Physicians Should Obtain Perioperative Cardiac Troponin Measurements in At-Risk Patients Undergoing Noncardiac Surgery

Surgery is common; the average American will undergo 7 operations during their lifetime (1). Although surgery has the potential to improve and prolong the quality and duration of life, postoperative death is the third leading cause of death worldwide (2). Approximately half of perioperative deaths are vascular, and myocardial ischemic injuries are the most common cause of perioperative vascular deaths (3). Most perioperative myocardial ischemic injuries are clinically asymptomatic, and without troponin monitoring after noncardiac surgery, these prognostically important complications will go unrecognized (4). Here, we review and comment on the evidence for monitoring perioperative troponin measurements in at-risk patients undergoing noncardiac surgery.

Perioperative Myocardial Infarction

In a 1938 publication, Master and colleagues reported a case series of patients who had perioperative myocardial infarctions (MI), and 60% of the patients did not experience ischemic pain (5). The authors stated the lack of ischemic symptoms, “may be accounted for, in part, by the liberal use of narcotics and sedatives after operation” (5). This study, from over 80 years ago, identified the challenge in diagnosing perioperative MI (i.e., most events are asymptomatic).

Asymptomatic perioperative MI portends a poor prognosis similar to patients who suffer a symptomatic perioperative MI. The POISE-1 Trial included 8351 patients who underwent noncardiac surgery in 190 centers in 23 countries. Participants had systematic monitoring of perioperative troponin measurements; 415 patients had a perioperative MI, and 65% of these patients did not experience an ischemic symptom (6). The 30-day mortality rate was 2.2% among the patients who did not have a perioperative MI, 9.7% among patients who had a symptomatic perioperative MI (adjusted odds ratio [aOR], 4.76; 95% confidence interval [CI] 2.68–8.43), and 12.5% among patients who had an asymptomatic perioperative MI (aOR, 4.00; 95% CI, 2.65–6.06) (6). Moreover, asymptomatic perioperative MI was associated with an increased risk of nonfatal cardiac arrest (OR, 12.87; 95% CI, 6.29–26.33) and congestive heart failure (OR, 8.33; 95% CI, 5.80–11.96).

Although randomized controlled trials of acute MI have not included perioperative patients, observational data suggest some therapies are likely beneficial in these patients. A multivariable logistic regression analysis demonstrated a lower risk of death at 30 days among the POISE-1 patients who had a perioperative MI and received aspirin (adjusted hazard ratio [aHR] 0.54; 95% CI, 0.24–0.99) and a statin (aHR, 0.26; 95% CI, 0.13–0.54) (6).

Studies suggest the majority of perioperative MIs are due to supply-demand mismatch (i.e., type 2 MI) and a minority are due to acute thrombosis (i.e., type 1 MI) (7). There is, however, a strong rationale to believe that patients who suffer a perioperative MI will benefit from long-term secondary prophylactic measures (e.g., aspirin, statin, angiotensin-converting enzyme inhibitor), which have been shown to be beneficial in large randomized controlled trials in patients with coronary artery disease. This rationale is based on knowledge that the vast majority of patients who have a perioperative MI have coronary artery disease.

The coronary tomography angiography (CTA) VISION Study was a prospective cohort study of 955 patients from 12 centers in 8 countries who had CTA before noncardiac surgery (8). Among the 71 patients (7%) who had a perioperative MI, the preoperative CTA demonstrated 72% of these patients had obstructive or extensive obstructive coronary artery disease, 24% had at least one coronary artery plaque with a < 50% stenosis, and only 4% of patients had normal coronary arteries.

Without perioperative troponin monitoring, the majority of perioperative MIs will go unrecognized, and this will impede physicians from administering acute and long-term interventions to improve prognosis. Physicians who choose to ignore symptomatic or asymptomatic perioperative MI do so at the peril of their patients.

There Are Reasons to Measure Perioperative Troponin beyond Perioperative MI

Many studies have demonstrated that a substantial proportion of patients undergoing noncardiac surgery sustain prognostically important ischemic myocardial injury that will not fulfill the universal definition of MI (4, 9). Myocardial injury after noncardiac surgery (MINS) includes MI and ischemic myocardial injury that does not satisfy the definition of MI (4). The diagnostic criteria for MINS include: an increased postoperative troponin measurement judged as resulting from myocardial ischemia (i.e., no evidence of a nonischemic etiology), during or within 30 days after noncardiac surgery, and without the requirement of an ischemic feature (e.g., ischemic symptom, ischemic electrocardiography finding) (9).

The VISION Study included a representative sample of 21 842 participants from 23 centers in 13 countries who were ≥45 years of age, underwent in-patient noncardiac surgery, and had high-sensitivity troponin T (hsTnT) measurements after surgery. Experts in perioperative ischemia adjudicated the etiology of elevated hsTnT measurements, and any patients with a non-ischemic etiology (e.g., rapid atrial fibrillation, sepsis, pulmonary embolism, chronic hsTnT increase) were excluded from the MINS analyses. Regression analyses demonstrated perioperative MI (846 patients [4%]; adjusted HR, 5.04; 95% CI, 3.56–7.12) and MINS that did not fulfill the universal definition of MI (3058 patients [14%]; adjusted HR, 3.20; 95%, CI, 2.37–4.32) were independently associated with 30-day mortality (9).

MINS is also associated with long-term mortality and major vascular complications. A prospective cohort study of 2018 consecutive adults who underwent noncardiac surgery and had perioperative hsTnT measurements demonstrated that MINS was independently associated with 1-year mortality (adjusted HR, 1.48; 95% CI, 1.07–2.06) (10). Table 1 demonstrates that patients with MINS are at substantial risk of major vascular complications at a mean of 16 months of follow-up (11).

The MANAGE Trial demonstrates that the poor prognosis of MINS is modifiable. MANAGE randomized 1754 patients, at 84 centers in 19 countries, who had MINS to dabigatran 110 mg twice daily (n = 877) or placebo (n = 877). Patients randomized to dabigatran had a lower risk of a major vascular complication at a mean of 16 months of follow-up compared to patients randomized to placebo (97 patients [11%] versus 133 patients [15%], respectively; HR, 0.72; 95% CI, 0.55–0.93) (11). The Kaplan-Meier curves for dabigatran and placebo separated immediately, continued to separate until about a year, and then remained parallel, suggesting that patients derived both acute and long-term benefit from dabigatran (11). Dabigatran reduced the risk of the arterial components (i.e., MI, nonhemorrhagic stroke, peripheral arterial thrombosis, amputation, and vascular death) of the primary composite outcome (HR, 0.73; 95% CI, 0.55–0.96). Patients randomized to dabigatran had an increased risk of minor bleeding but not an increased risk of a composite of life-threatening, major, or critical organ bleeding compared to placebo.

A substantial proportion (14%) of adults after noncardiac surgery will have an ischemic myocardial injury that is prognostically important but does not fulfill the universal definition of MI (9). These events will go undetected without systematic perioperative troponin monitoring, and MANAGE provides evidence of an effective treatment to improve their prognosis.

Which Patients Should Have Perioperative Troponin Monitoring

Several factors should inform which patients should undergo perioperative troponin monitoring including the cost-consequence and the practicality of implementation. A VISION cost-consequence analysis, based on screening troponin measurements daily for the first 3 days after surgery, demonstrated an incremental cost of $1309 (Canadian) to avoid missing a MINS event in patients ≥65 years of age or with a history of atherosclerotic disease (12). Given that it is practical to identify this patient population for perioperative troponin monitoring and the cost consequence to avoid missing a MINS is 10-fold cheaper than the cost to avoid missing a breast cancer (i.e., a condition for which the cost of screening is considered acceptable) (13), supports screening patients ≥65 years of age or with a history of atherosclerotic disease who are undergoing in-patient noncardiac surgery. In the US context, an economic analysis demonstrated that postoperative troponin monitoring after abdominal aortic aneurysm repair was cost-effective (US $12 641 per quality-adjusted life year) (14).

Interpretation and Management of a Perioperative Troponin Elevation

To facilitate interpretation of a postoperative troponin measurement, a preoperative troponin measurement should be considered. Large prospective cohort studies that have systematically obtained troponin measurements after noncardiac surgery have established the following perioperative troponin thresholds for MINS: 1. a non-high-sensitivity troponin T ≥ 30 ng/L; (4, 15) and 2. a hsTnT of 20 to <65 ng/L with an absolute change of at least 5 ng/L or an hsTnT level ≥65 ng/L (9). Until research establishes MINS troponin I thresholds, physicians should define an increase as any value above the 99th percentile upper reference limit for each specific troponin I assay.

Physicians should assess patients with an increased perioperative troponin measurement for ischemic symptoms, nonischemic etiologies, and obtain an electrocardiogram. If physicians identify a nonischemic etiology (e.g., sepsis), they should manage as per the underlying etiology. If physicians believe the troponin increase represents MINS, they should consider secondary prophylactic measures (i.e., aspirin, statin, angiotensin-converting enzyme inhibitor, dabigatran) and organize outpatient follow-up. Physicians should consider obtaining an echocardiogram and noninvasive stress testing, usually in the outpatient setting.

Conclusions

The majority of patients who undergo noncardiac surgery and have MINS will not experience ischemic symptoms. Physicians should not be lulled into a false sense of security because these events are asymptomatic. Asymptomatic MINS carries a poor prognosis. Cost-consequence analyses and practicality support monitoring troponin measurements in patients undergoing noncardiac surgery who are ≥65 years of age or have a history of atherosclerotic disease. Patients suffering MINS deserve follow-up and secondary prophylactic interventions.

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 4 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved.

Authors' Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest:

P.J. Devereaux is a member of a research group with a policy of not accepting honorariums or other payments from industry for our own personal financial gain. They do accept honorariums/payments from industry to support research endeavours and costs to participate in meetings.

Employment or Leadership: P.J. Devereaux, the McMaster University/Hamilton Health Sciences Chair in Perioperative Care and a Tier 1 Canada Research Chair in Perioperative Medicine. F.K. Borges holds a McMaster University Department of Medicine Career Research Award.

Consultant or Advisory Role: P.J. Devereaux, participation in an advisory board meeting for GlaxoSmithKline and an expert panel meeting with AstraZeneca, Boehringer Ingelheim, and Roche.

Stock Ownership: None declared.

Honoraria: None declared.

Research Funding: Based on study questions P.J. Devereaux originated and grants he has written, he has received grants from Abbott Diagnostics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers-Squibb, Coviden, Octapharma, Philips Healthcare, Roche Diagnostics, Siemens, and Stryker.

Expert Testimony: None declared.

Patents: None declared.

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