Insights from patients screened but not randomised in the HYPERION trial

Abstract

Background Few data are available about outcomes of patients screened for, but not enrolled in, randomised clinical trials. Methods We retrospectively reviewed patients who had non-inclusion criteria for the HYPERION trial comparing 33 °C to 37 °C in patients comatose after cardiac arrest in non-shockable rhythm, due to any cause. A good neurological outcome was defined as a day-90 Cerebral Performance Category score of 1 or 2. Results Of the 1144 patients with non-inclusion criteria, 1130 had day-90 information and, among these, 158 (14%) had good functional outcomes, compared to 7.9% overall in the HYPERION trial (10.2% with and 5.7% without hypothermia). Considerable centre-to-centre variability was found in the proportion of non-included patients who received hypothermia (0% to 83.8%) and who had good day-90 functional outcomes (0% to 31.3%). The proportion of patients with a good day-90 functional outcome was significantly higher with than without hypothermia (18.5% vs. 11.9%, P = 0.003). Conclusion Our finding of better functional outcomes without than with inclusion in the HYPERION trial, despite most non-inclusion criteria being of adverse prognostic significance (e.g., long no-flow and low-flow times and haemodynamic instability), raises important questions about the choice of patient selection criteria and the applicability of trial results to everyday practice. At present, reserving hypothermia for patients without predictors of poor prognosis seems open to criticism.

Outcomes of mild-to-moderate postresuscitation shock after non-shockable cardiac arrest and association with temperature management: a post hoc analysis of HYPERION trial data

“…One limitation of our study is that the findings apply only to patients with mild-to-moderate PRS, since major hemodynamic instability defined as a continuous epinephrine or norepinephrine infusion > 1 μg/kg/min was an exclusion criterion: only patients with mild-to-moderate shock were included in our analysis [ 35 ]. Surprisingly, the global prognosis for patients without PRS (9.1%) or with moderate PRS (7.1%) was poorer than for patients with severe PRS (defined as receiving norepinephrine > 1 µg/kg/min, 13.3%)).…”

“…In addition, several origins for shock state can coexist (septic shock related to inhalation pneumonia, cardiogenic shock related to acute coronary occlusion, PRS itself) and complicate interpretation of physiopathology. The prognosis of patients with severe PRS is difficult to assess at ICU admission [ 35 ]. Patients were not randomized according to the presence or absence of PRS.…”

Optimizing the Design and Analysis of Future AKI Trials

“…Although this trial design is well suited for assessing novel therapeutics, the time (often years) and effort required to enroll and monitor patients makes it impractical to conduct trials large enough to identify small but clinically relevant effects that would likely be expected for many therapies targeting AKI. Further, restrictive inclusion and exclusion criteria often result in trial populations that do not represent the broader population of patients who experience AKI, or fail to include groups of patients who might have benefited from the proposed intervention 10 .…”