Clinical trial NCT03002259: Dexamethasone for Cardiac Surgery-II Trial
Official title: Evaluation of Dexamethasone in Cardiac Surgery Using a Novel Trial Design
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Inflammatory Response
Keywords: cardiac surgery
Lead sponsor: Bayside Health
Sponsor class: OTHER_GOV
Collaborators: name: UMC Utrecht
First posted: 2016-12-23
Enrollment: 1956
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Background. Numerous studies have investigated high-dose corticosteroids in cardiac surgery, but with mixed results leading to ongoing variations in practice around the world. The Dexamethasone for Cardiac Surgery-II Trial (DECS-II) is a study comparing high-dose dexamethasone with placebo in patients undergoing cardiac surgery.

Methods. We discuss the rationale for conducting DECS-II, a 2800-patient, pragmatic, multicenter, assessor-blinded, randomized trial in cardiac surgery, and the features of the DECS-II study design (objectives, end points, target population, balanced clusters based on practice preference with post-randomization consent, treatments, patient follow-up and analysis).

Conclusions. The DECS-II Trial will use a novel, efficient trial design to evaluate whether high-dose dexamethasone has a patient-centered benefit of enhancing recovery and increasing the number of days at home after cardiac surgery.

Detailed description: High-dose corticosteroids attenuate the inflammatory response to surgery with CPB and are commonly used in some countries,but uncommonly in the US, Canada and Australia. Steroids can reliably attenuate activation of the complement pathways associated with cardiac surgery, but clinical trials have had mixed results. The current evidence is dominated by the results of two recent large randomized trials: DECS (n=4,494)6 and SIRS (n=7,507).

Both DECS and SIRS assigned patients undergoing cardiac surgery with CPB to receive either a high intraoperative dose of steroids (dexamethasone 1 mg/kg, or methylprednisolone 500 mg, respectively) or placebo. The point estimates of both trials suggested a possible reduction in serious complications and mortality. Planned subgroup analyses in the DECS trial steroids reduced the incidence of respiratory failure (3.0 % vs. 4.3%, P=0.02), infection (9.5% vs. 14.8%, P=0.009), and shortened hospital stay (median 8 \[7-13\] vs. 9 \[7-13\] days, P=0.009).6 Severe renal failure (need for RRT) was reduced, 0.4% vs. 1.0%, P=0.04.8 But SIRS found methylprednisolone was associated with a higher incidence of myocardial injury (as measured by elevation of CK-MB enzyme). Nether trial identified a higher risk of myocardial infarction (MI). The methylprednisolone-induced elevation of CK-MB may therefore be a class effect.

Another compelling finding in pre-planned subgroup analysis of patient age groups is that when limiting analysis to those aged less than 75 years in the DECS trial, dexamethasone reduced the risk of the primary composite endpoint, RR 0.74 (95% CI: 0.58-0.95), P=0.017; as well as respiratory failure RR 0.62 (95% CI: 0.42-0.91), P=0.014; and possibly mortality RR 0.53 (95% CI: 0.26-1.10), P=0.08.6 This age-interaction effect is supported by the demonstration of increased C-reactive protein concentrations in younger patients enrolled in the DECS trial.

Therefore, it is highly plausible that prophylactic steroids can suppress deregulated inflammation and thus improve outcomes in cardiac surgery, but only when used in a less elderly (i.e. \<75 years) patient population.

In retrospect, the primary endpoints of both DECS and SIRS trials can be challenged, in that they used composites heavily weighted by thrombotic events (MI, stroke) and not specific to inflammation (respiratory failure, kidney injury, sepsis, prolonged ICU and hospital stay, mortality). We thus plan to re-evaluate dexamethasone in cardiac surgery, using a patient-centred, clinically important endpoint focused on enhanced recovery and earlier hospital discharge: "days alive and at home up to 30 days after surgery".

Eligibility criteria: Inclusion Criteria:

1. Males and females, age 18 to 75 years undergoing elective cardiac surgery with cardiopulmonary bypass
2. EuroScore-II estimated risk of 1.5% or higher

Exclusion Criteria:

1. Poor language (English or Dutch) comprehension
2. Type I diabetes
3. Endocarditis or other evidence of sepsis
4. Preoperative steroid therapy

Primary outcomes:
measure: days at home up to 30 days after surgery
timeFrame: 30 days from Start of Surgery
Secondary outcomes:
measure: respiratory failure
timeFrame: 30 days from Start of Surgery
measure: Infection
timeFrame: 30 days from Start of Surgery
measure: Myocardial Infarction
timeFrame: 30 days from Start of Surgery
measure: Stroke
timeFrame: 30 days from Start of Surgery
measure: Peak blood glucose
timeFrame: 30 days from Start of Surgery
measure: Length of stay
timeFrame: 30 days from Start of Surgery
measure: Quick SOFA score
timeFrame: Each evening on days 1-3 after surgery
Other outcomes:
Locations:
city: Melbourne
country: Australia
facility: Alfred Health
state: Victoria
Study officials:
affiliation: Alfred Hospital, Monash University
name: Paul S Myles, MBBS, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Myles PS, Dieleman JM, Forbes A, Heritier S, Smith JA. Dexamethasone for Cardiac Surgery trial (DECS-II): Rationale and a novel, practice preference-randomized consent design. Am Heart J. 2018 Oct;204:52-57. doi: 10.1016/j.ahj.2018.06.008. Epub 2018 Jun 21.