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Pro-Con Debate: Cardiac Troponin Measurement as Part of Routine Follow-up of Myocardial Damage Following Noncardiac Surgery

Buse, Giovanna Lurati MD*; Matot, Idit MD

Author Information
doi: 10.1213/ANE.0000000000005714

Abstract

See Article, p 253

PRO: PERIOPERATIVE TROPONIN SCREENING AFTER NONCARDIAC SURGERY IN HIGH-RISK PATIENTS

The yearly burden of perioperative mortality, that is, death within 30 days after surgery, is estimated at 4 million worldwide.1 As such, perioperative mortality is the third cause of death after ischemic heart disease and stroke.1 An international cohort including more than 40,000 patients reported that among the 8 postoperative complications independently associated with 30 days of mortality, major bleeding (attributable fraction 17%), sepsis (attributable fraction 12%), and myocardial injury (attributable fraction 16%) predominated.2 (The attributable fraction is a measure that combines incidence and strength of the association to estimate the contribution of risk factors, in this case postoperative complications, to a specific event, in this case mortality.)

The fourth universal definition of myocardial infarction defines “myocardial injury” as troponin concentrations exceeding the 99th percentile. In contrast to myocardial infarction, this newly recognized entity does not require any additional electrocardiogram (ECG) changes or symptoms.3 In the perioperative setting, a large body of evidence demonstrated the prognostic impact of myocardial injury after noncardiac surgery (MINS): postoperative elevated troponins, independent of the presence of symptoms, were consistently independently associated with 30-day and 1-year mortality.4–12 Of notice, in spite of its relevant contribution to postoperative mortality,2 the vast majority of myocardial injuries are clinically silent and remain undetected without systematic troponin measurements. Consequently, perioperative troponin monitoring or surveillance has been endorsed by relevant professional societies13,14 not only to trigger further investigation to detect type 1 and type 2 myocardial infarction and for the initiation adequate therapy, but also for the detection of isolated myocardial injury. The Canadian guidelines13 appraised the evidence as “moderate” and strongly recommended systematic troponin monitoring in patients at elevated risk (>5%) for cardiovascular events. The task force responsible for the 2018 preoperative guidelines by the European Society of Anaesthesiology (ESA) also appraised the evidence as “moderate,” but issued only a weak recommendation (grade 2B) with regard to systematic perioperative troponin measurement in patients at high cardiovascular risk.14 Similarly, in the section on myocardial injury associated with noncardiac procedures, the fourth universal definition of myocardial infarction3 stated that “postoperative cTn [cardiac troponin] surveillance is recommended for high-risk individuals.”

If we are confronted with a clinically silent, potentially fatal, acute cardiac event (myocardial injury), and we have noninvasive, comparatively inexpensive tools to detect it early (troponin measurement), and if professional societies endorse myocardial injury screening, why publish a pro-con discussion?

Opponents of systematic postoperative troponin measurements to detect myocardial injury invoke the following arguments against it: first, they question the validity of postoperative troponin elevations to detect relevant myocardial ischemia, on one side due to the high prevalence of chronically elevated troponin concentrations in noncardiac surgery patients (argument: “postoperative troponin surveillance does not detect acute events but chronic troponinemia”) and on the other side, due to the unspecificity in terms of causes (argument: “sepsis and pulmonary embolism also result in elevated troponin concentrations”); second, they point to the limited randomized evidence on how to manage patients in whom myocardial injury is detected.15

I will now provide my answer to those arguments. Indeed, postoperative troponin concentrations were reported to exceed the 99th percentile in up to 64% of noncardiac surgery patients at elevated risk (cardiovascular history or aged ≥65 years undergoing in-hospital noncardiac surgery);12 and as such, the applicability of the 99th percentile in this setting appears limited; however, there are 2 approaches to solve this issue: (1) for some of the commercial troponin assays, setting-specific prognostic cut-offs derived from large samples were published;10 (2) baseline preoperative concentrations will overcome the difficulties of the interpretation of elevated postoperative concentrations that exist without knowledge of potential chronic troponin elevations. Indeed, according to the fourth universal definition, dynamic changes are required for the diagnosis of acute myocardial injury, namely in the order of 20% if the initial value exceeded the 99th percentile and of 50% to 60% if baseline concentrations were not elevated.3 Therefore, the argument of chronic troponinemia versus acute events can be rebutted by simply measuring preoperative concentrations. The importance of measuring baseline (preoperative concentrations) has been highlighted in the 2018 ESA preoperative guidelines14 and in the fourth universal definition of myocardial infarction.3 Of notice, several studies reported a high prevalence (up to more than 50%) of preoperative (high-sensitivity) troponin exceeding the 99th percentile in patients planned for noncardiac surgery.10,12,16 There is evidence suggesting the usefulness of preoperative troponin as a marker for increased perioperative cardiovascular risk;16–20 however, in asymptomatic patients, increased preoperative troponin concentrations will not point, in most cases, to acute events, but will indicate chronic myocardial injury, for example, secondary to heart failure and chronic kidney disease.3 Therefore, in our opinion (that we have been implementing in our clinical practice with a perioperative screening since 2014), surgery cancellation is not warranted in asymptomatic patients based on isolated troponin concentrations.

The fact that causes other than acute myocardial ischemia may result in troponin elevation after noncardiac surgery does not discredit troponin surveillance in my opinion: it will help early flagging of patients with poor outcome from nonischemic conditions that may clinically manifest only at a later point. Indeed, nonischemic postoperative complications triggering troponin release were associated with 26% 1-year mortality (adjusted hazard ratio [HR] 4.40 [95% confidence interval {CI}, 2.97–6.54]) in a cohort of nearly 7000 noncardiac surgery patients.21

To date, only 1 randomized controlled trial (MANAGE [Dabigatran in Patients With Myocardial Injury After Noncardiac Surgery]) evaluated a pharmacological treatment for MINS. Dabigatran (110 mg twice daily over 16 months) resulted in a reduction (HR 0.72 [95% CI, 0.55–0.93]) of a composite of vascular death and arterial and venous thrombotic events.22 The incidence of major bleeding appeared not to be increased.22 However, dabigatran is rarely initiated for MINS. Indeed, the evidence generated in this trial was questioned due to the inclusion of venous thromboembolism in the composite end point, the redefinition of the main end point after the study had started, and the important number of patients that opted to stop taking the medication.23,24 Finally, albeit the benefit of aspirin and statins is not evaluated in the setting of specific randomized trials, the fact that secondary prevention medication occurred in only approximately 60% of patients enrolled into MANAGE was a source of criticism.23,24 Therefore, opponents of postoperative troponin surveillance, even after the publication of the MANAGE trial, keep pointing to the lack of pharmacological treatment for perioperative myocardial injury established in randomized trials to justify their opposition to systematic troponin measurements.

Advocates of troponin monitoring support consideration of additional beneficial responses to detected myocardial injury: first, it might make apparent the relevance in terms of oxygen demand and supply25–29 of even modest and therefore otherwise potentially disregarded perioperative hypotension,30–32 anemia, or tachyarrhythmia. Second, due to the high prevalence of coronary artery disease of varying extent in myocardial injury patients,25–29 recognizing them as such using troponin surveillance will offer the opportunity to initiate secondary prevention, or in case of known cardiac disease and preexisting medication, detection of myocardial injury can result in optimization of medication and encourage patients to medication adherence. Based on observational data suggesting mortality reduction in myocardial injury patients who were administered aspirin and statin,33,34 the Canadian guidelines13 strongly suggest this approach. Finally, plaque rupture (type 1) infarctions, while much less common than myocardial injury,26,27,35 may also remain undetected without troponin surveillance. Early guideline-adherent management, however, is crucial for these events.36 In summary, while the pharmacological treatment of ischemic myocardial injury might not be established, troponin surveillance in patients at elevated cardiovascular risk is actionable and promises outcome benefit. Are recognition of oxygen demand/supply mismatch, introduction of secondary prevention, early flagging of patients at risk from myocardial injury of nonischemic origin, and avoidance of missing type 1 infarction not enough benefit to justify troponin surveillance? In such a case, allow me to refer to Edmund Burke (1729–1797), who wrote: “Nobody made a greater mistake than he who did nothing because he could do only a little.”

CON: THERE IS NO CLINICAL BENEFIT FROM ROUTINE FOLLOW-UP OF TROPONIN LEVELS AFTER NONCARDIAC SURGERY

In the general population, a high percentage of at-risk individuals, such as those with left ventricular hypertrophy, left ventricular dysfunction, or renal disease, have increased plasma concentrations of cardiac troponin.37–39 In these individuals, cardiac troponin is independently associated with all-cause mortality.37–40 Elevated cardiac troponin levels after noncardiac surgery are also associated with both early and late overall morbidity and mortality.4,5,10,41 Implementation of routine cardiac troponin monitoring practice is thus useful for risk stratification in these populations. To date, the potential of routine troponin monitoring to improve patients’ outcome has not been shown in the perioperative setting.

Over the past decades, there has been an exponential increase in the number of publications assessing the ability of various biomarkers to predict patient outcome and to improve risk assessment. Although many of these papers claim that routine utilization of molecular biomarkers is clinically useful, embarrassingly few are currently in clinical use. Several biomarkers have been shown to assist in risk stratification, follow-up, and prognostication. Nevertheless, perioperative biomarker-based interventions aimed at reducing mortality are at best not beneficial, usually costly and time consuming, and at worse harmful, as noted in the next section. If one searches for a (bio)marker that predicts perioperative adverse outcome in asymptomatic/symptomatic patients, one may choose to follow the case of preoperative hemoglobin levels. A significant association of anemia with increased perioperative morbidity/mortality has been confirmed in both cardiac and noncardiac surgery.42–43 Moreover, 30-day mortality and cardiac event rates significantly increase as anemia worsens.44 This case carries such a resemblance to the “Troponin saga.” These reports of association between anemia and postoperative adverse outcomes raised the question whether management of preoperative anemia will decrease postoperative mortality. Current evidence suggests that preoperative treatment of anemia has no effect on mortality nor on length of hospital stay.45,46 Moreover, an early systematic review reported that transfusion administration to increase hemoglobin in critically ill patients caused harm.47

While perioperative troponin elevations have been attributed to myocardial injury/infarction, numerous other noncoronary etiologies should be considered. Cardiac arrhythmias, infections, sepsis, pulmonary embolism, renal dysfunction, stroke, subarachnoid hemorrhage, chronic pulmonary diseases, and others may play a role in a considerable number of patients.48 Additionally, recent evidence suggests that there is a need to adjust to preexisting (preoperative) troponin values as many high-risk patients show elevated baseline levels.10,39 Specifically, patients with asymptomatic/stable ischemic heart disease, structural heart disease (eg, left ventricular hypertrophy), heart failure, chronic injury from small vessel ischemia, hypertension, metabolic abnormalities (eg, diabetes and thyroid abnormalities), and inflammatory or infectious processes might have chronically elevated plasma troponin concentrations, with associated poorer outcome, with and without a scheduled operation.

Preoperative cardiovascular testing is reasonable if results would change the clinical management. However, the approach to a patient with elevated troponin levels may widely vary. In a study involving 37 patients with type 2 diabetes and stable ischemic heart disease, an abnormal baseline cardiac troponin concentration was a powerful prognostic marker for cardiac and noncardiac morbidity and mortality. Importantly, median troponin concentration increased over 1-year follow-up despite aggressive medical therapy. Prompt revascularization in this population did not reduce troponin levels nor appeared to alter the risk of adverse outcomes. In contrast, in a different setup of acute coronary syndrome, an early invasive strategy improved outcomes only among patients with elevated troponin concentrations.49 Taken together, this illustration indicates that factors leading to elevated troponin levels in high-risk patients who do not show additional signs of an acute injury could result from a variety of causes that may be less responsive to traditional therapy than the ischemic injury that leads to troponin release in patients with acute coronary syndromes.

Several remarkable studies highlight the dangers in assuming that logical treatment would result in better outcome. In reality, the prescribed treatment induced substantial harm. Perioperative interventions that would be expected to benefit patients at risk of perioperative cardiac events were studied in randomized controlled trials. With metoprolol administration,50 fewer patients suffered perioperative myocardial infarction compared to placebo but had more strokes and increased overall mortality. Perioperative use of aspirin51 had no significant effect on the rate of a composite of death or nonfatal myocardial infarction but increased the risk of major bleeding. Administration of low-dose clonidine52 did not reduce the rate of the composite outcome of death or nonfatal myocardial infarction; it did, however, increase the risk of clinically important hypotension and nonfatal cardiac arrest. And last but not least, despite reasonable rationale, preoperative revascularization before surgery is not performed without specific indications independent of the planned surgery.53–55 This recommendation is based on the results from the Coronary Artery Revascularization Prophylaxis (CARP) trial, which showed that coronary artery revascularization before elective vascular surgery does not significantly alter the long-term outcome.53,54 Yet, it is important to note that the revascularization group in the CARP trial included both patients who underwent surgical (n = 99) and percutaneous (n = 141) interventions.

Moreover, I wish to raise the possibility that widespread routine perioperative troponin monitoring could lead to an increase in the use of additional resources—anesthesia and cardiology consultations, tests, procedures, and drugs that do not appear to offer benefit with respect to outcomes. In a recent study,56 a dedicated anesthesia team conducted follow-up on patients with postoperative troponin elevation. In these patients, increasing rates of both cardiovascular (including pulmonary embolism) and noncardiac complications (sepsis, respiratory failure, renal failure, and anemia) were noted. Additional tests were ordered in 75% of patients, and in about two-thirds, a cardiologist was consulted. Despite all these efforts, a clear cause of troponin elevation could not be identified, and there was no change in medication in the majority of patients. An observational study9 in a university medical center that implemented routine troponin monitoring after major noncardiac surgery reported that of 4050 patients, 20% did not have any postoperative troponin measurement. Of the remaining 3224 patients, 500 (15.5%) died at 1 year, with only 19 (0.6%) of cardiac cause (in accordance with the incidence of cardiac death in the PeriOperative ISchemic Evaluation-2 [POISE-2] trial, 0.7%). Troponin elevation was detected in 715 patients (22%) and was associated with 1-year all-cause mortality but not cardiac mortality. No significant differences were noted in cardiac mortality between patients with and without postoperative troponin elevation. Of note, sepsis/infection, cerebrovascular/brain injury, and pulmonary etiologies were the primary causes of death and were significantly more prevalent among patients with elevated troponin, whereas malignancy was more prevalent in the patients with no elevation in troponin levels. Regarding resource utilization, cardiac consultation was obtained in about 40% of patients. Only a small number of interventions were ordered, and the authors suggested that this was due to a low suspicion of a cardiac etiology in most patients and lack of consensus for standardized treatment. Another observational, single-center cohort study6 included 2216 consecutive intermediate- to high-risk noncardiac surgery patients aged ≥60 years. Postoperative troponin assays were performed in 1627 (73%) patients, while in the rest (589 patients), troponin was not measured. A total of 315 (19%) patients had increased troponin levels at least once. Troponin elevation was an independent predictor of all-cause 30-day mortality. The specific cause of death was not reported. A cardiologist was consulted in one-third of patients with elevated troponin, and in more than 50%, the clinical course was awaited without any intervention. Importantly, death occurred in 56 of the 1627 patients (3.4%; 95% CI, 2.7–4.4) in whom troponin was measured and interventions were taken according to recommendations compared with 20 of the 589 patients (3.4%; 95% CI, 2.2–5.2) in whom troponin was not measured (P = .96), indicating that regardless of troponin screening, mortality was not different between those screened versus not screened. Of note, patients in the latter group more often underwent emergency surgery and reoperation with, but less often high-risk surgery.

Only a few exceedingly small studies addressed treatment strategies. In a retrospective, single-center, case-controlled study of 66 high-risk patients undergoing very high-risk vascular surgery (mostly open abdominal aortic aneurism), intensified medical therapy was reported to improve 12-month mortality.34 The authors of the article acknowledged that the expert committee had several disagreements, and there were possible allocation errors that could affect the results. The authors therefore present in the paper simulations to evaluate the impact of allocation errors. This finding, however, was not reproduced in a randomized controlled trial of 70 patients with elevated troponin after emergency orthopedic surgery, in which cardiology care did not improve mortality after 1 year when compared to the group that did not receive intensified treatment.57

In a 4.5-year study involving 84 hospitals worldwide, 1754 patients (in accordance with the Canadian Cardiovascular Society Perioperative Guidelines) undergoing noncardiac surgery were randomized to receive dabigatran or placebo if diagnosed with MINS (defined as at least 1 elevated postoperative troponin measurement without an alternative explanation during the initial 35 postoperative days).22 The aim was to assess the long-term (>1 year) effect on a composite outcome (vascular mortality, nonfatal myocardial infarction, nonhemorrhagic stroke, peripheral arterial thrombosis, amputation, and symptomatic venous thromboembolism) in patients with MINS. The study drug was permanently discontinued in nearly half of the patients (46% and 43% of patients allocated to the dabigatran and placebo groups, respectively) at a median time of less than 3 months in both groups. Various troponin assays were used across centers. Preoperative measurements of troponin were not done, and it is thus unclear whether the abnormal troponin levels detected after surgery were already present preoperatively in this high-risk group. Because of slow recruitment, the authors reduced sample size by 1450 and added amputation and symptomatic proximal deep vein thrombosis to the composite outcome to enhance power. The findings indicated that in this population with elevated troponin values considered to have MINS, dabigatran administration improved the composite outcome during the >1-year follow-up. However, all-cause/vascular mortality as well myocardial infarction/cardiac revascularization procedures were not different between groups. Noteworthy, the study was not powered to assess these secondary outcomes. It is important also to mention that the study did not include a group of patients in whom troponin was not measured altogether or measured and did not increase. These patients could have benefitted from the therapy as well.

The medical community did not adopt the guidelines by the Canadian Cardiovascular Society Committee and key Canadian opinion leaders that order 48 to 72 hours of postoperative cardiac troponin surveillance in high-risk individuals.13 In a recent 2021 Canadian edition of the Guidelines to the Practice of Anesthesia by the Canadian Anesthesiologists’ Society, there is no reference to pre/postoperative troponin testing altogether, although these guidelines did not address patients with cardiovascular disease or any other group at risk presenting for surgery as well.58 The European Society of Cardiology/ESA guidelines59 recommend to consider postoperative troponin monitoring in high-risk patients to improve risk stratification (class IIb, level B [IIb: usefulness/efficacy is less well established by evidence/opinion; B: data derived from a single randomized clinical trial or large nonrandomized studies]). Similarly, the American College of Cardiology/American Heart Association (ACC/AHA)60 points out that troponin levels are only indicated in the setting of signs or symptoms suggestive of myocardial ischemia/infarct (level of evidence: A) while in patients at high risk without symptoms, the usefulness of postoperative screening with either ECG or troponin measurements is uncertain (level of evidence B for both). The authors conclude that routine screening with troponin provides a nonspecific assessment of risk, does not indicate a specific course of therapy, and is not clinically useful unless signs or symptoms of myocardial ischemia or infarct exist. Of note, both European and American guidelines were published before the second part of the VISION trial was published.10 Nevertheless, almost 5 years thereafter, there are still no updated guidelines that recommend routine pre/postoperative troponin measurements. In July 2020, a review in JAMA61 on cardiovascular risk assessment and management for noncardiac surgery noted that “the value of postoperative cardiac troponin surveillance in asymptomatic patients at risk for ischemic complications is uncertain because no studies have evaluated the benefits of a testing strategy.” With these recommendations (or lack of recommendations) on board, it is not surprising that the guidelines by the Canadian Cardiovascular Society are not widely implemented, even in Canada.62 The use of biomarkers to assist in cardiac risk stratification and postoperative monitoring remains scarce.

In summary, no doubt that troponin elevation represents increased patient risk. The hypothesis is that early detection of troponin elevation of myocardial origin would improve outcome. That has not been the case. Troponin is not specific for myocardial ischemia or infarction, but it is the result of a broad and multifactorial dysfunction that might occur during the complex and unique perioperative period (Figure).63–65 Its elevation might merely signify worse outcome and not causation. Further research into postoperative patients with elevated troponin levels should look beyond the narrow scope of ischemia/cardiologist consultation. In a recent study,66 elevated high-sensitivity C-reactive protein concentration at discharge in patients with elevated troponin levels after surgery was associated with increased 1-year and 30-day mortalities, suggesting an inflammatory origin for the increased all-cause mortality.

Figure.
Figure.:
Interpretation of troponin elevation in the perioperative period. Patients may present to surgery with elevated or nonelevated troponin. During surgery, multifactorial processes might cause an increase in troponin. AF indicates atrial fibrillation; AKI, acute kidney injury; CHF, congestive heart failure; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; cTn, cardiac troponin; DM, diabetes mellitus; GI, gastrointestinal; HF, heart failure; IHD, ischemic heart disease; LVH, left ventricular hypertrophy; MI, myocardial infarction; PE, pulmonary embolism; SIRS, systemic inflammatory response syndrome; TIA, transient ischemic attack.

In 2012, the estimated yearly global volume of surgery was 313 million.67 More than half are performed in patients >60 years. This number has and will increase with aging of the population and growth in surgical volume. Accordingly, about 15% to 20% of future patients might presumably experience postoperative myocardial injury, as indicated by an elevated troponin level. Consequently, millions of surgical patients will need pre- and postoperative troponin follow-up annually. The magnitude of resources spent for this will be enormous, including increased workload for medical personnel, additional noninvasive/invasive diagnostic workup, procedures, and requirement for highly monitored units—all of which for a cause yet to be justified. Thus, until better understanding of the pathogenesis is achieved and high-quality clinical evidence demonstrates true beneficial value of interventions that affect outcomes of patients with postoperative “troponitis,” the clinical routine to follow troponin levels preoperatively and postoperatively is at most, time- and cost-consuming, and at worst, might cause harm.

DISCLOSURES

Name: Giovanna Lurati Buse, MD.

Contribution: This author helped write the Pro section.

G. L. Buse: participated in an advisory board on perioperative myocardial injury hosted by Roche Diagnostics.

Name: Idit Matot, MD.

Contribution: This author helped write the Con section.

This manuscript was handled by: Stefan G. De Hert, MD.

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