Designing phase 3 sepsis trials: application of learned experiences from critical care trials in acute heart failure

Abstract

Substantial attention and resources have been directed to improving outcomes of patients with critical illnesses, in particular sepsis, but all recent clinical trials testing various interventions or strategies have failed to detect a robust benefit on mortality. Acute heart failure is also a critical illness, and although the underlying etiologies differ, acute heart failure and sepsis are critical care illnesses that have a high mortality in which clinical trials have been difficult to conduct and have not yielded effective treatments. Both conditions represent a syndrome that is often difficult to define with a wide variation in patient characteristics, presentation, and standard management across institutions. Referring to past experiences and lessons learned in acute heart failure may be informative and help frame research in the area of sepsis. Academic heart failure investigators and industry have worked closely with regulators for many years to transition acute heart failure trials away from relying on dyspnea assessments and all-cause mortality as the primary measures of efficacy, and recent trials have been designed to assess novel clinical composite endpoints assessing organ dysfunction and mortality while still assessing all-cause mortality as a separate measure of safety. Applying the lessons learned in acute heart failure trials to severe sepsis and septic shock trials might be useful to advance the field. Novel endpoints beyond all-cause mortality should be considered for future sepsis trials.

Keywords: Clinical trials as topic; Heart failure; Mortality; Multiple organ failure; Sepsis.

Fig. 1

In-hospital mortality rates for septicemia, respiratory failure, and acute heart failure. Acute coronary syndrome included as an example of a critical care cardiovascular condition where reductions in in-hospital mortality have been realized. Rates are per 100 discharges for acute coronary syndrome, septicemia, and respiratory failure and were extracted from National Hospital Discharge Survey [–68]. Rates for acute heart failure were based on published registry data [69] and represent percent of patients in the registries who died in the hospital. Data shown are from ADHERE [70] and OPTIMIZE [71] (2000), EHFS II (2004) [72], ALARM (2007) [73], AHEAD (2010) [74], and ATTEND (2011) [75]. The acute heart failure data should be interpreted considering the differences in registry populations and severity of illness

Fig. 2

Estimated sample sizes by baseline mortality and absolute mortality reduction. This figure examines the total sample size needed to identify an absolute mortality reduction of 3 to 15 % assuming three control group mortality rates (30, 20, and 10 %). The assumptions in this figure is that power is 80 % for a two-sided test and that 1:1 randomization will be employed (for example, a total N of 3000 on the y-axis implies a n = 1500 in each treatment arm). Source: author calculations (MOH)