Chapter 29 Left Main Intervention in the Light of EXCEL and NOBLE Trials

Chapter 29 Left Main Intervention in the Light of EXCEL and NOBLE Trials DEBDATTA BHATTACHARYYA AYAN KAR The incidence of angiographically significant left main stenosis described in various studies has been estimated at 5% 7% 1. Among the various subsets, the distal bifurcation is most commonly involved in up to 80% of cases. The earliest mention of thrombotic left main occlusion was described by James Herrick in 1912, accidentally in an autopsy specimen of a man who died of a sudden cardiac arrest 2. Due to the large mass of myocardium supplied by the left main coronary artery, nonrevascularized critical left main stenosis treated with medical therapy alone has mortality rates in excess of 50% over a 3-year period 3. Prior to the era of coronary angioplasty, coronary artery bypass grafting (CABG) was the only modality of revascularization in patients with significant left main coronary artery (LMCA) disease (class I recommendation). In the early days of balloon angioplasty, it was quickly realized by experienced operators that the left main did not lend itself as an easy target for balloon angioplasty. Following the development of bare-metal stents further attempts at dealing with the left main met with modest success. It was only after the discovery of drug-eluting stents that the first major efforts in left main percutaneous coronary intervention (LM PCI) were carried out, being pioneered by S.J. Park et al. 4, 5 which established the feasibility of LM PCI in low-risk subsets with drug-eluting stents. In this chapter, we will review the background and gradual development of LM PCI over the years and the impact of the two new trials EXCEL (Everolimus- Eluting Stents or Bypass Surgery For Left Main Coronary Artery Disease) and NOBLE (Nordic-Baltic- British Left Main Revascularization Study) and its implications in our day-to-day practise. PRE-EXCEL AND NOBLE ERA ( Fig 29-1 ) 1980 : The earliest attempts at balloon angioplasty to the unprotected left main was carried out in the early 1980s by none other than Andreas Gruentzig and was limited by abrupt closure, 1980:POBA to Left Main 1990:Advent of BMS:high TVR rates 20% 30% 2000:MAIN COMPARE registry; advent of DES reduced rates of TVR 2007: SYNTAX 2009: PRECOMBAT; left main intervention using IVUS 2016:EXCEL, NOBLE Figure 29-1. Timeline of left main intervention data. 221

222 SECTION IV Interventional Cardiology dissection, high rates of restenosis and sudden cardiac death. O Keefe et al. demonstrated that mortality rates were as high as 64% at 3 years after POBA to the left main 6. 1990 : The advent of bare-metal stents helped reduce acute recoil and abrupt closure of the vessel, but high rates of repeat revascularization (20% 30%) due to restenosis was a major concern 7. 2000 : First significant large Korean Registry (n 2240) by S.J. Park et al., MAIN COMPARE registry 4 showed that LM PCI had equivalent mortality rates in both CABG and PCI but also reported higher rates of serious ischaemic complications (death, non-q MI and stroke) in the PCI arm. With the advent of drug-eluting stents (DES), target vessel revascularization (TVR) rates were significantly reduced (from 20% to 10%) but CABG still remained the preferred alternative to PCI for reducing TVR rates. 2007 : The SYNTAX trial although not a dedicated left main trial (417 patients out of total 705 PCI patients underwent LM PCI), was one of the first trials to imply that the three-point Major Adverse Cardiovascular Events (MACE) (death, stroke, Myocardial Infarction [MI]) rates were similar in the PCI and CABG arm with first-generation paclitaxel-eluting stents, where SYNTAX scores were less than 33. The higher Major Adverse Cardiac and Cerebrovascular Events (MACCE) rates in the PCI cohort was mostly driven by repeat MI and target lesion revascularization (TLR) (23%). This trial also lead to the use of SYNTAX scores and suggested that patients with higher SYNTAX scores (complex disease) had worse outcomes with PCI compared to CABG 8. 2011: The SYNTAX trial was followed by the PRE- COMBAT trial by S.J. Park et al. (Premier of Randomized Comparison of Bypass Surgery versus Angioplasty Using Sirolimus-Eluting Stents in Patients with Left Main Coronary Artery Disease). This was one of the first trials to show that the systematic use of intravascular ultrasound (IVUS) (91.2%) might improve outcomes in the LM PCI subset, with comparable combined MACE rates (death, MI and stroke) for CABG and PCI 5. The common shortcoming of all these above trials was small cohorts, which were underpowered for events, usage of first-generation DES, inadequate usage of guideline directed medical therapy, variations in the duration of dual anti-platelet therapy (DAPT) usage and nonuniform use of intravascular imaging. 2016: This set the stage for more robust trials which would evaluate the safety and efficacy of contemporary LM PCI with newer generation stents of advanced design, by experienced operators in high-volume laboratories with access to intravascular imaging services The EXCEL and NOBLE trial. In this chapter, we summarize both trials and highlight salient interesting features, observations and their applicability in our patient population ( Table 29-1 ). Patient demographics: The EXCEL and NOBLE trials enrolled a predominantly elderly White male population with mean age,66 years, average BMI 28 kg/m 2 with preserved LV ejection fractions ( 57%). There was very little or no representation of Asian patients. Diabetic patients were higher in the EXCEL trial (30%) compared to the NOBLE trial (18%). Patients who presented with acute coronary syndromes were higher in the EXCEL trial, 38% when contrasted to 18% in the NOBLE trial. All the other patients had chronic stable angina with comparable cardiovascular risk factors apart from diabetes. Inclusion criteria: The EXCEL trial had more precise criteria for inclusion and included patients with visually estimated angiographic stenosis 70% or angiographic left main stenosis between 50% and 70% with an fractional flow reserve (FFR) 0.8 or IVUS minimal lumen area (MLA) 6.0 mm 2. Patients who did not meet criteria for clinical equipoise were included in a subsequent registry. On the other hand, the NOBLE trial included patients with angiographically estimated left main stenosis 50% or an FFR 0.8 with any other three noncomplex stenosis (where complex stenosis was defined as bifurcation, chronic total occlusion, calcification and tortuosity). Procedural characteristics: Both trials had comparable mean SYNTAX scores between 20 and 22 suggesting an overall less complex subset of left main disease which is generally associated with better outcomes for PCI. Although both trials stressed on the use of IVUS, only 74% 77% of patients actually had IVUS guidance and its use was left to operator discretion. There was no prespecified protocol for preassessment to decide on intervention strategy and postassessment of stented segments to decide on completeness of procedure. NOBLE data show pre-assessment of lesions in only 42% of the patients, whereas similar data for EXCEL were not readily available. Nonuniform use of IVUS in deciding stenting strategy implies that bifurcation

Chapter 29 Left Main Intervention in the Light of EXCEL and NOBLE Trials 223 TABLE 29-1 OVERVIEW OF EXCEL AND NOBLE TRIALS Parameter EXCEL NOBLE Patients enrolled 1905 (PCI 948, CABG 957) 1201 (PCI 592, CABG 592) Recruitment period September 2010 to March 2014 2008 2013 Median follow-up 3 years 5 years Statistical analysis Primary end points based on median follow-up of 3 years Primary end points based on median follow-up of 5 years Primary end points Death, MI, stroke Death, MI, stroke, TVR Age 66 years, predominantly White males 66.2 years, predominantly White males Diabetics 30% 15% Stable angina 62% 82% ACS 38% 18% Mean LVEF 57% 60% Inclusion criteria Visually estimated LM 70% or Visually estimated LM 50% 70% FFR 0.8 or IVUS MLAs 6.0 mm 2 Clinical equipoise for CABG or PCI 50% LM disease or FFR, 0.8 3 other noncomplex stenosis Clinical equipoise for CABG or PCI Distal LM bifurcation 81% 81% SYNTAX score 20.6 22.5 Heart team approach Yes Yes IVUS usage 77% 74% FFR 9% Precise data not available No of lesions treated 1.9 1.1 2.0 (1 3) Two-stent technique Precise data not available 35% Preferred bifurcation technique Operator choice Culotte with two stents Stent Everolimus-eluting stent (Xience) Initial 73 cases, sirolimus-eluting stents followed by biolimus-eluting stent (Biomatrix Flex) Rates of complete revascularization Precise data not available 92% DAPT duration 1 year Minimum 1 year Stent thrombosis (%) 6 (0.7%) 8 (2%) Graft thrombosis 48 (5.4%) 15 (4%) Stroke PCI 20 (2.3%), CABG 26 (2.9%) PCI 16 (5%), CABG 7 (2%) Major bleeds requiring blood transfusion MACE rates at 30 days; 1, 3 and 5 years Higher in CABG arm At 30 days: PCI 4.9%, CABG 7.9%, P.008 At 3 years: PCI 15.4%, CABG 14.7%, P.02 Higher in CABG arm At 1 years: PCI 7%, CABG 7%, P 1.00 At 5 years: PCI 28%, CABG 18%, P.004 Note. ACS, acute coronary syndrome; CABG, Coronary Artery Bypass Grafting; DAPT, dual anti-platelet therapy; FFR, fractional flow reserve; IVUS, intravascular ultrasound; LM, Left Main; MACE, major adverse cardiovascular Events; MI, myocardial infarction; PCI, percutaneous coronary intervention; MLA, minimal lumen area; TVR, target vessel revascularization. strategy was largely decided by angiographic appearance alone. Similarly, the end points regarding completeness of procedure did not have specific IVUS cut-offs. Presently, there seems to be widespread agreement regarding the 5, 6, 7 and 8 mm 2 as minimum IVUS MLA end points for left circumflex (LCX), left anterior descending artery (LAD), polygon of confluence (POC) and distal LMCA, respectively, in distal LMCA stenting 9. But this measurement was not used in either of the two trials. FFR usage was minimal in the EXCEL trial at 9%, whereas in the NOBLE trial, the exact data were not readily available. There was no real consensus on bifurcation stenting strategy in either trial. The chosen strategy largely depended on operator comfort and discretion with no objective end points. Both trials preferred the provisional stenting strategy, in which two-stent strategy was decided from the beginning, the NOBLE trial operators preferred the culotte technique, but similar data are not

224 SECTION IV Interventional Cardiology 120 100 80 60 40 20 0 Peri-Procedural 30 days 1 year 2 years 3 years Aspirin-PCI P2Y12-PCI Aspirin-CABG P2Y12-CABG Figure 29-2. Trends of percentage aspirin and clopidogrel usage in PCI and CABG over 3 years. available from EXCEL trial. The NOBLE trial operators preferred the culotte technique though all other techniques were used as well. In this context, it is worthwhile to mention the DK CRUSH III trial which showed that culotte had worse outcomes compared to DK CRUSH in left main bifurcation lesions 10. While the EXCEL trial used everolimus-eluting stents (XIENCE), the NOBLE trial used biolimuseluting stents (BIOMATRIX FLEX), except for the initial 73 patients (amounting to 12% of the PCI cohort) of the NOBLE trial, who received sirolimuseluting stents. There were, however, also a small group of patients in the EXCEL trial who did not receive Xience stents (31 out of 2282 stents), the reasons for which are not specified by the trial operators. In both the trials, surgeons attempted total arterial revascularization wherever possible. At least one arterial conduit was used in all CABG patients (in EXCEL 98% LIMA, 38% LIMA-RIMA Y graft). Off-pump CABG was also preferred but its use was lower compared to Indian trends (49.2% in EXCEL vs. 60% in India). Rigorous efforts were employed by surgeons to reduce stroke rates by the frequent use of epiaortic ultrasound and transoesophageal echocardiography in the EXCEL trial. Similar data are not available from the NOBLE trial. Medication usage: Both trials recommended modern contemporary guideline directed medical therapy for both patient groups. There was more uniform consensus on the usage of DAPT in PCI compared to CABG; DAPT was used for a minimum of 1 year post-pci. However, despite a growing consensus amongst surgeons regarding 60 50 40 30 20 10 0 liberal DAPT usage in post-cabg patients, in both the trials DAPT was given to only those CABG patients who presented with ACS 11 (38% in EXCEL and 18% in NOBLE) ( Fig 29-2 ). It is thus surprising that such crucial therapy was not protocolized and left to chance. This suboptimal medical therapy could have possibly translated into an increased risk of recurrent cardiovascular events in the CABG arm and is possibly one of the reasons behind the significantly increased number of symptomatic graft thromboses in the CABG arm compared to stent thrombosis in the PCI arm in the EXCEL trial (48 vs. 6) ( Fig 29-3 ). We also found it intriguing that there was an increased use of diuretics in the CABG arm that persisted up to 3 years ( Fig 29-4 ), suggesting a sustained need for anticongestive measures 6 6 Stent thrombosis 11 30 days 3 years 48 Graft thrombosis Figure 29-3. Number of stent and graft thrombosis at 30 days and 3 years - EXCEL Trial.

Chapter 29 Left Main Intervention in the Light of EXCEL and NOBLE Trials 225 40 30 20 10 0 29.8 5.4 36 37.3 10 30 days 1 year 2 years PCI 12.2 CABG compared to the PCI arm. This is despite the fact that absolute number of patients with congestive heart failure and renal impairment were higher in the PCI group to begin with. This discrepancy is difficult to explain, especially due to the fact that ejection fractions were well preserved in both CABG and PCI arms at the time of randomization. Statistical analysis: Both trials have used median follow-up data rather than actual total follow-up data. Published Kaplan Meier 5-year curves in case of NOBLE and 3-year curves in case of EXCEL are based on median follow-ups and do not represent the total data. Moreover, the prolonged recruitment period of NOBLE (6 years) and large number of operators (n 126) could have possibly given rise to inhomogeneity in revascularization techniques as they have been refined over the years. Similarly, EXCEL trial had 126 sites with possibly equal or more number of operators. It is also important to note that the NOBLE investigators acknowledge that a major limitation of this study was change in end point timing which was done due to low-event rates and the change in risk profile of subjects entering the study early and late. Hence, the actual events can only be determined at the end of full 5-year follow-up. Primary end points: The primary end points were different in the two trials. While EXCEL included death stroke and MI in their primary end points, NOBLE included death, MI, stroke and TVR rates too. RESULTS OF THE EXCEL TRIAL 38.9 3 years Figure 29-4. Percentage diuretic usage in PCI and CABG arms of EXCEL trial. The EXCEL trial showed that PCI with everolimuseluting stents was noninferior to CABG with 14 respect to primary composite of death, MI and stroke at 3 years. The prespecified secondary end point of combined death stroke and MI at 30 days was 4.9% in the PCI group and 7.9% in the CABG group hinting at the procedural safety of PCI. Although total ischaemia-driven revascularization rates were higher in the PCI group, rates of symptomatic graft occlusion (n 48) was much higher compared to rates of definite stent thrombosis (n 6) at 3 years establishing the safety of this procedure. Stroke rates were comparable in both arms which was a significant improvement for the CABG arm compared to the SYNTAX trial. RESULTS OF THE NOBLE TRIAL In this trial, the primary end point was a composite of death, MI, stroke and TVR. Median follow-up of 5 years showed that the primary end point was achieved in 28% of PCI patients compared to 18% of CABG patients establishing the superiority of CABG. Although rates of all-cause mortality were similar, rates of MI and TVR were higher in the PCI group. Stroke rates were unexpectedly higher in the PCI group over median 5 years follow-up despite rates of stroke remaining higher in the CABG group in the first 30 days from the index procedure. The rise in stroke rates in the PCI group coincided with the cessation of DAPT. When Kaplan Meier estimates were re-evaluated for SYNTAX tertiles of low, intermediate and high SYNTAX scores, unexpected separation of the Kaplan Meier curves were noted in all three tertiles, unlike the EXCEL trial which showed similar results in the low-risk cohort. CONCLUSION Interventionists can interpret these results with satisfaction and optimism that PCI has come a long way in terms of safety in treating left main stenosis in what was previously an exclusive domain for surgeons. However, before generalizing the results of EXCEL and NOBLE in our day-to-day left main practise, we should employ caution as the cohort of patients undergoing LM PCI were in the lower risk category, and attempts to extend these results into more complex subsets will invariably produce worse outcomes compared to the trial data. One sobering fact is the large number of patients who were sent to the registry at the time

226 SECTION IV Interventional Cardiology of randomization and eventually underwent CABG in the EXCEL trial. On the other hand, the future looks bright as increasing sophistication in stenting techniques and strategies based on IVUS analysis of the distal LMCA, POC, proximal LAD and proximal LCX is likely to improve outcomes further, especially once these approaches are more standardized and there is more consensus and less heterogeneity in assessment and stenting technique of the LMCA bifurcation and universal agreement on IVUS-guided end points. REFERENCES 1. De Caterina, A. R., Cuculi, F., & Banning, A. P. ( 2013 ). Incidence, predictors and management of left main coronary artery stent restenosis: A comprehensive review in the era of drug-eluting stents. EuroIntervention, 8 ( 11 ), 1326 1334. 2. Herrick, J. B. ( 1912 ). Clinical features of sudden obstruction of the coronary arteries. JAMA, 59, 2015 2020. 3. Mock, M. B., Ringqvist, I., Fisher, L. D., Davis, K. B., Chaitman, B. R., Kouchoukos, N. T., et al. ( 1982 ). Survival of medically treated patients in the coronary artery surgery study (CASS) registry. Circulation, 66 ( 3 ), 562 568. 4. Park, D. W., Seung, K. B., Kim, Y. H., Lee, J. Y., Kim, W. J., Kang, S. J., et al. ( 2010 ). Long-term safety and efficacy of stenting versus coronary artery bypass grafting for unprotected left main coronary artery disease: 5-year results from the MAIN-COMPARE (Revascularization for Unprotected Left Main Coronary Artery Stenosis: Comparison of Percutaneous Coronary Angioplasty Versus Surgical Revascularization) registry. Journal of the American College of Cardiology, 56 ( 2 ), 117 124. 5. Park, S. J., Kim, Y. H., Park, D. W., Yun, S. C., Ahn, J. M., Song, H. G., et al. ( 2011 ). Randomized trial of stents versus bypass surgery for left main coronary artery disease. New England Journal of Medicine, 364 ( 18 ), 1718 1727. 6. O Keefe, J. H., Jr., Hartzler, G. O., Rutherford, B. D., McConahay, D. R., Johnson, W. L., Giorgi, L. V., et al. ( 1989 ). Left main coronary angioplasty: early and late results of 127 acute and elective procedures. American Journal of Cardiology, 64 ( 3 ), 144 147. 7. Silvestri, M., Barragan, P., Sainsous, J., Bayet, G., Simeoni, J. B., Roquebert, P. O., et al. ( 2000 ). Unprotected left main coronary artery stenting: immediate and medium-term outcomes of 140 elective procedures. Journal of the American College of Cardiology, 35 ( 6 ), 1543 1550. 8. Morice, M. C., Serruys, P. W., Kappetein, A. P., Feldman, T. E., Ståhle, E., Colombo, A., et al. ( 2010 ). Outcomes in patients with de novo left main disease treated with either percutaneous coronary intervention using paclitaxel-eluting stents or coronary artery bypass graft treatment in the Synergy Between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery (SYNTAX) trial. Circulation, 121 ( 24 ), 2645 2653. 9. Kang, S. J., Mintz, G. S., Kim, W. J., Lee, J. Y., Oh, J. H., Park, D. W., et al. ( 2011 ). Changes in left main bifurcation geometry after a single-stent crossover technique: An intravascular ultrasound study using direct imaging of both the left anterior descending and the left circumflex coronary arteries before and after intervention. Circulation Cardiovascular Interventions, 4 ( 4 ), 355 361. 10. Chen, S. L., Xu, B., Han, Y. L., Sheiban, I., Zhang, J. J., Ye, F., et al. ( 2013 ). Comparison of double kissing crush versus Culotte stenting for unprotected distal left main bifurcation lesions: results from a multicenter, randomized, prospective DKCRUSH-III study. Journal of the American College of Cardiology, 61 ( 14 ), 1482 1488. 11. Bomb, R., Oliphant, C. S., & Khouzam, R. N. ( 2015 ). Dual antiplatelet therapy after coronary artery bypass grafting in the setting of acute coronary syndrome. American Journal of Cardiology, 116 ( 1 ), 148 154.