Cardiac Events after Noncardiac Surgery in Patients Undergoing Preoperative Dobutamine Stress Echocardiography: Findings From the Mayo Poce-DSE Investigators

Accepted Manuscript Title: Cardiac Events after Non-Cardiac Surgery in Patients Undergoing PreOperative Dobutamine Stress Echocardiography Findings From the Mayo Poce-DSE Investigators Author: R. Jay Widmer, Michael W. Cullen, Bradley R. Salonen, Karna K. Sundsted, David Raslau, Arya B. Mohabbat, Brian M. Dougan, D. Mike Bierle, Donna K. Lawson, A. Jimmy Widmer, Mary Bundrick, Prakriti Gaba, Rene Tellez, Darrell R. Schroeder, Robert B. McCully, Karen F. Mauck PII: DOI: Reference:

S0002-9343(18)30014-7 https://doi.org/10.1016/j.amjmed.2017.12.025 AJM 14464

To appear in:

The American Journal of Medicine

Please cite this article as: R. Jay Widmer, Michael W. Cullen, Bradley R. Salonen, Karna K. Sundsted, David Raslau, Arya B. Mohabbat, Brian M. Dougan, D. Mike Bierle, Donna K. Lawson, A. Jimmy Widmer, Mary Bundrick, Prakriti Gaba, Rene Tellez, Darrell R. Schroeder, Robert B. McCully, Karen F. Mauck, Cardiac Events after Non-Cardiac Surgery in Patients Undergoing Pre-Operative Dobutamine Stress Echocardiography Findings From the Mayo PoceDSE Investigators, The American Journal of Medicine (2018), https://doi.org/10.1016/j.amjmed.2017.12.025. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Cardiac events after non-cardiac surgery in patients undergoing preoperative dobutamine stress echocardiography Findings from the Mayo POCE-DSE investigators R. Jay Widmer, MD/PhD.a, Michael W. Cullen, MD.a, Bradley R. Salonen, MD.b, Karna K. Sundsted, MD.b, David Raslau, MD, MPH.b, Arya B. Mohabbat, MD.b, Brian M. Dougan, MD.b, D. Mike Bierle, MD.b, Donna K. Lawson, CCRP/LPN.c, A. Jimmy Widmer, MD, MPHd, Mary Bundrick, MSe, Prakriti Gabaf, Rene Tellezg, MD., Darrell R. Schroeder, MS.h, Robert B. McCully, MD.a, Karen F. Mauck, MD, MSc.b From: a. Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN b. Department of Internal Medicine, Division of General Internal Medicine, Mayo Clinic, Rochester MN c. Department of Internal Medicine, Division of Hospital Internal Medicine, Mayo Clinic, Rochester, MN d. Department of Internal Medicine, Baylor Scott and White Health, Central Texas e. Mary Bundrick, AbbVie, Inc., Chicago, IL f. Medical Student, Mayo Medical School, Rochester, MN g. Resident, General Surgery Residency Program, University of California, Irvine, CA h. Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN Word Count: Abstract - 250; Text – 2,974, Figures - 2; Tables - 3; References – 10 Running Head: Dobutamine Stress Echocardiography and perioperative events Funding Source: Mayo Clinic Department of General Internal Medicine Conflict of Interest: None All authors had access to the data and a role in writing the manuscript

Karen F. Mauck, MD 200 1st St, SW Rochester MN Ph: 507-284-2511 [email protected]

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Clinical Significance: 

Cardiac event rates including myocardial infarction, cardiac arrest, and death in this large, tertiary care pre-operative patient population are 2.3% among all patients



In low-risk surgical subtypes there were no major cardiac events.



The previously accepted construct of low, intermediate and high risk surgeries based on risk of major postoperative cardiac outcomes of <1%, 1-5%, and > 5% overestimate event rates in contemporary surgical settings.

Abstract: Background: Current guidelines support the use of dobutamine stress echocardiography (DSE) prior to non-cardiac surgery in higher risk patients who are unable to perform at least 4 metabolic equivalents of physical activity. We evaluated post-operative outcomes of patients in different operative risk categories after pre-operative DSE. Methods: We collected data from the medical record on 4,494 patients from January 1, 2006 to December 31, 2011 who had DSE up to 90 days prior to a non-cardiac surgery. Patients were divided into low, intermediate, and high pre-operative surgery-specific risk. Baseline demographic data and risk factors were abstracted from the medical record as were postoperative cardiac events including myocardial infarction, cardiac arrest, and mortality within 30 days after surgery.

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Results: There were 103 cardiac outcomes (2.3%), which included myocardial infarction (n=57, 1.3%), resuscitated cardiac arrest (n=26, 0.6%), and all-cause mortality (n=40, 0.9%). Cardiac event rates were 0.0% (95% C.I. 0.0% to 3.9%) in the low surgical risk group, 2.1% (95% C.I. 1.6% to 2.5%) in the intermediate surgical risk group, and 3.4% (95% C.I. 2.0% to 4.4%) in the high risk group. Thirty day post-operative mortality rates were 0%, 0.9%, and 0.8% for the low-risk, intermediate-risk, and high-risk surgical groups, respectively, and were not statistically different. Conclusions: These findings demonstrate low cardiac event rates in patients who underwent a DSE prior to non-cardiac surgery. The previously accepted construct of low, intermediate and high risk surgeries based on postoperative events of <1%, 1-5%, and > 5% overestimates the actual risk in contemporary settings. Key Words: perioperative medicine, dobutamine stress echocardiography, surgical outcomes

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Introduction: Patients undergoing surgery are increasingly older with more comorbidities contributing to operative risk (1). Patients undergoing non-cardiac surgery are at risk for adverse cardiac events including myocardial infarction, cardiac arrest, and death within 30 days after surgery. The reported incidence of major adverse cardiac events after non-cardiac surgery varies from 1.4% to 7.4%, depending on the definition of events and populations studied 1. Postoperative major adverse cardiac events rates from pooled data evaluating patients who had or were at risk for coronary artery disease was reported to be 3.9% (95% CI 3.3%-4.6%)2. However, these studies represented surgeries performed before 2000. Data on postoperative major adverse cardiac events in a more contemporary population of surgical patients is needed to account for the effect of surgical advances in the last two decades. Preoperative cardiac evaluation can identify higher risk patients for whom risk reduction strategies can minimize postoperative major adverse cardiac events (1-3). Current and prior guidelines support considering use of non-invasive stress testing in patients with an estimated risk of major adverse cardiac events of >1% and poor functional capacity (<4 metabolic equivalents)(4). However, there is a paucity of data available on postoperative cardiac outcomes from large patient populations who undergo dobutamine stress echocardiography (DSE) prior to non-cardiac surgery, and event rates after pre-operative risk stratification with DSE in the current era require further investigation. Our objective was to characterize the use of DSE and to describe the rate of post-operative major adverse cardiac outcomes in a contemporary patient population undergoing non-cardiac surgery.

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Methods: Patient Selection After approval from the Mayo Clinic Institutional Review Board, we identified patients who had a DSE performed for the indication of “pre-operative evaluation” from January 1, 2006 – December 31, 2011. Patients who did not undergo DSE for pre-operative evaluation purposes were excluded, as were patients who did not undergo non-cardiac surgery within 90 days of the DSE or those who underwent cardiac surgery. Patients who underwent DSE evaluation as part of solid organ transplantation were included if they underwent non-cardiac surgery within 90 days of the DSE. Also excluded were patients who underwent a second surgical procedure requiring general anesthesia within 30 days of the index surgical procedure, and those who had a cardiac event after the DSE but prior to the planned surgical procedure (Figure 1). Definition of Variables We collated patient demographic and anthropomorphic data, details of the surgical procedure, pre-operative comorbidities (heart failure, prior cardiovascular events, renal disease, stroke, diabetes requiring insulin, and others). Additionally, we recorded functional status, American Society of Anesthesiology (ASA) score, medications at the time of surgery, and any coronary revascularization done prior to surgical procedure. Functional status was estimated using the Duke Activity Status Index(5). Patients were placed into one of two categories based on ability to perform greater than or equal to four metabolic equivalents and those patients who could not perform four metabolic equivalents or functional capacity could not be identified in the medical record. Surgical procedures were grouped into categories defined by the American

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College of Surgery National Surgical Quality Improvement Program; these categories were used in the development of the Gupta risk score(6). Surgeries were also categorized by surgical risk, using the convention of low, intermediate and high risk categories used in previous versions of the ACC/AHA guidelines(3). Low risk surgeries were those with a combined incidence of cardiac death or nonfatal myocardial infarction less than 1% (eye, skin, breast, endoscopic procedures, etc). High-risk surgeries were those with a combined incidence of cardiac death or nonfatal myocardial infarction of 5% or greater (peripheral vascular and aortic surgeries, but not carotid endarterectomies). Intermediate risk surgeries were those with a risk between 1%-5% (carotid endarterectomies, and most other major surgical procedures)(4). Modified revised cardiac risk index (RCRI) components included history of coronary artery disease, congestive heart failure , diabetes requiring insulin, creatinine >2 mg/dl, and history of cerebrovascular disease(7). We did not take into account “high-risk surgical procedure” in our RCRI scoring system, in order to mirror how the RCRI was used in the AHA/ ACC guidelines(4). The components of the Gupta cardiac risk calculator utilized were 1) type of surgical procedure 2) functional status 3) creatinine 4) ASA class and 5) age(6). We identified patients meeting our inclusion criteria in the Mayo Clinic DSE database(8). DSE data included hemodynamic parameters, left ventricular function and regional wall motion at both rest and stress. DSE results were classified into four categories: normal, fixed, mixed, and ischemic. Patients with normal DSE results had normal left ventricular regional and global systolic function at baseline and no stress-induced regional wall motion abnormalities . Patients who had wall motion abnormalities at baseline that were unchanged with stress had a ‘fixed’ abnormality. Patients who had wall motion abnormalities at baseline and who developed new

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or worsening wall motion abnormalities with stress had a ‘mixed’ abnormality. Patients who had no wall motion abnormalities at baseline but new wall motion abnormalities with stress had an ‘ischemic’ abnormality. Patients who had DSE results that were positive for ischemia were those with a ‘mixed’ or an ‘ischemic’ abnormality. Patients in the ischemic, mixed, and fixed categories were considered abnormal. Patients in whom findings were consistent with dilated cardiomyopathy were considered ‘fixed’. The primary outcome was a composite of post-operative myocardial infarction, cardiac arrest, and all-cause mortality within 30 days after surgery. was defined as such if it occurred during or after surgery and manifested by electrocardiogram changes indicative of acute myocardial infarction (ST elevation >1 mm in two or more contiguous leads, new left bundle branch, or new Q-wave in two of more contiguous leads), a new elevation of troponin-T more than three times the upper level of the reference range in the setting of suspected myocardial ischemia, or physician diagnosis of myocardial infarction as noted in the electronic medical record. Cardiac arrest was verified by chart review with documentation of basic and/or advanced cardiac life support to reverse cardiac rhythms incompatible with life. Data Collection All clinical data, including baseline, surgical, and postoperative information, was collected from medical record review. Patient records, including all pertinent study information, were assigned unique patient identifier codes to provide anonymity and confidentiality. All data were entered into a uniquely designed and secure online data management system (REDCap, Vanderbilt

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University, 2016(9)) on a password protected secure institutional computer. Nurse data abstractors performed the initial review, and the primary authors confirmed these data. Data Analysis Data are summarized using mean ± standard deviation for continuous variables and frequency counts and percentages for categorical variables. Summaries are provided overall and also according to surgical risk categories (low, intermediate, high). Patient and procedural characteristics were compared across the three surgical risk groups using analysis of variance (ANOVA) for continuous variables and the chi-square test for categorical variables. The frequencies of post-operative cardiac events are summarized overall and according to surgical risk groups using point estimates and corresponding 95% confidence intervals. The frequency of any cardiovascular complication was compared across risk groups using the Cochran-Armitage Trend Test. Supplemental analyses were performed according to surgical risk group to compare the frequency of cardiovascular complications according to DSE result (normal, ischemic, fixed, mixed) and functional status (≥ 4 or < 4 metabolic equivalents). In all cases, two-tailed p-values <0.05 were considered statistically significant. Results: Of the 8,276 patients meeting initial inclusion criteria, patients were excluded for the following reasons: no surgery within 90 days (n=3,342) or second surgical procedure within 30 days after the index surgery (n=421) (Figure 1).

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Of those who did not undergo surgery within 90 days, most (1,853, 55%) were undergoing a solid organ transplantation evaluation. A small minority of those not undergoing surgery within 90 days had surgery cancelled or postponed as a result of an abnormal DSE (203, 6%). Sixteen patients died before their planned non-cardiac surgery. Results of baseline demographics with comorbidities are provided in Table 1. The average age in our cohort was 70 years; 56% were male. There was no difference in age across the surgical risk groups. Male gender, weight, hyperlipidemia, and smoking status were more prevalent in the intermediate- and high-risk surgical groups as were other comorbidities, such as prior coronary artery bypass graft surgery , vascular disease, diabetes, and chronic obstructive pulmonary disease. ASA score, modified RCRI score, and Gupta scores were all significantly different across the groups and more likely to be elevated in those undergoing higher risk procedures. The majority of patients had a normal DSE result (66%). Of the abnormal DSEs, 13% were fixed, 11% mixed, and 10% ischemic. Patients in the high surgical risk category were more likely to have an abnormal DSE compared to those in the low and intermediate risk categories. Pre-operative medications, stratified by surgical risk, are shown in Supplemental Table 1. Patients undergoing high-risk surgeries were more likely to be on an intensive outpatient cardiovascular regimen, including angiotensin converting enzyme inhibitors or angiotensin receptor blockers (ACEI/ARBs), beta-blockers, statins, aspirin, and clopidogrel.

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The specific types of surgery are reported in Table 2.The most common surgical procedures performed were orthopedic (24%), peripheral vascular (16%), urologic (10%), aortic (9%), and forgut/hepatopancreatobiliary (8%). Cardiac event rates are presented in Table 3 and Figure 2, and were greater in patients with higher surgical risk (Trend Test P=.01); event rates were 0.0% (95% C.I. 0.0% to 3.9%) in the low risk group, 2.1% (95% C.I. 1.6% to 2.5%) in the intermediate risk group, and 3.4% (95% C.I. 2.0% to 4.4%) in the high risk group. The difference across groups was largely driven by a higher rate of myocardial infarction (1.0% and 2.4% for the intermediate- and high-risk groups, respectively; P<.001). Rates of cardiac arrest and 30-day mortality were not significantly different across risk groups (p=0.52 and 0.99, respectively). Among patients in the intermediate surgical risk category, the cardiac event rates according to DSE result were 1.4% (32/2375), 3.2% (14/441), 5.0% (19/377) and 2.5% (8/321) for normal, fixed, mixed, and ischemic, results respectively (P<.001). Among those undergoing high risk surgery, the corresponding cardiac event rates were 1.8% (9/510), 4.6% (7/153), 8.7% (11/127) and 3.1% (3/96), respectively (P<.001). The cardiac event rates in patients undergoing intermediate risk surgery who could perform 4 metabolic equivalents or greater was 1.8% (25/1425) compared to 2.3% (48/2089) for who could perform less than 4 metabolic equivalents (or unknown) (P=.27). In patients undergoing high-risk surgery, those who could perform 4 metabolic equivalents or greater had a cardiac event rate of 1.9% (7/372) and for those that could perform less than 4 metabolic equivalents (or unknown) the rate was 4.5% (23/514) (P=.04).

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Of the 203 patients who had surgery cancelled as a result of the result of their DSE, the mean age was 68.5±11.0 years with 69% being male. Additionally, 3% had a normal DSE, 5% had a fixed defect, 53% had a mixed result, and 38% had an ischemic result. Of these patients, 121 (60%)went on to cardiac catheterization and 55 (27%) underwent subsequent coronary revascularization.

Discussion: Herein, we present a large single-center retrospective cohort study of post-operative major adverse cardiac events stratified by surgical risk category for patients who underwent DSE from 2006 to 2011 prior to non-cardiac surgery. These results show patients who undergo higher-risk surgeries have more traditional cardiac risk factors, are more likely to be on a comprehensive cardiovascular medication regimen, and have DSE findings that are suggestive of obstructive coronary artery disease. We also demonstrate post-operative events – namely post-operative myocardial infarction – occur at a low rate (2-3%), even in higher-risk patients undergoing highrisk surgery. Moreover, these data demonstrate that patients undergoing low-risk surgeries, regardless of underlying risk, have a negligibly low risk of post-operative events. These data provide important information regarding the risk of post-operative events across different surgical risk strata. Our findings support the recommendations in the the current version of the AHA/ACC perioperative cardiovascular risk assessment guideline to no longer stratify surgical risk into three risk groups (low, intermediate, or high)(4). Surgical risk is now incorporated into the

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clinical decision algorithm by accounting for it in the combined clinical/surgical risk calculators. Current guidelines recommend that additional cardiac testing is only recommended in patients who have a combined clinical/surgical risk of major adverse cardiac events in excess of 1% and not able to achieve 4 metabolic equivalents without symptoms. Additionally, our data demonstrate a very low risk of cardiac outcomes in patients undergoing low risk surgery (<1%) and a higher risk of cardiac outcomes in those who have surgical risk >1%. Indeed, there were no cardiac events in any patient undergoing low risk surgical procedures in our study, suggesting that the DSE is not necessary for stratifying risk in this group. Our data also suggest that the prior categorization of surgeries into low (<1%), intermediate (1%-5%) and high (>5%) risk may have overestimated the risk of cardiac outcomes in patients undergoing intermediate and high risk surgeries. In our cohort of patients, the overall major adverse cardiac events rate across all three surgical risk categories was 2.3%. This composite outcome rate is slightly higher than that reported in a 1999 publication where Lee and colleagues estimated the incidence of major postoperative cardiac events at 1.4% among unselected adults undergoing noncardiac (non-emergent) surgery that required hospitalization (10). One might have even expected a higher outcome rate than 3.4% in the higher-risk cohort who were preselected for preoperative DSE secondary to their established comorbidities. The important point is that the risk categories previously employed likely overestimate the true risk of postoperative cardiac outcomes in a contemporary surgical population. Not surprisingly, in patients undergoing higher-risk surgeries, we found a higher prevalence of risk factors such as hyperlipidemia, prior bypass grafting, diabetes, lung disease, renal disease, and smoking. This is consistent with the fact that high-risk surgeries are vascular in nature are

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closely associated with cardiovascular disease and attendant risk factors. Of interest, there was no age difference across the surgical risk groups in our study. It is likely that a preoperative DSE was requested more often in older patients with comorbid disease and increased cardiac risk. This might explain why we did not see a variation in outcomes based on age in the three risk categories. Only 54% of patients who had preoperative DSE underwent non-cardiac surgery within 90 days. When analyzed, the 46% of patients who had a preoperative DSE performed but no surgery within 90 days, we found that most of these patients were undergoing a routine solid organ transplant evaluation (54%) for which a DSE is a standard part of the pre-transplant workup. Importantly, only 6% of all patients who did not go on to surgery were postponed or cancelled as a result of the DSE findings. As with any retrospective analysis, these data do have the potential referral and selection bias which may limit generalizability. Mayo Clinic is a tertiary referral hospital that draws patients from regional, national, and international populations. All patients in this cohort were identified by having a DSE prior to surgery, making it likely that our cohort could represent a higher risk group of patients than the general population of surgical patients. Additionally, we only chose to include those patients who had their surgical procedure within 90 days of the preoperative DSE. This was to attempt to control for any new symptoms or comorbid conditions that might have developed from the time of the DSE and the surgery. In some cases, however, this also excluded patients who had their surgery postponed because of the need for additional cardiac intervention.

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In conclusion, we describe the characteristics and post-operative outcomes of a large contemporary cohort of patients who underwent pre-operative DSE before non-cardiac surgery. Notably, this cohort of patients undergoing a variety of surgical procedures across various risk strata had low overall post-operative cardiac events, even those undergoing highrisk surgery. Furthermore, patients undergoing low-risk surgeries, regardless of their RCRI or Gupta scores, have an exceedingly low risk of post-operative events. These data support the established role for DSE in pre-operative risk stratification for non-cardiac surgery in selected patients who are undergoing non-cardiac surgery with a greater than 1% risk of post-operative major cardiac outcomes. In addition, our data suggest that the construct of low, intermediate and high risk surgeries based on risk of major postoperative cardiac outcomes of <1%, 1-5%, and >5% likely overestimates the actual risk of intermediate and high-risk surgeries in contemporary surgical settings.

Acknowledgements: We would like to thank Donna Larson and her team of nurse abstractors who are part of the return to work program at Mayo Clinic for their countless hours abstracting scores of data on thousands of patients. We would also like to thank the generous statistical support as provided by the Department of Medicine Clinical Research Office.

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References: 1. Devereaux P, Sessler, DI. Cardiac Complications in Patients Undergoing Major Noncardiac Surgery. N Engl J Med. 2015;373(23):2258-69. 2. Fleisher L, Fleischmann, KE, Auerbach, AD, Barnason, SA, Beckman, JA, Bozkurt, B, DavilaRoman, VG, Gerhard-Herman, MD, Holly, TA, Kane, GC, Marine, JE, Nelson, MT, Spencer, CC, Thompson, A, Ting, HH, Uretsky, BF, Wijeysundera, DN; American College of Cardiology; American Heart Association. 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines. J Am Coll Cardiol. 2014;64(22):e77-137. 3. Fleisher L, Beckman, JA, Brown, KA, Calkins, H, Chaikof, E, Fleischmann, KE, Freeman, WK, Froehlich, JB, Kasper, EK, Kersten, JR, Riegel, B, Robb, JF; ACC/AHA TASK FORCE MEMBERS, 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. Circulation. 2007;116(17):11971-1996. 4. Fleisher L, Fleischmann, KE, Auerbach, AD, Barnason, SA, Beckman, JA, Bozkurt, B, DavilaRoman, VG, Gerhard-Herman, MD, Holly, TA, Kane, GC, Marine, JE, Nelson, MT, Spencer, CC, Thompson, A, Ting, HH, Uretsky, BF, Wijeysundera, DN; American College of Cardiology; American Heart Association. 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines. J Am Coll Cardiol. 2014;64(22):e77-e177. 5. Hlatky M, Boineau, RE, Higginbotham, MB, Lee, KL, Mark, DB, Califf, RM, Cobb, FR, Pryor, DB. A brief self-administered questionnaire to determine functional capacity (the Duke Activity Status Index). Am J Cardiol. 1989;64(10):651-4. 6. Gupta P, Gupta, H, Sundaram, A, Kaushik, M, Fang, X, Miller, WJ, Esterbrooks, DJ, Hunter, CB, Pipinos, II, Johanning, JM, Lynch, TG, Forse, RA, Mohiuddin, SM, Mooss, AN. Development and validation of a risk calculator for prediction of cardiac risk after surgery. Circulation. 2011;124(4):381-7. 7. Eagle KA, Rihal CS, Mickel MC, Holmes DR, Foster ED, Gersh BJ, et al. Cardiac Risk of Noncardiac Surgery: Influence of Coronary Disease and Type of Surgery in 3368 Operations. Circulation. 1997;96(6):1882-7. 8. Das M, Pellikka, PA, Mahoney, DW, Roger, VL, Oh, JK, McCully, RB, Seward, JB. Assessment of cardiac risk before nonvascular surgery: dobutamine stress echocardiography in 530 patients. J Am Coll Cardiol. 2000;35(6):1647-53. 9. Harris P, Taylor, R, Thielke, R, Payne, J, Gonzalez, N, Conde, JG. Research electronic data capture (REDCap) - A metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42(2):377-81. 10. Lee T, Marcantonio, ER, Mangione, CM, Thomas, EJ, Polanczyk, CA, Cook, EF, Sugarbaker, DJ, Donaldson, MC, Poss, R, Ho, KK, Ludwig, LE. Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation. 1999;100(10):1043-9.

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Figures AJM DSE:

Figure 1: CONSORT-style flow-chart in patient selection for data analysis.

8,276 Preoperative DSEs identified

421 Patients with second operation within 30 days

3,342 No surgery within 90 days

19 Miscellaneous

- 1,853 Pre-Transplant

- 336 No surgery needed - 311 Surgery postponed, non-cardiac - 203 Surgery postponsed, cardiac reasons - 290 Surgery performed under local anesthesia - 202 Surgery declined by patient - 81 Surgery performed elsewhere - 50 Unknown/Other - 16 Died after DSE and prior to surgery

4,494 Patients with PreOperative DSEs analyzed

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Figure 2: Post-operative cardiac outcomes after non-cardiac surgery in patients undergoing preoperative dobutamine stress echocardiography (DSE) stratified by surgical risk category. The first grouping presents all cardiac events – myocardial infarction, cardiac arrest, and 30-day mortality – in the entire cohort. The subsequent groupings present similar data in patients undergoing low, intermediate, and high-risk surgeries.

4

All Pa ents

Event Rate (%)

3.5

Low Risk Surgery

3

Medium Risk Surgery High Risk Surgery

2.5 2 1.5 1 0.5 0 Any Event

Myocardial Cardiac Arrest Infarc on

30-Day Mortality

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Tables AJM DSE:

Table 1: Patient characteristics

Characteristic Age Gender (male) Weight BMI Hyperlipidemia CAD Prior PCI Prior CABG Heart Failure Cerebrovascular Disease Central Vascular Disease Peripheral Vascular Disease Diabetes (any) Diabetes on Insulin COPD CKD Smoking Current Past Never Metabolic Equivalents (METS) METS < 4 METS > 4 METS Unknown ASA Score Unknown I / II III IV, V Modified RCRI Score 0 1 2 3 >4

Overall (N=4494) 70.0±10.8 2517 (56.0) 86.7±21.9 30.1±6.9 3061 (68.1) 1784 (39.7) 769 (17.1) 643 (14.3) 352 (7.8) 850 (18.9) 674 (15.0) 904 (20.1) 1395 (31.0) 548 (12.2) 680 (15.1) 1087 (24.2)

Surgical Risk Category Low Medium High (N=94) (N=3514) (N=886) 69.7±12.8 70.1±10.9 69.9±10.2 28 (29.8) 1862 (53.0) 627 (70.8) 83.6±22.8 87.4±22.2 84.6±20.4 30.3±7.5 30.5±7.0 28.3±5.8 56 (59.6) 2301 (65.5) 704 (79.5) 25 (26.6) 1344 (38.2) 415 (46.8) 12 (12.8) 596 (17.0) 161 (18.2) 5 (5.3) 456 (13.0) 182 (20.5) 4 (4.3) 290 (8.3) 58 (6.6) 7 (7.5) 607 (17.3) 236 (26.6) 4 (4.3) 218 (6.2) 452 (51.0) 17 (18.1) 406 (11.6) 481 (54.3) 27 (28.7) 1152 (32.8) 216 (24.4) 11 (11.7) 466 (13.3) 71 (8.0) 10 (10.6) 467 (13.3) 203 (22.9) 25 (26.6) 847 (24.1) 215 (24.3)

682 (15.2) 2198 (48.9) 1615 (35.9)

10 (10.4) 38 (40.4) 46 (48.9)

943 (12.6) 1618 (46.0) 1454 (41.4)

P* 0.82 <0.001 0.001 <0.001 <0.001 <0.001 0.37 <0.001 0.10 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.85 <0.001

229 (25.9) 542 (61.2) 115 (13.0) 0.01

2053 (45.7) 1836 (40.9) 605 (13.5)

34 (36.2) 39 (41.5) 21 (22.3)

1602 (45.6) 1425 (40.6) 487 (13.9)

417 (47.1) 372 (42.0) 97 (11.0)

5 (0.1) 999 (22.2) 3255 (72.4) 235 (5.2) 0.85±0.91 1910 (42.5) 1637 (36.4) 706 (15.7) 199 (4.4) 42 (0.9)

0 (0.0) 35 (37.2) 58 (61.7) 1 (1.1) 0.62±0.80 53 (56.4) 26 (27.7) 13 (13.8) 2 (2.10 0 (0.0)

4 (0.1) 898 (25.6) 2422 (68.9) 190 (5.4) 0.84±0.91 1520 (43.3) 1277 (36.3) 527 (15.0) 157 (4.5) 33 (0.9)

1 (0.1) 66 (7.5) 775 (87.5) 44 (5.0) 0.93±0.92 337 (38.0) 334 (37.7) 166 (18.7) 40 (4.5) 9 (1.0)

<0.001

<0.001

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Gupta Score < 1% > 1% Functional Status Totally independent Partially dependent Totally dependent Type of Anesthesia General Regional Combination DSE result Normal Fixed/DCM Mixed Ischemic

0.94±1.30 3133 (69.7) 1361 ( 30.3)

0.24±0.46 88 (93.6) 6 (6.4)

0.85±1.32 2648 (75.4) 866 (24.6)

1.38±1.18 397 (44.8) 489 (55.2)

<0.001

0.002 3853 (85.7) 579 (12.9) 62 (1.4)

84 (89.4) 7 (7.5) 3 (3.2)

2979 (84.8) 982 (13.7) 53 (1.5)

790 (89.2) 90 (10.2) 6 (0.7) <0.001

3673 (81.7) 265 (5.9) 556 (12.4)

90 (95.7) 3 (3.2) 1 (1.1)

2712 (77.2) 256 (7.3) 546 (15.5)

871 (98.3) 6 (0.7) 9 (1.0)

2949 (65.6) 605 (13.5) 512 (11.4) 428 (9.5)

64 (68.1) 11 (11.7) 8 (8.5) 11 (11.7)

2375 (67.6) 441 (12.6) 377 (10.7) 321 (9.1)

510 (57.6) 153 (17.3) 127 (14.3) 96 (10.8)

<0.001

*Characteristics are compared across risk categories using analysis of variance (ANOVA) for continuous variables and the chi-square test for categorical variables.

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Table 2: Surgical Description

Surgical Category Anorectal Aortic Bariatric Brain Breast Ear Nose and Throat Foregut and Hepatopancreatobilliary* Gallbladder, Appendix, Adrenals, Spleen Gynecologic Hernia Intestine Neck Non-esophageal Thoracic** Orthopedic Other Abdomen Peripheral Vascular Skin Spinal Urology*** Veins

Overall (N=4494) 49 (1.1) 398 (8.9) 18 (0.4) 47 (1.1) 50 (1.1) 108 (2.4) 356 (7.9) 85 (1.9) 161 (3.6) 71 (1.6) 208 (4.6) 50 (1.1) 230 (5.1) 1079 (24.0) 138 (3.1) 719 (16.0) 23 (0.5) 246 (5.5) 437 (9.7) 21 (0.5)

Surgical Risk Category Low Medium High (N=94) (N=3514) (N=886) 49 (1.4) 398 (44.9) 18 (0.5) 47 (1.3) 50 (53.2) 108 (3.1) 356 (10.1) 85 (2.4) 161 (4.6) 71 (2.0) 208 (5.9) 50 (1.4) 230 (6.5) 1079 (30.7) 138 (3.9) 231 (6.6) 488 (55.1) 23 (24.5) 246 (7.0) 437 (12.4) 21 (22.3)

*Includes 71 liver transplants, 8 combined liver/kidney transplants, and 2 pancreas transplants. **Includes 1 lung transplant. ***Includes 70 kidney transplants.

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Table 3: Outcomes

Cardiac Outcome Any event Myocardial Infarction Cardiac Arrest 30-day mortality

Overall (N=4494) 103 (2.3) 57 (1.3) 26 (0.6) 40 (0.9)

Surgical Risk Category Low Medium High (N=94) (N=3514) (N=886) 0 (0.0) 73 (2.1) 30 (3.4) 0 (0.0) 36 (1.0) 21 (2.4) 0 (0.0) 20 (0.6) 6 (0.7) 0 (0.0) 33 (0.9) 7 (0.8)

P* 0.006 <0.001 0.52 0.99

Surgical Risk Category Low Medium High (N=94) (N=3514) (N=886) 40 (42.6) 1526 (43.4) 435 (49.1) 25 (26.6) 816 (23.2) 230 (26.0) 49 (52.1) 1991 (56.6) 567 (64.0) 2 (2.1) 162 (4.6) 30 (3.4) 42 (44.7) 1805 (51.4) 573 (64.7) 46 (48.9) 1857 (52.8) 618 (69.8) 1 (1.1) 257 (7.3) 118 (13.3) 4 (4.3) 348 (9.9) 73 (8.2) 9 (9.6) 413 (11.8) 106 (12.0)

P* 0.009 0.19 <0.001 0.16 <0.001 <0.001 <0.001 0.07 0.79

*Cochran-Armitage Trend Test

Supplemental Table AJM DSE:

Supplemental Table 1: Perioperative Medications

Medication ACEI/ARB Calcium Channel Blocker Beta-blocker Digoxin Statins ASA Clopidogrel Nitrate Warfarin

Overall (N=4494) 2001 (44.5) 1071 (23.8) 2607 (58.0) 194 (4.3) 2420 (53.8) 2521 (56.1) 376 (8.4) 425 (9.5) 528 (11.8)

*Chi-square test

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