Biccard, Bruce M.
The most sensitive marker of myocardial injury is a ‘cardiac selective’ troponin leak , and hence troponins form the cornerstone of the diagnosis of a myocardial infarction (MI) . The current American Heart Association/American College of Cardiology (AHA/ACC) guidelines for the perioperative cardiovascular evaluation and care of the cardiac patient for noncardiac surgery recommend postoperative troponin surveillance in patients with electrocardiogram (ECG) changes suggestive of myocardial ischemia or typical ischemic chest pain (Class I indication, Level of Evidence: C), and give a weak recommendation (Class IIb indication, Level of Evidence: C) for troponin surveillance in clinically stable patients who have undergone vascular or intermediate-risk surgery . These guidelines, therefore, suggest that the utility of postoperative troponin surveillance is only established in patients who have clinical symptoms of myocardial ischemia. Recent evidence from studies published following the release of the AHA/ACC guidelines suggest that the recommendations for perioperative troponin surveillance need to be updated. Specifically, this research suggests that troponin surveillance should be considered the gold standard for detection of perioperative myocardial ischemia and may be appropriate for a broad spectrum of noncardiac surgical patients.
A POSTOPERATIVE TROPONIN LEAK IS A LEADING CAUSE OF PERIOPERATIVE MORTALITY
Cardiac troponins are highly specific for myocardial injury, with only 4–6% of the troponin leaks being associated with nonspecific cytosolic leaks . Recent studies suggest that perioperative cardiac troponin release is common and strongly associated with mortality. In the Vascular events In noncardiac Surgery patIents cOhort evaluatioN (VISION) Study [4▪], 11.6% of unselected patients 45 years or older undergoing noncardiac surgery who required a postoperative night in-hospital were troponin positive, and 1.9% [95% confidence interval (CI) 1.7–2.1%] of these patients died within 30 days of surgery. Postoperative troponin T (TnT; Roche fourth-generation Elecsys assay) elevation above the upper reference limit (99th percentile) was the strongest independent predictor of 30-day mortality with a population-attributable risk of over 40% [4▪].
THE LIMITATIONS OF THE CURRENT RECOMMENDATIONS FOR DETECTION OF MYOCARDIAL ISCHEMIA
It would be reasonable to follow the current AHA/ACC guidelines for postoperative troponin surveillance, that is, perform selective troponin screening, if we could either reliably predict or identify the patients who would leak troponins perioperatively. Unfortunately, the current literature suggests that we cannot reliably achieve either of these objectives, and thus the ACC/AHA guidelines for selective troponin surveillance are flawed.
PREOPERATIVE PREDICTION AND POSTOPERATIVE IDENTIFICATION OF A PERIOPERATIVE TROPONIN LEAK
The current tool used for risk stratification in the AHA/ACC algorithm is Lee's Revised Cardiac Risk Index (RCRI) . Unfortunately, this risk stratification tool can only reliably exclude low-risk patients, that is, identify patients who are unlikely to have cardiovascular complications. It cannot reliably identify which patients are likely to have perioperative cardiovascular complications .
In the postoperative period, it is difficult to identify patients with a myocardial injury, as the majority of patients who leak troponins are asymptomatic. Only 14% (95% CI 3–28%) of surgical patients present with chest pain , and 65.3% of perioperative patients are entirely asymptomatic for MI .
RECENT NONCARDIAC SURGERY COHORT STUDIES OF PERIOPERATIVE TROPONIN LEAKS
The presentation of perioperative patients who have suffered a troponin leak from the recently published cohorts are shown in Table 1[4▪,9▪,10▪,11–15]. These studies confirm that in excess of 80% of patients who leak troponins perioperatively are clinically asymptomatic for myocardial ischemia, ischemic ECG changes are not universally present in patients who leak troponins, and a cardiac troponin leak above the upper reference limit of the assay is independently associated with postoperative short-term and long-term mortality.
These studies are consistent with the previous meta-analyses. In vascular patients, a postoperative troponin leak, without defining features of myocardial ischemia, was associated with an increased risk of 30-day mortality (odds ratio [OR] 5.03, 95% CI 2.88–8.79) . In noncardiac surgical patients, an elevated troponin independently predicted mortality (OR 3.4, 95% CI 2.2–5.2). The risk was greatest within the first year following surgery (OR 6.7, 95% CI 4.1–10.9) compared with beyond a year after surgery (OR 1.8, 95% CI 1.4–2.3) . In summary, an isolated perioperative cardiac troponin leak is associated with short-term [4▪,10▪,12,16] and long-term [11,17] postoperative mortality.
There is a growing appreciation that elevated cardiac biomarkers are also associated with a risk for noncardiovascular mortality . This has now also been confirmed in the perioperative period, in which a postoperative cardiac troponin leak has been found to be independently associated with nonvascular deaths following surgery [4▪]. It has been suggested that early postoperative myocardial injury (as reflected by a postoperative troponin leak) may make a patient more susceptible to a subsequent nonvascular postoperative complication [4▪]. A postoperative troponin leak is, therefore, a harbinger of an increased risk for both vascular and nonvascular deaths.
Although these studies have used different cardiac troponin assays, the independent association with mortality is maintained even with the most sensitive (highly sensitive) assays currently in use . This would suggest that until such time as ‘perioperative troponin reference limits’ are established, any postoperative cardiac troponin leak above the upper reference limit of any of the currently used cardiac troponin assays should be considered clinically important.
SHOULD ROUTINE POSTOPERATIVE TROPONIN SURVEILLANCE BE CONSIDERED IN NONCARDIAC SURGERY PATIENTS?
If we conduct selective postoperative troponin surveillance, we will miss the majority of patients who have prognostically important troponin leaks (Table 1). In response to these limitations, the recently published ‘third universal definition of myocardial infarction’ recommends routine postoperative troponin surveillance following noncardiac surgery in ‘high-risk’ patients . Although the characteristics of ‘at-risk’ patients have been documented [9▪], it is likely that the ability to predict the patient who will sustain a perioperative myocardial injury will continue to be elusive in the foreseeable future . Currently, we can expect patients to leak troponins following all but low-risk surgeries [9▪]. It is necessary to consider the feasibility of routine postoperative surveillance following noncardiac surgery. A pharmacoeconomic analysis modeled on the VISION data suggests that should we be able to decrease cardiovascular morbidity and mortality by 25% through modification or addition of statin and aspirin therapy in postoperative troponin positive patients, then routine troponin surveillance would be cost-effective in South Africa (A. Torborg, L. Ryan, G. Kantor, B. Biccard, unpublished observation).
PREDICTORS OF OUTCOME ASSOCIATED WITH A POSTOPERATIVE TROPONIN RELEASE
There are two independent predictors of outcome associated with a perioperative troponin leak.
The extent of the troponin leak
The current data suggest that the strongest independent predictor of outcome following a troponin leak is the extent of the troponin leak and not the presence of associated clinical symptomatology of myocardial ischemia [4▪,10▪]. The mortality associated with a leak of fourth-generation TnT in unselected noncardiac surgical patients at least 45 years of age is shown in Table 2.
The type of postoperative ECG change
The published cohort studies suggest that for postoperative ECG changes to be associated with postoperative mortality, they have to occur concomitantly with a troponin leak, and only then are certain specific ECG changes potentially independently predictive of mortality.
Some postoperative ECG changes occur in the absence of a postoperative troponin leak . However, in a multivariate model, it is the postoperative troponin leak and not the postoperative ECG change which has been associated with postoperative cardiovascular complications .
In patients who are troponin positive, ECG changes are also more common in patients with greater troponin leaks [12,15], and it is the postoperative troponin leak that has been shown to be independently associated with new postoperative ECG changes .
In all the recently published cohorts (with the exception of the VISION study) [4▪], ECG changes were not independently associated with postoperative morbidity in the presence of a postoperative troponin leak (Table 1). It is likely that the prognostic importance of the different types of ischemic ECG changes varies, and thus a single category of ‘ischemic ECG changes’ as used in the smaller cohort studies, has limited prognostic importance and hence utility. The VISION cohort was of a sufficient sample size to assess specific postoperative ECG changes and the associations of these changes with mortality. The prevalence and clinical significance of various new postoperative ischemic ECG changes are shown in Table 3.
In all the cohort studies, new postoperative T wave inversion had the highest prevalence. As T wave inversion was independent of troponin elevation , it is unlikely to be of prognostic importance for postoperative mortality. In the VISION study, three new postoperative ECG changes which were independently associated with 30-day mortality in the presence of troponin elevation were ST elevation, left bundle branch block and anterior ischemic ECG changes [9▪].
Most new ischemic ECG changes are observed on the first postoperative day . During the hospital admission, these new postoperative ECG changes resolve in over a third of patients . It is, therefore, important to actively attempt to identify these new ECG changes in the early postoperative period.
A NEW CLINICAL ENTITY: MYOCARDIAL INJURY AFTER NONCARDIAC SURGERY
Recently, a new perioperative clinical entity has been proposed: myocardial injury after noncardiac surgery (MINS) [9▪]. In the VISION study, it was possible to determine whether a troponin leak alone had a similar mortality to a traditional diagnosis of MI and the prognostic level of this troponin leak. On the basis of VISION data, it was shown that with a fourth-generation TnT, a peak TnT of at least 0.03 ng/ml judged to be due to myocardial ischemia, had the same predicted 30-day mortality as an MI diagnosis which fulfilled the universal definition criteria [9▪]. Importantly, however, if we only responded clinically to patients with a postoperative universal definition MI diagnosis, we would miss 67% of patients postoperatively who have a similar 30-day prognosis, based on an isolated cardiac troponin leak without any other features of myocardial ischemia [9▪]. This is an important observation that suggests the need to adopt MINS into clinical practice so as not to miss two-thirds of patients postoperatively with troponin leaks of prognostic significance.
Importantly, although decreasing renal function is a predictor of MINS, it is not an independent predictor of 30-day mortality in the presence of MINS [9▪]. Therefore, the prognostic importance of a raised troponin in the perioperative period should not be discounted because of associated renal dysfunction.
MINS is a dominant cause of 30-day mortality. The population-attributable risk for MINS in the VISION study was 34.0% (95% CI 26.6–41.5), which was comparable to postoperative sepsis and infection (30.5%, 95% CI 23.7–37.2) [9▪]. Postoperative stroke and pulmonary embolism had much lower population-attributable risks for 30-day mortality (3–5%) [9▪].
A SUGGESTED APPROACH TO DETECTION OF MYOCARDIAL ISCHEMIA IN 2014
On the basis of these recent publications, a new approach to the detection of perioperative myocardial ischemia is required. The following approach is proposed:
Troponin surveillance needs to be proactive
We need to adopt a proactive approach to troponin surveillance in order not to miss patients with prognostically important troponin leaks, as a large proportion of patients are asymptomatic. Retrospective database publications support this notion. For example, in the Vascular Study Group of New England registry, only 1.3% of the patients were reported to have positive troponins and 1.6% fulfilled MI criteria . These percentages are significantly lower than that reported in prospective cohorts, suggesting that when surveillance is dependent on physician suspicion or patient symptoms, a large proportion of patients with clinically significant myocardial injury will go undetected.
Fortunately, implementation of postoperative troponin surveillance is feasible [10▪]. Furthermore, a pharmacoeconomic analysis suggests that it is likely to be cost-effective to institute routine postoperative troponin surveillance in patients who fulfill VISION study inclusion criteria (A. Torborg, L. Ryan, G. Kantor, B. Biccard, unpublished observation).
In the presence of a troponin leak, it is important to exclude secondary causes before ascribing it to myocardial injury after noncardiac surgery
As MINS does not require confirmatory evidence of myocardial injury (such as ECG ischemic changes or regional wall motion abnormalities on echocardiography), as would be required to make a diagnosis of an MI , it is important to exclude patients with a secondary ‘nonischemic’ cause for a troponin leak. Patients with a low pretest probability for MINS are the ones most likely to have a potential secondary cause for a troponin leak. Once these patients have been identified and excluded, then the sensitivity of troponin elevation for MINS is improved .
In the VISION study, troponin leaks which were judged to be independent of primary myocardial ‘ischemic’ injury were found in 0.6% of the VISION cohort. Over 90% of these leaks were secondary to sepsis, which was defined as a clinical syndrome defined by the presence of both infection and a systemic inflammatory response [9▪]. As MINS was diagnosed in 8.0% of the VISION patients, the patients who leak troponins secondary to sepsis constitute a small (<10% of troponin leaks) but important group. The troponin leak associated with sepsis is probably associated with a leak from the small cytosolic pool of cardiac troponins .
Postoperative ECGs are mandatory in all troponin-positive patients with a diagnosis of myocardial injury after noncardiac surgery
It is important to obtain postoperative ECG because ST elevation, new left bundle branch block and anterior ischemic ECG changes add further prognostic information [9▪].
MANAGEMENT OF MYOCARDIAL INJURY AFTER NONCARDIAC SURGERY IN 2014
Even in 2014, there remain no prospective randomized controlled trials on the management of perioperative myocardial injury after noncardiac surgery. However, data suggest that there is the potential to improve patient outcomes.
First, the Peri Operative ISchemic Evaluation (POISE) trial showed that the use of statin and aspirin therapy was associated with cardiovascular protection in patients who had had a perioperative cardiovascular event . There is an opportunity to further optimize the use of these medical therapies, as studies have shown that between one-third and two-thirds of patients with postoperative troponin elevations have not been prescribed these medications by the time of hospital discharge [8,13].
Second, a prospective observational study by Le Manach et al. suggested that approximately 50% of patients have a 24-h window period of a sustained low troponin leak prior to further troponin elevation. As mortality is correlated with peak troponin leak [4▪], there is, therefore, a 24-h window period in which predicted patient survival could be significantly improved should effective therapies be instituted and the peak troponin be limited. This is further supported by data which show that troponins can be leaked by ischemic myocytes alone, prior to cell death . Furthermore, with the greater application of high sensitivity troponins, we may even be able to identify myocardial injury earlier, as these troponin assays detect a troponin leak earlier than standard troponin assays  and, therefore, may extend the time of the therapeutic window.
Finally, even after the peak troponin leak, the median time to death in patients with MINS varies from 9 [4▪] to 12 days [10▪]. This provides a short window for intensive therapeutic interventions which may improve outcome.
Although there is no prospective randomized clinical trial for patients with MINS, a management algorithm has been proposed in Fig. 1.
An asymptomatic troponin leak in the perioperative period is prognostically and clinically important. It is time for perioperative physicians to embrace the concept of myocardial injury after noncardiac surgery or MINS. Future research should focus on determining how routine postoperative troponin surveillance can become a clinical reality, as MINS is an important public health problem. As there are currently no randomized controlled therapy trials for patients who suffer this perioperative complication, perioperative physicians need to organize themselves into large collaborative groups in order to adequately address therapeutic interventions for these patients .
B.M.B. was supported by a Medical Research Council (MRC) self-initiated research grant, the University of Kwazulu-Natal (Competitive Research Grant) and the South African Society of Anaesthesiologists (Jan Pretorius Research Fund).
Conflicts of interest
B.M.B. is an investigator in the Vascular events In noncardiac Surgery patIents cOhort evaluatioN (VISION) Study.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
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