REVIEW URRENT C OPINION
Myocardial injury after noncardiac surgery James Khan a,b,c, Pablo Alonso-Coello d, and P.J. Devereaux b,c,e
Purpose of review Recent investigations have substantially improved our understanding of myocardial injury after noncardiac surgery (MINS). Recent findings MINS is defined as a prognostically relevant myocardial injury due to ischemia that occurs during or within 30 days after noncardiac surgery. MINS occurs in 8% of adults undergoing major noncardiac surgery and is diagnosed with an elevated postoperative troponin measurement. MINS is associated with significant morbidity, and approximately 10% of patients experiencing MINS will die within 30 days. There is a dosegraded response in mortality and time to death with increasing levels of postoperative troponin elevations. Most patients (>80%) suffering from MINS will not experience an ischemic symptom. Without troponin monitoring, the majority of MINS events would go undetected. To avoid missing these prognostically relevant events, guidelines now recommend perioperative troponin monitoring in high-risk patients having noncardiac surgery. In patients who suffer MINS, risk-adjusted observational data suggest that aspirin and a statin can reduce the risk of 30-day mortality. Summary Among adults, MINS is the most common cardiovascular complication that occurs after noncardiac surgery. Given that worldwide 200 million adult patients undergo major noncardiac surgery each year, at least 8 million of these patients will suffer MINS making this a substantial public health problem. Keywords cardiovascular, myocardial ischemia, perioperative, surgery
INTRODUCTION Worldwide over 200 million adults undergo a major noncardiac surgery each year [1]. Despite improvements in surgical approaches, approximately 1–2% of patients will die within 30 days of noncardiac surgery [2,3,4 ,5]. Perioperative cardiovascular events are the leading cause of morbidity and mortality after noncardiac surgery with perioperative myocardial injury accounting for the majority of these complications [6]. As the number of elderly patients and those with cardiovascular comorbidities undergoing noncardiac surgery continues to rise [7,8], the incidence of perioperative myocardial injury will also increase. Myocardial injury after noncardiac surgery (MINS), hence, represents a significant international public health concern. This review summarizes our current understanding of MINS with respect to its definition, incidence, prognostic significance, risk factors, and future areas for research. &
MYOCARDIAL INJURY AFTER NONCARDIAC SURGERY Most noncardiac surgery studies interested in cardiac complications focus on perioperative
myocardial infarction [2,9]. The most commonly used definition and diagnostic criteria of myocardial infarction comes from the joint task force of the European Society of Cardiology, American College of Cardiology Foundation, American Heart Association, and the World Heart Federation. Recently, this task force published the third universal definition of myocardial infarction. They defined myocardial infarction as myocardial necrosis in a clinical setting consistent with acute myocardial ischemia, a Department of Anesthesia, University of Toronto, Toronto, bDepartment of Clinical Epidemiology and Biostatistics, McMaster University, c Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada, dBiomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain and eDepartment of Medicine, McMaster University, Hamilton, Ontario, Canada
Correspondence to Dr P.J. Devereaux, Associate Professor, Department of Clinical Epidemiology and Biostatistics and Medicine, McMaster University, Scientific Leader of the Population Health Research Institute’s Perioperative Medicine and Surgical Research Unit, 237 Barton Street East, David Braley Research Building, Hamilton, ON L8L 2X2, Canada. Tel: +1 905 527 4322 x40654; fax: +1 905 297 3778; e-mail: [email protected] Curr Opin Cardiol 2014, 29:307–311 DOI:10.1097/HCO.0000000000000069
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KEY POINTS MINS is common, occurring with an incidence of 8%. MINS is defined as prognostically relevant myocardial injury caused by ischemia that occurs during or within 30 days after noncardiac surgery. MINS is associated with a 10% risk of death within 30 days after surgery. Eighty-four percent of those with MINS do not describe an ischemic symptom (e.g., chest pain or shortness of breath). Troponin screening after surgery is recommended in high-risk patients.
and the most common diagnostic criterion consists of an elevated troponin value with either ischemic symptoms or ECG findings [10]. Although there are potential arguments as to why the noncardiac surgery community should focus on myocardial infarction in the noncardiac surgery setting (e.g., the universal definition is highly referenced and known), some authors have advocated moving to the concept of myocardial injury [11]. Arguments for introducing a new diagnosis of myocardial injury due to myocardial ischemia in the noncardiac surgery setting include the following. First, the universal definition of myocardial infarction excludes many prognostically relevant perioperative myocardial ischemic events [6]. Secondly, some prognostically relevant perioperative myocardial insults may represent myocardial injury as opposed to myocardial necrosis (a requirement for the diagnosis of myocardial infarction) [3]. Finally, a new diagnosis may minimize the risk that individuals will assume that what is known about nonoperative myocardial infarctions (e.g., pathophysiology and treatment) automatically applies to these perioperative myocardial events. For these reasons, the Vascular events In noncardiac Surgery patIents cOhort evaluatioN (VISION) investigators recently proposed the new diagnosis of MINS [12 ]. They defined MINS as the following: myocardial injury caused by ischemia (that may or may not result in necrosis), has prognostic relevance (i.e., independently impacts the risk of 30-day mortality), and occurs during or within 30 days after noncardiac surgery. The definition of MINS is broader than the definition of myocardial infarction in that it not only includes myocardial infarction but also includes the other prognostically relevant perioperative myocardial injuries due to ischemia. MINS does not include perioperative myocardial injury that is due to a &&
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documented nonischemic cause (e.g., pulmonary embolism, sepsis and cardioversion). The VISION Study is a large international prospective cohort study evaluating major vascular complications in patients undergoing noncardiac surgery requiring hospital admission [3]. In September 2013, the VISION Study completed recruitment of 40 000 patients. This study included a representative sample of patients undergoing noncardiac surgery who were at least 45 years of age and underwent in-hospital elective or urgent/emergent surgery. All patients were closely monitored, and perioperative complications were recorded. In the first 15 000 VISION patients, a fourth-generation Troponin T (TnT) assay was measured 6–12 h after surgery and on postoperative days 1 through 3. On the basis of the statistical analyses performed on the first 15 000 patients recruited in the VISION Study, the diagnostic criterion for MINS is a peak TnT of at least 0.03 ng/ml that is judged as resulting from myocardial ischemia (i.e., there is no evidence of a nonischemic cause causing the troponin elevation) [12 ]. All elevated troponin measurements after surgery were adjudicated by two independent physicians. Both physicians had to come to an agreement regarding whether there was any evidence to support a nonischemic cause for the troponin elevation. The vast majority (93%) of the elevated troponin measurements occurring in the first 30 days after noncardiac surgery were adjudicated as resulting from myocardial ischemia. The VISION data demonstrated among patients of at least 45 years of age undergoing noncardiac surgery that 8.0% [95% confidence interval (CI), 7.5–8.4] fulfilled the MINS diagnostic criterion. Given that it is estimated that 100 million adults at least 45 years of age undergo noncardiac surgery, suggests that globally at least 8 million adults suffer MINS annually [1]. VISION analyses also demonstrated that the majority (87%) of MINS events occurred within the first 2 days after surgery, when most patients are receiving analgesic medications that can mask ischemic symptoms. Only a minority (16%) of patients suffering MINS experienced an ischemic symptom. Therefore, without troponin monitoring, 84% of the MINS events would have gone undetected. Contemporary screening methods for perioperative ischemia (i.e., relying on patients complaining of angina or shortness of breath) and conventional diagnostic criteria are inadequate to appropriately address the silent nature of perioperative myocardial ischemia. In the VISION Study, patients had an ECG performed after an elevated troponin measurement was detected. Among MINS patients, only 35% of the patients had an ischemic ECG finding [T wave &&
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Myocardial injury after noncardiac surgery Khan et al.
inversion (23%) and ST depression (16%) were the most common ischemic findings]. It is probable that a substantially higher proportion of patients who suffer MINS experience ischemic ECG changes; however, these findings are likely frequently missed for the following reasons. First, most patients do not experience ischemic symptoms to trigger obtaining an ECG during the period of ischemia. Secondly, most ECGs are only obtained after detection of an elevated troponin, which is usually obtained at 24-h intervals after surgery. Finally, a troponin elevation only occurs hours after the initiation of an ischemic event. Considering how infrequent ischemic symptoms and detected ischemic ECG findings occur among patients suffering MINS, it is not surprising that only a minority (42%) of patients experiencing MINS fulfill the universal definition of myocardial infarction, which requires an elevated troponin and ischemic symptoms or ECG findings. Therefore, 58% of MINS patients do not fulfill the universal definition of myocardial infarction. Importantly, MINS events that do not fulfill the universal definition of myocardial infarction are not benign events. These events result in an adjusted hazard ratio of 3.3 for 30-day mortality [12 ]. &&
PROGNOSTIC SIGNIFICANCE OF MYOCARDIAL INJURY AFTER NONCARDIAC SURGERY Numerous studies have demonstrated the shortterm and long-term prognostic significance of a troponin elevation after noncardiac surgery. Levy et al. [13] have assessed the long-term prognostic value of an elevated troponin after noncardiac surgery in a meta-analysis. In the 10 studies that assessed mortality up to 12 months after surgery, 6.2% of the patients who did not have an elevated troponin died, whereas 30.4% of patients who had an elevated troponin died. The independent prognostic capabilities of an elevated troponin value after surgery to predict mortality had an odds ratio (OR) of 6.7 (95% CI, 4.1–10.9; I2 ¼ 0%). Therefore, these findings suggest that an increased troponin value after noncardiac surgery is also a strong independent predictor of 1-year mortality. Moreover, this systematic review also identified five studies that assessed the impact of an elevated troponin after noncardiac surgery on major cardiovascular complications. All five studies demonstrated that an elevated troponin measurement after surgery was an independent predictor of a major cardiovascular event in the subsequent 6–18 months. In the VISION Study, patients suffering MINS have a 30-day mortality rate of 10%, whereas
patients who do not suffer MINS have a 30-day mortality rate of 1%. VISION analyses suggest that 34% of the deaths that occur during the first 30 days after surgery are due to MINS. Moreover, MINS not only impacts 30-day mortality but it also increases a patient’s 30-day risk of a nonfatal cardiac arrest (OR ¼ 15), congestive heart failure (OR ¼ 10), and stroke (OR ¼ 5) [12 ]. The impact of MINS on 30-day mortality is also supported by a cohort study by van Waes et al. [4 ] Myocardial injury in this study was defined as a troponin I elevation more than 0.06 mg/l using a third-generation troponin I assay. A total of 27 of 315 patients with myocardial injury (8.6%; 95% CI 6.0–12.2%) died within 30 days compared with 29 of the 1312 patients without myocardial injury (2.2%; 95% CI 1.5–3.2%, P < 0.01). In an adjusted analysis, the relative risk of 30-day mortality with a troponin I was 2.4 (95% CI 1.3–4.2, P < 0.01) for a minor elevation of 0.07–0.59 mg/l compared with the relative risk of 4.2 (95% CI 2.1–8.6, P < 0.01) for a troponin elevation at least 0.60 mg/l. Only 3.2% of patients experienced typical chest pain, and 9.5% had ECG changes indicative of ischemic. Findings from this study support the silent and imminent lethal consequences of MINS. Beattie et al. [14] conducted a large retrospective review on 51 071 patients undergoing noncardiac surgery. Similar to the VISION analysis, they found that increasing levels of peak troponin were associated with an increased risk of mortality and a decreased time to death. They also compared clinically based troponin testing versus routine troponin surveillance on detecting postoperative myocardial injury. At their institution, vascular surgery patients underwent routine troponin surveillance and served as a routine screening group. They found that routine troponin screening was associated with a three-fold increase in the frequency of detecting an elevated troponin. This study underscores the requirement of troponin screening to appropriately identify which patients have suffered a myocardial injury after surgery. VISION Investigators have also developed a model to predict 30-day mortality among patients suffering MINS. In those who suffered MINS, age at least 75 years, ST elevation or new left bundle branch block, or anterior ischemic ECG changes were independent predictors of 30-day mortality. A scoring system was developed using these predictors to determine the risk of 30-day mortality in those with MINS. The scoring system assigned the following points: 1 point for age at least 75 years, 1 point for anterior ischemic ECG findings, and 2 points for ST elevation or new left bundle branch block. Patients with a score of 0, 1, 2, 3, or 4 had an
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expected mortality rate of 5, 10, 19, 33, and 50%, respectively at 30 days [12 ]. &&
WHAT CAN BE DONE FOR PATIENTS SUFFERING MYOCARDIAL INJURY AFTER NONCARDIAC SURGERY Multivariable analyses among patients suffering MINS in the PeriOperative ISchemic Evaluation (POISE) Trial demonstrated that two drugs (i.e., aspirin and a statin) were associated with a statistically significant, risk-adjusted reduction in 30-day mortality [6]. Although these data are observational, several points suggest that there is a high likelihood that these drugs will benefit patients suffering MINS. First, there is overwhelming evidence regarding the benefits of aspirin and a statin in secondary prevention, including patients who have suffered a nonoperative myocardial infarction. Secondly, a majority of MINS patients have atherosclerotic disease [15]. Finally, it is usually the recurrent cardiac event that happens in the weeks after an MINS event that results in a patient’s demise, and it is highly probable that these recurrent events are thrombotic in nature. Despite the poor prognosis of patients suffering MINS, these patients rarely receive modification to their medical management [6]. Among patients suffering MINS, approximately 50% will not receive a statin, and over one-third will not receive aspirin.
NEXT STEPS As MINS is difficult to detect using clinical signs and symptoms of ischemia, postoperative troponin surveillance is imperative for identifying patients with myocardial injury. The updated universal definition of MI now recommends screening high-risk patients after noncardiac surgery to diagnose those with myocardial ischemia [10]. The first VISION analysis indicated several groups of patients at high risk of postoperative myocardial injury. Those that are at least 65 years of age, have recent high-risk coronary artery disease, peripheral vascular disease, stroke history, chronic obstructive pulmonary disease, active cancer, or those undergoing urgent/emergency surgery, general or neurosurgical procedures are at risk of an elevated postoperative troponin [3]. Thus, these groups of patients are likely to benefit most from postoperative troponin screening. There is now a need to implement this knowledge into clinical practice. Future steps also require determining a diagnostic threshold for the fifth-generation high-sensitivity troponin (hsTnT) assay. Many institutions worldwide have shifted toward the hsTnT assay 310
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because of its superior precision and sensitivity to detect myocardial injury [16]. An MINS diagnostic criteria using hsTnT levels will be determined from 25 000 VISION patients who received hsTnT monitoring. A study comparing TnT and hsTnT on detecting postoperative myocardial injury found an incidence rate of 6 and 26%, respectively [17]. Further, a study on preoperative hsTnT found that 41% of patients had an elevated hsTnT concentration (>14 ng/l), whereas only 4% of patients had an elevated contemporary Siemens Troponin I assay (>0.07 mg/l) [18 ]. An elevated preoperative hsTnT measurement predicted a patient’s 3-year mortality rate. Finally, there is a need for large clinical trials to establish effective treatment strategies for MINS. Such trials are starting to happen. The Management of myocardial injury After NoncArdiac surGEry (MANAGE) Trial will evaluate the impact of an anticoagulant (dabigatran) in patients who have suffered MINS. &
CONCLUSION MINS is an independent predictor of short-term mortality and complications after noncardiac surgery. MINS is common, with an incidence of 8%. With over 200 million adults undergoing a major noncardiac surgery each year and MINS associated with a 10% mortality rate, it is estimated that upward of a million deaths occur annually due to MINS. Currently, the only method of identifying patients with MINS is through postoperative troponin screening in susceptible patients. Putting perioperative troponin monitoring into clinical care has substantial potential to improve patient outcomes. Future research on MINS should focus on prevention and management strategies to reduce the impact of this life-threatening complication and improve the safety of those undergoing surgery. Acknowledgements We would like to acknowledge the dedicated VISION Study Investigators who made the VISION study possible. A full list of investigators can be found in the first VISION analysis [3]. All authors have completed and submitted the Authorship Responsibility, Disclosure, and Copyright Transfer Form to the COC Journal. Funding: None. Conflicts of interest P.J.D. and P.A.C. report receipt of a grant(s) to their institution from Roche Diagnostics Global Office. P.J.D. also reports receipt of an institutional grant from the Canadian Institute of Health Research (CIHR), Volume 29 Number 4 July 2014
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Boehringer Ingelheim, Abbott Diagnostics, Covidien, and Stryker.
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 1. Weiser TG, Regenbogen SE, Thompson KD, et al. An estimation of the global volume of surgery: a modelling strategy based on available data. Lancet 2008; 372:139–144. 2. Devereaux PJ, Yang H, Yusuf S, et al. Effects of extended-release metoprolol succinate in patients undergoing noncardiac surgery (POISE trial): a randomised controlled trial. Lancet 2008; 371:1839–1847. 3. Devereaux P, Chan M, Alonso-Coello P, et al. Association between postoperative troponin levels and 30-day mortality among patients undergoing noncardiac surgery. J Am Med Assoc 2012; 307:2295–2304. 4. van Waes JAR, Nathoe HM, de Graaff JC, et al. Myocardial injury after & noncardiac surgery and its association with short-term mortality. Circulation 2013; 127:2264–2271. A well conducted study that supports the silent nature and short-term mortality risk of an elevated postoperative troponin after noncardiac surgery. 5. Fleisher LA, Eagle KA, Anderson GF, Shaffer T. Perioperative and longterm mortality rates after major vascular surgery: the relationship to preoperative testing in the medicare population. Anesth Analg 1999; 89:849– 855. 6. Devereaux P, Xavier D, Pogue J, et al. Characteristics and short-term prognosis of perioperative myocardial infarction in patients undergoing noncardiac surgery. Ann Intern Med 2011; 154:523–528. 7. Pumberger M, Chiu Y-L, Ma Y, et al. National in-hospital morbidity and mortality trends after lumbar fusion surgery between 1998 and 2008. J Bone Joint Surg Br 2012; 94:359–364.
8. Baillot R, Joanisse D, Stevens L, et al. Recent evolution in demographic and clinical characteristics and in-hospital morbidity in patients undergoing coronary surgery. Can J Surg 2009; 52:394–400. 9. McFalls E, Ward H, Moritz T, et al. Coronary-artery revascularization before elective major vascular surgery. N Engl J Med 2004; 351:2795–2804. 10. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. J Am Coll Cardiol 2012; 60:1581–1598. 11. Ali Z, Callaghan CJ, Ali A, et al. Perioperative myocardial injury after elective open abdominal aortic aneurysm repair predicts outcome. Eur J Vasc Endovasc Surg 2008; 35:413–419. 12. Botto F, Alonso-Coello P, Chan MTV, and the VISION Investigators. Myo&& cardial injury after noncardiac surgery: a large international prospective cohort study establishing diagnostic criteria, characteristics, predictors, and 30-day outcomes. Anesthesiology 2014; 120:564–578. Second analysis of the VISION study that reports the diagnostic criteria of MINS, characteristics, and risk factors, and provides a scoring system for the risk of mortality. 13. Levy M, Heels-Ansdell D, Hiralal R, et al. Prognostic value of troponin and creatine kinase muscle and brain isoenzyme measurement after noncardiac surgery: a systematic review and meta-analysis. Anesthesiology 2011; 114:796–806. 14. Beattie WS, Karkouti K, Tait G, et al. Use of clinically based troponin underestimates the cardiac injury in noncardiac surgery: a single-centre cohort study in 51 701 consecutive patients. Can J Anaesth 2012; 59:1013–1022. 15. Gualandro DM, Campos CA, Calderaro D, et al. Coronary plaque rupture in patients with myocardial infarction after noncardiac surgery: frequent and dangerous. Atherosclerosis 2012; 222:191–195. 16. Januzzi JL, Bamberg F, Lee H, et al. High-sensitivity troponin T concentrations in acute chest pain patients evaluated with cardiac computed tomography. Circulation 2010; 121:1227–1234. 17. Alcock RF, Kouzios D, Naoum C, et al. Perioperative myocardial necrosis in patients at high cardiovascular risk undergoing elective noncardiac surgery. Heart 2012; 98:792–798. 18. Nagele P, Brown F, Gage BF, et al. High-sensitivity cardiac troponin T in & prediction and diagnosis of myocardial infarction and long-term mortality after noncardiac surgery. Am Heart J 2013; 166:325–332. A study that informs the prognostic relationship between an elevated preoperative troponin measurement and perioperative myocardial infarction and mortality.
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Myocardial injury after noncardiac surgery James Khan a,b,c, Pablo Alonso-Coello d, and P.J. Devereaux b,c,e
Purpose of review Recent investigations have substantially improved our understanding of myocardial injury after noncardiac surgery (MINS). Recent findings MINS is defined as a prognostically relevant myocardial injury due to ischemia that occurs during or within 30 days after noncardiac surgery. MINS occurs in 8% of adults undergoing major noncardiac surgery and is diagnosed with an elevated postoperative troponin measurement. MINS is associated with significant morbidity, and approximately 10% of patients experiencing MINS will die within 30 days. There is a dosegraded response in mortality and time to death with increasing levels of postoperative troponin elevations. Most patients (>80%) suffering from MINS will not experience an ischemic symptom. Without troponin monitoring, the majority of MINS events would go undetected. To avoid missing these prognostically relevant events, guidelines now recommend perioperative troponin monitoring in high-risk patients having noncardiac surgery. In patients who suffer MINS, risk-adjusted observational data suggest that aspirin and a statin can reduce the risk of 30-day mortality. Summary Among adults, MINS is the most common cardiovascular complication that occurs after noncardiac surgery. Given that worldwide 200 million adult patients undergo major noncardiac surgery each year, at least 8 million of these patients will suffer MINS making this a substantial public health problem. Keywords cardiovascular, myocardial ischemia, perioperative, surgery
INTRODUCTION Worldwide over 200 million adults undergo a major noncardiac surgery each year [1]. Despite improvements in surgical approaches, approximately 1–2% of patients will die within 30 days of noncardiac surgery [2,3,4 ,5]. Perioperative cardiovascular events are the leading cause of morbidity and mortality after noncardiac surgery with perioperative myocardial injury accounting for the majority of these complications [6]. As the number of elderly patients and those with cardiovascular comorbidities undergoing noncardiac surgery continues to rise [7,8], the incidence of perioperative myocardial injury will also increase. Myocardial injury after noncardiac surgery (MINS), hence, represents a significant international public health concern. This review summarizes our current understanding of MINS with respect to its definition, incidence, prognostic significance, risk factors, and future areas for research. &
MYOCARDIAL INJURY AFTER NONCARDIAC SURGERY Most noncardiac surgery studies interested in cardiac complications focus on perioperative
myocardial infarction [2,9]. The most commonly used definition and diagnostic criteria of myocardial infarction comes from the joint task force of the European Society of Cardiology, American College of Cardiology Foundation, American Heart Association, and the World Heart Federation. Recently, this task force published the third universal definition of myocardial infarction. They defined myocardial infarction as myocardial necrosis in a clinical setting consistent with acute myocardial ischemia, a Department of Anesthesia, University of Toronto, Toronto, bDepartment of Clinical Epidemiology and Biostatistics, McMaster University, c Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada, dBiomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain and eDepartment of Medicine, McMaster University, Hamilton, Ontario, Canada
Correspondence to Dr P.J. Devereaux, Associate Professor, Department of Clinical Epidemiology and Biostatistics and Medicine, McMaster University, Scientific Leader of the Population Health Research Institute’s Perioperative Medicine and Surgical Research Unit, 237 Barton Street East, David Braley Research Building, Hamilton, ON L8L 2X2, Canada. Tel: +1 905 527 4322 x40654; fax: +1 905 297 3778; e-mail: [email protected] Curr Opin Cardiol 2014, 29:307–311 DOI:10.1097/HCO.0000000000000069
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KEY POINTS MINS is common, occurring with an incidence of 8%. MINS is defined as prognostically relevant myocardial injury caused by ischemia that occurs during or within 30 days after noncardiac surgery. MINS is associated with a 10% risk of death within 30 days after surgery. Eighty-four percent of those with MINS do not describe an ischemic symptom (e.g., chest pain or shortness of breath). Troponin screening after surgery is recommended in high-risk patients.
and the most common diagnostic criterion consists of an elevated troponin value with either ischemic symptoms or ECG findings [10]. Although there are potential arguments as to why the noncardiac surgery community should focus on myocardial infarction in the noncardiac surgery setting (e.g., the universal definition is highly referenced and known), some authors have advocated moving to the concept of myocardial injury [11]. Arguments for introducing a new diagnosis of myocardial injury due to myocardial ischemia in the noncardiac surgery setting include the following. First, the universal definition of myocardial infarction excludes many prognostically relevant perioperative myocardial ischemic events [6]. Secondly, some prognostically relevant perioperative myocardial insults may represent myocardial injury as opposed to myocardial necrosis (a requirement for the diagnosis of myocardial infarction) [3]. Finally, a new diagnosis may minimize the risk that individuals will assume that what is known about nonoperative myocardial infarctions (e.g., pathophysiology and treatment) automatically applies to these perioperative myocardial events. For these reasons, the Vascular events In noncardiac Surgery patIents cOhort evaluatioN (VISION) investigators recently proposed the new diagnosis of MINS [12 ]. They defined MINS as the following: myocardial injury caused by ischemia (that may or may not result in necrosis), has prognostic relevance (i.e., independently impacts the risk of 30-day mortality), and occurs during or within 30 days after noncardiac surgery. The definition of MINS is broader than the definition of myocardial infarction in that it not only includes myocardial infarction but also includes the other prognostically relevant perioperative myocardial injuries due to ischemia. MINS does not include perioperative myocardial injury that is due to a &&
308
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documented nonischemic cause (e.g., pulmonary embolism, sepsis and cardioversion). The VISION Study is a large international prospective cohort study evaluating major vascular complications in patients undergoing noncardiac surgery requiring hospital admission [3]. In September 2013, the VISION Study completed recruitment of 40 000 patients. This study included a representative sample of patients undergoing noncardiac surgery who were at least 45 years of age and underwent in-hospital elective or urgent/emergent surgery. All patients were closely monitored, and perioperative complications were recorded. In the first 15 000 VISION patients, a fourth-generation Troponin T (TnT) assay was measured 6–12 h after surgery and on postoperative days 1 through 3. On the basis of the statistical analyses performed on the first 15 000 patients recruited in the VISION Study, the diagnostic criterion for MINS is a peak TnT of at least 0.03 ng/ml that is judged as resulting from myocardial ischemia (i.e., there is no evidence of a nonischemic cause causing the troponin elevation) [12 ]. All elevated troponin measurements after surgery were adjudicated by two independent physicians. Both physicians had to come to an agreement regarding whether there was any evidence to support a nonischemic cause for the troponin elevation. The vast majority (93%) of the elevated troponin measurements occurring in the first 30 days after noncardiac surgery were adjudicated as resulting from myocardial ischemia. The VISION data demonstrated among patients of at least 45 years of age undergoing noncardiac surgery that 8.0% [95% confidence interval (CI), 7.5–8.4] fulfilled the MINS diagnostic criterion. Given that it is estimated that 100 million adults at least 45 years of age undergo noncardiac surgery, suggests that globally at least 8 million adults suffer MINS annually [1]. VISION analyses also demonstrated that the majority (87%) of MINS events occurred within the first 2 days after surgery, when most patients are receiving analgesic medications that can mask ischemic symptoms. Only a minority (16%) of patients suffering MINS experienced an ischemic symptom. Therefore, without troponin monitoring, 84% of the MINS events would have gone undetected. Contemporary screening methods for perioperative ischemia (i.e., relying on patients complaining of angina or shortness of breath) and conventional diagnostic criteria are inadequate to appropriately address the silent nature of perioperative myocardial ischemia. In the VISION Study, patients had an ECG performed after an elevated troponin measurement was detected. Among MINS patients, only 35% of the patients had an ischemic ECG finding [T wave &&
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Myocardial injury after noncardiac surgery Khan et al.
inversion (23%) and ST depression (16%) were the most common ischemic findings]. It is probable that a substantially higher proportion of patients who suffer MINS experience ischemic ECG changes; however, these findings are likely frequently missed for the following reasons. First, most patients do not experience ischemic symptoms to trigger obtaining an ECG during the period of ischemia. Secondly, most ECGs are only obtained after detection of an elevated troponin, which is usually obtained at 24-h intervals after surgery. Finally, a troponin elevation only occurs hours after the initiation of an ischemic event. Considering how infrequent ischemic symptoms and detected ischemic ECG findings occur among patients suffering MINS, it is not surprising that only a minority (42%) of patients experiencing MINS fulfill the universal definition of myocardial infarction, which requires an elevated troponin and ischemic symptoms or ECG findings. Therefore, 58% of MINS patients do not fulfill the universal definition of myocardial infarction. Importantly, MINS events that do not fulfill the universal definition of myocardial infarction are not benign events. These events result in an adjusted hazard ratio of 3.3 for 30-day mortality [12 ]. &&
PROGNOSTIC SIGNIFICANCE OF MYOCARDIAL INJURY AFTER NONCARDIAC SURGERY Numerous studies have demonstrated the shortterm and long-term prognostic significance of a troponin elevation after noncardiac surgery. Levy et al. [13] have assessed the long-term prognostic value of an elevated troponin after noncardiac surgery in a meta-analysis. In the 10 studies that assessed mortality up to 12 months after surgery, 6.2% of the patients who did not have an elevated troponin died, whereas 30.4% of patients who had an elevated troponin died. The independent prognostic capabilities of an elevated troponin value after surgery to predict mortality had an odds ratio (OR) of 6.7 (95% CI, 4.1–10.9; I2 ¼ 0%). Therefore, these findings suggest that an increased troponin value after noncardiac surgery is also a strong independent predictor of 1-year mortality. Moreover, this systematic review also identified five studies that assessed the impact of an elevated troponin after noncardiac surgery on major cardiovascular complications. All five studies demonstrated that an elevated troponin measurement after surgery was an independent predictor of a major cardiovascular event in the subsequent 6–18 months. In the VISION Study, patients suffering MINS have a 30-day mortality rate of 10%, whereas
patients who do not suffer MINS have a 30-day mortality rate of 1%. VISION analyses suggest that 34% of the deaths that occur during the first 30 days after surgery are due to MINS. Moreover, MINS not only impacts 30-day mortality but it also increases a patient’s 30-day risk of a nonfatal cardiac arrest (OR ¼ 15), congestive heart failure (OR ¼ 10), and stroke (OR ¼ 5) [12 ]. The impact of MINS on 30-day mortality is also supported by a cohort study by van Waes et al. [4 ] Myocardial injury in this study was defined as a troponin I elevation more than 0.06 mg/l using a third-generation troponin I assay. A total of 27 of 315 patients with myocardial injury (8.6%; 95% CI 6.0–12.2%) died within 30 days compared with 29 of the 1312 patients without myocardial injury (2.2%; 95% CI 1.5–3.2%, P < 0.01). In an adjusted analysis, the relative risk of 30-day mortality with a troponin I was 2.4 (95% CI 1.3–4.2, P < 0.01) for a minor elevation of 0.07–0.59 mg/l compared with the relative risk of 4.2 (95% CI 2.1–8.6, P < 0.01) for a troponin elevation at least 0.60 mg/l. Only 3.2% of patients experienced typical chest pain, and 9.5% had ECG changes indicative of ischemic. Findings from this study support the silent and imminent lethal consequences of MINS. Beattie et al. [14] conducted a large retrospective review on 51 071 patients undergoing noncardiac surgery. Similar to the VISION analysis, they found that increasing levels of peak troponin were associated with an increased risk of mortality and a decreased time to death. They also compared clinically based troponin testing versus routine troponin surveillance on detecting postoperative myocardial injury. At their institution, vascular surgery patients underwent routine troponin surveillance and served as a routine screening group. They found that routine troponin screening was associated with a three-fold increase in the frequency of detecting an elevated troponin. This study underscores the requirement of troponin screening to appropriately identify which patients have suffered a myocardial injury after surgery. VISION Investigators have also developed a model to predict 30-day mortality among patients suffering MINS. In those who suffered MINS, age at least 75 years, ST elevation or new left bundle branch block, or anterior ischemic ECG changes were independent predictors of 30-day mortality. A scoring system was developed using these predictors to determine the risk of 30-day mortality in those with MINS. The scoring system assigned the following points: 1 point for age at least 75 years, 1 point for anterior ischemic ECG findings, and 2 points for ST elevation or new left bundle branch block. Patients with a score of 0, 1, 2, 3, or 4 had an
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Clinical trials
expected mortality rate of 5, 10, 19, 33, and 50%, respectively at 30 days [12 ]. &&
WHAT CAN BE DONE FOR PATIENTS SUFFERING MYOCARDIAL INJURY AFTER NONCARDIAC SURGERY Multivariable analyses among patients suffering MINS in the PeriOperative ISchemic Evaluation (POISE) Trial demonstrated that two drugs (i.e., aspirin and a statin) were associated with a statistically significant, risk-adjusted reduction in 30-day mortality [6]. Although these data are observational, several points suggest that there is a high likelihood that these drugs will benefit patients suffering MINS. First, there is overwhelming evidence regarding the benefits of aspirin and a statin in secondary prevention, including patients who have suffered a nonoperative myocardial infarction. Secondly, a majority of MINS patients have atherosclerotic disease [15]. Finally, it is usually the recurrent cardiac event that happens in the weeks after an MINS event that results in a patient’s demise, and it is highly probable that these recurrent events are thrombotic in nature. Despite the poor prognosis of patients suffering MINS, these patients rarely receive modification to their medical management [6]. Among patients suffering MINS, approximately 50% will not receive a statin, and over one-third will not receive aspirin.
NEXT STEPS As MINS is difficult to detect using clinical signs and symptoms of ischemia, postoperative troponin surveillance is imperative for identifying patients with myocardial injury. The updated universal definition of MI now recommends screening high-risk patients after noncardiac surgery to diagnose those with myocardial ischemia [10]. The first VISION analysis indicated several groups of patients at high risk of postoperative myocardial injury. Those that are at least 65 years of age, have recent high-risk coronary artery disease, peripheral vascular disease, stroke history, chronic obstructive pulmonary disease, active cancer, or those undergoing urgent/emergency surgery, general or neurosurgical procedures are at risk of an elevated postoperative troponin [3]. Thus, these groups of patients are likely to benefit most from postoperative troponin screening. There is now a need to implement this knowledge into clinical practice. Future steps also require determining a diagnostic threshold for the fifth-generation high-sensitivity troponin (hsTnT) assay. Many institutions worldwide have shifted toward the hsTnT assay 310
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because of its superior precision and sensitivity to detect myocardial injury [16]. An MINS diagnostic criteria using hsTnT levels will be determined from 25 000 VISION patients who received hsTnT monitoring. A study comparing TnT and hsTnT on detecting postoperative myocardial injury found an incidence rate of 6 and 26%, respectively [17]. Further, a study on preoperative hsTnT found that 41% of patients had an elevated hsTnT concentration (>14 ng/l), whereas only 4% of patients had an elevated contemporary Siemens Troponin I assay (>0.07 mg/l) [18 ]. An elevated preoperative hsTnT measurement predicted a patient’s 3-year mortality rate. Finally, there is a need for large clinical trials to establish effective treatment strategies for MINS. Such trials are starting to happen. The Management of myocardial injury After NoncArdiac surGEry (MANAGE) Trial will evaluate the impact of an anticoagulant (dabigatran) in patients who have suffered MINS. &
CONCLUSION MINS is an independent predictor of short-term mortality and complications after noncardiac surgery. MINS is common, with an incidence of 8%. With over 200 million adults undergoing a major noncardiac surgery each year and MINS associated with a 10% mortality rate, it is estimated that upward of a million deaths occur annually due to MINS. Currently, the only method of identifying patients with MINS is through postoperative troponin screening in susceptible patients. Putting perioperative troponin monitoring into clinical care has substantial potential to improve patient outcomes. Future research on MINS should focus on prevention and management strategies to reduce the impact of this life-threatening complication and improve the safety of those undergoing surgery. Acknowledgements We would like to acknowledge the dedicated VISION Study Investigators who made the VISION study possible. A full list of investigators can be found in the first VISION analysis [3]. All authors have completed and submitted the Authorship Responsibility, Disclosure, and Copyright Transfer Form to the COC Journal. Funding: None. Conflicts of interest P.J.D. and P.A.C. report receipt of a grant(s) to their institution from Roche Diagnostics Global Office. P.J.D. also reports receipt of an institutional grant from the Canadian Institute of Health Research (CIHR), Volume 29 Number 4 July 2014
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Myocardial injury after noncardiac surgery Khan et al.
Boehringer Ingelheim, Abbott Diagnostics, Covidien, and Stryker.
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 1. Weiser TG, Regenbogen SE, Thompson KD, et al. An estimation of the global volume of surgery: a modelling strategy based on available data. Lancet 2008; 372:139–144. 2. Devereaux PJ, Yang H, Yusuf S, et al. Effects of extended-release metoprolol succinate in patients undergoing noncardiac surgery (POISE trial): a randomised controlled trial. Lancet 2008; 371:1839–1847. 3. Devereaux P, Chan M, Alonso-Coello P, et al. Association between postoperative troponin levels and 30-day mortality among patients undergoing noncardiac surgery. J Am Med Assoc 2012; 307:2295–2304. 4. van Waes JAR, Nathoe HM, de Graaff JC, et al. Myocardial injury after & noncardiac surgery and its association with short-term mortality. Circulation 2013; 127:2264–2271. A well conducted study that supports the silent nature and short-term mortality risk of an elevated postoperative troponin after noncardiac surgery. 5. Fleisher LA, Eagle KA, Anderson GF, Shaffer T. Perioperative and longterm mortality rates after major vascular surgery: the relationship to preoperative testing in the medicare population. Anesth Analg 1999; 89:849– 855. 6. Devereaux P, Xavier D, Pogue J, et al. Characteristics and short-term prognosis of perioperative myocardial infarction in patients undergoing noncardiac surgery. Ann Intern Med 2011; 154:523–528. 7. Pumberger M, Chiu Y-L, Ma Y, et al. National in-hospital morbidity and mortality trends after lumbar fusion surgery between 1998 and 2008. J Bone Joint Surg Br 2012; 94:359–364.
8. Baillot R, Joanisse D, Stevens L, et al. Recent evolution in demographic and clinical characteristics and in-hospital morbidity in patients undergoing coronary surgery. Can J Surg 2009; 52:394–400. 9. McFalls E, Ward H, Moritz T, et al. Coronary-artery revascularization before elective major vascular surgery. N Engl J Med 2004; 351:2795–2804. 10. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. J Am Coll Cardiol 2012; 60:1581–1598. 11. Ali Z, Callaghan CJ, Ali A, et al. Perioperative myocardial injury after elective open abdominal aortic aneurysm repair predicts outcome. Eur J Vasc Endovasc Surg 2008; 35:413–419. 12. Botto F, Alonso-Coello P, Chan MTV, and the VISION Investigators. Myo&& cardial injury after noncardiac surgery: a large international prospective cohort study establishing diagnostic criteria, characteristics, predictors, and 30-day outcomes. Anesthesiology 2014; 120:564–578. Second analysis of the VISION study that reports the diagnostic criteria of MINS, characteristics, and risk factors, and provides a scoring system for the risk of mortality. 13. Levy M, Heels-Ansdell D, Hiralal R, et al. Prognostic value of troponin and creatine kinase muscle and brain isoenzyme measurement after noncardiac surgery: a systematic review and meta-analysis. Anesthesiology 2011; 114:796–806. 14. Beattie WS, Karkouti K, Tait G, et al. Use of clinically based troponin underestimates the cardiac injury in noncardiac surgery: a single-centre cohort study in 51 701 consecutive patients. Can J Anaesth 2012; 59:1013–1022. 15. Gualandro DM, Campos CA, Calderaro D, et al. Coronary plaque rupture in patients with myocardial infarction after noncardiac surgery: frequent and dangerous. Atherosclerosis 2012; 222:191–195. 16. Januzzi JL, Bamberg F, Lee H, et al. High-sensitivity troponin T concentrations in acute chest pain patients evaluated with cardiac computed tomography. Circulation 2010; 121:1227–1234. 17. Alcock RF, Kouzios D, Naoum C, et al. Perioperative myocardial necrosis in patients at high cardiovascular risk undergoing elective noncardiac surgery. Heart 2012; 98:792–798. 18. Nagele P, Brown F, Gage BF, et al. High-sensitivity cardiac troponin T in & prediction and diagnosis of myocardial infarction and long-term mortality after noncardiac surgery. Am Heart J 2013; 166:325–332. A study that informs the prognostic relationship between an elevated preoperative troponin measurement and perioperative myocardial infarction and mortality.
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