Effect of statin therapy in reducing the risk of serious non-AIDS-defining events and nonaccidental death.

BACKGROUND: Excessive inflammation persists despite antiretroviral treatment. Statins decrease cardiovascular (CV) disease risk by reducing low-density lipoprotein cholesterol and inflammation. We performed an exploratory analysis to evaluate whether statin therapy decreased risk of non-AIDS-defining events and nonaccidental death. METHODS: A total of 3601 subjects not on a statin from the AIDS Clinical Trials Group Longitudinal Linked Randomized Trials cohort were included. Outcome was time to first clinical event (CV event, renal or hepatic disease, incident diabetes, thrombotic/embolic event, nontraumatic fracture, non-AIDS-defining malignancy, serious bacterial infection, or nonaccidental death); event categories were also analyzed separately. Inverse probability of treatment and censoring weighted Cox proportional hazard models were used to assess the causal statin effect. Differential statin effects by baseline covariates were evaluated. RESULTS: Over 15 135 person-years (PY) of follow-up, 484 subjects initiated statins; 616 experienced an event (crude event rate, 4.4/100 PY on a statin and 4.1/100 PY not on a statin); the unadjusted hazard ratio (HR) was 1.17 (95% confidence interval [CI], .91-1.50). In a final weighted model, the adjusted HR (AHR) was 0.81 (95% CI, .53- 1.24). Results for other clinical events were similar, except for malignancies (AHR, 0.43 [95% CI, .19-.94]) and bacterial infections (AHR, 1.30 [95% CI, .64-2.65]). No differential statin effects by baseline covariates were detected. CONCLUSIONS: Although statin therapy was not associated with a reduction in time to all non-AIDS-defining event or nonaccidental death, it was associated with a statistically significant 57% reduction in non-AIDS-defining malignancies. Confirmatory studies are needed to evaluate statin-associated reduction in risk of cancer and non-AIDS-associated morbidities.

Considerations in choosing a primary endpoint that measures durability of virological suppression in an antiretroviral trial.

OBJECTIVES: At present, many clinical trials of anti-HIV-1 therapies compare treatments by a primary endpoint that measures the durability of suppression of HIV-1 replication. Several durability endpoints are compared. DESIGN: Endpoints are compared by their implicit assumptions regarding surrogacy for clinical outcomes, sample size requirements, and accommodations for inter-patient differences in baseline plasma HIV-1-RNA levels and in initial treatment response. METHODS: Virological failure is defined by the non-suppression of virus levels at a prespecified follow-up time T(early virological failure), or by relapse. A binary virological failure endpoint is compared with three time-to-virological failure endpoints: time from (i) randomization that assigns early failures a failure time of T weeks; (ii) randomization that extends the early failure time T for slowly responding subjects; and (iii) virological response that assigns non-responders a failure time of 0 weeks. Endpoint differences are illustrated with Agouron's trial 511. RESULTS: In comparing high with low-dose nelfinavir (NFV) regimens in Agouron 511, the difference in Kaplan-Meier estimates of the proportion not failing by 24 weeks is 16.7% (P = 0.048), 6.5% (P = 0.29) and 22.9% (P = 0.0030) for endpoints (i), (ii) and (iii), respectively. The results differ because NFV suppresses virus more quickly at the higher dose, and the endpoints weigh this treatment difference differently. This illustrates that careful consideration needs to be given to choosing a primary endpoint that will detect treatment differences of interest. CONCLUSION: A time from randomization endpoint is usually recommended because of its advantages in flexibility and sample size, especially at interim analyses, and for its interpretation for patient management.

The analysis of repeated multivariate binary quality of life data: a hierarchical model approach.

Many quality of life measuring instruments consist of a number of questions that are answered on ordinal scales. Often these responses are then totalled to give a summary score for each quality of life domain within the instrument. This, however, may lose valuable information about individual aspects of patient quality of life and also can have little intuitive meaning. Here we present an alternative analysis, in which dichotomized individual items of the questionnaire are analyzed. We first show how a hierarchical logistic regression model for repeated binary data can be extended to the multivariate case. We then use such a model for analyzing the prevalence of six symptoms in a palliative treatment trial in non-small-cell lung cancer. The analysis provides information about the correlations between symptoms, both between and within person. If appropriate, it also permits the estimation of a treatment effect common to all symptoms. Methods for model checking are discussed. We conclude that this methodology can provide a more intuitive and informative analysis of quality of life data than that obtained by considering summary scores.

A joint analysis of quality of life and survival using a random effect selection model.

In studies of patients with advanced disease, longitudinal quality of life data may be truncated as a result of early death. Since survival and quality of life are likely to be related, modelling of the quality of life response needs to account for these different survival patterns. Here we discuss the application of a random effect selection model, in the form of a trivariate Normal model for the joint analysis of quality of life response (intercept and slope) and log survival time. Under certain assumptions this can give an unbiased description of the quality of life responses and valid inferences comparing treatment strategies in a clinical trial. It also indicates how quality of life and survival are related, by estimating the expected quality of life responses conditional on different survival times. Model parameters can be estimated using a restricted iterative generalized least-squares (RIGLS) procedure within standard software, extended to handle censoring of survival outcome using an EM algorithm. The model is applied to a physical quality of life score and survival data from a trial of treatment for patients with colorectal hepatic metastases. Survival differed between the treatment groups, and quality of life repsonse tended to be worse, both in initial level and change over time, for those patients who died earlier. The parameter estimates obtained agreed well with those from analysing the extended trial data set with complete survival information. Residual diagnostics used to check the necessary underlying assumptions of the model are exemplified. We conclude that such models can give an informative description of longitudinal responses when these are truncated by differential survival patterns.

Quality of life following surgery for intracranial meningiomas at Brigham and Women's Hospital: a study of 164 patients using a modification of the functional assessment of cancer therapy-brain questionnaire.

The objective of this study was to determine the subjectively reported quality of life (QOL) of patients with meningiomas surgically treated. Demographic, medical and outcomes data on 164 patients were retrospectively analyzed with the use of the Brain Tumor Center database at the Brigham and Women's Hospital, Boston, MA. The patients were contacted via a telephone survey and were asked 26 standardized QOL questions based on a modification of the validated Functional Assessment of Cancer Therapy-Brain (FACT-BR) Study, which used only questions adjuvant to brain tumor patients. The patients' ages ranged from 23 to 87 years. The mean follow-up time after intracranial surgery was 33 months and median follow-up time was 28 months, with a range of 0 to 165 months. Of those 164 patients still living, 95% (155) participated in the telephone survey. 80% reported being satisfied with their post-treatment quality of life; 86% reported that they could write, read, drive and return to work at their pre-morbid level of functioning; 87% described themselves as 'independent' and able to act on their own initiatives. Our study found a high level of satisfaction for QOL in patients who have undergone surgery for intracranial meningiomas. Patients, by their own report, are able to lead independent, personally satisfying, meaningful and productive lives. This provides useful information to share with patients in discussions regarding surgical treatment of these lesions.