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

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

Prevention of Intradialytic Hypotension in Hemodialysis Patients: Current Challenges and Future Prospects

Seyed Mehrdad Hamrahian,1 Salem Vilayet,2 Johann Herberth,2,3 Tibor Fülöp2,3 1Department of Medicine - Nephrology, Thomas Jefferson University, Philadelphia, PA, USA; 2Department of Medicine - Division of Nephrology, Medical University of South Carolina, Charleston, SC, USA; 3Medicine Services, Ralph H. Johnson VA Medical Center, Charleston, SC, USACorrespondence: Tibor Fülöp, Department of Medicine - Division of Nephrology, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC, 29525, USA, Tel +1 843 792-4123, Fax +1 843 792-2995, Email [email protected]; [email protected]: Intradialytic hypotension, defined as rapid decrease in systolic blood pressure of greater than or equal to 20 mmHg or in mean arterial pressure of greater than or equal to 10 mmHg that results in end-organ ischemia and requires countermeasures such as ultrafiltration reduction or saline infusion to increase blood pressure to improve patient’s symptoms, is a known complication of hemodialysis and is associated with several potential adverse outcomes. Its pathogenesis is complex and involves both patient-related factors such as age and comorbidities, as well as factors related to the dialysis prescription itself. Key factors include the need for volume removal during hemodialysis and a suboptimal vascular response which compromises the ability to compensate for acute intravascular volume loss. Inadequate vascular refill, incorrect assessment or unaccounted changes of target weight, acute illnesses and medication interference are further potential contributors. Intradialytic hypotension can lead to compromised tissue perfusion and end-organ damage, both acutely and over time, resulting in repetitive injuries. To address these problems, a careful assessment of subjective symptoms, minimizing interdialytic weight gains, individualizing dialysis prescription and adjusting the dialysis procedure based on patients’ risk factors can mitigate negative outcomes.Keywords: end-stage renal disease, dialysis, hemodialysis, hypotension, ultrafiltratio