Incremental Risk of Prior Coronary Arterial Stents for Pulmonary Resection

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1 Incremental Risk of Prior Coronary Arterial Stents for Pulmonary Resection Felix G. Fernandez, MD, Traves D. Crabtree, MD, Jingxia Liu, PhD, and Bryan F. Meyers, MD, MPH Section of General Thoracic Surgery, Emory University School of Medicine, Atlanta, Georgia, and Section of General Thoracic Surgery and Division of Biostatistics, Washington University in St. Louis, St. Louis, Missouri Background. Many patients requiring lung cancer resection have concomitant coronary artery disease. Preoperative coronary artery stenting has been associated with increased risk of cardiac events after noncardiac surgery. Our aim was to determine the incidence of major adverse cardiac events (MACE) in patients undergoing pulmonary resection for lung cancer after percutaneous coronary stenting. Methods. This study uses Surveillance, Epidemiology, and End Results-Medicare data (1998 to 2005). Patients undergoing lung cancer resection within 1 year after coronary stenting were compared with patients without preoperative coronary intervention. The incidence and predictors of MACE within 30 days after surgery were determined. Results. Five hundred nineteen patients underwent lung cancer resection after coronary stenting (stent), and 21,892 patients underwent lung cancer resection without a preceding coronary intervention (no stent). The stent group had higher comorbidity scores (p < ) and more males (66% versus 50%; p < ). There were no differences in age (74 versus 74 years), tumor size (33.7 versus 33.6 mm), stage (53% versus 54% stage I), and resections of lobectomy or greater (83% versus 80%) between stent and no-stent groups (all p > 0.05). Thirtyday MACE and mortality rates were 9.3% and 7.7% in the stent group and 4.9% and 4.6% in the no-stent group (both p < ). Multivariable predictors of MACE were coronary stent, age, male sex, comorbidity score, tumor size, and stage. Conclusions. Patients undergoing lung cancer surgery within 1 year of coronary stenting are at high risk for perioperative MACE. The presence of a coronary stent should be an important component of risk assessment before resection for lung cancer. (Ann Thorac Surg 2013;95: ) 2013 by The Society of Thoracic Surgeons Patients with coronary artery disease (CAD) requiring pulmonary resection for non-small cell lung cancer (NSCLC) can present difficult management problems. A major pulmonary resection may lead to an increased risk of perioperative myocardial infarction (MI) in patients with severe untreated CAD. Coronary revascularization before noncardiac surgery may decrease risk in selected groups of patients [1]. Percutaneous coronary intervention (PCI) with a stent is commonly performed in patients with CAD requiring noncardiac surgery. After stent placement, patients are generally maintained on dual antiplatelet therapy (aspirin and clopidogrel or equivalent) to decrease the risk of stent thrombosis [1 4]. Current practice guidelines recommend continuation of dual antiplatelet therapy for 4 to 6 weeks after bare-metal stent (BMS) placement and 12 months for a drug-eluting stent (DES) [1 3]. Discontinuation of dual antiplatelet therapy for noncardiac surgery before these time points Accepted for publication Jan 11, Presented at the Fifty-ninth Annual Meeting of the Southern Thoracic Surgical Association, Naples, FL, Nov 7 10, Address correspondence to Dr Fernandez, The Emory Clinic, 1365 Clifton Rd NE, Ste A2214, Atlanta, GA 30322; felix.fernandez@ emoryhealthcare.org. is associated with a high risk of major adverse cardiac events (MACE) [5 7]. Operating in the presence of dual anti-platelet therapy may increase the risk of perioperative bleeding complications [4, 8]. The risk of MI in all patients undergoing lung resection for NSCLC is 0.36% according to The Society of Thoracic Surgeons (STS) General Thoracic Surgery Database (GTSD) [9]. A retrospective report from the Mayo Clinic found a MACE rate of 5.4% for noncardiac surgery after PCI with DES [10]. Another study from the same group reported a 5.2% rate of MACE after PCI with a BMS before noncardiac surgery [11]. Finally, Brichon and colleagues [12] found that major lung resection within 3 months of coronary stenting with a BMS was associated with an incidence of 9% of MI and a 3% mortality rate. In this study, we aim to determine the incidence and risk of perioperative MACE in patients undergoing preoperative coronary intervention with a stent before surgical resection of NSCLC. We also compare long-term survival in these patients with those patients not having had a preoperative coronary stent placed. Such data will help risk stratify patients with severe coronary disease requiring intervention before surgical resection of NSCLC by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc

2 Ann Thorac Surg FERNANDEZ ET AL 2013;95: RISK OF PRIOR CORONARY STENTS Abbreviations and Acronyms BMS bare-metal stents CAD coronary artery disease DES drug-eluting stents GTSD General Thoracic Surgery Database MACE major adverse cardiac event MI myocardial infarction NSCLC non-small cell lung cancer PCI percutaneous coronary intervention SEER Surveillance, Epidemiology, and End Results STS The Society of Thoracic Surgeons Patients and Methods We performed a retrospective cohort study using the Surveillance, Epidemiology, and End Results (SEER)- Medicare database to evaluate outcomes in patients with NSCLC treated with pulmonary resection after percutaneous placement of a coronary stent from 1998 through Patients undergoing pulmonary resection without prior placement of a coronary stent within 1 year of surgery served as the control group. The SEER database is a tumor registry sponsored by the National Cancer Institute capturing roughly 14% to 25% of incident tumors in the United States. Medicare beneficiaries within the registry have had their tumor records linked to all their claims data. The quality, validity, and generalizability of the SEER-Medicare data have been described previously [13]. The Washington University Medical Center Human Studies Committee reviewed this study and found it not to constitute human subject research based on the regulatory definition of a human subject; therefore, subsequent review by the Human Studies Committee was not deemed necessary. Among all lung cancer patients from 1998 through 2005 in the SEER-Medicare dataset, the following sequential exclusions were made: patients younger than 66 years, patients treated with therapy other than surgery, and patients with partial fee-for-service or concurrent health maintenance organization enrollment, or both, 1 year before lung cancer diagnosis. Only full fee-for-service beneficiaries not enrolled in other insurance programs would have complete claims records; therefore, all other patients were excluded. Patients who were 65 years old at the time of diagnosis were excluded because they do not have Medicare claims data in the year before diagnosis of lung cancer. Patient, disease, and treatment information were available through the SEER registry and Medicare database. Specifically, placement of a percutaneous coronary stent was determined by querying the Centers for Medicare and Medicaid Services data files for Healthcare Common Procedure Coding System Current Procedural Terminology codes and We considered any coronary stent placed within 1 year preceding lung cancer resection, as our cohort selection criteria described above 1213 included patients with complete Medicare claims data for at least 1 year preceding surgery. This period was selected as clinically relevant also, as American College of Cardiology/American Heart Association guidelines recommend that elective surgery in patients with coronary stents be delayed from 4 to 6 weeks to 12 months, dependent on stent type (BMS versus DES, respectively) [1]. To reduce confounding, any patient undergoing coronary artery bypass grafting after coronary stenting was excluded from analysis. Because DES were approved by the US Food and Drug Administration in 2004, making BMS the most common stent placed during the study period, we consider all types of cardiac stents together in this analysis [14]. For analysis of patient characteristics, indicators of low income or education were based on the lowest quartiles of median income and proportion with a high school education within a given zip code from Census Tract data. Area of residence is stratified into metropolitan, urban, and rural based on population size. Medicare claims within the Physician/Supplier and Outpatient files in the year before diagnosis were used to calculate a Klabunde-modified Charlson Comorbidity Index, which was used for risk adjustment [15]. Tumor size, stage (American Joint Committee on Cancer, 7th edition), and histologic identification were all based on information within 4 months of diagnosis. All tumors were restaged to the American Joint Committee on Cancer, 7th edition. The primary outcome measure was development of perioperative MACE. Major adverse cardiac events were defined as death, ST-elevation MI, non ST-elevation MI, stent thrombosis, and repeat revascularization with either coronary artery bypass grafting, stenting, or angioplasty, as done is prior studies [10, 11]. The perioperative period was defined as from the day of surgery to 30 days postoperative. Occurrence of MACE was determined by the presence of International Classification of Diseases, 9th revision (ICD-9) or Current Procedural Terminology codes within the Medicare Analysis Provider and Review, Outpatient and Physician/Supplier files (Appendix). SAS version 9.3 (SAS Institute, Cary, NC) was used to perform all statistical analysis. Continuous and categorical variables were compared by a Kruskal-Wallis test and the test, respectively. Kaplan-Meier curves were generated that provide unadjusted survival estimates at postoperative points for patients overall and across strata of other variables. Differences among strata were determined by log-rank tests. Cox proportional-hazards models were used to evaluate the relationships between percutaneous coronary stents and MACE while adjusting for patient and tumor characteristics. Variables in Table 1 were selected a priori and examined by means of univariate analysis. Variables with a probability value of less than 0.20 were included in the multivariable analysis. All statistical tests were two-sided using a level of significance of 0.05 for. GENERAL THORACIC

3 1214 FERNANDEZ ET AL Ann Thorac Surg RISK OF PRIOR CORONARY STENTS 2013;95: Table 1. Patient and Disease Characteristics for Stent and No Stent Groups Variable No Stent (n 21,892) Stent (n 519) p Value a Age, years (%) ,551 (29.9) 149 (28.7) ,331 (33.5) 173 (33.3) ,351 (24.4) 140 (27.0) 81 2,659 (12.2) 57 (11.0) Age, years (mean SD) Male (%) 10,960 (50.1) 345 (66.5) Race (%) White 19,552 (89.3) 476 (91.7) Black 1,185 (5.4) 23 (4.4) Other 1,155 (5.3) 20 (3.9) Education (%) b Lowest quartile 16,213 (75.9) 378 (73.7) Census tract percent poverty for all 2000 (%) b Lowest quartile 19,343 (91.3) 467 (91.8) Marital status (%) Married 12,691 (58.0) 348 (67.1) Unmarried/separated/divorced/widowed 8,418 (38.5) 155 (29.9) Missing 783 (3.6) 16 (3.1) Comorbidity index (%) b 0 9,445 (45.4) 141 (27.5) 1 7,074 (34.0) 121 (23.6) 2 2,644 (12.7) 123 (24.0) 3 1,633 (7.9) 127 (24.8) Days from intervention to surgery (mean SD) NA Days from intervention to surgery (%) 0 90 NA 289 (55.7) (44.3) Histology (%) Squamous 6,618 (30.2) 191 (36.8) Adenocarcinoma 12,609 (57.6) 255 (49.1) Large cell 1,078 (4.9) 27 (5.2) Adenosquamous 603 (2.8) 11 (2.1%) NSCLC NOS 984 (4.5) 35 (6.7) Tumor stage (%) b I 11,652 (53.8) 272 (53.0) II 2,252 (10.4) 59 (11.5) III 3,728 (17.2) 101 (19.7) IV 1,149 (5.3) 19 (3.7) NOS 2,882 (13.3) 62 (12.1) Tumor grade (%) Well differentiated 2,329 (10.6) 50 (9.6) Moderately differentiated 8,191 (37.4) 188 (36.2) Poorly differentiated 7,850 (35.9) 205 (39.5) Undifferentiated 857 (3.9) 20 (3.9) Cell type not determined 2,665 (12.2) 56 (10.8) Tumor size (%) b mm 1,058 (9.3) 17 (6.3) mm 4,941 (43.3) 119 (44.1) mm 5,401 (47.4) 134 (49.6) (Continued)

4 Ann Thorac Surg FERNANDEZ ET AL 2013;95: RISK OF PRIOR CORONARY STENTS Table 1. Continued Variable No Stent (n 21,892) Stent (n 519) p Value a Tumor size, mm (mean SD) Tumor location (%) b Right upper lobe 6,045 (29.8) 173 (35.2) Right middle lobe 925 (4.6) 21 (4.3) Right lower lobe 3,537 (17.4) 82 (16.7) Left upper lobe 5,230 (25.8) 123 (25.0) Left lower lobe 2,878 (14.2) 65 (13.2) Right lung overlapping lesion 336 (1.7) 11 Left lung overlapping lesion 74 (0.4) 0 Right lung NOS 307 (1.5) 11 Left lung NOS 212 (1.0) 11 Right other 391 (1.9) 11 Left other 361 (1.8) 11 Radiation before surgery (%) 355 (1.6) Type of surgery (%) Sublobar resection 4,441 (20.3) 88 (17.0) Lobectomy and greater 17,451 (79.7) 431 (83.0) 1215 GENERAL THORACIC a 2 or Fisher s exact test for categorical variable; Kruskal-Wallis test for continuous variable. b The denominator for the percentages is the sum of patients across all categories in the control or stent group, respectively, excluding missing values. NA not available; NOS not otherwise specified; NSCLC non-small cell lung cancer; SD standard deviation. Results In the SEER-Medicare dataset from 1998 through 2005, 519 patients underwent surgical resection for NSCLC within 1 year after placement of a percutaneous coronary stent (stent group). During the same period, 21,892 patients underwent surgical resection of NSCLC without having had a PCI with a stent within the preceding year (no-stent group). Table 1 summarizes patient and disease characteristics for the two cohorts. Patients in the stent group were more likely to be male, had higher comorbidity scores, had a higher percentage of squamous cell cancers, and were more likely to be married. There was no statistical difference in age, race, education level, poverty level, tumor stage, size, grade or location, administration of neoadjuvant radiation, or extent of surgical resection between the stent and no-stent groups. More than half of the patients in the stent group underwent pulmonary resection for lung cancer within 90 days of PCI with a stent. The 30-day incidence of MACE was 9.3% in the stent group and 4.9% in the no-stent group (log-rank test, p ). In the stent group, 30-day mortality was 7.7% compared with 4.6% in the no-stent group, and 90-day mortality was 13.1% and 8.5%, respectively (log-rank test, p ). In the stent group, 3.1% of patients were documented either to have an MI or stent thrombosis or to undergo revascularization in the perioperative period, in comparison to 0.32% of patients in the no-stent group (p ). Among the 40 perioperative mortalities in the stent group, 35% were attributed to cardiovascular causes by the SEER registry data compared with 11% in the no-stent group. Long-term survival was superior in the no-stent group, although the survival curves become parallel within the first year (Fig 1). Six hundred five patients considered in the no-stent group underwent coronary stent placement more than 1 year before lung cancer resection. The 30-day MACE and mortality rates in this group were 6.3% and 6.0%, respectively. To assess whether the duration of time from PCI with a stent to surgery was associated with the risk of MACE, days from stent placement to surgery was assessed as a continuous and categorical variable ( 90, , and days). These time categories were selected based on the prior work of others [10, 11]. In this analysis, there was no significant association of time from stent place- Fig 1. Kaplan-Meier overall survival curves for surgically treated lung cancer patients having undergone percutaneous coronary intervention with a stent within 1 year preceding surgery compared with those who did not.

5 1216 FERNANDEZ ET AL Ann Thorac Surg RISK OF PRIOR CORONARY STENTS 2013;95: ment to lung surgery with risk of MACE, 8.3% at both less than 90 and 91 to 180 days, and 12.3% at 181 to 365 days (p 0.37). Unadjusted hazard ratios were determined for each independent variable. On univariate analysis, predictors of development of perioperative MACE after lung cancer resection were the following: percutaneous coronary stent, increasing age, male sex, more education, poverty, higher comorbidity score, increasing tumor size, and higher tumor grade (Table 2). In an adjusted multivariate analysis of prognostic variables, predictors of perioperative MACE were the following: percutaneous coronary stent, increasing age, male sex, higher comorbidity score, increasing tumor size, higher tumor stage, and surgical resection of lobectomy or greater (Table 3). Comment Lung cancer is the leading cause of cancer-related mortality in the United States [16]. Coronary artery disease is the leading overall cause of mortality. Patients frequently present to a thoracic surgeon with both of these deadly diseases. Coronary artery disease is often managed with a PCI with a stent. Our study demonstrates that patients undergoing surgical therapy for lung cancer within 1 year of placement of a coronary stent are at increased risk for MACE. These patients require special consideration before undertaking potentially curative surgical resection for lung cancer. Thirty-day operative mortality was 7.7% in the stent group in this study, compared with 4.6% in patients without a coronary stent placement within 1 year preceding lung cancer surgery. After adjustment for patient variables, this represents an approximately 50% greater risk of operative mortality for lung cancer resection in patients who have undergone PCI with a stent within the preceding year. In fact, 35% of 30-day mortalities in the stent group was attributable to a cardiovascular cause according to the cause of death data fields in the SEER registry. The 4.6% mortality observed in the control group (no stent) is higher that the 30-day operative mortality reported in the STS-GTSD of 1.8% [9]. Data from the Nationwide Inpatient Sample demonstrates a 30-day mortality rate of 3.0% after pulmonary resection for lung cancer [17]. These data from the Nationwide Inpatient Sample are more consistent with the operative mortality for lung cancer surgery observed in our study and likely more representative of lung cancer surgery in the United States. Our study examines only Medicare beneficiaries undergoing lung cancer surgery. Therefore, this represents an elderly cohort of patients. The mean age in our study is 73.9 years compared with 67 and 68 years, respectively, in the STS-GTSD and Nationwide Inpatient Sample. In the stent group, 3.1% of patients had a MACE in the perioperative period of 30 days, as defined by administrative billing codes for MI, stent thrombosis, or coronary revascularization in the Medicare data files. This rate is almost tenfold greater than the 0.36% incidence of MI Table 2. Univariate Analyses Examining Predictors of Perioperative Major Adverse Cardiac Events Characteristic p Value Treatment group Stent No stent Age, years Age, years (%) Male (%) Race (%) White Black Other Education (%) Lowest quartile Census tract percent poverty for all 2000 (%) Lowest quartile Marital status (%) Married Not married Comorbidity index (%) Histology (%) Squamous Adenocarcinoma Large cell Adenosquamous NSCLC NOS Tumor stage I II III IV NOS Tumor grade (%) Well differentiated Moderately differentiated Poorly differentiated Undifferentiated Cell type not determined Tumor size (%) 10 mm mm mm Tumor size (mm) Radiation before surgery (%) Type of surgery (%) Sublobar resection Lobectomy and greater NOS not otherwise specified; NSCLC non-small cell lung cancer.

6 Ann Thorac Surg FERNANDEZ ET AL 2013;95: RISK OF PRIOR CORONARY STENTS Table 3. Cox Proportional Hazards Examining Predictors of Perioperative Major Adverse Cardiac Events Characteristic p Value Hazard Ratio (95% CI) Treatment group Stent 1.53 (1.12, 2.10) No stent 1.0 Age, years 1.04 (1.03, 1.05) Male (%) 1.53 (1.34, 1.75) Comorbidity index (%) (0.38, 0.56) (0.51, 0.75) (0.65, 1.00) Tumor stage I 0.91 (0.72, 1.16) II 0.99 (0.74, 1.34) III 1.40 (1.09, 1.82) IV 1.90 (1.38, 2.62) NOS 1.0 Tumor size (mm) (1.002, 1.005) Type of surgery (%) Sublobar resection 0.84 (0.71, 1.00) Lobectomy and greater 1.0 CI confidence interval; NOS not otherwise specified after lung cancer surgery reported in the STS-GTSD. Patients in the no-stent group in our study were determined to have a 0.31% incidence of coronary events in the perioperative period, consistent with data from the STS-GTSD. As explained below, the rates of coronary events in this study are likely underreported in this study because of the fact that they are abstracted from a purely administrative dataset. Our study fails to demonstrate any differences in risk of MACE based on time interval from stent placement to lung cancer resection, given that the surgical procedure occurred within 1 year of PCI. Other studies that have examined the time-related risk of noncardiac surgery after PCI with a stent (BMS or DES) have not found a statistically significant association with time from stenting to surgery [10, 11]. A recent meta-analysis, however, does show a significant decrease in MACE when surgery is performed more than 1 year after stent placement [18]. Although not a primary focus of this study, patients having undergone PCI with a stent more than 1 year before pulmonary surgery also seem to be at elevated risk. However, this risk appears to be somewhat less than the risk of mortality associated with surgery within 1 year of PCI. The perioperative management of patients with CAD presenting with potentially resectable lung cancer requires special attention. Placement of a coronary stent commits a patient to dual antiplatelet therapy and may increase the risk of MACE or perioperative bleeding, delay surgery, or change management to nonresectional therapy such as stereotactic body radiation therapy. Current recommendations are that patients having undergone PCI with a stent should receive dual antiplatelet therapy for 6 weeks for a BMS and 12 months for a DES [1 3]. Perioperative stent thrombosis is a devastating event, with mortality rates of up to 50% reported [2, 19]. Owing to the time period of this study, the majority of stents placed were BMS, as DES received US Food and Drug Administration approval in 2004 [14]. For patients requiring revascularization or presenting with a stent, management is not standardized. Options for patients with coronary stents include delay of surgery, operating in the presence of dual antiplatelet therapy, cessation of dual antiplatelet therapy, or nonresectional therapy for lung cancer [20 22]. Before stent placement, it is important to consider whether preoperative revascularization would reduce the patient s cardiac risk associated with pulmonary resection. McFalls and colleagues [23] reported a study on asymptomatic patients presenting for major vascular surgery with noninvasive cardiac stress tests positive for ischemia. These patients were randomly assigned to revascularization (stent or coronary artery bypass grafting) versus medical management, and no difference in perioperative MI rates associated with the vascular surgery was detected in this study. Guidelines from the American College of Cardiology/American Heart Association do not recommend noninvasive cardiac testing for asymptomatic patients undergoing thoracic surgery with good functional status (exercise capacity 4 METS) [1]. This study has the following limitations. The data are abstracted from a large population-based registry, and thus it is a retrospective analysis. The incidence of MACE was determined by ICD-9 and Current Procedural Terminology diagnosis and procedure codes. It is likely that diagnostic codes were underreported in the Medicare Analysis Provider and Review data files, thus underestimating the true incidence of MACE. A more robust clinical registry, such as the STS-GTSD, would allow for greater capture of perioperative MACE. In addition, risk adjustment was performed using comorbidity scores generated from administrative data. Again, use of the clinical variables in the STS-GTSD would allow for better risk adjustment. Also, more contemporary data would allow a comparison of BMS and DES. Finally, the use or discontinuation of antiplatelet therapy cannot be determined with the available dataset. In conclusion, patients undergoing lung cancer surgery within 1 year of percutaneous coronary stenting are at high risk for perioperative MACE and mortality. The presence of a coronary stent should be an important component of the risk assessment before resection for lung cancer. We recommend that high-risk patients with significant CAD and lung cancer be managed by a multidisciplinary tumor board and a cardiologist to maximize oncologic therapy while minimizing treatmentrelated morbidity. This study used the linked SEER-Medicare database. The interpretation and reporting of these data are the sole responsibility of the authors. The authors acknowledge the efforts of the GENERAL THORACIC

7 1218 FERNANDEZ ET AL Ann Thorac Surg RISK OF PRIOR CORONARY STENTS 2013;95: Applied Research Program, National Cancer Institute; the Office of Research, Development and Information, Centers for Medicare and Medicaid Services; Information Management Services (IMS), Inc; and the Surveillance, Epidemiology, and End Results (SEER) Program tumor registries in the creation of the SEER- Medicare database. References 1. Fleisher LA, Beckman JA, Brown KA, et al. ACC/AHA 2007 guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery: 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:e Wilson SH, Fasseas P, Orford Jl, et al. Clinical outcome of patients undergoing non-coronary surgery in the two months following coronary stenting. J Am Coll Cardiol 2003;42: Grines CL, Bonow RO, Casey DE Jr, et al; American Heart Association; American College of Cardiology; Society for Cardiovascular Angiography and Interventions; American College of Surgeons; American Dental Association; American College of Physicians. Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: a science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons and American Dental Association with representation from the American College of Physicians. Circulation 2007;415: Leon MB, Baim DS, Popma JJ, et al. A clinical trial comparing three antithrombotic drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators. N Engl J Med 1998;339: Eisenberg MJ, Richard PR, Libersan D, Filion KB. Safety of short-term discontinuation of antiplatelet therapy in patients with drug-eluting stents. Circulation 2009;119: McFadden EP, Stabile E, Regar E, et al. Late thrombosis in drug-eluting coronary stents after discontinuation of antiplatelet therapy. Lancet 2004;364: van Kuijk JP, Flu WJ, Schouten O, et al. Timing of noncardiac surgery after coronary stenting with bare metal or drugeluting stents. Am J Cardiol 2009;104: Kunadian B, Thornley AR, Tanos M, Dunning J. Should clopidogrel be stopped prior to urgent cardiac surgery? Interact Cardiovasc Thorac Surg 2006;5: Kozower BD, Sheng S, O Brien SM, et al. STS database risk models: predictors of mortality and major morbidity for lung cancer resection. Ann Thorac Surg 2010;90: Rabbitts JA, Nuttall GA, Brown MJ, et al. Cardiac risk of noncardiac surgery after percutaneous coronary intervention with drug-eluting stents. Anesthesiology 2008;109: Nuttall GA, Brown MJ, Stombaugh JW, et al. Time and cardiac risk of surgery after bare-metal stent percutaneous coronary intervention. Anesthesiology 2008;109: Brichon PY, Boitet P, Dujon A, et al. Perioperative in-stent thrombosis after lung resection performed within 3 months of coronary stenting. Eur J Cardiothorac Surg 2006;30: Warren JL, Klabunde CN, Schrag D, Bach PB, Riley GF. Overview of the SEER-Medicare data: content, research applications, and generalizability to the United States elderly population. Med Care 2002;40(8 Suppl):IV Serruys PW, Kutryk MJ, Ong AT. Coronary-artery stents. N Engl J Med 2006;354: Klabunde CN, Potosky AL, Legler JM, Warren JL. Development of a comorbidity index using physician claims data. J Clin Epidemiol 2000;53: Siegel R, Naishadham D, Jemal A. Cancer statistics, CA Cancer J Clin 2012;62: LaPar DJ, Bhamidipati CM, Lau CL, Jones DR, Kozower BD. The Society of Thoracic Surgeons General Thoracic Surgery Database: establishing generalizability to national lung cancer resection outcomes. Ann Thorac Surg 2012;94: Hollis RH, Graham LA, Richman JS, Deierhoi RJ, Hawn MT. Adverse cardiac events in patients undergoing noncardiac surgery: a systematic review. Am J Surg 2012;204: Kałuza GL, Joseph J, Lee JR, Raizner ME, Raizner AE. Catastrophic outcomes of noncardiac surgery soon after coronary stenting. J Am Coll Cardiol 2000;35: Brilakis ES, Banerjee S, Berger PB. Perioperative management of patients with coronary stents. J Am Coll Cardiol 2007;49: Cerfolio RJ, Minnich DJ, Bryant AS. General thoracic surgery is safe in patients taking clopidogrel (Plavix). J Thor Cardiovasc Surg 2010;140: Crabtree TD, Denlinger CE, Meyers BF, et al. Stereotactic body radiation therapy versus surgical resection for stage I non-small cell lung cancer. J Thorac Cardiovasc Surg 2010; 140: McFalls EO, Ward HB, Moritz TE, et al. Coronary-artery revascularization before elective major vascular surgery. N Engl J Med 2004;351: Appendix: Billing Codes Used to Define Major Adverse Cardiac Events Major adverse cardiac event Code Angioplasty HCPCS 92982, Coronary stent HCPCS 92980, Coronary artery bypass grafting HCPCS 33510, 33511, 33512, 33513, 33514, 33516, 33533, 33534, 33535, 33536, 33517, 33518, 33519, 33521, 33522, Acute myocardial infarction ICD-9 STEMI , , NSTEMI Unspecified MI Stent thrombosis ICD HCPCS Healthcare Common Procedure Coding System; ICD-9 International Classification of Diseases, 9th revision; MI myocardial infarction; NSTEMI non ST-elevation MI; STEMI ST-elevation MI.

8 Ann Thorac Surg FERNANDEZ ET AL 2013;95: RISK OF PRIOR CORONARY STENTS DISCUSSION DR KEITH S. NAUNHEIM (St. Louis, MO): Great work, Felix. I would like to congratulate Dr Fernandez on an excellent presentation and thank both him and his coauthors for providing the manuscript in advance of the meeting. Their study is an important one due to the high incidence of CAD (coronary artery disease) and the frequent usage of stents in smokers, many of whom will eventually become our lung cancer patients. The study is particularly valuable due to the low incidence of cardiovascular events, not only in stent patients but in our operative lung cancer cohort overall. With an incidence of less than 1% of cardiovascular events, they occur so infrequently that even busy surgeons will encounter the complication only once every few years. This situation often results in our making decisions anecdotally or with only last-case bias rather than in any evidence-based fashion. I believe this paper both brings attention to and helps identify the scope of this infrequent but potentially devastating complication. The manuscript was very well written, and they did us the favor of pointing out their limitations, including the retrospective nature of the analysis as well as the administrative data they used. But probably one of the weakest areas or the greatest limit of this paper, and it s unavoidable, was the fact that after their study accrual ended, drug-eluting stents became much more popular, and, as you know, they tend to have a somewhat higher propensity for thrombosis and eventual infarction once medication is stopped. So that leads to the first of my three questions. If you analyzed from 2005 to 2010, which was certainly the heyday for drug-eluting stents, do you believe that you would have found different results than you found now in terms of the incidence of cardiovascular events, specifically infarction, because they do tend to epithelialize much more slowly? The second question has to do with your standard diagnostic algorithm. A lot of these patients obviously had a stent placed in preparation for surgery, and in that case the question is, how long do you wait between the time the stent was placed and the time you do surgery? If it was placed, on the other hand, 6, 8, 12 months ago, how do you handle that patient? When do you stop their Plavix? Do you stop their aspirin? Do you use Lovenox or aspirin or some other antiplatelet medication before? And how soon do you start the Plavix after their surgery? And lastly, with the new and improved antiplatelet drugs that are coming out, do you think it is going to change or should change the way we handle these patients, or do you still believe that these new antiplatelet drugs like Plavix will continue to be the bane of our existence? 1219 DR FERNANDEZ: Thank you, Dr Naunheim, for your comments. Drug-eluting stents were introduced into clinical practice in 2003 and received FDA (US Food and Drug Administration) approval in Due to the time period of our study, we couldn t analyze these. In our opinion, we feel that drug-eluting stents would pose a higher risk. Intuitively it seems to be so. They do endothelialize slower, and that is the impression of many surgeons. However, there has been no clinical study that has definitively shown a higher incidence of major adverse cardiac events postoperatively in patients with drug-eluting or bare-metal stents. That needs to be elucidated further. In terms of an algorithm as to how to treat a patient presenting with a stent, I had one additional slide here that I didn t show. There are a lot of options. If you look at ACC/AHA (American College of Cardiology/American Heart Association) guidelines, for a bare-metal stent they recommend 6 weeks of dual antiplatelet therapy after stent placement prior to surgery. For a drug-eluting stent, the ACC/AHA guidelines are a full 12 months. So if we follow those guidelines, that leaves us with these strategies, and we have no evidence that I am aware of to guide us with these. One is to continue dual antiplatelet therapy and accept a higher risk of bleeding. We can delay surgery as long as possible. That is probably not the best thing for lung cancer, and our data presented in this study don t seem to support this strategy. And nonsurgical options also enter consideration. Your last question is an important one, how are these newer antiplatelet agents going to impact our clinical practice, and the honest answer is I don t know, but they are coming. We are starting to see patients show up in our clinic on these agents. DR ROBERT J. CERFOLIO (Birmingham, AL): Felix, congratulations. Well done. If I was a test-taker and you put that question up there, that would be real easy, wouldn t it? But the option of Delay the surgery? is not realistic that s not going to happen. B is gone, not going to happen, C, offer nonsurgery? The guy has lung cancer, not going to happen. D, aggressive medical therapy? Too late, stents in. CABG (coronary artery bypass grafting)? Too late, stents in. So you re left with A and A only. We have written, and you and I talked about the article that we wrote, and our data is really no better than yours, is it? Unfortunately, it s a retrospective series of our experience with it. But the point is, you are not going to get a cardiologist or an anesthesiologist to put them to sleep if you stop the Plavix; anesthesia is going to stop you before you go in the OR (operating room). So that s not an option. The options of stopping the aspirin is good though. If you stop the aspirin and just operate them on Plavix, 20% of the people don t respond to the Plavix anyhow. The operative field is just the same as if they weren t on it and you look like a hero, and cardiologists are thrilled. So keep them on the Plavix and stop their aspirin, and our experience is they do pretty well. I wish I had never written that article, because we get patient after patient sent to us on Plavix. DR DAVID C. RICE (Houston, TX): I enjoyed the presentation. If I m correct, you had a 4.4% absolute difference and a 3.1% absolute difference in MACE (major adverse cardiac event) and mortality rates, respectively, between the stent and the no-stent group. Did you look or do you know what the risk of mortality and MACE just from having a stent is without operating at all? I m trying to figure out what the relative contribution of the surgery is to MACE and mortality. DR FERNANDEZ: That s a good question and I don t have those numbers off the top of my head, but it is a much lower rate. DR SAEID KHANSARINIA (Atlanta, GA): We sat down with a task force of interventional cardiologists, because we have the same problem with this similar group of patients. We approach these patients with a standard protocol similar to a mechanical valve patient on chronic anticoagulation. We agreed to the use of IV (intravenous) Aggrastat. In our protocol, we stop Plavix 3 days prior to admission and subsequently admit patient for 24 hours prior to the procedure and placed him on IV Aggrastat. We discontinue IV Aggrastat at midnight prior to the operation and proceeded with intended procedure the next morning, on an Aggrastat-free period or Aggrastat window, similar to a hep- GENERAL THORACIC

9 1220 FERNANDEZ ET AL Ann Thorac Surg RISK OF PRIOR CORONARY STENTS 2013;95: arin window. Our approach has been very successful and without any postoperative bleeding or any stents, coronary artery occlusion, or perioperative MIs (myocardial infarctions). We don t have enough numbers yet to publish it. But what do you think about doing that as a bridging mechanism? DR FERNANDEZ: In a few patients I have used that strategy as well. I have stopped the Plavix and brought them in and put them on Integrilin and then operated on them and loaded them with Plavix postoperatively. The argument against that is the highest risk for in-stent thrombosis is in the immediate perioperative period where they are not covered by appropriate antiplatelet therapy. DR KHANSARINIA: Did you continue the aspirin, like a baby aspirin? DR FERNANDEZ: I don t stop aspirin in any of my patients. DR KHANSARINIA: We have done 12 and we have had zero postoperative problems. Those are the ones that we are following aggressively and saying that we have had zero. And we got all the cardiologists and our pharmacists to sit together and we came up with this protocol, so in our institution it is now a standard protocol. And there is some level II data for this in the literature. We continue their baby aspirin, too, and we just stop their Plavix 3 days before we bring them, the night before stop Aggrastat, so by the time that fifth day rolls around they re on Aggrastat, or, in your case, Integrilin. In our hospital, Aggrastat is cheaper. And then we stop the night before the Aggrastat, operate on them the next day. If there is no evidence of bleeding or any other problems postop day, that morning when we come back and see that patient, we load them with Plavix. DR FERNANDEZ: Right. I understand that needs to be looked at further. But immediately after the operation when they are most prothrombotic, they are not covered with appropriate antiplatelet therapy.