Author + information
- W. Scott Beattie, MD, PhD∗ (, )
- Duminda N. Wijeysundera, MD, PhD,
- Matthew T.V. Chan, MBBS, PhD,
- Philip J. Peyton, MBBS, MD, PhD,
- Kate Leslie, MBBS, MD,
- Michael J. Paech, MBBS, DM,
- P.J. Devereaux, MD, PhD,
- Daniel I. Sessler, MD,
- Sophie Wallace, MPH,
- Paul S. Myles, MBBS, MD, MPH, DSc,
- on behalf of the ANZCA Clinical Trials Network and the ENIGMA-II Investigators
- ↵∗Department of Anesthesia and Pain Management, University Health Network, 200 Elizabeth Street, 3n-464, Toronto, Ontario M5G 2C4, Canada
Post-operative myocardial injury (MI) (1,2) represents a spectrum that ranges from MI to the more common post-operative troponin elevation that does not fulfill the Universal Definition of MI (3). These troponin elevations, which exceed the 99th centile for a normal population, we will refer to as isolated myocardial injury (IMI). The prevailing evidence would suggest that most physicians do not consider IMI clinically important in that many of these patients lack an in-depth post-operative evaluation, treatment, or follow-up (4). The purpose of this pre-planned substudy was to examine the incremental risk of death in patients with IMI. We analyzed the international population of the ENIGMA-II (Nitrous Oxide Anaesthesia and Cardiac Morbidity After Major Surgery: a Randomised Controlled Trial; NCT00430989).
The ENIGMA-II trial randomized 7,112 patients of age 45 years or older, at risk of post-operative cardiovascular events who received nitrous oxide or not during non-cardiac surgery (5). Plasma troponin concentrations and electrocardiograms were obtained at 6 to 12 h and daily during the first 3 post-operative days. MI was adjudicated blindly and independently according to the third Universal Definition (3). Medical records were reviewed and patients were contacted at 1 year. We identified patients with IMI (i.e., patients with an elevated troponin level who did not fulfil the diagnostic criteria for MI) and did not experience a potential nonischemic event that could have caused an elevated troponin (i.e., we excluded patients who had sepsis, pulmonary embolism, renal failure, and respiratory failure) and compared their outcome to patients who experienced no adverse events or IMI. To adjust for any potential differences in pre-operative cardiac or surgical risk, we constructed a propensity score–matched pair cohort using logistic regression, creating a nonparsimonious model estimating the probability of IMI. All patient characteristics, pre-operative laboratory results, medications, and procedural factors associated with IMI were entered into the model. The probability of IMI was matched, in a 1:1 ratio, with patients without IMI. The 1-year mortality in the matched cohort was compared using the McNemar test and plotted using the Kaplan-Meier method.
In the ENIGMA-II trial, troponin was measured in 6,957 (99.2%) patients, and 1,296 (18.6%) patients had troponin elevation. MI occurred in 435 (6.2%) patients within 30 days of surgery. The remaining 861(12.4%) patients with a biomarker elevation had no signs or symptoms of MI and were blindly adjudicated as not having had an MI. The propensity score analysis matched 521 patients with IMI to 521 patients with a similar cardiac risk, but without IMI. The matched cohorts had similar characteristics where the mean standardized difference ranged from −0.05% to 0.09%. The median troponin elevation, for the 521 patients with IMI, was 2.1 times the upper reference limit (25th to 75th centile 1.1 to 7.6). The group of patients with IMI had more deaths at 1 year, 55 (10.6%) versus 24 (4.6%) patients who did not have IMI; p < 0.001. The 1-year mortality analyses for the matched cohort are compared in Figure 1 showing early separation that continues to diverge for the duration of follow-up.
In this study of moderate-to-high-risk cardiac patients, post-operative IMI was both frequent and asymptomatic. This analysis shows that IMI was associated with an almost 2-fold increase in 1-year mortality. The divergent mortality seen in Figure 1 shows that IMI is associated with continuing mortality risk for up to 1 year. These findings highlight the need to establish the etiology and effective therapies for post-operative IMI.
Please note: This work was funded by the Australian National Health and Medical Research Council; Australian and New Zealand College of Anaesthetists; Heart and Stroke Foundation of Quebec, Heart and Stroke Foundation of Ontario, Canada; and General Research Fund of the Research Grant Council, Hong Kong Special Administrative Region, China. Dr. Devereaux has received investigator-initiated grants form Abbott Diagnostics, Boehringer Ingelheim, Philips Healthcare, and Roche Diagnostics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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