Why Are Clinicians Not Embracing the Results from Pivotal Clinical Trials in Severe Sepsis? A Bayesian Analysis

PLOS ONE, May 2008

Background Five pivotal clinical trials (Intensive Insulin Therapy; Recombinant Human Activated Protein C [rhAPC]; Low-Tidal Volume; Low-Dose Steroid; Early Goal-Directed Therapy [EGDT]) demonstrated mortality reduction in patients with severe sepsis and expert guidelines have recommended them to clinical practice. Yet, the adoption of these therapies remains low among clinicians. Objectives We selected these five trials and asked: Question 1-What is the current probability that the new therapy is not better than the standard of care in my patient with severe sepsis? Question 2-What is the current probability of reducing the relative risk of death (RRR) of my patient with severe sepsis by meaningful clinical thresholds (RRR >15%; >20%; >25%)? Methods Bayesian methodologies were applied to this study. Odds ratio (OR) was considered for Question 1, and RRR was used for Question 2. We constructed prior distributions (enthusiastic; mild, moderate, and severe skeptic) based on various effective sample sizes of other relevant clinical trials (unfavorable evidence). Posterior distributions were calculated by combining the prior distributions and the data from pivotal trials (favorable evidence). Main Findings Answer 1-The analysis based on mild skeptic prior shows beneficial results with the Intensive Insulin, rhAPC, and Low-Tidal Volume trials, but not with the Low-Dose Steroid and EGDT trials. All trials' results become unacceptable by the analyses using moderate or severe skeptic priors. Answer 2-If we aim for a RRR>15%, the mild skeptic analysis shows that the current probability of reducing death by this clinical threshold is 88% for the Intensive Insulin, 62–65% for the Low-Tidal Volume, rhAPC, EGDT trials, and 17% for the Low-Dose Steroid trial. The moderate and severe skeptic analyses show no clinically meaningful reduction in the risk of death for all trials. If we aim for a RRR >20% or >25%, all probabilities of benefits become lower independent of the degree of skepticism. Conclusions Our clinical threshold analysis offers a new bedside tool to be directly applied to the care of patients with severe sepsis. Our results demonstrate that the strength of evidence (statistical and clinical) is weak for all trials, particularly for the Low-Dose Steroid and EGDT trials. It is essential to replicate the results of each of these five clinical trials in confirmatory studies if we want to provide patient care based on scientifically sound evidence.

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

http://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0002291&type=printable

Why Are Clinicians Not Embracing the Results from Pivotal Clinical Trials in Severe Sepsis? A Bayesian Analysis

Citation: Kalil AC, Sun J ( Why Are Clinicians Not Embracing the Results from Pivotal Clinical Trials in Severe Sepsis? A Bayesian Analysis Andre C. Kalil 0 Junfeng Sun 0 Adam J. Ratner, Columbia University, United States of America 0 1 Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, United States of America, 2 Assistant Professor, Department of Biostatistics, College of Public Health, University of Nebraska , Omaha, Nebraska , United States of America Background: Five pivotal clinical trials (Intensive Insulin Therapy; Recombinant Human Activated Protein C [rhAPC]; LowTidal Volume; Low-Dose Steroid; Early Goal-Directed Therapy [EGDT]) demonstrated mortality reduction in patients with severe sepsis and expert guidelines have recommended them to clinical practice. Yet, the adoption of these therapies remains low among clinicians. Objectives: We selected these five trials and asked: Question 1-What is the current probability that the new therapy is not better than the standard of care in my patient with severe sepsis? Question 2-What is the current probability of reducing the relative risk of death (RRR) of my patient with severe sepsis by meaningful clinical thresholds (RRR .15%; .20%; .25%)? Methods: Bayesian methodologies were applied to this study. Odds ratio (OR) was considered for Question 1, and RRR was used for Question 2. We constructed prior distributions (enthusiastic; mild, moderate, and severe skeptic) based on various effective sample sizes of other relevant clinical trials (unfavorable evidence). Posterior distributions were calculated by combining the prior distributions and the data from pivotal trials (favorable evidence). Main Findings: Answer 1-The analysis based on mild skeptic prior shows beneficial results with the Intensive Insulin, rhAPC, and Low-Tidal Volume trials, but not with the Low-Dose Steroid and EGDT trials. All trials' results become unacceptable by the analyses using moderate or severe skeptic priors. Answer 2-If we aim for a RRR.15%, the mild skeptic analysis shows that the current probability of reducing death by this clinical threshold is 88% for the Intensive Insulin, 62-65% for the LowTidal Volume, rhAPC, EGDT trials, and 17% for the Low-Dose Steroid trial. The moderate and severe skeptic analyses show no clinically meaningful reduction in the risk of death for all trials. If we aim for a RRR .20% or .25%, all probabilities of benefits become lower independent of the degree of skepticism. Conclusions: Our clinical threshold analysis offers a new bedside tool to be directly applied to the care of patients with severe sepsis. Our results demonstrate that the strength of evidence (statistical and clinical) is weak for all trials, particularly for the Low-Dose Steroid and EGDT trials. It is essential to replicate the results of each of these five clinical trials in confirmatory studies if we want to provide patient care based on scientifically sound evidence. - If we begin with certainties, we shall end in doubts; but if we begin with doubts, and are patient with them, we shall end with certainties. More than 20 clinical trials involving over 10,000 patients have been performed in patients with sepsis and severe sepsis in the last 15 years with little success in reducing mortality [1]. More recently, five published clinical trials: Early Goal-Directed Therapy [2], Recombinant Human Activated Protein C [3], Low-Dose Steroid [4], Low-Tidal Volume-ARDS Network [5], and Intensive Insulin Therapy [6] demonstrated positive outcome results and brought the prospect of improving the survival of patients with severe sepsis. Ten multinational medical societies sponsored a joint statement, Surviving Sepsis Campaign, in which recommendations are made to include the results of these trials in the standard of care for patients with severe sepsis [7]. These recommendations have also been evaluated by the Joint Commission on Accreditation of Healthcare Organizations [8]. Despite these positive outcomes and recommendations, scientists and clinicians have been either slow or resistant to adopt the results of these trials at face value in order to apply them to patient care [925]. Still, strong endorsement by the medical societies is not coming without criticisms and opposition by the medical community [8,26]. Why is this resistance to accept statistically significant results from large clinical trials so accentuated in the sepsis field? We propose that the genesis for most of these issues lies in the confounding interpretation and poor translation of these results to the bedside, and the lack of formal analysis combining previous evidence and the current positive clinical trials. While controversy is necessary for the progression of science [27], when it comes to treating a patient with severe sepsis, a clinical decision is also necessary for the betterment of this patients outcome. In the following paragraphs, we argue that the best solution (...truncated)


This is a preview of a remote PDF: http://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0002291&type=printable

Andre C. Kalil, Junfeng Sun. Why Are Clinicians Not Embracing the Results from Pivotal Clinical Trials in Severe Sepsis? A Bayesian Analysis, PLOS ONE, 2008, Volume 3, Issue 5, DOI: 10.1371/journal.pone.0002291