Supplementary Appendix

Transcription

1 Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Park S-J, Ahn J-M, Kim Y-H, et al. Trial of everolimus-eluting stents or bypass surgery for coronary disease. N Engl J Med 2015;372: DOI: /NEJMoa

2 Table of Contents Supplementary Appendix Item Page I. Investigators and Trial Personnel List 3 II. Inclusion/Exclusion Criteria 6 III. Definitions of Trial End Points 9 IV. Monitoring of Data Quality 13 V. Premature Termination of the Trial 14 VI. Figures Figure S1. Enrollment, Randomization and Follow-up 15 Figure S2. Kaplan-Meier Curves of the composite primary outcome of 16 death, myocardial infarction, or Stroke. Figure S3. Kaplan-Meier Curves for the Landmark Analyses 17 Figure S4. Kaplan-Meier Curves for Repeat Revascularization 18 Figure S5. Subgroup Analyses of the Composite of Death, Myocardial 19 Infarction, Stroke, or Any Repeat Revascularization. Figure S6. Clinical Outcomes According to the Type of Revascularization 20 and Diabetes VII. Tables Table S1. Reasons for Screening Failure for Study Enrollment 21 Table S2. Medications at discharge and follow up 22 Table S3. Clinical End Points in the CABG and PCI Groups In As- 25 Treated Analysis 2

3 I. Investigators and Trial Personnel List The following persons participated in the enrollment of patients, data collection, or study coordination and number of patients enrolled per site. Investigators: Seung-Jung Park, Jung-Min Ahn, Young-Hak Kim, Duk-Woo Park, Sung- Cheol Yun, Jong-Young Lee, Soo-Jin Kang, Seung-Whan Lee, Cheol Whan Lee, Seong-Wook Park, Suk Jung Choo, Cheol-Hyun Chung, and Jae-Won Lee, Asan Medical Center, Seoul, Korea (487); David J. Cohen, Saint Luke s Mid America Heart Institute, University of Missouri-Kansas City, Kansas City, MO, USA; Alan C. Yeung, Stanford University School of Medicine, Palo Alto, California, USA; Seung Ho Hur, Keimyung University Dongsan Medical Center, Daegu, Korea (54); Ki Bae Seung, Catholic University of Korea, St. Mary s Hospital, Seoul, Korea (52); Damras Tresukosol, Siriraj Hospital, Thailand (50); Tae Hoon Ahn, Gachon University Gil Hospital, Incheon, Korea (49); Hyuck Moon Kwon, Gangnam Severance Hospital, Seoul, Korea (39); Do-Sun Lim, and Seung-Woon Rha, Korea University Anam (23) and Guro Hospital (28), Seoul, Korea; Myung-Ho Jeong, Chonnam National University Hospital, Gwangju, Korea (18); Bong-Ki Lee, Kangwon National University Hospital, Chuncheon, Korea (17); Guo Sheng Fu, Sir Run Run Shaw Hospital, China (10); Kyoung Soo Kim, Hanyang University Medical Center, Seoul, Korea (9); Jang Ho Bae, Konyang University Hospital, Daejeon, Korea (9); Byung Ok Kim, Inje University Sanggye Paik Hospital, Seoul, Korea (6); Tiong Kiam Ong, Sarawak General Hospital, Malaysia (6); Junghan Yoon, Wonju Christian Hospital, Wonju, Korea (5); Tae-Hyun Yang, Inje University Pusan Paik Hospital, Pusan, Korea (3); Yang-Soo Jang, Yonsei University Severance Hospital, Seoul, Korea (3); Joo-Young Yang, National Health Insurance Corporation Center, Goyang, Korea (2); Jong-Seon Park, Yeungnam University Medical Center, Daegu, Korea (2); JunBo Ge, Zhongshan Hospital, China (1); Sung Yun Lee, Inje University Ilsan Paik Hospital, Goyang, Korea (1); Jun Hong Kim, Pusan National University Yangsan Hospital, Yangsan, 3

4 Korea (1); Jang-Hyun Cho, St. Carollo Hospital, Suncheon, Korea (1); Yun Seok Choi, Yeouido St. Mary s Hospital, Seoul, Korea (1); Sang-Gon Lee, Ulsan University Hospital, Ulsan, Korea (1); and Robaaya Zambahari, National Heart Institute, Malaysia (1). Author Contributions: conception and design Seung-Jung Park, Jung-Min Ahn, Young- Hak Kim, Sung-Cheol Yun and Jae-Won Lee; analysis and interpretation of data Seung- Jung Park, Jung-Min Ahn and Sung-Cheol Yun; drafting of the manuscript Seung-Jung Park, Jung-Min Ahn, Young-Hak Kim and Sung-Cheol Yun; critical revision of the manuscript for important intellectual content Seung-Jung Park, Jung-Min Ahn, Young-Hak Kim, Duk-Woo Park, Sung-Cheol Yun, Jong-Young Lee, Soo-Jin Kang, Seung-Whan Lee, Cheol Whan Lee, Seong-Wook Park, Suk Jung Choo, Cheol-Hyun Chung, Jae-Won Lee, David J. Cohen, Alan C. Yeung, Seung Ho Hur, Ki Bae Seung, Damras Tresukosol, Tae Hoon Ahn, Hyuck Moon Kwon, Do-Sun Lim, Seung-Woon Rha, Myung-Ho Jeong, Bong-Ki Lee, Guo Sheng Fu and Tiong Kiam Ong; final approval of the manuscript Seung-Jung Park, Jung-Min Ahn, Young-Hak Kim, Duk-Woo Park, Sung-Cheol Yun, Jong-Young Lee, Soo-Jin Kang, Seung-Whan Lee, Cheol Whan Lee, Seong-Wook Park, Suk Jung Choo, Cheol-Hyun Chung, Jae-Won Lee, David J. Cohen, Alan C. Yeung, Seung Ho Hur, Ki Bae Seung, Damras Tresukosol, Tae Hoon Ahn, Hyuck Moon Kwon, Do-Sun Lim, Seung-Woon Rha, Myung-Ho Jeong, Bong-Ki Lee, Guo Sheng Fu and Tiong Kiam Ong; statistical expertise Sung-Cheol Yun, Seung-Jung Park, and Jung-Min Ahn; obtaining of public funding Seung-Jung Park; administrative, technical, or logistic support Seung-Jung Park, Jung-Min Ahn, Young-Hak Kim, Duk-Woo Park, Sung-Cheol Yun, Jong-Young Lee, Soo-Jin Kang and Seung-Whan Lee; acquisition of data Seung-Jung Park, Jung-Min Ahn, Young-Hak Kim, Duk-Woo Park, Sung-Cheol Yun, Jong-Young Lee, Soo-Jin Kang, Seung-Whan Lee, Cheol Whan Lee, Seong- Wook Park, Suk Jung Choo, Cheol-Hyun Chung, Jae-Won Lee, Seung Ho Hur, Ki Bae Seung, 4

5 Damras Tresukosol, Tae Hoon Ahn, Hyuck Moon Kwon, Do-Sun Lim, Seung-Woon Rha, Myung-Ho Jeong, Bong-Ki Lee, Guo Sheng Fu and Tiong Kiam Ong. Executive Committee: Seung-Jung Park, Jung-Min Ahn, Young-Hak Kim, Duk-Woo Park, Sung-Cheol Yun, Jong-Young Lee, Soo-Jin Kang, Seung-Whan Lee, Cheol Whan Lee, Seong- Wook Park and Jae-Won Lee (University of Ulsan College of Medicine). Data and Safety Monitoring Board: Moo Song Lee (University of Ulsan College of Medicine), Jae-Joong Kim (University of Ulsan College of Medicine) and Goo-Yeong Cho (Seoul National University Bundang Hospital). Event-Adjudication Committee: Gyung-Min Park (University of Ulsan College of Medicine) and Young-Rak Cho (University of Ulsan College of Medicine). 5

6 II. Inclusion and Exclusion Criteria Inclusion criteria 1. Age 18 years. 2. Angiographically confirmed multivessel CAD [critical (> 70%) lesions in at least two major epicardial vessels ( 2.0 mm in diameter) in at least two separate coronary artery territories (LAD, LCX, RCA)] expected to be equally treatable with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) by clinicians at the investigating site. 3. Indication for revascularization based on symptoms of angina and/or objective evidence of myocardial ischemia. 4. Geographically accessible and willing to come in for required study visits. 5. Agreement by the patient or guardian to the study protocol and the clinical follow-up schedule, including the provision of written informed consent, as approved by the appropriate Institutional Review Board/Ethical Committee at the respective clinical site. Exclusion criteria 1. Known hypersensitivity or contraindication to any of the following: Heparin Aspirin Clopidogrel Everolimus Stainless steel and/or Contrast media (patients with documented sensitivity to contrast who can be effectively pre-medicated with steroids and diphenhydramine [e.g., for rash] may be enrolled. Patients with true anaphylaxis to prior contrast media, 6

7 however, should not be enrolled). 2. Severe congestive heart failure (class III or IV according to NYHA, or pulmonary edema) at the time of enrollment. The left ventricular ejection fraction was not considered a criterion for exclusion. 3. Planned simultaneous surgical procedure unrelated to coronary revascularization (e.g., valve repair/replacement, aneurysmectomy, carotid endarterectomy or carotid stent). 4. Previous bypass surgery. 5. Prior percutaneous coronary intervention (PCI) with DES implantation within 1 year. 6. Two or more chronic total occlusions in major coronary territories. 7. Acute ST-elevation myocardial infarction (Q-wave) within 72 hours prior to enrollment requiring revascularization. 8. Abnormal creatine kinase (CK > 2 normal) and/or abnormal CK-MB levels and/or elevated troponin levels at the time of randomization. Enrollment was allowed when these cardiac enzymes returned to normal. 9. Previous stroke within 6 months or stroke at more than 6 months with significant residual neurologic involvement. 10. Extra-cardiac illness expected to limit survival to less than 2 years, e.g., oxygendependent chronic obstructive pulmonary disease, active hepatitis, significant hepatic failure, or severe renal disease. 11. Prior history of significant bleeding (within the previous 6 months) that might be expected to recur during coronary artery bypass grafting (CABG) or PCI/DES-related anticoagulation. 12. Contraindication to either CABG or PCI/DES due to a coexisting clinical condition. 13. Intolerance or contraindication to aspirin or clopidogrel. 7

8 14. Suspected pregnancy. 15. Concurrent enrollment in another clinical trial. 16. Left main coronary artery stenosis ( 50% diameter). 8

9 III. Definitions of Trial End Points Complete Revascularization No residual stenosis > 50% in any major coronary artery or their large branches with reference diameters of the arteries adjacent to the site of stenosis >2 mm, or a bypass graft feeding the territory distal to a diseased segment. Death The primary end point includes death from any cause. In addition, the cause of death (cardiac vs. non-cardiac) will be adjudicated. If the cause of death cannot be adjudicated the most severe cause will be considered. Death is divided into 2 categories: Cardiac death is defined as death due to any of the following: 1. Acute myocardial infarction. 2. Cardiac perforation/pericardial tamponade. 3. Arrhythmia or conduction abnormality. 4. Cerebrovascular accident within 30 days of the procedure or cerebrovascular accident suspected of being related to the procedure. 5. Death due to complication of the procedure 6. Any death in which a cardiac cause cannot be excluded. Non-cardiac death is defined as a death not due to cardiac causes (as defined above), including bleeding-related death. Major Bleeding (protocol) Major Bleeding is defined as the occurrence of any of the following: intracranial bleeding, intraocular bleeding, retroperitoneal bleeding, access site hemorrhage requiring surgery or a radiological or interventional procedure, hematoma 5cm in 9

10 diameter at the puncture site, reduction in hemoglobin concentration of 4g/dL without an overt source of bleeding, reduction in hemoglobin concentration of 3g/dL with an overt source of bleeding, re-operation for bleeding, or use of any blood product transfusion. Bleeding complications will be adjudicated as either related to or unrelated to surgery. Myocardial Infarction 1. AMI prior to enrollment (if occurred within the past 1 week, it is an exclusion criterion and subject should not be enrolled) Typical rise and gradual fall of troponin or more rapid rise and fall of CK for detecting myocardial necrosis with at least one of the following: a. Ischemic symptoms or atypical symptoms of ischemia; b. Development of pathologic Q waves on the ECG, or new LBBB; OR c. ECG changes indicative of ischemia (ST segment elevation or depression); Troponin rise is defined as at least one value exceeding the 99th percentile of the value for reference control group. CK rise is defined as at least 2 values exceeding the 99th percentile for the reference group or at least one value exceeding twice the upper limit of normal for the specific institution AND an elevated CK-MB. 2. AMI within first 48 hours after the procedure The presence of new Q waves in at least 2 or more contiguous leads, or new LBBB. AND- One plasma level of CK-MB 5X upper normal limit. Periprocedural cardiac enzyme elevations in the absence of Q waves will not be considered an event. 3. AMI more than 48 hours after the procedure 10

11 Typical rise and gradual fall of troponin or more rapid rise and fall of CK-MB for detecting myocardial necrosis with at least one of the following: a. Ischemic symptoms or atypical symptoms of ischemia; b. Development of pathologic Q waves on the ECG, or new LBBB; AND c. Enzyme changes defined as one or more than one plasma level of CK- MB above upper normal level. Stent Thrombosis 1. Definite ST Angiographic confirmation of ST and at least 1 of the following signs present within 48 h: new onset of ischemic symptoms at rest, new electrocardiographic changes suggestive of acute ischemia, or typical rise and fall in cardiac biomarkers. 2. Probable ST Any unexplained death within the first 30 days after intracoronary stenting. 3. Possible ST Any unexplained death occurring from 30 days after intracoronary stenting until the end of the follow-up period. Stent thrombosis was further characterized as acute (0 h to <24 h), subacute ( 1 day to <30 days), late ( 30 days to <1 year), and very late ( 1 year to 15 months). Stroke Stroke is defined as a focal neurological deficit of central origin lasting more than 72 hours. The definitive evaluation for stroke will be conducted in both treatment arms, using the Neurological Assessment (defined in the trial protocol) at baseline, at 72 hours or hospital discharge, whichever comes first, 30 days and 24 months after the assigned 11

12 treatment is performed. Target Lesion Revascularization Any repeat PCI of the target lesion due to recurrent target lesion stenosis. A target lesion revascularization will be considered ischemia-driven if the target lesion diameter stenosis is 50% by QCA (analysis segment measurement, involving the lesion itself and/or 5 mm of proximal and/or distal margin) and any of the following occur: The subject has a positive functional study corresponding to the area served by the target lesion; ischemic ECG changes at rest in a distribution consistent with the target vessel; or ischemic symptoms referable to the target lesion. A target lesion revascularization for a diameter stenosis less than 50% might also be considered ischemia-driven by the CEC if there was a markedly positive functional study or ECG changes corresponding to the area served by the target lesion. A target lesion revascularization will also be considered as ischemia-driven if the lesion diameter stenosis is 70% in the absence of documented clinical or functional ischemia. A target lesion revascularization will be considered clinically-driven if the patient has one of the following: The subject had a positive functional study corresponding to the area served by the target lesion; ischemic ECG changes at rest in a distribution consistent with the target vessel; or ischemic symptoms referable to the target lesion. Target Vessel Revascularization Any repeat PCI or bypass surgery to target vessel. 12

13 IV. Monitoring of Data Quality For the informed consent form, enrollment criteria, and major outcomes, the research team in the Data Coordinating Center in the CardioVascular Research Foundation visited all participating centers and performed monitoring through Source Document Verification. For other variables, the central monitoring method was used. Based on the electronic case reporting form, the research team issued a Data Clarification Form identifying any logical errors, which was sent to each institution. Each investigator corrected the issues on the electronic case reporting form. Additionally, during visits to participating centers, the research team did Source Document Verification of roughly 10% of all cases. 13

14 V. Premature Termination of the Trial This study was prematurely terminated due to slow enrollment. The reason for slow enrollment was presumed to be due to the rapid spread of the clinical use of fractional flow reserve measurement (FFR). Because this study had angiographic inclusion criteria, the clinical use of FFR reduced the enrollment rate of study participants. In addition, the evolution of FFR measurement led the investigators to conclude that this trial no longer represents state-of-the-art PCI and therefore would be less relevant to future therapy. Finally, competing enrollment in another trial (FAME 3 trial [NCT ]) also limited patient enrollment. The executive committee, which also served as the steering committee, asked the data and safety monitoring board (DSMB) to consider premature termination of the trial, blinded to the clinical outcomes. The DSMB recommended stopping enrollment, as it was acknowledged that the past slow rate of enrollment would not be likely to improve in the future, and thus continuing enrollment would be futile. The executive committee accepted the DSMB recommendation. 14

15 VI. Figures Figure S1. Enrollment, Randomization and Follow-up 15

16 Figure S2. Kaplan-Meier Curves of the composite primary outcome of death, myocardial infarction, or Stroke. Event rates shown are Kaplan-Meier estimates. The P value was calculated by means of the log-rank test on the basis of all available follow-up data. 16

17 Figure S3. Kaplan-Meier Curves for the Landmark Analyses. Shown are the cumulative incidences of death (A), the composite of death or myocardial infarction (B), and myocardial infarction (C) in the two study groups, stratified on the basis of a landmark point at 30 days after randomization (vertical dashed line). 17

18 Figure S4. Kaplan-Meier Curves for Repeat Revascularization. Shown are the cumulative incidences of any repeat revascularization (A), target lesion revascularization (B), and new lesion revascularization (C) after randomization. 18

19 Figure S5. Subgroup Analyses of the Composite of Death, Myocardial Infarction, Stroke, or Any Repeat Revascularization. 19

20 Figure S6. Clinical Outcomes According to the Type of Revascularization and Diabetes. Blue bar is PCI and red bar is CABG 20

21 VII. Tables Table S1. Reasons for Screening Failure for Study Enrollment Reasons Number of Patients Left main stenosis (at least 50% diameter stenosis) 766 Concurrent enrollment in another clinical trial 639 Two or more chronic total occlusions in major coronary territories 248 Planned simultaneous surgical procedure unrelated to coronary revascularization 235 Prior CABG surgery 209 Acute ST-elevation MI (Q-wave) within 72 hours prior to enrollment requiring revascularization 253 Prior PCI with DES implantation within 1 year 192 Elevated cardiac enzymes at time of randomization 145 Heart failure (NYHA class III or IV) 83 Extra-cardiac illness that is expected to limit survival to less than 2 years 58 Contraindication to either CABG or PCI/DES because of a coexisting clinical condition 42 Previous stroke within 6 months or patients with stroke at more than 6 months with significant residual neurologic involvement 30 Prior history of significant bleeding (< 6 months) 10 Not possible to access the research center 7 Hypersensitivity or contraindication to medication 6 Intolerance or contraindication to aspirin or both clopidogrel and ticlopidine 6 21

22 Table S2. Medications at Discharge and Follow-up Medication PCI CABG P-value (N=438) (N=442) Aspirin At discharge 425/438 (97.0) 427/442 (96.6) year after randomization 397/426 (93.2) 401/433 (92.6) year after randomization 369/394 (93.7) 375/401 (93.5) year after randomization 288/342 (84.2) 286/354 (80.8) year after randomization 232/276 (84.1) 235/288 (81.6) year after randomization 136/174 (78.2) 140/184 (76.1) 0.64 Thienopyridine At discharge 423/438 (96.6) 395/442 (89.4) < year after randomization 376/426 (88.3) 299/433 (69.1) < year after randomization 277/394 (70.3) 205/401 (51.1) < year after randomization 199/342 (58.2) 174/354 (49.2) year after randomization 135/276 (48.9) 118/288 (41.0) year after randomization 93/173 (53.8) 88/182 (48.4) 0.31 Any antiplatelet drug At discharge 434/438 (99.1) 430/442 (97.3) year after randomization 420/426 (98.6) 420/433 (97.0) year after randomization 389/394 (98.7) 389/401 (97.0) year after randomization 325/342 (95.0) 323/354 (91.2) year after randomization 261/276 (94.6) 266/288 (92.4) year after randomization 160/174 (92.0) 167/184 (90.8) 0.69 Beta-blocker 22

23 At discharge 300/438 (68.5) 189/442 (42.8) < year after randomization 379/426 (89.0) 358/433 (82.7) year after randomization 257/394 (65.2) 216/401 (53.9) year after randomization 189/342 (55.3) 161/354 (45.5) year after randomization 129/276 (46.7) 123/288 (42.7) year after randomization 87/174 (50.0) 68/184 (37.0) Calcium-channel blocker At discharge 254/438 (58.0) 205/442 (46.4) year after randomization 246/426 (57.7) 225/433 (52.0) year after randomization 255/394 (57.1) 203/401 (50.6) year after randomization 160/342 (46.8) 150/354 (42.4) year after randomization 125/276 (45.3) 103/288 (35.8) year after randomization 96/174 (55.2) 67/184 (36.4) <0.001 ACE inhibitor or ARB At discharge 195/438 (44.5) 112/442 (25.3) < year after randomization 176/426 (41.3) 155/433 (35.8) year after randomization 176/394 (44.7) 143/401 (35.7) year after randomization 124/342 (36.3) 116/354 (32.8) year after randomization 89/276 (32.2) 76/288 (26.4) year after randomization 60/174 (34.5) 40/184 (21.7) Statin At discharge 364/438 (83.1) 369/442 (83.5) year after randomization 383/426 (89.9) 370/433 (85.8) year after randomization 343/394 (87.1) 333/401 (83.0) year after randomization 280/342 (81.9) 267/354 (75.4)

24 4 year after randomization 223/276 (80.8) 217/288 (75.3) year after randomization 138/174 (79.3) 138/184 (75.0) 0.33 * NE, not evaluable ACE denotes angiotensin-converting enzyme, ARB angiotensin II receptor blocker. 24

25 Table S3. Long-Term Clinical End Points in the CABG and PCI Groups In As-Treated Analysis End points PCI CABG Hazard ratio* P-value (N=464) (N=401) (95% CI) Number (percentage) Primary End Point Death, Myocardial Infarction, or Target 72 (15.5) 40 (10.0) 1.57 ( ) Vessel Revascularization Secondary End Points Death 28 ( (5.5) 1.08 ( ) 0.78 Cardiac Death 18 ( (3.7) 1.03 ( ) 0.94 Non Cardiac Death 10 (2.2) 7 (1.7) 1.21 ( ) 0.71 Myocardial Infarction 22 (4.7) 10 (2.5) 1.88 ( ) Fatal Myocardial Infarction 3 (0.6) 7 (0.2) 2.57 ( ) 0.40 Spontaneous Myocardial Infarction 20 (4.3) 5 (1.2) 3.43 ( ) Q wave Myocardial Infarction 4 (0.9) 2 (0.5) 1.69 ( )

26 Death or Myocardial Infarction 44 (9.5) 31 (7.7) 1.21 ( ) 0.42 Stroke 12 (2.6) 10 (2.5) 1.03 ( ) 0.94 Ischemic Stroke 9 (2.1) 10 (2.5) 0.77 ( ) 0.57 Hemorrhagic Stroke 3 (0.6) 0 (0) NA NA Death, Myocardial Infarction, or stroke 53 (11.4) 39 (9.7) 1.17 ( ) 0.46 Cardiac Death, Myocardial Infarction, or Stroke 44 (9.5) 33 (8.2) 1.15 ( ) 0.55 Any Repeat Revascularization 54 (11.6) 17 (4.2) 2.82 ( ) <0.001 Target Vessel Revascularization 36 (7.8) 12 (3.0) 2.63 ( ) Target Lesion Revascularization 30 (6.5) 12 (3.0) 2.18 ( ) 0.19 New Lesion Revascularization 27 (5.8) 6 (1.5) 3.93 ( ) Death, Myocardial Infarction, Stroke, or Any Repeat Revascularization Cardiac Death, Myocardial Infarction, Stroke, or Any Repeat Revascularization 92 (19.8) 52 (13.0) 1.57 ( ) (18.1) 46 (11.5) 1.62 ( ) Bleeding 26

27 TIMI Major Bleeding 23 (5.0) 139 (34.7) 0.12 ( ) <0.001 Fatal Bleeding 5 (1.1) 5 (1.2) 0.85 ( ) 0.80 *Hazard ratio and 95% confidence interval (CI) were assessed for events on the basis of all available follow-up data. P-values were calculated using the log-rank test on the basis of all available follow-up data. Thrombolysis in Myocardial Infarction (TIMI) major bleeding refers to events that were adjudicated on the basis of previously used TIMI criteria. CABG denotes coronary artery bypass graft, NA not applicable, PCI percutaneous coronary intervention. 27