Clinical trial NCT00427388: Steroids In caRdiac Surgery Trial (SIRS Trial)
Official title: Phase IV Study of Perioperative Steroid's Effects on Death or MI in High-Risk Patients Undergoing Cardiac Surgery Requiring Cardiopulmonary Bypass
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Cardiac Surgical Procedures
Cardiopulmonary Bypass
Systemic Inflammatory Response Syndrome
Keywords: Cardiac Surgical Procedures
Cardiopulmonary Bypass
Systemic inflammatory Response Syndrome
Steroid
Myocardial Infarction
Randomized Clinical Trial
Lead sponsor: McMaster University
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
First posted: 2007-01-29
Enrollment: 7507
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: SIRS trial is a large simple study in which high-risk patients undergoing cardiac surgery requiring the use of cardiopulmonary bypass (CPB) are randomly allocated to receive a pulse dose of Methylprednisolone or a matching placebo. Cardiopulmonary bypass initiates a systemic inflammatory response that facilitates development of post-operative complications. SIRS will confirm or deny the potential clinical benefits of suppressing this response through the use of systemic steroids. Specifically, does 250 mg of intravenous Methylprednisolone given twice, once on anesthetic induction and again on CPB initiation, result in improved early survival and less myocardial infarction in high-risk cardiac surgery patients requiring CPB?

Detailed description: Cardiopulmonary bypass (CPB) is a commonly performed surgical procedure with over 500,000 per year in North America. CPB initiates a systemic inflammatory response characterized by both cell and protein activation. Platelets, neutrophils, monocytes, macrophages, coagulation, fibrinolytic, and kallikrein cascades all take part in what results in increased endothelial permeability, vascular, and parenchymal damage. These inflammatory pathways facilitate development of post-operative complications including thrombosis, myocardial injury and infarction, respiratory failure, renal and neurological dysfunction, bleeding disorders, altered liver function and ultimately, multiple organ failure.

In an attempt to minimize the deleterious effects of CPB, investigators have tested a variety of strategies in cardiac surgery ranging from the complete avoidance of CPB, to the use of biocompatible circuits and pharmacologic agents to abrogate the systemic response. Investigators have consistently demonstrated the efficacy of steroids as the most potent anti-inflammatory agent for use during CPB. In fact, from the available evidence, the 2004 AHA guidelines for coronary artery bypass grafting (CABG) "support liberal prophylactic use in patients undergoing extracorporeal circulation". However, the trials that do exist within this literature are focused on biochemical endpoints and are insufficiently powered to make conclusions on hard clinical endpoints. Our pilot RCT, SIRS I, demonstrated the efficacy of a low dose steroid protocol in the suppression of this inflammatory cascade. We hypothesize that this low dose protocol will yield clinical benefit while avoiding the potential adverse effects of steroids which are known to be dose dependent.

The primary aim of the SIRS trial is to determine if perioperative pulse dose Methylprednisolone results in improved early survival and less myocardial infarction in cardiac surgery requiring CPB. Additional secondary aims of the SIRS trial are to determine the effect of steroids on other clinical outcomes including length of stay, new onset atrial fibrillation, transfusion requirements, infectious, wound, and gastrointestinal complications.

The design of the SIRS trial is a prospective multicentre international double-blind placebo controlled randomized clinical trial. The sample size of 7500 patients will have 80% to 90% power to detect a 20-30% RRR for the primary outcome with an α=0.05 (two-sided), anticipating a 6% rate of death in the control arm. Our aim is to have 85 international centers participate which, recruiting at 5 patients per month, would complete recruitment in 36 months. This will be a large trial with a simple design and objective outcomes.

A sub-group of patients will be enrolled in a renal sub-study. This sub-study will determine if the risk of acute kidney injury is lower in patients treated with intravenous steroid versus placebo, if steroids lead to better preservation of kidney function six months after cardiac surgery, and whether the impact of steroid exposure differs in patients with and without pre-operative chronic kidney disease.

Eligibility criteria: Inclusion Criteria:

1. Age greater than 18 years
2. Require CPB for any cardiac surgical procedure (such as CABG, Valve, Aorta, or combined procedures)
3. Must have a EuroSCORE ≥ 6
4. Provide written informed consent

NOTE: For participating sites in India, China and Hong Kong, the following eligibility criteria will be applied:

1. Age greater than 18 years
2. Require CPB for any cardiac surgical procedure (such as CABG, Valve, Aorta, or combined procedures)
3. Must have at least one of the following:

   1. EuroSCORE greater than or equal to 4 and undergoing valvular surgery
   2. EuroSCORE greater than or equal to 6 and undergoing any other cardiac surgery procedure (i.e. CABG, Aorta)
4. Provide written informed consent

Exclusion Criteria:

1. Use of systemic corticosteroids
2. History of bacterial or fungal infection in last 30 days
3. Allergy/intolerance to corticosteroids
4. Will receive Aprotinin
5. Previous participation in study

Primary outcomes:
measure: Mortality at 30 days
timeFrame: 30 days post-randomization
measure: Composite
timeFrame: 30 days post-randomization
Secondary outcomes:
measure: MI or Mortality at 30 days
timeFrame: 30 days post-randomization
measure: Mortality at 6 months
timeFrame: 6 months post-randomization
measure: Atrial Fibrillation
timeFrame: 30 days post-randomization
measure: Transfusion Requirements
timeFrame: 24 hours post-surgery
measure: Chest Tube Output
timeFrame: 24 hours post-surgery
measure: ICU and Hospital Length of Stay
timeFrame: Hospital Discharge
measure: Infection
timeFrame: 30 days post-randomization
measure: Delirium
timeFrame: 3 days post-surgery
measure: Wound Complication
timeFrame: 30 days post-randomization
measure: GI Hemorrhage
timeFrame: 30 days post-randomization
measure: Insulin Use
timeFrame: 24 hours post-surgery
measure: Peak Blood Glucose
timeFrame: 24 hours post-surgery
Other outcomes:
Locations:
city: Hamilton
country: Canada
facility: Hamilton General Hospital
state: Ontario
Study officials:
affiliation: Pranic Healing Research Institute
name: Salim Yusuf, MD, DPhil
role: PRINCIPAL_INVESTIGATOR
affiliation: McMaster University
name: Kevin Teoh, MD, MSc
role: PRINCIPAL_INVESTIGATOR
affiliation: McMaster University
name: Richard P Whitlock, MD, MSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: Whitlock RP, Young E, Noora J, Farrokhyar F, Blackall M, Teoh KH. Pulse low dose steroids attenuate post-cardiopulmonary bypass SIRS; SIRS I. J Surg Res. 2006 May 15;132(2):188-94. doi: 10.1016/j.jss.2006.02.013. Epub 2006 Mar 29.
citation: Whitlock RP, Rubens FD, Young E, Teoh KH. Pro: Steroids should be used for cardiopulmonary bypass. J Cardiothorac Vasc Anesth. 2005 Apr;19(2):250-4. doi: 10.1053/j.jvca.2005.02.010. No abstract available.
citation: Whitlock R, Teoh K, Vincent J, Devereaux PJ, Lamy A, Paparella D, Zuo Y, Sessler DI, Shah P, Villar JC, Karthikeyan G, Urrutia G, Alvezum A, Zhang X, Abbasi SH, Zheng H, Quantz M, Yared JP, Yu H, Noiseux N, Yusuf S. Rationale and design of the steroids in cardiac surgery trial. Am Heart J. 2014 May;167(5):660-5. doi: 10.1016/j.ahj.2014.01.018. Epub 2014 Mar 1.
citation: Garg AX, Vincent J, Cuerden M, Parikh C, Devereaux PJ, Teoh K, Yusuf S, Hildebrand A, Lamy A, Zuo Y, Sessler DI, Shah P, Abbasi SH, Quantz M, Yared JP, Noiseux N, Tagarakis G, Rochon A, Pogue J, Walsh M, Chan MT, Lamontagne F, Salehiomran A, Whitlock R; SIRS Investigators. Steroids In caRdiac Surgery (SIRS) trial: acute kidney injury substudy protocol of an international randomised controlled trial. BMJ Open. 2014 Mar 5;4(3):e004842. doi: 10.1136/bmjopen-2014-004842.
citation: Garg AX, Chan MTV, Cuerden MS, Devereaux PJ, Abbasi SH, Hildebrand A, Lamontagne F, Lamy A, Noiseux N, Parikh CR, Perkovic V, Quantz M, Rochon A, Royse A, Sessler DI, Shah PJ, Sontrop JM, Tagarakis GI, Teoh KH, Vincent J, Walsh M, Yared JP, Yusuf S, Whitlock RP; SIRS Investigators. Effect of methylprednisolone on acute kidney injury in patients undergoing cardiac surgery with a cardiopulmonary bypass pump: a randomized controlled trial. CMAJ. 2019 Mar 4;191(9):E247-E256. doi: 10.1503/cmaj.181644.
citation: Theriault S, Whitlock R, Raman K, Vincent J, Yusuf S, Pare G. Gene Expression Profiles for the Identification of Prevalent Atrial Fibrillation. J Am Heart Assoc. 2017 Jun 30;6(7):e006057. doi: 10.1161/JAHA.117.006057.
citation: Whitlock RP, Devereaux PJ, Teoh KH, Lamy A, Vincent J, Pogue J, Paparella D, Sessler DI, Karthikeyan G, Villar JC, Zuo Y, Avezum A, Quantz M, Tagarakis GI, Shah PJ, Abbasi SH, Zheng H, Pettit S, Chrolavicius S, Yusuf S; SIRS Investigators. Methylprednisolone in patients undergoing cardiopulmonary bypass (SIRS): a randomised, double-blind, placebo-controlled trial. Lancet. 2015 Sep 26;386(10000):1243-1253. doi: 10.1016/S0140-6736(15)00273-1.