Why are clinicians not embracing the results from pivotal clinical trials in severe sepsis? A Bayesian analysis

Andre C Kalil, Junfeng Sun

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numbere2291
JournalPloS one
Volume3
Issue number5
DOIs
StatePublished - May 28 2008

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Bayes Theorem
Bayesian theory
clinical trials
Sepsis
relative risk
Clinical Trials
death
tidal volume
therapeutics
steroids
Protein C
patient care
Steroids
Tidal Volume
Insulin
dosage
Therapeutics
Patient Care
insulin
proteins

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Why are clinicians not embracing the results from pivotal clinical trials in severe sepsis? A Bayesian analysis. / Kalil, Andre C; Sun, Junfeng.

In: PloS one, Vol. 3, No. 5, e2291, 28.05.2008.

Research output: Contribution to journalArticle

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abstract = "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.",
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