Comparison of Percutaneous Coronary Intervention With Coronary Artery Bypass Grafting in Unprotected Left Main Coronary Artery Disease

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1 1282 SHIOMI H et al. Circulation Journal ORIGINAL ARTICLE Official Journal of the Japanese Circulation Society Cardiovascular Intervention Comparison of Percutaneous Coronary Intervention With Coronary Artery Bypass Grafting in Unprotected Left Main Coronary Artery Disease 5-Year Outcome From CREDO-Kyoto PCI/CABG Registry Cohort-2 Hiroki Shiomi, MD; Takeshi Morimoto, MD, PhD; Yutaka Furukawa, MD; Yoshihisa Nakagawa, MD; Ryuzo Sakata, MD; Hitoshi Okabayashi, MD; Michiya Hanyu, MD; Mitsuomi Shimamoto, MD; Noboru Nishiwaki, MD; Tatsuhiko Komiya, MD; Takeshi Kimura, MD on behalf of the CREDO-Kyoto PCI/CABG registry cohort-2 investigators Background: Studies evaluating long-term ( 5 years) outcome of percutaneous coronary intervention (PCI) compared with coronary artery bypass grafting (CABG) in patients with unprotected left main coronary artery disease (ULMCAD) are still limited, despite concerns for late adverse events after drug-eluting stents implantation. Methods and Results: We identified 1,004 patients with ULMCAD (PCI: n=364, CABG: n=640) among 15,939 patients with first coronary revascularization enrolled in the CREDO-Kyoto PCI/CABG registry cohort-2. The primary outcome measure in the current analysis was a composite of death, myocardial infarction, and stroke (death/mi/ stroke). The cumulative 5-year incidence of and the adjusted risk for death/mi/stroke were significantly higher in the PCI group than in the CABG group (34.5% vs. 24.1%, log-rank P<0.001, adjusted hazard ratio (HR): 1.48 [95% confidence interval (CI): , P=0.02]). The adjusted risks for all-cause death was not significantly different between the 2 groups. Regarding the stratified analysis by the SYNTAX score, the adjusted risk for death/mi/stroke was not significantly different between the 2 groups in patients with low (<23) or intermediate (23 33) SYNTAX score, whereas it was significantly higher in the PCI group than in the CABG group in patients with high ( 33) SYNTAX score. Conclusions: CABG as compared with PCI was associated with better long-term outcome in patients with ULMCAD, especially those with high anatomical complexity. (Circ J 2015; 79: ) Key Words: Coronary artery bypass grafting; Drug-eluting stents; Left main disease; Percutaneous coronary intervention Several studies have reported favorable short- and mid-term outcomes of percutaneous coronary intervention (PCI) using drug-eluting stents (DES) in patients with unprotected left main coronary artery disease (ULMCAD), leading to the update of clinical guidelines in which PCI is regarded as an acceptable alternative to coronary artery bypass grafting (CABG) in selected patients with ULMCAD. 1 8 On the other hand, late adverse events beyond 1 year after DES implantation, such as very late stent thrombosis (VLST) and late targetlesion revascularization (TLR), are reported to be a continuous hazards up to 5 years after DES implantation and still a major concern after PCI using DES Studies evaluating long-term Received January 12, 2015; revised manuscript received February 22, 2015; accepted February 23, 2015; released online March 30, 2015 Time for primary review: 15 days Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto (H.S., T. Kimura); Department of Clinical Epidemiology, Hyogo College of Medicine, Nishinomiya (T.M.); Division of Cardiology, Kobe City Medical Center General Hospital, Kobe (Y.F.); Division of Cardiology, Tenri Hospital, Tenri (Y.N.); Department of Cardiovascular Surgery, Graduate School of Medicine, Kyoto University, Kyoto (R.S.); Department of Cardiovascular Surgery, Iwate Medical University, Morioka (H.O.); Division of Cardiovascular Surgery, Kokura Memorial Hospital, Kitakyushu (M.H.); Division of Cardiovascular Surgery, Shizuoka City Shizuoka Hospital, Shizuoka (M.S.); Division of Cardiovascular Surgery, Nara Hospital, Kinki University Faculty of Medicine, Ikoma (N.N.); and Division of Cardiovascular Surgery, Kurashiki Central Hospital, Kurashiki (T. Komiya), Japan Mailing address: Takeshi Kimura, MD, Department of Cardiovascular of Medicine, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto , Japan. taketaka@kuhp.kyoto-u.ac.jp ISSN doi: /circj.CJ All rights are reserved to the Japanese Circulation Society. For permissions, please cj@j-circ.or.jp

2 5-Year Outcome in Patients With ULMCAD 1283 Figure 1. Comparison of percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) in unprotected left main coronary artery disease: study flow chart. ( 5 years) outcome of PCI compared with CABG in patients with ULMCAD are still limited We previously reported 3-year outcome in patients with ULMCAD from the Coronary REvascularization Demonstrating Outcome Study in Kyoto (CREDO-Kyoto) PCI/CABG registry cohort-2, demonstrating that (1) 3-year clinical outcome of PCI was comparable with that of CABG in terms of serious cardiovascular events in patients with ULMCAD and (2) the risk for serious cardiovascular events was not significantly different between PCI and CABG in patients with low or intermediate SYNTAX score, but was markedly higher after PCI as compared with CABG in patients with high SYNTAX score. 16 In the current report, we extended the follow-up to evaluate longer-term ( 5 years) outcome of PCI compared with CABG in patients with ULMCAD in real-world clinical practice. Editorial p 1201 Methods Study Population As previously described in detail, the CREDO-Kyoto PCI/ CABG registry cohort-2 is a physician-initiated non-company sponsored multicenter registry enrolling consecutive patients undergoing their first coronary revascularization in 26 centers in Japan between January 2005 and December The relevant ethics committees in all 26 participating centers (Appendix S1) approved the research protocol. Because of the retrospective enrollment, the requirement for written informed consent from the patients was waived; however, we excluded patients who refused participation in the study when contacted for follow-up. This strategy is concordant with the guidelines of the Japanese Ministry of Health, Labor and Welfare. Among the 15,939 patients enrolled in the registry, the study population for the current analysis consisted of 1,004 patients with ULMCAD (PCI: 364 patients, CABG: 640 patients), excluding those patients refusing study participation (n=99), concomitant non-coronary surgery (n=609), acute myocardial infarction (MI) presentation (n=4,892), and without ULMCAD (n=9,336) (Figure 1). Definitions and Endpoints The primary outcome measure in the current study was a composite of death, MI, and stroke. The secondary outcome measures included cardiac death, sudden cardiac death, noncardiac death, MI, stroke, hospitalization for heart failure, major bleeding, any coronary revascularization, and ischemia-driven coronary revascularization. Death was regarded as cardiac in origin unless an obvious non-cardiac cause could be identified. Any death during the index hospitalization for coronary revascularization was regarded as cardiac death. MI was defined according to the definition in the Arterial Revascularization Therapy Study. 19 Stroke was defined as ischemic or hemorrhagic stroke either occurring during the index hospitalization or requiring hospitalization with symptoms lasting >24 h. Hospitalization for heart failure was defined as hospitalization for worsening heart failure requiring intravenous drug therapy. Bleeding was defined according to the Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries (GUSTO) classification; 20 GUSTO moderate or severe bleeding was adjudicated as a bleeding event. Any coronary revascularization was defined as either PCI or CABG

3 1284 SHIOMI H et al. for any reason. Scheduled staged coronary revascularization procedures performed within 3 months of the initial procedure were not regarded as follow-up events, but were included in the index procedure. Detailed definitions of baseline clinical characteristics and endpoints were reported previously. 16,17,21,22 Data Collection for Baseline Characteristics and Follow-up Events Experienced clinical research coordinators from an independent clinical research organization (Research Institute for Production Development, Kyoto, Japan; Appendix S2) collected baseline clinical, angiographic and procedural characteristics from hospital charts or hospital databases according to prespecified definitions. Collection of follow-up information was mainly conducted through review of inpatient and outpatient hospital charts by the clinical research coordinators, and additional follow-up information was collected through contact with patients, relatives and/or referring physicians by mail with questions regarding vital status, subsequent hospitalizations, and status of antiplatelet therapy. Death, MI, and stroke were Table 1. Comparison of the Baseline Characteristics of the PCI and CABG Groups PCI (n=364) CABG (n=640) P value Clinical characteristics Age (years) 71.4± ± years* 151 (41%) 208 (33%) Male* 258 (71%) 490 (77%) Body mass index <25.0* 270 (74%) 467 (73%) 0.68 Unstable angina 51 (14%) 71 (11%) 0.18 Hypertension* 312 (86%) 542 (85%) 0.66 Diabetes mellitus* 154 (42%) 291 (45%) 0.33 On insulin therapy 34 (9.3%) 93 (15%) 0.02 Current smoking* 78 (21%) 157 (25%) 0.26 LDL cholesterol (mg/dl) 117±34 112± Heart failure* 76 (21%) 131 (20%) 0.88 Ejection fraction 40% 34 (12%) 56 (9.5%) 0.30 Mitral regurgitation grade 3/4* 25 (6.9%) 17 (2.7%) Prior MI* 70 (19%) 105 (16%) 0.26 Prior stroke (symptomatic)* 54 (15%) 75 (12%) 0.16 Peripheral vascular disease* 45 (12%) 76 (12%) 0.82 egfr <30, without hemodialysis* 19 (5.2%) 38 (5.9%) 0.63 Hemodialysis* 25 (6.9%) 44 (6.9%) Anemia (hemoglobin <11.0 g/dl)* 72 (20%) 128 (20%) 0.93 Thrombocytopenia (platelets < )* 3 (0.8%) 19 (3.0%) 0.02 Chronic obstructive pulmonary disease* 12 (3.3%) 17 (2.7%) 0.56 Liver cirrhosis* 9 (2.5%) 19 (3.0%) 0.64 Malignancy* 58 (16%) 69 (11%) 0.02 Procedural characteristics No. of target lesions or anastomoses 2.00± ±1.04 <0.001 Target of proximal LAD* 174 (48%) 451 (70%) <0.001 Target of chronic total occlusion* 45 (12%) 166 (26%) <0.001 Emergency procedure 34 (9.3%) 50 (7.8%) 0.40 Extent of coronary artery disease <0.001 Isolated ULMCA disease 31 (8.5%) 57 (8.9%) ULMCA+1-vessel disease 89 (24.5%) 108 (16.9%) ULMCA+2-vessel disease 131 (36.0%) 182 (28.4%) ULMCA+3-vessel disease 113 (31.0%) 293 (45.8%) SYNTAX score 26.5 (21 34) 30 (22 40) <0.001 Low < (34.2%) 154 (26.8%) <0.001 Intermediate (36.7%) 177 (30.8%) High (29.1%) 243 (42.3%) Total no. of stents 2.79±1.70 Total stent length (mm) 58.8±41.1 Stent use 356 (98%) DES use 276 (78%) ITA use 629 (98%) Off pump 414 (65%) (Table 1 continued the next page.)

4 5-Year Outcome in Patients With ULMCAD 1285 PCI (n=364) CABG (n=640) P value Baseline medications Antiplatelet therapy Thienopyridine 361 (99%) 72 (11%) <0.001 Ticlopidine 315 (87%) 67 (94%) 0.07 Clopidogrel 46 (13%) 4 (5.6%) Aspirin 360 (99%) 632 (99%) 0.83 Cilostazol* 45 (12%) 41 (6.4%) Other medications Statins* 184 (51%) 199 (31%) <0.001 β-blockers* 109 (30%) 174 (27%) 0.35 ACEI/ARB* 190 (52%) 211 (33%) <0.001 Nitrates* 170 (47%) 230 (36%) Calcium-channel blockers* 170 (47%) 332 (52%) 0.12 Nicorandil* 94 (26%) 277 (43%) <0.001 Warfarin* 30 (8.2%) 244 (38%) <0.001 Proton-pump inhibitors* 92 (25%) 263 (41%) <0.001 Histamine type-2 receptor blockers* 77 (21%) 204 (32%) <0.001 *Risk-adjusting variables selected for Cox proportional hazard models. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CABG, coronary artery bypass grafting; DES, drug-eluting stents; egfr, estimated glomerular filtration rate; ITA, internal thoracic artery; LAD, left anterior descending coronary artery; MI, myocardial infarction; PCI, percutaneous coronary intervention; SYNTAX, Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery; ULMCA, unprotected left main coronary artery. adjudicated by the clinical event committee (Appendix S3). Median follow-up duration for the surviving patients was 1,959 (inter-quartile range [IQR]: 1,695 2,200) days. Complete 1-, 3-, and 5-year clinical follow-up information was obtained for 97.9%, 96.3%, and 72.5% of patients, respectively. Statistical Analysis Categorical variables were presented as number and percentage and compared with the chi-square test. Continuous variables were expressed as mean ± standard deviation (SD) or median with IQR. Continuous variables were compared using Student s t-test or the Wilcoxon rank sum test based on their distributions. Cumulative incidence was estimated by the Kaplan-Meier method and differences were assessed with the log-rank test. The effects of PCI relative to CABG for individual endpoints were expressed as hazard ratios (HR) with 95% confidence intervals (CI). We estimated the HR by Cox proportional hazard models adjusting for 30 clinically relevant factors listed in Table 1. Continuous variables were dichotomized by clinically meaningful reference values or median values. Proportional hazard assumptions for potential independent risk-adjusting variables were assessed on the plots of log (time) vs. log [ log (survival)] stratified by the variable, and the assumptions were verified to be acceptable for all the variables. We incorporated the 26 participating centers in the Cox proportional hazard models as the stratification variable. The unadjusted and adjusted risks of PCI relative to CABG for the primary outcome measure were evaluated in each SYNTAX score category as a subgroup analysis. In addition to the modes of coronary revascularization (PCI vs. CABG), variables with P<0.05 in the previously described full model were included in the multivariable models for the subgroup analysis, reflecting our preference for parsimonious models to avoid over-fitting. All statistical analyses were conducted using JMP 8.0 software (SAS Institute Inc, Cary, NC, USA) and SAS 9.2 (SAS Institute Inc). All reported P values were 2-tailed, and P<0.05 was considered statistically significant. Results Baseline Characteristics The study population reflected real-world clinical practice, including large proportions of patients with advanced age, diabetes mellitus, past history of heart failure, prior stroke, and renal insufficiency (Table 1). Compared with the CABG group, the PCI group included more elderly patients and those with malignancy and severe mitral regurgitation. Patients with diabetes on insulin therapy and thrombocytopenia were more common in the CABG group than in the PCI group (Table 1). Regarding the lesion characteristics, approximately twothirds of the patients in the entire cohort had multivessel coronary artery disease in addition to ULMCAD. The CABG group included more patients with complex coronary anatomy represented by the SYNTAX score (mean SYNTAX score: 26.5 vs. 30, P<0.001) and greater numbers of target lesions or anastomoses (2.00±1.03 vs. 3.09±1.04, P<0.001) (Table 1). In the PCI group, the majority of patients received stents (98%) and 78% of patients received at least 1 DES. DES were used for ULMCAD in 69% of patients. In the CABG group, the vast majority of patients received at least 1 internal thoracic artery bypass graft (98%), and the prevalence of off-pump CABG was high (65%). The patients in the PCI group more often experienced evidence-based medicine such as statins and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker compared with those in the CABG group (Table 1). Long-Term Clinical Outcome: PCI vs. CABG The cumulative 5-year incidence of death/mi/stroke (primary outcome measure) in the PCI group was significantly higher than that in the CABG group (34.5% vs. 24.1%, log-rank P<0.001) (Figure 2, Table 2). After adjusting for confounders, the risk for death/mi/stroke remained significantly higher in the PCI group than in the CABG group (adjusted HR: 1.48, 95% CI: , P=0.02) (Table 2). Regarding survival outcome, the adjusted risk for all-cause death was not significantly

5 1286 SHIOMI H et al. Figure 2. Kaplan-Meier event curves for (A) death/mi/stroke, and (B) all-cause death. PCI, percutaneous coronary intervention; CABG, coronary artery bypass grafting; MI, myocardial infarction. Table 2. Crude and Adjusted 5-Year Clinical Outcomes: PCI vs. CABG PCI (n=364) CABG (n=640) Endpoint No. of events No. of events (Incidence) (Incidence) Crude HR (95% CI) P value Adjusted HR (95% CI) P value All-cause death 88 (25.3%) 109 (18.0%) 1.54 ( ) ( ) 0.16 Cardiac death 44 (13.2%) 41 (7.2%) 1.99 ( ) < ( ) 0.02 Sudden cardiac death 15 (4.9%) 9 (1.6%) 2.71 ( ) Non-cardiac death 44 (13.9%) 68 (11.7%) 1.26 ( ) ( ) 0.95 MI 25 (7.7%) 19 (3.3%) 2.53 ( ) ( ) 0.04 Stroke 27 (8.6%) 42 (7.1%) 1.32 ( ) ( ) 0.81 Hospitalization for heart failure 43 (13.4%) 51 (9.0%) 1.65 ( ) ( ) 0.21 Major bleeding 56 (17.0%) 350 (54.9%) 0.25 ( ) < ( ) <0.001 Major bleeding beyond 30 days after procedure 41 (13.1%) 62 (10.7%) 1.32 ( ) ( ) 0.52 Any coronary revascularization 148 (45.7%) 84 (14.3%) 3.81 ( ) < ( ) <0.001 Ischemia-driven coronary revascularization 74 (23.8%) 35 (6.2%) 4.18 ( ) < ( ) <0.001 Death/MI/stroke 121 (34.5%) 147 (24.1%) 1.66 ( ) < ( ) 0.02 CI, confidence interval; HR, hazard ratio. Other abbreviations as in Table 1. different between the 2 groups (adjusted HR: 1.32, 95% CI: , P=0.16), although the cumulative 5-year incidence of all-cause death was significantly higher in the PCI group than in the CABG group (25.3% vs. 18.0%, log-rank P=0.001) (Figure 2, Table 2). The cumulative 5-year incidences of and the adjusted risks for cardiac death, MI, and any coronary revascularization were significantly higher in the PCI group than in the CABG group (adjusted HR: 2.00 [95% CI: , P=0.02], adjusted HR: 2.25 [95% CI: , P=0.04], and adjusted HR: 4.31 [95% CI: , P<0.001], respectively) (Table 2). The adjusted risk for hospitalization for heart fail- ure was not significantly different between the 2 groups (HR: 1.43, 95% CI: , P=0.21). The risk for major bleeding beyond 30 days after procedure was also not significantly different between the 2 groups (HR: 1.18, 95% CI: , P=0.52), although the overall risk for major bleeding, including bleeding events during the perioperative period, was significantly higher in the CABG group than in the PCI group (HR: 0.20, 95% CI: , P<0.001) (Table 2). SYNTAX Score and Clinical Outcome: PCI vs. CABG The SYNTAX scores were available for 931 patients (92.7%).

6 5-Year Outcome in Patients With ULMCAD 1287 Figure 3. Kaplan-Meier event curves comparing PCI with CABG for death/mi/stroke stratified by SYNTAX score tertile. (A) Low SYNTAX score category (<23), (B) intermediate SYNTAX score category (23 32), (C) high SYNTAX score category ( 33). PCI, percutaneous coronary intervention; CABG, coronary artery bypass grafting; MI, myocardial infarction. The median SYNTAX score was significantly higher in the CABG group than in the PCI group (30 vs. 26.5, P<0.001) (Table 1). The cumulative 5-year incidence of the primary outcome measure (death/mi/stroke) was not significantly different between the 2 groups in patients with low (<23) SYNTAX score (31.9% vs. 24.1%, log-rank P=0.16) (Figure 3). In patients with intermediate (23 33) and high ( 33) SYNTAX score, however, the measure was significantly higher in the PCI group than in the CABG group (35.8% vs. 21.8%, log-rank P<0.001, and 37.3% vs. 27.5%, log-rank P=0.009, respectively) (Figure 3). After adjusting for confounders, the risk for death/mi/stroke was not significantly different between the 2 groups for patients with low and intermediate SYNTAX scores (adjusted HR: 1.76 [95% CI: , P=0.0504], and adjusted HR: 1.53 [95% CI: , P=0.14], respectively), whereas it was signifi-

7 1288 SHIOMI H et al. cantly higher in the PCI group than in the CABG group for patients with high SYNTAX score (adjusted HR: 2.09, 95% CI: , P=0.004). Discussion The main findings of the current analysis were as follows: (1) CABG as compared with PCI was associated with better longterm outcome in patients with ULMCAD in real-world clinical practice, and (2) consistent with our previous 3-year report and the SYNTAX randomized trial, the long-term risk for serious cardiovascular events was not significantly different between PCI and CABG in patients with low or intermediate SYNTAX scores, but was markedly higher after PCI as compared with CABG in patients with high SYNTAX score. Extended 5-year follow-up in the current study made it possible to demonstrate an advantage of CABG over PCI in terms of the long-term outcome of patients with ULMCAD in realworld clinical practice, which could not be demonstrated in our previous 3-year follow-up results. In fact, late adverse events occurring beyond 1 year after DES implantation, such as VLST and late TLR, are major concerns of DES, and have been reported to continue occurring for up to 5 years at least However, studies evaluating long-term ( 5 years) outcomes of PCI compared with CABG in patients with ULMCAD are still limited The long-term risks for both MI and repeat coronary revascularization were significantly lower after CABG than after PCI in the current study. Subgroup analysis of ULMCAD patients in the SYNTAX randomized trial recently reported comparable 5-year cardiovascular outcomes for PCI and CABG. 13 The randomized control trial is the gold standard for comparing treatments, but generally enrolls selective patients without high risk profiles. On the other hand, observational study reflects real-world clinical practice, where there are many patients considered high risk such as the elderly, diabetics, and those with surgical ineligibility. The MAIN-COMPARE registry and several other studies reported comparable long-term cardiovascular outcomes for PCI and CABG, except for excess risk with PCI for repeat revascularization in patients with ULMCAD. 12,14,15 Consistent with the current study result, however, the RERIC and REAL investigators reported the long-term risks for death and MI as significantly lower after CABG than after PCI in patients with ULMCAD. 23 The reason for this discrepancy between studies might be the different characteristics of the patient populations in each study, especially differences in the proportions of high-risk patients with such as the elderly, diabetics, and those with a past history of heart failure, or complex multivessel disease. Consistent with both our previous 3-year follow-up results and the 5-year follow-up results from the SYNTAX randomized trial, the current 5-year follow-up study in real-world clinical practice confirmed the utility of the SYNTAX score for risk stratification and selection of mode of revascularization procedure, supporting the current updated clinical guidelines for ULMCAD. 5 7,13,16 Therefore, in ULMCAD patients with relatively less anatomical complexity, represented by a low or intermediate SYNTAX score, PCI using DES is a reasonable alternative to CABG in real-world clinical practice. On the other hand, CABG still remains the preferable treatment for ULMCAD patients with high anatomical complexity (ie, high SYNTAX score or complex multivessel disease), because the clinical outcome after CABG is not affected by anatomical complexity. Study Limitations First and most importantly, the observational study design precludes drawing definitive conclusions regarding the superiority of either PCI or CABG, because of selection bias and unmeasured confounders, despite appropriate statistical adjustment for potential confounders. Second, the number of patients enrolled was still small, although longer-term follow-up made it possible to demonstrate an advantage of CABG over PCI in the entire cohort. Finally, because patient demographics, practice patterns, and clinical outcomes in patients undergoing PCI and CABG in Japan may be different from those outside Japan, generalizing these results to populations outside Japan should be done with caution. Conclusions CABG as compared with PCI was associated with better longterm outcome for patients with ULMCAD, especially those with high anatomical complexity. Acknowledgments We appreciate the support and collaboration of the co-investigators participating in the CREDO-Kyoto PCI/CABG Registry Cohort-2. We are indebted to the outstanding effort of the clinical research coordinators for data collection. Disclosures Conflict of Interest: None of the authors has any conflict of interest to disclose. Funding Sources: This study was supported by the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan. References 1. Serruys PW, Morice MC, Kappetein AP, Colombo A, Holmes DR, Mack MJ, et al. Percutaneous coronary intervention versus coronaryartery bypass grafting for severe coronary artery disease. N Engl J Med 2009; 360: Morice MC, Serruys PW, Kappetein AP, Feldman TE, Stahle E, Colombo A, et al. 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