Benjamin Trzaskoma

Early changes in organ function predict eventual survival in severe sepsis

Objective:Early identification and treatment of severe sepsis can significantly reduce mortality rate. We hypothesized that a risk prediction model based on early (baseline to day 1 of study) response to standard care should be significantly related to 28-day survival. Design:Analysis of organ dysfunction data from two placebo-controlled severe sepsis trials (PROWESS and secretory phospholipase A2 inhibitor trials). Setting:Research laboratory. Patients:The placebo arms of two randomized, double-blind sepsis trials were combined (n = 1036). These patients met criteria for severe sepsis and received supportive standard intensive care and fluid resuscitation. Interventions:None. Measurements and Main Results:Sequential Organ Failure Assessment (SOFA) scores were calculated daily using the most aberrant physiologic or laboratory variables. Baseline and postbaseline SOFA scores categorized as improved, unchanged, or worsened were used in regression analyses correlating organ dysfunction changes with 28-day mortality. Improvement in cardiovascular (p = .0010), renal (p < .0001), or respiratory (p = .0469) function from baseline to day 1 was significantly related to survival. Odds ratios (95% confidence intervals) associated with improved vs. worsened respiratory, cardiovascular, or renal function before start of day 1 were 0.56 (0.35–0.91), 0.33 (0.18–0.59), and 0.30 (0.17–0.52), respectively. Continued improvement in cardiovascular function before start of day 2 and start of day 3 was associated with further improvement in survival (p <. 0001), with odds ratios of 0.15 (0.06–0.39) and 0.11 (0.04–0.31) for patients who improved compared with those who worsened. No other organ system was retained in the model, and improvement beyond day 1 in any other organ function did not add to the models predictive power. Conclusions:These analyses suggest that outcomes for patients with severe sepsis are closely related to early (baseline to day 1 here) improvement, or lack thereof, in organ function. Also, clinical improvement on subsequent days may have little additional impact on the likelihood of survival. LEARNING OBJECTIVESOn completion of this article, the reader should be able to: Explain organ function abnormalities associated with poor patient outcomes from sepsis. Describe the significant time periods to predict outcome. Use this information in a clinical setting. Dr. Levy has disclosed that he is/was the recipient of direct grant/research funds from Eli Lilly & Co., Chiron, Moguel, Phillips, and Edwards; is a consultant for Chiron and Phillips; and is/was on the speakers bureau of Eli Lilly & Co., Edwards, Phillips, and Ortho. Dr. Macias has disclosed that he is/was an employee and a current stock shareholder of Eli Lilly & Co. Dr. Vincent has disclosed that he is/was the recipient of direct grant/research funds from, a consultant for, and on the speakers bureau of Eli Lilly & Co. Mr. Trzaskoma and Dr. Williams have disclosed that they were/are employees and stock shareholders of Eli Lilly & Co. Dr. Silva has disclosed that he is/was a consultant for and was on the speakers bureau of Eli Lilly & Co. Dr. Russell has disclosed that he has no financial relationships with or interests in any commercial companies pertaining to this educational activity. Wolters Kluwer Health has identified and resolved all faculty conflicts of interests regarding this educational activity. Visit the Critical Care Medicine Web site (www.ccmjournal.org) for information on obtaining continuing medical education credit.

Use of an integrated clinical trial database to evaluate the effect of timing of drotrecogin alfa (activated) treatment in severe sepsis

IntroductionSeveral studies have indicated that early identification and treatment of patients with severe sepsis using standard supportive care improves outcomes. Earlier treatment with drotrecogin alfa (activated) (DrotAA) may also improve outcomes in severe sepsis. Using a recently constructed integrated severe sepsis database, our objectives in this study were to describe the influence of baseline clinical characteristics on timing of DrotAA treatment in patients with severe sepsis, to evaluate the efficacy of DrotAA with respect to timing of administration, and to examine the association between early intervention with DrotAA and patient outcomes, using adjustments for imbalances.MethodsThe database comprises data from 4,459 patients with severe sepsis (DrotAA, n = 3,228; placebo, n = 1,231) included in five clinical trials conducted in tertiary care institutions in 28 countries. Placebo data came only from randomized trials, whereas data for the DrotAA group came from randomized (PROWESS) and open-label/observational (ENHANCE) trials.ResultsIncreased time-to-treatment with DrotAA was significantly associated with more organ dysfunction, greater need of mechanical ventilation, vasopressor use, or recent surgery. Earlier treatment was associated with higher baseline Acute Physiology and Chronic Health Evaluation (APACHE II) scores. Adjusted and unadjusted survival analyses suggested that compared with placebo, DrotAA treatment provided a potential survival benefit, regardless of time to treatment. Survival curves of DrotAA patients treated early compared with those treated late began to separate at 14 days. By 28 days, patients treated earlier had higher survival than those treated later (76.4% versus 73.5%, p = 0.03). Sepsis-induced multiorgan dysfunction was the most common cause of death followed by refractory shock and respiratory failure. Modeling of the treatment effect, as a function of time to treatment, suggested increased benefit with earlier treatment.ConclusionUsing an integrated database of five severe sepsis trials and appropriate statistical adjustments to reduce sources of potential bias, earlier treatment with DrotAA seemed to be associated with a lower risk-adjusted mortality than later treatment. These data suggest that earlier treatment with DrotAA may provide most benefit for appropriate patients.

ADDRESS (ADministration of DRotrecogin alfa [activated] in Early stage Severe Sepsis) long-term follow-up: one-year safety and efficacy evaluation.

Objective:To demonstrate that drotrecogin alfa (activated) has an acceptable safety profile 1 yr from randomization. Design:One-year follow-up of patients participating in a placebo-controlled clinical study of drotrecogin alfa (activated) in severe sepsis patients at low risk of death (the ADDRESS study). Setting:The study was conducted at 516 hospitals in 34 countries. Patients:The study included 2,640 patients. Interventions:One-year follow-up was performed as an addendum to the placebo-controlled ADDRESS study. Treatment groups were compared using the chi-square test and Kaplan-Meier estimates. Measurements and Main Results:Survival status at 1 yr was obtained for 90% of patients enrolled in the study (n = 2,376). The difference in mortality rate between drotrecogin alfa (activated) and placebo patients was numerically smaller at 1 yr (34.2% and 34.0%, respectively, p = .94) than at 28 days (18.5% and 17.0%, respectively, p = .34). In the subgroups defined by organ dysfunction class (single or multiple) and Acute Physiology and Chronic Health Evaluation II score (<25 or ≥25), the differences in mortality rate between treatment groups at 1 yr were consistent with those observed at 28 days; no significant differences in mortality rates between treatment groups were observed. No additional serious adverse events were reported during the period between hospital discharge and 1 yr. Conclusions:No increased risk of death or evidence of harm at 1 yr was associated with drotrecogin alfa (activated) administration in patients with severe sepsis at lower risk of death.

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

ABSTRACT 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 μg/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 non-randomized 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.

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.