not entirely dependent on, the presence of acute emesis, and that aprepitant has a favorable effect against nausea throughout 5 days postchemotherapy. In addition, even among patients who had emesis or needed rescue therapy, aprepitant was associated with a lower frequency of these events compared with the control regimen.

Aprepitant: an oral NK1 antagonist for the prevention of nausea and vomiting induced by highly emetogenic chemotherapy.

This paper reviews the clinical profile of aprepitant, the first neurokinin-1 (NK(1)) receptor antagonist to be approved for use in the prevention of chemotherapy-induced nausea and vomiting. When given to patients receiving highly emetogenic chemotherapy, aprepitant in combination with a 5-hydroxytryptamine type-3 (5HT(3)) receptor antagonist and a corticosteroid provides significantly improved protection from chemotherapy-induced nausea and vomiting over that which has been previously achievable with current antiemetics.

Ertapenem versus ceftriaxone for the treatment of community-acquired pneumonia in adults: combined analysis of two multicentre randomized, double-blind studies.

The efficacy and safety of ertapenem, 1 g once a day, for the treatment of community-acquired pneumonia (CAP) requiring parenteral therapy were compared with those of ceftriaxone, 1 g once a day, in 866 hospitalized adults randomized in two prospective, double-blind, multicentre studies. Patients were stratified according to Pneumonia Severity Index (< or = 3 or >3) or age (< or = 65 or >65 years). After > or = 3 days of parenteral antimicrobial therapy, patients who had clinically improved could be switched to oral co-amoxiclav. The median durations of parenteral, oral and total therapy in the 658 clinically evaluable patients, of whom 88% were switched to oral therapy, were 4, 7 and 12 days, respectively, in both treatment groups. The most common pathogen was Streptococcus pneumoniae, of which 79% (143/181) were penicillin susceptible and 3.3% (6/181; three in each treatment group) were penicillin resistant. Cure rates for the two treatments were equivalent: 91.9% for ertapenem and 92.0% for ceftriaxone (95% confidence interval for the difference, adjusted for strata: -4.5 to 4.4). Cure rates in the different severity and age strata and bacterial eradication rates for both treatment groups were also similar. The most common drug-related adverse events in both treatment groups were diarrhoea and mild-to-moderate elevations in aminotransferase levels. The results of these studies demonstrate that ertapenem, 1 g once a day, was highly effective therapy for CAP in hospitalized adults with moderate-to-severe disease.