Predictors of medical events and of their competitive interactions in the Cardiac Insufficiency Bisoprolol Study 2 (CIBIS-2).

AIMS: Predictive factors for medical events and interactions between events were not reported in the Cardiac Insufficiency Bisoprolol Study 2 (CIBIS-2). We examined the interactions among death, permanent treatment withdrawals, nonlethal cardiovascular hospitalizations and their own occurrence in a given patient, the treatment received, and baseline variables during CIBIS-2. METHODS AND RESULTS: A Cox model for censored data was used to analyze the relations among baseline variables, medical events, and their interactions with treatment. We used competitive risk analysis to examine the interactions between successive events in a given patient during follow-up. No baseline variable predicted the reduction of mortality with bisoprolol. Withdrawal from bisoprolol therapy was more frequent in patients whose baseline heart rate was in the lower tertile of the distribution (P =.0002) but otherwise was not different between patients randomized to bisoprolol and to placebo. Event history analysis revealed that bisoprolol reduced mortality (P =.0006) and hospitalizations for nonlethal cardiovascular events (P =.003) in patients in whom treatment was not permanently withdrawn. Analysis of survival curves in patients who permanently discontinued treatment showed that bisoprolol did not reduce mortality compared with placebo in this population (relative risk 1.03, 95% CI 0.67-1.59; P =.88). Recurrent nonlethal events were reduced by bisoprolol. CONCLUSION: In CIBIS-2, medical events were significantly influenced by treatment withdrawal. Patients who derive benefit from bisoprolol therapy are those in whom treatment is not permanently withdrawn.

Induction and maintenance therapy of cytomegalovirus central nervous system infection in HIV-infected patients.

OBJECTIVE: To evaluate the efficacy and safety of the foscarnet-ganciclovir combination in induction therapy (IT) and maintenance therapy (MT) for cytomegalovirus (CMV) central neurological disorders in HIV-infected patients. DESIGN: An open pilot non-comparative multicentre study. METHODS: Thirty-one patients with acute CMV encephalitis (CMVe) (n = 17) or CMV myelitis (CMVm) (n = 14) during the era before highly active antiretroviral therapy (HAART) received intravenous IT with foscarnet 90 mg/kg plus ganciclovir 5 mg/kg twice a day followed by MT. The primary endpoint was clinical efficacy, assessed at the end of the induction phase. RESULTS: The foscarnet-ganciclovir combination in IT resulted in a 74% (23 out of 31 patients) clinical improvement or stabilization. Eight patients did not respond clinically. Side-effects leading to drug discontinuation occurred in 10 patients during IT. Among the 23 patients who qualified for the maintenance phase, CMV disease progressed in 10, with a median time to the first relapse of 126 days (range 64-264 days). Overall, the median survival time was 3 months [95% confidence interval (CI), 2-4 months]. CONCLUSION: The combination of foscarnet and ganciclovir can safely be used for CMV central nervous system (CNS) infection, with an improvement or stabilization in 74% of patients. Life-long MT with this combination is recommended as long as the immune system is profoundly impaired.

Factors associated with clinical and virological failure in patients receiving a triple therapy including a protease inhibitor.

OBJECTIVE: To determine the predictors of virological and clinical failure in patients receiving a protease inhibitor as part of triple therapy. METHODS: From the French Hospital Database on HIV, 1402 protease inhibitor-naive patients starting a highly active antiretroviral therapy regimen with ritonavir, saquinavir-hard gel capsule (hgc) or indinavir between July 1996 and March 1997, and with measured HIV RNA at baseline and at 12 months, were studied for progression to a new AIDS-defining event (ADE) or death. Virological failure was defined as plasma HIV RNA > 1000 copies/ml at 12 months. Multivariate analyses were performed using Cox models for clinical outcomes and logistic regression for virological outcomes. RESULTS: During a median follow-up of 14.1 months, 94 (6.7%) patients experienced an ADE or died. At 12 months, 700 patients (49.9%) had virological failure. In the multivariate analysis, baseline CD4 cell count and viral load were found to be independent predictors of both virological and clinical failure. Neither the type of the first protease inhibitor taken nor previous antiretroviral therapy experience was associated with risk of clinical progression. For virological failure, the use of saquinavir-hgc was associated with a significant 1.96-fold increase in risk compared with indinavir; pre-treated patients were at higher risk than antiretroviral therapy-naive patients. CONCLUSION: In this study with large samples of patients, the use of saquinavir-hgc was associated with higher risk of virological failure at 12 months than were ritonavir and indinavir; no differences between protease inhibitors were found for clinical progression. As biases cannot be excluded, a longer duration of follow-up will be necessary to answer the question of whether the results are really discrepant or simply reflect the delay between virological failure and clinical manifestations.

Predictors of medical events in patients enrolled in the cardiac insufficiency bisoprolol study (CIBIS): a study of the interactions between beta-blocker therapy and occurrence of critical events using analysis of competitive risks.

BACKGROUND: The risk of occurrence of medical events in a clinical trial is competitive in nature; that is, in a given patient the risk of having a critical event depends on the amount of time elapsed since random assignment and on the previous events that may have occurred in the patient. The purpose of this study was to examine the relations between baseline variables, the interactions between treatment, bisoprolol, or placebo, and the occurrence of critical events during the CIBIS trial, a mortality and morbidity trial of beta-blockade in patients with heart failure. METHODS AND RESULTS: A Cox model for censored data was used to analyze the relations between baseline variables, total deaths, permanent treatment withdrawals, nonlethal cardiovascular events, and their interactions with bisoprolol or placebo. We examined the influence of treatment on the occurrence of deaths, permanent treatment withdrawals, and nonlethal cardiovascular events by using the technique of event history analysis, which takes into account competitive risks between events. Compared with placebo, bisoprolol reduced mortality rates in patients with a left ventricular ejection fraction < or =20% (relative risk [RR] 0.49; 95% confidence interval [CI] 0.27 to 0.88; P =.02). In patients whose baseline heart rate was in the upper tertile of distribution, permanent treatment withdrawals were less frequent in patients randomly assigned to bisoprolol than in patients randomly assigned to placebo (RR 0.50; 95% CI 0.28 to 0.88; P =.02). Bisoprolol reduced the incidence of nonlethal cardiac events in patients in whom heart failure was present for at least 4 years (RR 0.44; 95% CI 0.27 to 0.71; P <.01). Event history analysis revealed that among patients who died under treatment after having at least 1 nonlethal cardiovascular event, 20 patients were treated with placebo but only 7 patients were treated with bisoprolol (RR 0.41; 95% CI 0.17 to 0.98; P <.05). CONCLUSIONS: Some patients with heart failure derive more benefit from beta-blocker therapy than others. In the CIBIS trial, they are those patients with the lower left ventricular ejection fractions and those who have nonlethal cardiovascular events but in whom beta-blocker therapy is not permanently discontinued.

[Robust analysis methods for multivariate survival times]. / Méthodes robustes d'analyse de temps de survie multivariés.

In a long term clinical study, the subjects may experience repeated occurrences of the same type of events or multiple events of entirely different nature during the following period. In this article, we reviewed the three most frequently used extensions to the proportional hazards model for analysing such multivariate failure time data. Specifically, we explored the underlying hypotheses for each of these extensions. The three procedures were applied to a bladder cancer study.

[Survival analysis example based on an event history model from a clinical trial in cardiology]. / Exemple d'utilisation d'un modèle d'histoire de vie pour l'analyse d'un essai thérapeutique en cardiologie.

BACKGROUND: The main purpose of this paper is to present a survival analysis example based on an event history model in a competitive risks framework. Our example is derived from a clinical trial designed for comparing survival of a beta-blocker therapy group and a placebo group. METHODS: Competitive risks under study were non lethal cardiovascular events, permanent treatment withdrawals and deaths. The event history model was assumed to be semi-Markovian. The Cox proportional hazards model was used for modeling effects of treatments and regression variables on the transition rates. RESULTS: After taking into account all covariables influencing survival, mortality in patients who had one non lethal cardiovascular event after randomization but remained treated was shown to be reduced in the beta-blocker therapy group (RR=0.41; CI 95%=[0.17-0.98], p=0.04). CONCLUSIONS: Our analysis indicates that beta-blocker therapy should not necessarily be stopped in patients who experience a non lethal cardiovascular event under treatment. This finding requires confirmation in a separate setting.

Efficacy and tolerability of stavudine plus lamivudine in treatment-naive and treatment-experienced patients with HIV-1 infection.

BACKGROUND: A combination of two nucleoside analogues is currently the core of any antiretroviral regimen for HIV-1 infection. Stavudine plus lamivudine has shown an additive effect in vitro, as well as an absence of overlapping toxicity and cross-resistance. OBJECTIVE: To evaluate the antiviral efficacy of stavudine plus lamivudine in treatment-naive patients and in patients previously treated with other nucleoside reverse transcriptase inhibitors. DESIGN: Prospective, open-label pilot study. SETTING: Three urban clinical centers in Paris. PATIENTS: 83 patients with CD4+ cell counts between 50 and 400 cells/mm3 (42 treatment-naive and 41 treatment-experienced patients). INTERVENTIONS: Stavudine, 40 mg twice daily (30 mg twice daily in patients with a body weight < or = 60 kg), and lamivudine, 150 mg twice daily. MEASUREMENTS: Primary end points for efficacy included changes in plasma viral load and CD4+ cell count at 24 weeks compared with baseline. RESULTS: Therapy with stavudine plus lamivudine resulted in a median decrease of 1.66 log10 (10(1.66)) (range, -3.04 to -0.79 log10) in plasma HIV-1 RNA; the median increase in CD4+ cell count was 108 cells/mm3 (range, -58 to 406 cells/mm3) at week 24 in treatment-naive patients. In treatment-experienced patients, the median reduction in plasma HIV-1 RNA was 0.55 log10 (range, -2.86 to 0.52 log10), and the median increase in CD4+ cell count was 46 cells/mm3 (range, -188 to 311 cells/mm3). The percentages of patients with less than 3000 HIV-1 RNA copies/mL and less than 400 copies/mL at 24 weeks were, respectively, 57% (95% CI, 41% to 72%) and 26% (CI, 12% to 40%) among treatment-naive patients and 22% (CI, 10% to 38%) and 5% (CI, 1% to 17%) among treatment-experienced patients. Of 82 patients, 14 (17%) experienced grade 3 or 4 toxicity and 2 discontinued therapy because of intolerance toward treatment. CONCLUSION: Stavudine plus lamivudine seems to have a potent antiviral effect in treatment-naive and treatment-experienced patients. No major drug-limiting toxicity was found. This two-nucleoside combination should be considered in multidrug therapy for HIV.

Non-parametric methods for analysing recurrent complications of varying severity.

Non-parametric methods have recently been proposed to take into account the recurrent nature of complications in clinical trials, by estimating the prevalence Q(t), defined as the probability of relapse-free patients being in a complication state at time t. Recoveries are also considered. These methods have been adapted in this paper to take into consideration not only the recurrent nature of complications but also their severity through the interpretation of average weight functions. Results of a randomized trial comparing late complications following two alternative doses of pre-operative internal brachytherapy in patients with localized stage cervix carcinoma are used to illustrate the methods.

Lymph node prognostic factors in head and neck squamous cell carcinomas.

BACKGROUND: This retrospective study included 914 patients who underwent a lymph node dissection at our institute between 1980 and 1985. The primary tumor sites were oral cavity, 287; hypopharynx, 249; larynx, 247; and oropharynx, 131. PATIENTS AND METHODS: On the basis of anatomic considerations, the sentinel nodes for well-lateralized oral cavity tumors were defined as homolateral levels I, II, and III; for oropharyngeal, hypopharyngeal, and laryngeal tumors, the sentinel nodes were defined as levels II and III. We took into account the ipsilateral side of the neck for well-lateralized tumors, and both sides for medium or large tumors. For clinically positive nodes of more than 3 cm, a radical neck dissection was performed. Other patients underwent a selective neck dissection on sentinel nodes, with immediate pathologic evaluation. Modified radical neck dissections with contralateral selective dissection were performed when frozen sections were positive. Patients with positive nodes were given postoperative radiotherapy. RESULTS: The prognostic factors studied, using the Cox survival model adjusted on the primary tumor site, surprisingly showed a nonsignificant value for extracapsular spread (P = 0.09), and a significant value for the number of positive nodes (P < 0.001) and for the positive node in or out of the sentinel node sites (P < 0.001). Although the node location factor can be used instead of positive node in or out of the sentinel node site, it has a less significant prognostic value. CONCLUSIONS: The most significant prognostic factors are the site of the positive node in or out of the sentinel node and the number of positive nodes; and a more accurate approach can be obtained by combining both factors. Node location in the upper or lower neck remains a substitute prognostic factor for the site of the positive node in or out of the sentinel node.

[Method for evaluating long term complications. A study from a phase III trial comparing two low dose rates in gynecologic brachytherapy]. / Méthode d'évaluation des complications tardives. Etude basée sur un essai de phase III comparant deux faibles débits de dose en curiethérapie gynécologique.

When treatment complications are the main criteria of a study, the simplest way for estimating the complication rate over time is to use the Kaplan-Meier method. The failure is the onset of the first complication. A new way is proposed here which takes into account the time to an eventual second, and third complication, and their duration as well. Results from a phase III randomized trial comparing two preoperative brachytherapy low dose rates in localized stage cervix carcinoma patients are used to illustrate both methods. The new method showed a greater long term complication rate in the higher dose rate group.

Analysis of complications in a prospective randomized trial comparing two brachytherapy low dose rates in cervical carcinoma.

PURPOSE: The analysis of complications in a prospective randomized trial comparing two preoperative brachytherapy low-dose rates in early stage cervical cancer is presented. METHODS AND MATERIALS: Between 1985 and 1988, 204 patients with Stage I and limited Stage II cervical cancer were randomized to receive one of two preoperative brachytherapy low-dose rates (0.4 and 0.8 Gy/hr). The objective of this trial was to determine the benefits, if any, of the higher-dose rate within the therapeutic arsenal for this patient population, in terms of survival, local control, and complications. The type and severity of all complications were evaluated according to a common glossary and a strict follow-up schedule was established given that the treatment of cervical cancer is multidisciplinary, involving gynecologists, surgeons, and radiotherapists. RESULTS: Overall survival: 85% at 2 years and local control: 93% at 2 years, were similarly distributed between the two groups. Regardless of their nature and severity, 139 and 175 complications were observed among 63% and 75% of patients, in the 0.4 and 0.8 Gy/h dose rate groups respectively. Gynecologic and urinary complications were the most frequent (38% and 28% of all complications), followed by vascular (15%), digestive (10%), nervous (5%) and cutaneous (5%). A total of 14 and 17 severe complications (Grade 3) were observed in 7% and 13% of patients, respectively in the 0.4 and 0.8 Gy/h dose rate groups (p = 0.12). Nonparametric survival methods used to compare the time to the first complication did not show a significant difference between the two groups: 62% and 72% at 2 years (p = 0.27). When the first complication and its evolution were considered (early complications), the prevalence of complications was not significantly different between the two groups: 28% vs. 34% at 2 years (p = 0.31). In this prospective trial, patients were regularly followed-up and complications of varying nature and severity were observed in succession during follow-up. When successive complications and their evolution were taken into account, the prevalence of complications was significantly greater in the higher-dose rate group: 30% vs. 45% at 2 years (p = 0.03). CONCLUSION: The results of this trial showed that long-term effects of treatment, when represented by prevalence of complications over time, were more frequent in the higher dose rate group. This underlines the importance of the regular follow-up of patients and of coding, not only the occurrence of all complications, but also their evolution over time.