Bayesian survival extrapolation for cost-effectiveness analysis: a case study of RELAY for ramucirumab in combination with erlotinib in the treatment of non-small-cell lung cancer.

AIM: Increasing trend for progression-free survival (PFS)-based primary endpoint in oncology has led to lack of mature overall survival (OS) data at the time of approval. To address this evidence gap in economic evaluations, we used a joint Bayesian approach to predict survival outcomes using immature OS data from the RELAY trial. METHODS: Patient data from RELAY and systematic literature review (SLR) of phase 3 randomized clinical trials with hazard ratio (HR) estimates of mature PFS and immature OS were considered. OS and PFS were analyzed individually using a univariate model; bivariate analysis was performed using a joint model based on modified Bayesian normal induced copula estimation model. First, a Bayesian univariate model incorporated informative priors based on predicted HR and acceleration factor for OS and PFS. Second, a Bayesian-based joint model of RELAY PFS and OS data was based on the correlation between PFS and OS established in trials of similar populations. Marginal distribution of PFS was used to estimate the same for OS. RESULTS: Publications (N = 122) of first-line treatments in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer were identified in the SLR, of which 36 trials were linked to RELAY. Twenty-six trials with HR data were used. The univariate model could predict OS with reduced uncertainty compared with the frequentist approach. In the joint model, the marginal OS distribution borrowed strength from the marginal PFS distribution through the established correlation coefficient. LIMITATIONS: Bayesian approach was successfully used in RELAY analysis but may not be universally applied to oncology trials due to the different associations of OS and PFS and different trial patient populations. CONCLUSIONS: We demonstrated that both the univariate and joint Bayesian models reduced uncertainty in predicting OS compared to frequentist method. The methodology introduced here will have potential applications in clinical decision-making for other oncology trials.

Phase III study of selpercatinib versus chemotherapy ± pembrolizumab in untreated RET positive non-small-cell lung cancer.

Selpercatinib, a novel, highly selective and potent, inhibitor of RET, demonstrated clinically meaningful antitumor activity with manageable toxicity in heavily pretreated and treatment-naive RET fusion-positive non-small-cell lung cancer patients in a Phase I/II clinical trial. LIBRETTO-431 (NCT04194944) is a randomized, global, multicenter, open-label, Phase III trial, evaluating selpercatinib versus carboplatin or cisplatin and pemetrexed chemotherapy with or without pembrolizumab in treatment-naive patients with locally advanced/metastatic RET fusion-positive nonsquamous non-small-cell lung cancer. The primary end point is progression-free survival by independent review. Key secondary end points include overall survival, response rate, duration of response and progression-free survival. Clinical trial registration: NCT04194944 (ClinicalTrials.gov).

Antiangiogenic therapy for patients with aggressive or refractory advanced non-small cell lung cancer in the second-line setting.

A majority of patients with advanced or metastatic non-small cell lung cancer (NSCLC) will experience disease progression after first-line therapy. Patients who have advanced NSCLC that is especially aggressive, which is defined as disease that rapidly progresses on first-line treatment or disease that is refractory to first-line treatment, have a critical unmet medical need. These patients have a poor prognosis in the second-line setting. Several studies have recently shown that treatment with an antiangiogenic therapy may benefit these patients. This review summarizes the approved antiangiogenic therapies for the treatment of patients with advanced NSCLC in the second-line setting, specifically focusing on the outcomes from subgroups of patients with rapidly progressing or refractory disease. Several antiangiogenic agents, as monotherapy or in combination with other treatments, have been or are currently being studied in patients with advanced NSCLC. Antiangiogenics that are approved for use in patients with advanced NSCLC are limited to bevacizumab in combination with chemotherapy (nonsquamous NSCLC), ramucirumab in combination with docetaxel (all histologies), and nintedanib in combination with docetaxel (adenocarcinoma histology). This review focuses on the efficacy, safety, and quality of life outcomes in the subpopulation of patients with rapidly progressing or refractory NSCLC treated with approved antiangiogenic therapies in the second-line setting. We also discuss the impact of newly approved immunotherapy agents on the outcomes of patients with aggressive or refractory disease. Studies in progress and planned future research will determine if combination treatment with antiangiogenics and immunotherapies will benefit patients with aggressive, advanced NSCLC.

Association of baseline absolute neutrophil counts and survival in patients with metastatic colorectal cancer treated with second-line antiangiogenic therapies: exploratory analyses of the RAISE trial and validation in an electronic medical record data set.

BACKGROUND: In the RAISE trial, ramucirumab+leucovorin/fluorouracil/irinotecan (FOLFIRI) improved the median overall survival (mOS) of patients with previously treated metastatic colorectal cancer versus patients treated with placebo+FOLFIRI but had a higher incidence of neutropaenia, leading to more chemotherapy dose modifications and discontinuations. Thus, we conducted an exploratory post-hoc analysis of RAISE and a retrospective, observational analysis of electronic medical record (EMR) data to determine and verify the association of neutropaenia, baseline absolute neutrophil count (ANC) and survival. METHODS: The RAISE analysis used the study safety population (n=1057). IMS Health Oncology Database (IMS EMR) was the source for the real-world data set (n=617). RESULTS: RAISE patients with treatment-emergent neutropaenia had improved mOS compared with those without (ramucirumab arm: 16.1 vs 10.7 months, HR=0.57, p<0.0001; placebo arm: 12.7 vs 10.7 months, HR=0.76, p=0.0065). RAISE patients with low ANC versus high baseline ANC also had longer mOS (ramucirumab arm: 15.2 vs 8.9 months, HR=0.49, p<0.0001; placebo arm: 13.2 vs 7.3 months, HR=0.50, p<0.0001). The results were similar for IMS EMR low versus high baseline ANC (bevacizumab+FOLFIRI patients: 14.9 vs 7.7 months, HR=0.59, p<0.0001; FOLFIRI alone: 14.6 vs 5.4 months, HR=0.37, p<0.0001). Patients in the RAISE trial with low baseline ANC were more likely to develop neutropaenia (OR: ramucirumab arm=2.62, p<0.0001; placebo arm=2.16, p=0.0003). CONCLUSION: Neutropaenia during treatment, and subsequent dose modifications or discontinuations, do not compromise treatment efficacy. Baseline ANC is a strong prognostic factor for survival and is associated with treatment-emergent neutropaenia in the analysed population. TRIAL REGISTRATION NUMBER: NCT01183780, Results.

Efficacy and Safety of Ramucirumab With Docetaxel Versus Placebo With Docetaxel as Second-Line Treatment of Advanced Non-Small-Cell Lung Cancer: A Subgroup Analysis According to Patient Age in the REVEL Trial.

INTRODUCTION: Ramucirumab, a recombinant human immunoglobulin G1 monoclonal antibody receptor antagonist designed to block the ligand-binding site of vascular endothelial growth factor receptor-2 (VEGFR-2), was evaluated as second-line treatment in combination with docetaxel in patients with non-small-cell lung cancer in the REVEL trial (NCT01168973). Ramucirumab significantly improved overall survival (OS) and progression-free survival (PFS). We report age subgroup analysis results primarily on the basis of a 65-year cutoff. PATIENTS AND METHODS: Patients were randomized 1:1 to ramucirumab with docetaxel or placebo with docetaxel (n = 1253). Of these, 798 were younger than 65 years (ramucirumab, n = 391; control, n = 407) and 455 were 65 years or older (ramucirumab, n = 237; control, n = 218). Treatment comprised 21-day cycles of 75 mg/m2 docetaxel with 10 mg/kg ramucirumab or placebo. Prespecified age subgroup analyses were performed, including OS, PFS, and objective response rate. Quintiles age analysis was conducted to establish a relationship between efficacy and age. The Lung Cancer Symptom Scale (LCSS) measured quality of life outcomes. Safety was assessed according to adverse events (AEs). RESULTS: Patients younger than 65 years showed favorable OS outcomes with ramucirumab treatment (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.62-0.87; P < .001) and PFS (HR, 0.68; 95% CI, 0.59-0.79; P < .001). In patients 65 years or older, benefits of ramucirumab were not as evident; after model adjustment for prognostic factors, OS and PFS HRs were 0.96 (95% CI, 0.77-1.21; P = .04) and 0.87 (95% CI, 0.71-1.05; P = .03), respectively. Age analysis according to quintiles showed HRs favoring ramucirumab for all age groupings. LCSS scores and AEs did not considerably differ between age groups. CONCLUSION: In this subgroup analysis, true treatment effect differences on the basis of age have not been established, and treatment should not be deterred solely because of age.

Outcomes in patients with aggressive or refractory disease from REVEL: A randomized phase III study of docetaxel with ramucirumab or placebo for second-line treatment of stage IV non-small-cell lung cancer.

OBJECTIVES: The REVEL study demonstrated improved efficacy for patients with advanced non-small cell lung cancer treated with ramucirumab plus docetaxel, independent of histology. This exploratory analysis characterized the treatment effect in REVEL patients who were refractory to prior first-line treatment. MATERIALS AND METHODS: Refractory patients had a best response of progressive disease to first-line treatment. Endpoints included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), quality of life (QoL), and safety. Kaplan-Meier and Cox proportional hazards regression were performed for OS and PFS, and Cochran-Mantel-Haenszel test was used for response. QoL was assessed with the Lung Cancer Symptom Scale. Sensitivity analyses were performed on subgroups of the intent-to-treat population with limited time on first-line therapy. RESULTS: Of 1253 randomized patients in REVEL, 360 (29%) were refractory to first-line treatment. Baseline characteristics were largely balanced between treatment arms. In the control arm, median OS for refractory patients was 6.3 versus 10.3 months for patients not meeting this criterion, demonstrating the poor prognosis of refractory patients. Median OS (8.3 vs. 6.3 months; HR, 0.86; 95% CI, 0.68-1.08), median PFS (4.0 vs. 2.5 months; HR, 0.71; 95% CI, 0.57-0.88), and ORR (22.5% vs. 12.6%) were improved in refractory patients treated with ramucirumab compared to placebo, without new safety concerns or further deteriorating patient QoL. CONCLUSIONS: The effect of ramucirumab in refractory patients is similar to that in the intent-to-treat population. The benefit/risk profile for refractory patients suggests that ramucirumab plus docetaxel is an appropriate treatment option even in this difficult-to-treat population.

Prognostic Factor Analysis of Overall Survival in Gastric Cancer from Two Phase III Studies of Second-line Ramucirumab (REGARD and RAINBOW) Using Pooled Patient Data.

PURPOSE: To identify baseline prognostic factors for survival in patients with disease progression, during or after chemotherapy for the treatment of advanced gastric or gastroesophageal junction (GEJ) cancer. MATERIALS AND METHODS: We pooled data from patients randomized between 2009 and 2012 in 2 phase III, global double-blind studies of ramucirumab for the treatment of advanced gastric or GEJ adenocarcinoma following disease progression on first-line platinum- and/or fluoropyrimidine-containing therapy (REGARD and RAINBOW). Forty-one key baseline clinical and laboratory factors common in both studies were examined. Model building started with covariate screening using univariate Cox models (significance level=0.05). A stepwise multivariable Cox model identified the final prognostic factors (entry+exit significance level=0.01). Cox models were stratified by treatment and geographic region. The process was repeated to identify baseline prognostic quality of life (QoL) parameters. RESULTS: Of 1,020 randomized patients, 953 (93%) patients without any missing covariates were included in the analysis. We identified 12 independent prognostic factors of poor survival: 1) peritoneal metastases; 2) Eastern Cooperative Oncology Group (ECOG) performance score 1; 3) the presence of a primary tumor; 4) time to progression since prior therapy <6 months; 5) poor/unknown tumor differentiation; abnormally low blood levels of 6) albumin, 7) sodium, and/or 8) lymphocytes; and abnormally high blood levels of 9) neutrophils, 10) aspartate aminotransferase (AST), 11) alkaline phosphatase (ALP), and/or 12) lactate dehydrogenase (LDH). Factors were used to devise a 4-tier prognostic index (median overall survival [OS] by risk [months]: high=3.4, moderate=6.4, medium=9.9, and low=14.5; Harrell's C-index=0.66; 95% confidence interval [CI], 0.64-0.68). Addition of QoL to the model identified patient-reported appetite loss as an independent prognostic factor. CONCLUSIONS: The identified prognostic factors and the reported prognostic index may help clinical decision-making, patient stratification, and planning of future clinical studies.

On the Interpretation of the Hazard Ratio and Communication of Survival Benefit.

This brief communication will clarify the difference between a relative hazard and a relative risk. We highlight the importance of this difference, and demonstrate in practical terms that 1 minus the hazard ratio should not be interpreted as a risk reduction in the commonly understood sense of the term. This article aims to provide a better understanding of the type of risk reduction that a hazard ratio implies, thereby clarifying the intent in the communication among practitioners and researchers and establishing an accurate and realistic foundation for communicating with patients. The Oncologist 2017;22:484-486.

Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial.

BACKGROUND: Ramucirumab is a human IgG1 monoclonal antibody that targets the extracellular domain of VEGFR-2. We aimed to assess efficacy and safety of treatment with docetaxel plus ramucirumab or placebo as second-line treatment for patients with stage IV non-small-cell-lung cancer (NSCLC) after platinum-based therapy. METHODS: In this multicentre, double-blind, randomised phase 3 trial (REVEL), we enrolled patients with squamous or non-squamous NSCLC who had progressed during or after a first-line platinum-based chemotherapy regimen. Patients were randomly allocated (1:1) with a centralised, interactive voice-response system (stratified by sex, region, performance status, and previous maintenance therapy [yes vs no]) to receive docetaxel 75 mg/m(2) and either ramucirumab (10 mg/kg) or placebo on day 1 of a 21 day cycle until disease progression, unacceptable toxicity, withdrawal, or death. The primary endpoint was overall survival in all patients allocated to treatment. We assessed adverse events according to treatment received. This study is registered with ClinicalTrials.gov, number NCT01168973. FINDINGS: Between Dec 3, 2010, and Jan 24, 2013, we screened 1825 patients, of whom 1253 patients were randomly allocated to treatment. Median overall survival was 10·5 months (IQR 5·1-21·2) for 628 patients allocated ramucirumab plus docetaxel and 9·1 months (4·2-18·0) for 625 patients who received placebo plus docetaxel (hazard ratio 0·86, 95% CI 0·75-0·98; p=0·023). Median progression-free survival was 4·5 months (IQR 2·3-8·3) for the ramucirumab group compared with 3·0 months (1·4-6·9) for the control group (0·76, 0·68-0·86; p<0·0001). We noted treatment-emergent adverse events in 613 (98%) of 627 patients in the ramucirumab safety population and 594 (95%) of 618 patients in the control safety population. The most common grade 3 or worse adverse events were neutropenia (306 patients [49%] in the ramucirumab group vs 246 [40%] in the control group), febrile neutropenia (100 [16%] vs 62 [10%]), fatigue (88 [14%] vs 65 [10%]), leucopenia (86 [14%] vs 77 [12%]), and hypertension (35 [6%] vs 13 [2%]). The numbers of deaths from adverse events (31 [5%] vs 35 [6%]) and grade 3 or worse pulmonary haemorrhage (eight [1%] vs eight [1%]) did not differ between groups. Toxicities were manageable with appropriate dose reductions and supportive care. INTERPRETATION: Ramucirumab plus docetaxel improves survival as second-line treatment of patients with stage IV NSCLC. FUNDING: Eli Lilly.

A portfolio-based approach to optimize proof-of-concept clinical trials.

Improving proof-of-concept (PoC) studies is a primary lever for improving drug development. Since drug development is often done by institutions that work on multiple drugs simultaneously, the present work focused on optimum choices for rates of false positive (α) and false negative (ß) results across a portfolio of PoC studies. Simple examples and a newly derived equation provided conceptual understanding of basic principles regarding optimum choices of α and ß in PoC trials. In examples that incorporated realistic development costs and constraints, the levels of α and ß that maximized the number of approved drugs and portfolio value varied by scenario. Optimum choices were sensitive to the probability the drug was effective and to the proportion of total investment cost prior to establishing PoC. Results of the present investigation agree with previous research in that it is important to assess optimum levels of α and ß. However, the present work also highlighted the need to consider cost structure using realistic input parameters relevant to the question of interest.

International integrated database for the evaluation of severe sepsis and drotrecogin alfa (activated) therapy: 28-day survival and safety.

PURPOSE: To enhance the understanding of severe sepsis, a database of patients from multiple clinical trials spanning a 6-year period was constructed. Initial analyses evaluated the 28-day survival in the placebo group and further assessed the treatment effect of drotrecogin alfa (activated) (DrotAA). METHODS: Five severe sepsis studies with similar entry criteria were combined, and baseline characteristics and 28-day mortality were evaluated (4459 severe sepsis patients; placebo, n = 1231; DrotAA, n = 3228). An integrated data analysis with propensity score adjustment was performed. Twenty-one variables selected by stepwise logistic regression were included in a propensity score of differences between the 2 groups of patients. RESULTS: Over the 6-year period of these trials, there was no change in placebo mortality rates overall (P = .67), nor in subgroups of Acute Physiology and Chronic Health Evaluation score >/=25 (P = .73) or multiple organ dysfunction (P = .38). The adjusted relative hazard risk for DrotAA patients was 0.84 (95% confidence interval, 0.73-0.95; P = .007). Serious bleeding (0.8% in placebo vs 3.5% in DrotAA, P < .0001) was increased during the DrotAA infusion period. CONCLUSIONS: Initial analyses indicate that placebo mortality remained unchanged over a recent 6-year period. These analyses also further substantiate that treatment with DrotAA is associated with improved survival.

Predictive probability of success and the assessment of futility in large outcomes trials.

We consider a class of futility rules based on a Bayesian approach for computing the predictive probability of success for large clinical trials, given a certain amount of observed data. This paper focuses on outcomes trials in particular, thus we are concerned with binary response variables. The proposed method determines the likelihood of observing a statistically significant treatment effect at the end of a study, conditional on the data observed at an interim time point and assuming that event rates governing future observations follow beta distributions. In particular, the prior distributions for the event rates of interest are updated based on the observed data at an interim time point, such that means and variances are intuitive functions of the data. Computational aspects will be discussed for the case in which event counts are functions of sample size and event rates only, and for situations in which they are functions of sample size, event rates, and exposure duration. We will discuss appropriate thresholds for declaring futility based on this approach, and the potential impact of overdispersion, a common phenomenon particularly in global outcomes trials.

International INtegrated Database for the Evaluation of severe sePsis and drotrecogin alfa (activated) THerapy: component trials and statistical methods for INDEPTH.

OBJECTIVES: To better understand the effects of drotrecogin alfa (activated) (DrotAA) in severe sepsis patients, and the natural progression of severe sepsis, by creating a database of severe sepsis patients using the appropriate statistical analysis methods to integrate data from various trials. PATIENTS AND METHODS: Patient-level data from five severe sepsis trials, conducted by the same sponsor (Eli Lilly and Company, Indianapolis, IN, USA), were combined in an integrated database. Patients from various studies were included and received either DrotAA at 24 microg/kg/h for 96 hours (n = 3228) or placebo (n = 1231), in addition to standard supportive care. The following adjustments to the analyses were made to allow for the combined, and thus non-randomized, nature of the data: (1) differences in observed outcomes between studies were investigated to assess the extent of study-to-study variation before combining study-level data across trials for statistical analysis; (2) random study effects were included in models for patient-level data to capture potential extraneous study-to-study variation; and (3) propensity scores were computed and included as covariates in models for patient-level data to adjust for the nonrandomized nature of the data. RESULTS: Baseline characteristics were similar across the studies, supporting the combination of study-level data across trials. Comparing aggregate event rates between the two treatment arms yielded a relative risk for mortality (DrotAA versus placebo) of 0.79 (95% confidence interval [CI] 0.71-0.88), p < 0.0001. For patient-level analyses, after adjustment for 13 independent variables and random study effects, the odds ratio for mortality in the DrotAA versus placebo patients was 0.71 (95% CI 0.59-0.86), p = 0.0003. With adjustment for 13 independent variables and propensity score, the odds ratio was 0.79 (95% CI 0.67-0.93), p = 0.006. Limitations of this integrated database include the modest total number of the trials in the database and the fact that only one component trial in the database contributed data from both placebo and DrotAA-treated patients. SUMMARY: A robust severe sepsis database was developed which will be suitable for future studies on the progression of severe sepsis and the mechanism of action of DrotAA. Initial analysis of data from INDEPTH provides additional evidence that treatment of severe sepsis patients with DrotAA is associated with a sustained survival advantage throughout 28-day follow-up.

Lack of evidence for qualitative treatment by disease severity interactions in clinical studies of severe sepsis.

INTRODUCTION: The design of clinical trials of interventions aimed at reducing mortality in patients with severe sepsis assumes that the relative treatment effect of the intervention is independent of the patients' risk for death. We reviewed published data from phase III clinical studies of severe sepsis to determine whether a relationship exists between risk for death and the relative benefit of the investigational agent. Such an interaction might warrant a change in the assumptions that underlie current trial designs. METHODS: We conducted a systematic review of published phase III, randomized, placebo-controlled trials in adult patients with sepsis, severe sepsis, or septic shock up to November 2004. All studies enrolled patients with known or suspected infection, evidence of a systemic response to the infection, and one or more organ dysfunctions resulting from the systemic response. RESULTS: Twenty-two publications, investigating 17 molecular entities, fulfilled criteria for phase III or equivalent studies aimed at reducing mortality in adult patients with severe sepsis or septic shock. Three studies achieved the prospectively defined primary end-point of a statistically significant reduction in 28-day all-cause mortality. The control group mortality rates for these studies were 31%, 43% and 61%, indicating that the beneficial effects of adjunct therapies could be demonstrated over a wide range of illness severity. Analysis of subgroup data from failed studies provided no evidence that the efficacy of the therapeutics being investigated varied by baseline placebo mortality rates. Among all studies, interventions with anticoagulant activity or anti-inflammatory activity did not appear to be harmful in patients with evidence of less coagulopathy or less inflammation. CONCLUSION: Our review of published clinical data does not support the hypothesis that mortality risk of the population studied alters the relative treatment effect associated with anti-inflammatory or other agents used to treat severe sepsis. Clinical studies in severe sepsis should continue to enroll patients over a wide range of disease severity, as long as patients enrolled have evidence of sepsis-induced organ dysfunction(s), patients are at an appreciable risk for death (e.g. as evidenced by admission to an intensive care unit), and the potential for benefit outweighs the potential for harm.

Year-by-year analysis of cardiovascular events in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial.

OBJECTIVE: To assess the effect of raloxifene 60 mg/day (RLX) on year-by-year cardiovascular (CV) events in postmenopausal women participating in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, a double-blind, placebo-controlled osteoporosis treatment trial. RESEARCH DESIGN AND METHODS: Post hoc analysis, using data from participants receiving placebo (N = 2576) or RLX 60 mg/day (N = 2557) in MORE, was performed to determine the relative risk (RR, 95% CI) of CV events in each individual trial year. Analyses were performed for the overall cohort and for women in high and low risk subsets. Women were retrospectively assessed as high CV risk using established criteria and the remaining women were considered low CV risk. RESULTS: The incidence of CV events did not differ between the RLX and placebo groups in the overall cohort (RR 0.86, 95% Cl 0.64-1.15), or the low CV risk subset (RR 1.01, 95% Cl 0.70-1.46). In the high-risk subset, the incidence of CV events was less in the RLX group (RR 0.60, 95% Cl 0.38-0.95). There was no significant increase in CV risk during any single year in the RLX group for either the overall cohort or the low or high CV risk subsets. CONCLUSION: In this post hoc analysis, the risk of CV events was not increased in any single year of MORE in women taking RLX, either in the overall cohort or in the low and high CV risk subsets.

Risk-benefit profile for raloxifene: 4-year data From the Multiple Outcomes of Raloxifene Evaluation (MORE) randomized trial.

UNLABELLED: Posthoc analysis of the MORE osteoporosis treatment trial assessed risk-benefit profile of raloxifene in 7705 postmenopausal women. A major disease outcomes global index resulted in annual rates of 1.39% and 1.83% in the raloxifene and placebo groups, respectively (HR, 0.75; 95% CI, 0.62-0.92), compatible with a favorable risk-benefit profile for raloxifene for treating postmenopausal osteoporosis. INTRODUCTION: The Women's Health Initiative (WHI) trial reported overall risks that exceeded benefits from use of estrogen-progestin in healthy postmenopausal women. The objective of this posthoc analysis of the Multiple Outcomes of Raloxifene Evaluation (MORE) trial was to assess the safety profile of raloxifene, a selective estrogen receptor modulator indicated for the prevention and treatment of osteoporosis, using the global index method from the WHI trial. MATERIALS AND METHODS: A total of 7705 postmenopausal women (mean age, 67 years) were enrolled in the MORE osteoporosis treatment trial and randomly assigned to receive placebo or one of two doses of raloxifene (60 or 120 mg/day) for 4 years. A global index of clinical outcomes, defined as described for the WHI trial (the earliest occurrence of coronary heart disease, stroke, pulmonary embolism, invasive breast cancer, endometrial cancer, colorectal cancer, hip fracture, or death because of other causes) was applied to the MORE trial data. Physicians blinded to treatment assignment adjudicated events. Intention-to-treat survival analysis of time-to-first-event was performed using a proportional hazards model. RESULTS AND CONCLUSIONS: The annualized rate of global index events was 1.83% in the placebo group and 1.39% in the combined raloxifene dose groups (hazard ratio [HR], 0.75; 95% CI, 0.62-0.92). Analyzing individual dose groups separately yielded the same results (HR for 60 mg/day, 0.75; 95% CI, 0.60-0.96: HR for 120 mg/day, 0.75; 95% CI, 0.59-0.95). Subgroup analyses showed no significant interactions between age or hysterectomy status and the effect of raloxifene on the global index (interaction p > 0.1), whereas the global index risk reduction seemed to be greater in obese women compared with nonobese women (interaction p = 0.03). The significant 25% reduction in global index is compatible with a favorable risk-benefit safety profile when raloxifene is used for osteoporosis treatment in postmenopausal women. These results require confirmation in ongoing clinical trials.

Post hoc analysis of data from the Multiple Outcomes of Raloxifene Evaluation (MORE) trial on the effects of three years of raloxifene treatment on glycemic control and cardiovascular disease risk factors in women with and without type 2 diabetes.

BACKGROUND: The long-term effects of the selective estrogen-receptor modulator raloxifene hydrochloride on glycemic control and markers of cardiovascular disease risk in postmenopausal women with type 2 diabetes mellitus are unknown. OBJECTIVE: The aim of this analysis was to compare the effects of 3-year treatment with raloxifene 60 mg/d versus placebo on glycemic control and markers of cardiovascular disease risk in osteoporotic postmenopausal women with and without type 2 diabetes. METHODS: In this analysis, we included women from the Multiple Outcomes of Raloxifene Evaluation trial (a multicenter, double-masked trial) who were randomized to receive raloxifene 60 mg/d (n = 2557) or placebo (n = 2576). Baseline and 36-month fasting plasma glucose (FPG) and total cholesterol (TC) were measured for all participants. Glycated hemoglobin (HbA1c), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TGs), apolipoprotein (apo) A-I, apo B, and fibrinogen were assessed in approximately 1800 participants from selected larger sites. RESULTS: At baseline, 202 of all 5133 women (3.9%) had type 2 diabetes. Of the approximately 1800 women who were assessed for HbA1c, LDL-C, TGs, apo A-I, apo B, and fibrinogen, 70 (3.9%) had type 2 diabetes at baseline. Compared with placebo, raloxifene did not significantly affect HbA1c, FPG, HDL-C, or TGs in women with or without diabetes. Raloxifene produced statistically significant reductions in TC, LDL-C, and fibrinogen both in women with diabetes (all P < or = 0.004) and without diabetes (all P < 0.001). Raloxifene significantly increased apo A-I (P < 0.001) and reduced apo B (P < 0.001) in women without diabetes. In the raloxifene-treated group, body weight increased by a mean 0.31 kg (P < 0.001) in women without diabetes. CONCLUSIONS: In osteoporotic postmenopausal women with or without type 2 diabetes, raloxifene 60 mg/d did not affect glycemic control and had favorable effects on TC, LDL-C, and fibrinogen levels.