The first analysis evaluated the survival difference among 3 groups: (1) patients without perioperative MI, (2) patients with perioperative MI without treatment intensification, and (3) patients with perioperative MI with treatment intensification. Patients with a perioperative MI and no modification of their cardiovascular treatment had a HR of 1.77 (95% CI, 1.13–2.42; P = 0.004) for the primary study outcome as compared with the control group. In contrast, patients with a perioperative MI who received intensified postoperative cardiovascular treatment had a HR of 0.63 (95% CI, 0.10–1.19; P = 0.45) for the primary outcome as compared with the control group (Fig. 4); When conducting the simulation analysis for this first survival analysis, we found that even when introducing 4 allocation errors, 95% of the simulated results still remained statistically significant (i.e., P ≤ 0.05) (Appendix).
The second survival analysis compared 2 groups: (1) patients with perioperative MI receiving postoperative treatment intensification, and (2) patients with perioperative MI not receiving treatment intensification. Patients with a perioperative MI who did not receive treatment intensification had a HR of 2.80 (95% CI, 1.05–24.2; P = 0.04) compared with patients with a perioperative MI who did receive treatment intensification. The simulation analysis conducted in this smaller population found that the introduction of allocation errors had a greater impact on the robustness of our results (Appendix). The introduction of 3 allocation errors resulted in nonsignificant (i.e., P > 0.05) results in >35% of the cases.
The main finding of this study was that a long-term increase in adverse cardiovascular events (HR: 2.80; 95% CI, 1.05–24.2; P = 0.04) was observed in patients with perioperative cTnI elevation when they did not receive evidence-based medical therapy for the treatment of coronary artery disease. Furthermore, using Monte Carlo simulations, we demonstrated that this result was not dramatically affected by potential allocation errors related to the expert committee’s disagreements (i.e., even when introducing 4 allocation errors, 54% of the simulated results still remained statistically significant). Our results further provide a rationale for a postoperative strategy of screening patients undergoing vascular surgery for elevations in cTnI after surgery and intensifying therapy using evidence-based medical treatments for coronary artery disease in patients demonstrating myocardial injury as a means for improving patient survival.
With the introduction of sensitive, cardiac-specific biomarkers such as cTnI, the ability to identify patients with perioperative MIs even in the absence of ECG changes or symptoms of myocardial ischemia has been greatly enhanced. Indeed, even small increases in perioperative cTnI concentrations have been found to be associated with poorer short-term25 and long-term outcomes.6 This correlation between perioperative cTnI concentration and the incidence of cardiac complications in the months after noncardiac surgery confirms the specificity of this biological marker as an indicator of myocardial injury. It is important to note that as was the case in this study, troponin elevations occur in most patients in the absence of anginal symptoms or ECG changes and, therefore, often go undetected by caregivers. Perioperative cTnI surveillance, thus, may not only enable early detection of patients at risk for short- and long-term morbidity and mortality, but they may also allow for the early initiation of appropriate therapeutic interventions.
Patients who suffer an acute coronary event are at very high risk of further coronary events. Although improvements in medical therapy over the past 2 decades have reduced this risk significantly, it still remains high. In the medical setting, recent developments in secondary prevention have been suggested,26 based on the findings of large, randomized trials. The routine use of 4 main prophylactic drug groups (antiplatelet drugs, β-blockers, ACE inhibitors, and statins) is now recommended by international guidelines for the secondary prevention of coronary artery disease.27,28 Most postoperative patients suffer non-ST segment elevation MI29, and it is likely that the use of these therapies in patients with isolated cTnI elevation30 may improve patient outcomes.31 It must, however, be appreciated that guidelines developed in nonoperative populations cannot necessarily be extrapolated to operative populations. The hemodynamic impact of instituting aggressive ACE or β-blocker therapy is unclear, and the bleeding risk associated with aggressive antiplatelet therapy remains to be investigated.
Our study has several limitations. First, this was a single-center, retrospective study, involving only 1 type of surgery (major vascular surgery), and therefore, we cannot generalize our results to all noncardiac surgeries. Second, elevation of cTnI plasma concentration was the single criterion for patient selection, and although troponin I offers high tissue specificity, it does not indicate the mechanism of myocardial injury.32–34 We did not discern the etiology of the elevation of cTnI (coronary or otherwise) but treated it as a coronary injury using cardioprotective drugs. Third, there was a limited number of patients in this study that may further confound its interpretation for other groups of patients. As is the case in all survival analyses using a primary end point other than mortality, the possibility of competing risks cannot be excluded. Fourth, it is possible that, due to the small number of patients in the study, variation in how patients were allocated to treatment groups by the expert committee may impact the validity of the study finding. However, for both κ estimates, the lower bound of the 95% CI was well above 0.61, the threshold denoting substantial agreement. Finally, due to the small sample size, we were unable to obtain complete balance of the preoperative risk factors among the groups despite propensity matching.
The main finding of this study was that in patients with a perioperative MI, long-term outcomes may likely be improved by following evidence-based recommendations for the medical management of acute coronary syndromes.
In our methodology, an expert committee evaluated whether, in their opinion, patients received postoperative intensification of cardiovascular treatment. Errors in the accuracy of this evaluation process would impact on the estimation of our treatment effect. We therefore conducted a simulation analysis to explore the impact of such errors on our results.
We generated simulated populations using the original study population. Patients from the original population and their treatment allocations were changed to simulate allocation errors. When a randomly selected patient was “treated” in the original population, we considered him as “not treated” for the simulation. Conversely, when he was “not treated,” we changed his allocation to “treated.” We allowed the number of allocation errors (i.e., the number of patients who had their allocation changed) to vary from 1 to 4, and we conducted 10,000 replications for each scenario (i.e., 1 to 4 allocation changes). This procedure therefore generated 40,000 simulation populations.
The first survival analysis included 198 patients and compared 3 groups: (1) patients without postoperative myocardial necrosis, (2) patients with postoperative myocardial necrosis without treatment intensification, and (3) patients with postoperative myocardial necrosis with treatment intensification. The results observed in the original population showed a HR of 1.77 (95% CI, 1.13–2.42; P = 0.004). When conducting the simulation analysis for this outcome (Appendix Figure 1), we found that even when introducing 4 allocation errors, 95% of the simulated results still remained statistically significant (i.e., P ≤ 0.05). We therefore concluded that this analysis was unlikely to have been impacted by allocation errors made by the expert committee.
Although expert disagreements and allocation errors are not interchangeable, we considered that allocation errors are more likely to happen when incomplete agreement occurred. Pushing this argument to the extreme, we considered that any incomplete agreement (i.e., 1 expert disagreed with the 2 others regarding 1 patient's treatment) was an allocation error. As such, incomplete agreement was observed in 4 cases for this analysis; we concluded that these potential allocation errors had a limited impact on the estimation of the treatment effect in this analysis.
In a second simulation, we evaluate the survival analysis comparing patients with postoperative myocardial necrosis, with or without postoperative cardiovascular treatment intensification (2 groups, 66 patients). In the original population we found that long-term adverse cardiovascular events were more frequent (HR: 2.80; 95% CI, 1.05–24.2; P = 0.04) in patients without postoperative cardiovascular treatment intensification.
In this smaller population, the introduction of allocation errors had a greater impact on the robustness of our results (Appendix Figure 2). The introduction of 1 allocation error resulted in nonsignificant study results (i.e., P > 0.05) in 11.23% of cases, 3 allocation errors resulted in nonsignificant study results in 35% of cases, and 4 allocation errors resulted in nonsignificant study results in 45.41% of cases.
In this analysis, incomplete agreement was observed in 3 patients. Assuming that they all correspond to allocation errors, the observed treatment effect would remain significant in >65% of the cases (Appendix Figure 2). We therefore concluded that, while the results of this analysis were more sensitive to allocation errors, the robustness of the results warrant serious consideration.
1. Devereaux PJ, Xavier D, Pogue J, Guyatt G, Sigamani A, Garutti I, Leslie K, Rao-Melacini P, Chrolavicius S, Yang H, Macdonald C, Avezum A, Lanthier L, Hu W, Yusuf SPOISE (PeriOperative ISchemic Evaluation) Investigators. . Characteristics and short-term prognosis of perioperative myocardial infarction in patients undergoing noncardiac surgery: a cohort study. Ann Intern Med. 2011;154:523–8
2. Redfern G, Rodseth RN, Biccard BM. Outcomes in vascular surgical patients with isolated postoperative troponin leak: a meta-analysis. Anaesthesia. 2011;66:604–10
3. Rodseth R, Devereaux PJ. ACP Journal Club. Review: Perioperative statins reduce perioperative MI and AF in statin-naïve patients. Ann Intern Med. 2012;156:JC6–2
4. Levy M, Heels-Ansdell D, Hiralal R, Bhandari M, Guyatt G, Yusuf S, Cook D, Villar JC, McQueen M, McFalls E, Filipovic M, Schünemann H, Sear J, Foex P, Lim W, Landesberg G, Godet G, Poldermans D, Bursi F, Kertai MD, Bhatnagar N, Devereaux PJ. 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
5. Le Manach Y, Perel A, Coriat P, Godet G, Bertrand M, Riou B. Early and delayed myocardial infarction after abdominal aortic surgery. Anesthesiology. 2005;102:885–91
6. Landesberg G, Shatz V, Akopnik I, Wolf YG, Mayer M, Berlatzky Y, Weissman C, Mosseri M. Association of cardiac troponin, CK-MB, and postoperative myocardial ischemia with long-term survival after major vascular surgery. J Am Coll Cardiol. 2003;42:1547–54
7. Smith SC Jr, Benjamin EJ, Bonow RO, Braun LT, Creager MA, Franklin BA, Gibbons RJ, Grundy SM, Hiratzka LF, Jones DW, Lloyd-Jones DM, Minissian M, Mosca L, Peterson ED, Sacco RL, Spertus J, Stein JH, Taubert KA. AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation endorsed by the World Heart Federation and the Preventive Cardiovascular Nurses Association. J Am Coll Cardiol. 2011;58:2432–46
8. Wright RS, Anderson JL, Adams CD, Bridges CR, Casey DE Jr, Ettinger SM, Fesmire FM, Ganiats TG, Jneid H, Lincoff AM, Peterson ED, Philippides GJ, Theroux P, Wenger NK, Zidar JP, Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE Jr, Chavey WE 2nd, Fesmire FM, Hochman JS, Levin TN, Lincoff AM, Peterson ED, Theroux P, Wenger NK, Wright RS. 2011 ACCF/AHA focused update of the Guidelines for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial Infarction (updating the 2007 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in collaboration with the American College of Emergency Physicians, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2011;57:1920–59
9. Devereaux PJ, Yang H, Yusuf S, Guyatt G, Leslie K, Villar JC, Xavier D, Chrolavicius S, Greenspan L, Pogue J, Pais P, Liu L, Xu S, Malaga G, Avezum A, Chan M, Montori VM, Jacka M, Choi P. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial. Lancet. 2008;371:1839–47
10. Juul AB, Wetterslev J, Gluud C, Kofoed-Enevoldsen A, Jensen G, Callesen T, Nørgaard P, Fruergaard K, Bestle M, Vedelsdal R, Miran A, Jacobsen J, Roed J, Mortensen MB, Jørgensen L, Jørgensen J, Rovsing ML, Petersen PL, Pott F, Haas M, Albret R, Nielsen LL, Johansson G, Stjernholm P, Mølgaard Y, Foss NB, Elkjaer J, Dehlie B, Boysen K, Zaric D, Munksgaard A, Madsen JB, Øberg B, Khanykin B, Blemmer T, Yndgaard S, Perko G, Wang LP, Winkel P, Hilden J, Jensen P, Salas NDIPOM Trial Group. . Effect of perioperative beta blockade in patients with diabetes undergoing major non-cardiac surgery: randomised placebo controlled, blinded multicentre trial. BMJ. 2006;332:1482
11. Feringa HH, Bax JJ, Schouten O, Poldermans D. Protecting the heart with cardiac medication in patients with left ventricular dysfunction undergoing major noncardiac vascular surgery. Semin Cardiothorac Vasc Anesth. 2006;10:25–31
12. Barrett TW, Newton K, Koudelka C, Mori M, Radcliffe L. Impact of combination medical therapy on mortality in vascular surgery patients. J Hosp Med. 2010;5:218–25
13. von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JPSTROBE Initiative. . The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet. 2007;370:1453–7
14. Godet G, Riou B, Bertrand M, Fléron MH, Goarin JP, Montalescot G, Coriat P. Does preoperative coronary angioplasty improve perioperative cardiac outcome? Anesthesiology. 2005;102:739–46
15. Le Manach Y, Godet G, Coriat P, Martinon C, Bertrand M, Fléron MH, Riou B. The impact of postoperative discontinuation or continuation of chronic statin therapy on cardiac outcome after major vascular surgery. Anesth Analg. 2007;104:1326–33
16. Eagle KA, Berger PB, Calkins H, Chaitman BR, Ewy GA, Fleischmann KE, Fleisher LA, Froehlich JB, Gusberg RJ, Leppo JA, Ryan T, Schlant RC, Winters WL Jr, Gibbons RJ, Antman EM, Alpert JS, Faxon DP, Fuster V, Gregoratos G, Jacobs AK, Hiratzka LF, Russell RO, Smith SC JrAmerican College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1996 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery). . ACC/AHA guideline update for perioperative cardiovascular evaluation for noncardiac surgery—executive summary a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1996 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery). Circulation. 2002;105:1257–67
17. Fleisher LA, Beckman JA, Brown KA, Calkins H, Chaikof EL, Chaikof E, Fleischmann KE, Freeman WK, Froehlich JB, Kasper EK, Kersten JR, Riegel B, Robb JF, Smith SC Jr, Jacobs AK, Adams CD, Anderson JL, Antman EM, Buller CE, Creager MA, Ettinger SM, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Hunt SA, Lytle BW, Nishimura R, Ornato JP, Page RL, Riegel B, Tarkington LG, Yancy CW. ACC/AHA 2007 Guidelines on Perioperative Cardiovascular Evaluation and Care for Noncardiac Surgery: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery) Developed in Collaboration With the American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Rhythm Society, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, and Society for Vascular Surgery. J Am Coll Cardiol. 2007;50:1707–32
18. Luepker RV, Apple FS, Christenson RH, Crow RS, Fortmann SP, Goff D, Goldberg RJ, Hand MM, Jaffe AS, Julian DG, Levy D, Manolio T, Mendis S, Mensah G, Pajak A, Prineas RJ, Reddy KS, Roger VL, Rosamond WD, Shahar E, Sharrett AR, Sorlie P, Tunstall-Pedoe HAHA Council on Epidemiology and Prevention; AHA Statistics Committee; World Heart Federation Council on Epidemiology and Prevention; European Society of Cardiology Working Group on Epidemiology and Prevention; Centers for Disease Control and Prevention; National Heart, Lung, and Blood Institute. . Case definitions for acute coronary heart disease in epidemiology and clinical research studies: a statement from the AHA Council on Epidemiology and Prevention; AHA Statistics Committee; World Heart Federation Council on Epidemiology and Prevention; the European Society of Cardiology Working Group on Epidemiology and Prevention; Centers for Disease Control and Prevention; and the National Heart, Lung, and Blood Institute. Circulation. 2003;108:2543–9
19. Apple FS, Parvin CA, Buechler KF, Christenson RH, Wu AH, Jaffe AS. Validation of the 99th percentile cutoff independent of assay imprecision (CV) for cardiac troponin monitoring for ruling out myocardial infarction. Clin Chem. 2005;51:2198–200
20. Thygesen K, Alpert JS, White HDJoint ESC/ACCF/AHA/WHF Task Force for the Redefinition of Myocardial Infarction. . Universal definition of myocardial infarction. Eur Heart J. 2007;28:2525–38
21. Lee TH, Marcantonio ER, Mangione CM, Thomas EJ, Polanczyk CA, Cook EF, Sugarbaker DJ, Donaldson MC, Poss R, Ho KK, Ludwig LE, Pedan A, Goldman L. Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation. 1999;100:1043–9
22. Fraker TD Jr, Fihn SD, Gibbons RJ, Abrams J, Chatterjee K, Daley J, Deedwania PC, Douglas JS, Ferguson TB Jr, Fihn SD, Fraker TD Jr, Gardin JM, O’Rourke RA, Pasternak RC, Williams SV, Smith SC Jr, Jacobs AK, Adams CD, Anderson JL, Buller CE, Creager MA, Ettinger SM, Halperin JL, Hunt SA, Krumholz HM, Kushner FG, Lytle BW, Nishimura R, Page RL, Riegel B, Tarkington LG, Yancy CWAmerican College of Cardiology; American Heart Association; American College of Cardiology/American Heart Association Task Force on Practice Guidelines Writing Group. . 2007 chronic angina focused update of the ACC/AHA 2002 Guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Writing Group to develop the focused update of the 2002 Guidelines for the management of patients with chronic stable angina. Circulation. 2007;116:2762–72
23. Kheterpal S, O’Reilly M, Englesbe MJ, Rosenberg AL, Shanks AM, Zhang L, Rothman ED, Campbell DA, Tremper KK. Preoperative and intraoperative predictors of cardiac adverse events after general, vascular, and urological surgery. Anesthesiology. 2009;110:58–66
25. Kim LJ, Martinez EA, Faraday N, Dorman T, Fleisher LA, Perler BA, Williams GM, Chan D, Pronovost PJ. Cardiac troponin I predicts short-term mortality in vascular surgery patients. Circulation. 2002;106:2366–71
26. Dalal H, Evans PH, Campbell JL. Recent developments in secondary prevention and cardiac rehabilitation after acute myocardial infarction. BMJ. 2004;328:693–7
27. Brady AJ, Oliver MA, Pittard JB. Secondary prevention in 24, 431 patients with coronary heart disease: survey in primary care. BMJ. 2001;322:1463
28. Murchie P, Campbell NC, Ritchie LD, Simpson JA, Thain J. Secondary prevention clinics for coronary heart disease: four year follow up of a randomised controlled trial in primary care. BMJ. 2003;326:84
29. Landesberg G, Mosseri M, Wolf Y, Vesselov Y, Weissman C. Perioperative myocardial ischemia and infarction: identification by continuous 12-lead electrocardiogram with online ST-segment monitoring. Anesthesiology. 2002;96:264–70
30. Le Manach Y, Coriat P, Collard CD, Riedel B. Statin therapy within the perioperative period. Anesthesiology. 2008;108:1141–6
31. Le Manach Y, Ibanez Esteves C, Bertrand M, Goarin JP, Fléron MH, Coriat P, Koskas F, Riou B, Landais P. Impact of preoperative statin therapy on adverse postoperative outcomes in patients undergoing vascular surgery. Anesthesiology. 2011;114:98–104
32. Hamm CW, Giannitsis E, Katus HA. Cardiac troponin elevations in patients without acute coronary syndrome. Circulation. 2002;106:2871–2
33. Melanson SE, Morrow DA, Jarolim P. Earlier detection of myocardial injury in a preliminary evaluation using a new troponin I assay with improved sensitivity. Am J Clin Pathol. 2007;128:282–6
34. Roongsritong C, Warraich I, Bradley C. Common causes of troponin elevations in the absence of acute myocardial infarction: incidence and clinical significance. Chest. 2004;125:1877–84