Influence of enrollment sequence effect on observed outcomes in the ADDRESS and PROWESS studies of drotrecogin alfa (activated) in patients with severe sepsis

INTRODUCTION: We performed a study to determine whether an enrollment sequence effect noted in the PROWESS (recombinant human activated Protein C Worldwide Evaluation in Severe Sepsis) trial exists in the ADDRESS (Administration of Drotrecogin Alfa [Activated] [DrotAA] in Early Stage Severe Sepsis) trial. METHODS: We evaluated prospectively defined subgroups from two large phase 3 clinical trials: ADDRESS, which included 516 sites in 34 countries, and PROWESS, which included 164 sites in 11 countries. ADDRESS consisted of patients with severe sepsis at low risk of death not indicated for treatment with DrotAA. PROWESS consisted of patients with severe sepsis with one or more organ dysfunctions. DrotAA (24 microg/kg per hour) or placebo was infused for 96 hours. RESULTS: In ADDRESS and PROWESS, there was a statistically significant interaction between the DrotAA treatment effect and the sequence in which patients were enrolled. In both trials, higher mortality was associated with DrotAA use in the subgroup of patients enrolled first at study sites. Compared with placebo, PROWESS mortality was lower with DrotAA treatment for the second and subsequent patients enrolled, whereas in ADDRESS, mortality remained higher for the second patient enrolled but thereafter was lower for DrotAA-treated patients. Comparison of patients enrolled first with subsequent patients enrolled indicated that the characteristics of patients changed. Subsequently enrolled patients were treated earlier, were less likely to suffer nonserious bleeds (ADDRESS), and experienced fewer protocol violations (PROWESS). CONCLUSIONS: Analyses suggest that an enrollment sequence effect was present in the ADDRESS and PROWESS trials. Analysis of this effect on outcomes suggests that it is most apparent in patients at lower risk of death. In PROWESS, this effect appeared to be associated with a reduction of the DrotAA treatment effect for the first patients enrolled at each site. In ADDRESS, this effect may have contributed to early termination of the study. The finding of an enrollment sequence effect in two separate trials suggests that trial designs, site selection and training, data collection and monitoring, and statistical analysis plans may need to be adjusted for these potentially confounding events. TRIAL REGISTRATION: ADDRESS trial registration number: NCT00568737. PROWESS was completed before trial registration was required

Unblinding plan of PROWESS-SHOCK trial

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Estimate of the number of patients eligible for treatment with drotrecogin alfa (activated) based on differing international indications: Post-hoc analysis of an inception cohort study in Australia and New Zealand

We aimed to estimate the potential number of patients eligible for treatment with drotrecogin alfa (activated) when applying different international criteria

Confirmatory platelet-activating factor receptor antagonist trial in patients with severe gram-negative bacterial sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. BN 52021 Sepsis Investigator Group.

OBJECTIVE: To determine the efficacy and safety of using natural platelet-activating factor receptor antagonist (PAFra), BN 52021, to treat patients with severe Gram-negative bacterial sepsis. DESIGN: A prospective, randomized, double-blind, placebo-controlled, multicenter clinical trial. SETTING: Fifty-nine academic medical center intensive care units in Europe. PATIENTS: Six hundred nine patients with severe sepsis, suspected to be related to Gram-negative bacterial infection, who received PAFra or placebo. INTERVENTIONS: Patients were randomized to receive either a dose of PAFra (120 mg iv) every 12 hrs over a 4-day period or placebo over a 4-day period. MEASUREMENTS AND MAIN RESULTS: The patients were well matched at study entry for severity of illness and for risk factors known to influence the outcome of sepsis. Among all randomized patients, the 28-day, all-cause mortality rate was 49% (152/308) in the placebo group, and 47% (140/300) in the PAFra group (p=.50). When analyzed on the basis of the previously defined target population, the 28-day, all-cause mortality rate was 50% (115/232) in the placebo group and 44% (94/212) in the PAFra group, yielding a 12% reduction in mortality rate (p=.29). In patients with documented infection involving other organisms, there was no difference between treated and placebo groups. When the outcomes of organ dysfunctions were examined in the overall population and in the documented Gram-negative bacterial infection population, the number of patients who resolved hepatic dysfunction tended to be higher in the treated group than in the placebo group (p=.06). The number of adverse events reported were not different between the two groups. CONCLUSIONS: A 4-day administration of the studied PAFra (BN 52021) failed to demonstrate a statistically significant reduction in the mortality rate of patients with severe sepsis suspected to be related to Gram-negative bacterial infection. If PAFra treatment has any therapeutic activity in severe Gram-negative bacterial sepsis, the incremental benefits are small and will be difficult to demonstrate in a patient population as defined by this clinical trial

POSIÇÃO CORPORAL E OXIGENAÇÃO PARTE I - PACIENTES COM DISFUNÇÃO PULMONAR UNILATERAL

Este estudo verificou o efeito das posições sentada, supina e laterais sobre os gases do sangue arterial, em pacientes com disfunção pulmonar unilateral, no pós-operatório recente de cirurgia cardíaca. Os gases sangüíneos foram mensurados após o paciente permanecer 15 minutos em cada posição. Concluiu-se que quando o paciente deitava-se sobre o lado do pulmão considerado sadio ou em supino, a Pa02 foi significativamente superior. No entanto, na posição deitada sobre o lado afetado, houve piora significativa da Pa02.The purpose of this study was to analyse the effects of sitting, supine and laterals positions on arterial oxygen tension (Pa02) and arterial carbon dioxide tension (PaC02), in 21 adults patients, carier of some pulmonary unilateral disfunction, in recent post-operative cardiac surgery. The diagnosis of the pulmonary disfunction was done through radiographic torax evaluation. The patients stayed during 15 minutes in each position and after this, the arterial blood gases were measured. Based on Friedman test and Multiple Comparation test (a = 0,05), it was found that the Pa02 was significantly higher when the patients were lying on the "healthy'' side or in supine position; the Pa02 was significantly lower when the patients where lying on the "sick" side. No significant changes in PaC02 were noted