Preoperative Troponin in Patients Undergoing Noncardiac Surgery: Is Timing Everything?

In Brief

Published ahead of print May 6, 2016

The 3-protein troponin complex and tropomyosin combine to form the major regulator of actin-myosin interaction in the myocardial contractile apparatus.¹ Each cardiac troponin (cTn) protein serves a distinct yet complimentary role: troponin C, identified by virtue of its calcium-binding ability; troponin I, the primary inhibitor of actin-myosin cycling when coupled with tropomyosin; and troponin T, so named because of its ability to bind the other troponin molecules and tropomyosin. Myocardial ischemia, trauma, infection, or inflammation releases cTn into the systemic circulation in proportion to the magnitude of injury.^2–5 Plasma cTn concentration is most often measured to quantify the severity of myocardial necrosis associated with acute myocardial infarction with a high degree of sensitivity and specificity for both cTnI (77% and 93%, respectively) and cTnT (80% and 90%, respectively) proteins.^6–8 As a result, plasma cTn concentration supplanted earlier serological markers, including aspartate transaminase,⁹ lactate dehydrogenase,¹⁰ and creatine kinase-myocardial band,¹¹ as the “gold standard” biochemical index for acute coronary syndrome in the European Society of Cardiology/American College of Cardiology definition of myocardial infarction.¹² Elevation of cTn concentration above the 99th percentile of the upper reference limit in healthy subjects (<0.01 ng/mL measured using currently available high-sensitivity cTn laboratory assays)¹³ is required to establish the diagnosis of, and to predict the adverse outcome associated with, acute myocardial infarction,^12,14,15 although some controversy remains about whether this cTn upper reference limit value also applies to patients with known risk factors for coronary artery disease.¹⁶

Elevated postoperative cTn concentrations have been shown to be powerful predictors of morbidity and mortality in patients undergoing noncardiac surgery.^17–20 The Vascular Events in Noncardiac Surgery Patients Cohort Evaluation (VISION) trial prospectively measured cTnT concentrations at selected intervals during the first 3 postoperative days in 15,133 patients.¹⁷ The authors reported that 11.6% of the patients had elevated postoperative peak cTnT concentrations (≥0.02 ng/mL) that were highly predictive of increased 30-day mortality. Notably, the risk of death increased dramatically in proportion to the magnitude of cTnT elevation, because patients with peak cTnT concentrations exceeding 0.3 ng/mL had a 4-fold greater 30-day mortality rate versus those with peak cTnT levels of 0.02 ng/mL.¹⁷ A reanalysis of the VISION trial verified the original findings, showing that myocardial necrosis (defined as cTnT ≥0.04 ng/mL in this study) after noncardiac surgery predicted 30-day mortality and postoperative complication rate.¹⁸ The results also indicated that only 15.8% of patients with elevated postoperative cTnT concentrations reported classical symptoms of acute myocardial ischemia. Furthermore, the universal definition of myocardial infarction could not be definitely established in more than half of these patients.¹⁸ These data emphasized that typical clinical and diagnostic criteria for myocardial ischemia and infarction were often inconclusive if not largely absent in this at-risk postoperative population. Beattie et al.¹⁹ independently demonstrated a postoperative cTnI concentration-dependent association with 30-day mortality in their single-center, retrospective cohort analysis of 51,701 inpatients. Most recently, Noordzij et al.²⁰ conducted a prospective observational single-center study of 203 patients at risk for coronary artery disease undergoing major abdominal operations. The authors measured cTnT concentrations before and 1, 3, and 7 days after surgery and demonstrated that a 2-fold or greater increase in peak cTnT concentration above the preoperative baseline strongly predicted postoperative complications, prolonged hospital length of stay, and in-hospital mortality.²⁰

It is within this context that Maile et al.²¹ examined what would initially appear to be an intuitively obvious hypothesis, that is, whether elevated preoperative cTn concentration also predicts postoperative mortality in patients undergoing noncardiac surgery. The authors retrospectively examined the University of Michigan electronic medical record database to identify 7137 patients who underwent preoperative cTn testing before noncardiac surgery because of chest pain, abnormal electrocardiography, or cardiovascular instability. Patients who underwent preoperative myocardial revascularization or percutaneous coronary intervention (i.e., those in whom marked elevations in cTn could be anticipated because of these procedures) before noncardiac surgery were excluded from analysis. The experimental design was composed of a 3 × 3 matrix of 9 separate groups based on terciles of the magnitude of preoperative cTn elevation (≤0.23, >0.23 but <1.02, and ≥1.02 ng/mL, respectively) and the timing of its measurement before surgery (≤3.36, >3.36 but <11.59, and ≥11.59 days, respectively). A reference group of patients with undetectable preoperative cTn (<0.01 ng/mL) served as the study’s control. This approach allowed the authors not only to ascertain the prognostic significance of progressive elevations in preoperative cTn concentration but also to determine whether delays between cTn measurement and subsequent surgery were associated with postoperative mortality. The study’s results provide new insight into the significance of elevated preoperative cTn levels and the timing of their measurement. Not surprisingly, the authors found that an increase in preoperative cTn concentration above the limit of detection was associated with greater postoperative 30-day mortality. These data confirm and extend previous findings, suggesting that preoperative high-sensitivity cTnT concentrations were associated with postoperative myocardial infarction and long-term mortality after noncardiac surgery.²² The current authors further demonstrated a direct relationship between the magnitude of preoperative cTn level and the subsequent postoperative mortality rate (11.4%, 14.6%, and 15.7% for the 3 cTn tercile cohorts versus 6.9% for control patients [indicating that the enrolled subjects represent a relatively high-risk cohort]), similar to the findings of previous investigations correlating with postoperative cTn concentration and mortality after noncardiac surgery.^17–20 As expected, the unadjusted risk of 30-day mortality was highest in patients who had the greatest degree of myocardial injury and the shortest duration between cTn measurement and surgery (odds ratio of 3.080). A longer delay between cTn measurement and subsequent surgery was associated with a decrease in mortality, but such delays were only effective at reducing risk in patients with relatively minor elevations in preoperative cTn levels (the ≤0.23 ng/mL tercile). This latter observation is particularly important because delays before noncardiac surgery in patients with more pronounced elevations in preoperative cTn concentrations did not meaningfully reduce the incidence of postoperative mortality.

The authors’ findings suggest that routine preoperative measurement of cTn in patients undergoing noncardiac surgery, especially those scheduled for higher risk procedures (e.g., major abdominal, thoracic, vascular), may be warranted and that a delay of elective surgery, perhaps in combination with intensive cardiovascular therapy,²³ may be justified when cTn values are elevated. The results are provocative and also raise a number of intriguing questions, many of which will require future prospective studies to answer. Whether patients with elevated preoperative cTn levels should be referred for additional evaluation and treatment before elective surgery is not clear based on the current data. The precise nature and timing of such treatment and its relative impact on the outcomes of patients with elevated preoperative cTn concentrations also remain to be characterized. The current data also do not define the optimal duration of time that elective noncardiac surgery should be postponed when more pronounced elevations in preoperative cTn concentration are identified. The authors²¹ suggest that waiting between 1 and 3 months for cTn concentration to return to normal may be sufficient, but unfortunately, their study was not designed to confirm or refute this hypothesis. It is also unclear how the perioperative management of patients with preoperative cTn elevation requiring urgent or emergent noncardiac operations should be tailored to minimize postoperative risk of major adverse cardiac events. The most recent American College of Cardiology/American Heart Association guidelines on preoperative evaluation and management of patients undergoing noncardiac surgery²⁴ suggest that such treatment should most likely follow current recommendations for the management of patients with stable ischemic heart disease,^23,25 but the guidelines do not specifically address patients with elevated preoperative cTn concentration. Thus, as is the hallmark of any high-quality study, this investigation raises more questions than it answers, motivating us to perform more prospective research for the benefit of our patients.

DISCLOSURES

Name: Harish Ramakrishna, MD, FASE, FACC.

Contribution: This author helped draft and revise the manuscript.

Attestation: Harish Ramakrishna approved the final manuscript.

Name: Paul S. Pagel, MD, PhD.

Contribution: This author helped draft and revise the manuscript.

Attestation: Paul S. Pagel approved the final manuscript.

This manuscript was handled by: Sorin J. Brull, MD.