Coronary Revascularization for Patients with Severe Coronary Artery Disease: An Overview of Current Evidence and Treatment Strategies

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1 Review J Jpn Coron Assoc 2015; 21: Coronary Revascularization for Patients with Severe Coronary Artery Disease: An Overview of Current Evidence and Treatment Strategies Hiroki Shiomi, Takeshi Kimura The technical and device refinements in percutaneous coronary intervention (PCI) and coronary artery bypass grafting () has achieved the improvement of outcome in patients with coronary artery disease (CAD). Optimal revascularization methods (PCI or ) for severe CAD such as multivessel and/or left main CAD is still in debate in the current clinical practice. In this review, therefore, we discuss the current status of coronary revascularization and outcome in patients with severe CAD on the basis of the evidence of clinical trials in DES era. KEY WORDS: coronary revascularization, PCI, I. Introduction Coronary artery disease (CAD) is still one of the leading cause of death worldwide. Coronary revascularization as well as medical treatment is an established key treatment for both acute coronary syndrome and stable CAD over the past several decades. Coronary artery bypass grafting () was started in the 1960s and the introduction of internal thoracic artery (ITA) grafts use improved the long-term patency of graft as compared with saphenous vein grafts (SVG) use. 1) Balloon angioplasty was firstly performed in 1977 by Andreas Grüentzig. The development of coronary stent overcame acute occlusion by coronary dissection and acute recoil. These device and technical improvement in percutaneous coronary intervention (PCI) has gradually shifted the selection of coronary revascularization procedure from to PCI, especially after the introduction of drug-eluting stents (DES), which could dramatically reduce the rate of restenosis. 2) However, optimal revascularization methods (PCI or ) for severe CAD such as multivessel and/or left main (LM) CAD is still in debate in the current clinical practice. In this review, therefore, we discuss the current status of coronary revascularization and outcome in patients with severe CAD on the basis of the evidence of clinical trials in DES era. II. The SYNTAX trial Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, , Japan doi: /jcoron The SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) randomized trial is the first dedicated trial comparing PCI using first-generation DES of paclitaxel-eluting stents (PES) with in patients with LM/3-vessels CAD. 3) In this trial, 1,800 patients were randomly assigned to (n=897) or PCI using PES (n=903), and a composite endpoints of major adverse cardiac and cerebrovascular events () were evaluated as a primary endpoint. Recently published 5-year clinical follow-up demonstrated that the cumulative incidences of (26.9% versus 37.3%, log-rank P<0.0001), myocardial infarction (MI: 3.8% versus 9.7%, log-rank P<0.0001), and repeat revascularization (13.7% versus 25.9%, log-rank P<0.0001) were ly lower in the group than in the PCI group, although those of all-cause death (11.4% versus 13.9%, log-rank P=0.10) and (3.7% versus 2.4%, log-rank P=0.09) were not ly different between the 2 groups. 4) In the SYNTAX trial, however, clinical outcomes of PCI as compared with were quite different between LM and 3-vessels CAD stratum. 4) In the following sections, therefore, we review the clinical outcomes of coronary revascularization for multivessel CAD (including 3-vessels CAD) and LM CAD separately. III. Multivessel disease Several studies reported the clinical outcomes of patients with multivessel CAD after PCI as compared with those after (Table 1). 5-14) In the 3-vessels CAD stratum of the SYNTAX trial, the cumulative 5-year incidence of was ly higher in the PCI group than in the group (37.5% versus 24.2%, P). 10) Furthermore, the cumulative 5-year incidence of all- 267

2 Study NY State Cardiac Registry-3VD (2008) ARTS II (2010) ASAN Multivessel Registry (2011) ASCERT (2012) FREEDOM (2012) SYNTAX-3VD (2014) CREDO-Kyoto Cohort-2 (2015) Yonsei University Registry (2013) Study type Histrical comparison RCT J Jpn Coron Assoc 2015; 21: Table 1 Clinical studies comparing PCI and in multivessel CAD in the DES era Patient profile Follow-up (years) 3VD 1.5 MVD 5 MVD 5 MVD 4 MVD with DM RCT 3VD 5 5 3VD 5 3VD 3 BEST (2015) RCT MVD 4.6 NY State Registry (2015) MVD 2.9 Groups 1G-DES Era (N=5, 202) PCI with DES (N=2, 481) (N=605) PCI with SES (N=607) (N=1, 495) PCI with DES (N=1, 547) (N=86, 244) PCI (N=103, 549, DES: 78%) (N=947) PCI with DES (N=953) (N=545) PCI with PES (N=543) (N=1,154)PCI (N=1,824, DES: 77%) 2G-DES Era OPCAB (N=799) PCI with 2G-DES (N=847) (N=442) PCI with EES (N=438) (N=9,223) PCI with EES (N=9,223) Primary endpoint Death/MI Death s TVR Death 7.9% 10.5% 21.1% 27.5% 14.5% 10.6% 16.4% 20.8% 18.7% 26.6% 24.2% 37.5% 24.0% 28.2% 5.2% 11.5% 10.6% 15.3% 2.9%/year 3.1%/year NA but Mortality 6.0% 7.3% 7.4% 5.5% 11.0% 8.2% 16.4% 20.8% 10.9% 16.3% 9.2% 14.6% 17.5% 20.5% 2.6% 4.6% 5.0% 6.6% 2.9%/year 3.1%/year NA but clinical outcomes of PCI using 2-G DES of everolimus-eluting stents (EES) with. 14) In this using a propensity matched cohort, mortality risk was not ly different between PCI with EES and (3.1%/year versus 2.9%/year, HR: 1.04, 95%CI: , P=0.50), although PCI with EES as compared with was ly associated with higher risk for MI (HR: 1.51, 95%CI: , P) and repeat revascularization (HR: 2.35, 95%CI: , P). On the other hand, the BEST (Randomized Comparison of Coronary Artery Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment of Patients with Multivessel Coronary Artery Disease) trial, in which 880 patients with multivessel CAD randomly assigned to PCI using EES or, reported that the risk of PCI with EES relative to for the primary endpoint of death/mi/target-vessel revascularization was ly higher (15.3% versus 10.6%, log-rank P=0.04). 13) IV. Treatment selection according to anatomical complexity In the SYNTAX trial, SYNTAX score based on anatomical complexity of CAD was introduced and successfully stratified the different risk of PCI relative to for clinical outcomes. 10) Reflecting the of the SYNTAX trial, the current clinical guidelines updated the recommendations of PCI for 3-vessels CAD according to SYNTAX score. 15, 16) Discordant with the SYNTAX trial, however, the CREDO-Kyoto registry cohort-2 and the FREEDOM trial could not demonstrate the utility of the SYNTAX score in selecting the mode of revascularizacause death (14.6% versus 9.2%, P=0.006) as well as that of MI (22.0% versus 14.0%, P) was ly higher in the PCI group than in the group. On the other hand, the risk for was not ly different between PCI and (3.0% versus 3.5%, P=0.66). The FREEDOM (the Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease) trial was a multi-center randomized clinical trial (RCT) in which 1900 MV- CAD patients with diabetes mellitus (DM) were randomly assigned to undergo PCI using DES or, and reported that the primary endpoint of a composite of death/mi/ was ly lower in the group than in the PCI group (18.7% versus 26.6%, P=0.005). 9) In Japan, the CREDO-Kyoto (Coronary REvascularization Demonstrating Outcome Study in Kyoto) registry cohort-2 reported long-term clinical outcomes after PCI and in patients with 3-vessels CAD in DES era. 11) Consistent with the in RCTs and observational studies in foreign countries, the CREDO-Kyoto registry cohort-2 reported that the excess risks of PCI relative to for death/mi/ (hazard ratio [HR]: 1.38 [95% confidence interval (CI): ], P=0.002), all-cause death (HR: 1.38, 95%CI: , P=0.006), MI (HR: 2.81, 95%CI: , P), and any coronary revascularization (HR: 4.10, 95%CI: , P) were 8, 10, 11) even after adjusting for confounders. In the second-generation (2-G) DES era, a large-scale observational in New York State in the United State compared 268

3 Study MAIN- COMPARE: DES stratum (2010) Milan-LMT registry(2010) PRECOMBAT (2011) Study type Table 2 Clinical studies comparing PCI and in LM CAD in the DES era Patient profile Follow-up (years) RCT LM-CAD 2 LE MANS (2011) RCT LM-CAD 1 SYNTAX-LM (2014) CREDO-Kyoto Cohort-2 (2015) PRECOMBAT-2 (2012) Yonsei University Registry (2013) RCT Histrical comparison LM-CAD 1.5 LM-CAD 3 Groups Primary endpoint 1G-DES Era (N=690) PCI with DES (N=784) (N=142) PCI with DES (N=142) (N=300) PCI with SES (N=300) (N=101) PCI with SES (N=100) (N=348) PCI with PES (N=357) (N=640) PCI (N=364, DES: 78%) MACE 2G-DES Era (N=272) PCI with EES (N=334) OPCAB (N=251) PCI with s 2G-DES (N=236) 16.3% 12.7% 38.3% 32.4% 8.1% 12.2% 13.9% 19.0% 31.0% 36.9% 24.1% 34.5% 6.7% 8.9% 3.6% 15.4% (P for noninferiority) Mortality 15.4% 12.1% 18.3% 15.9% 3.4% 2.4% 5.0% 2.0% 14.6% 12.8% 18.0% 25.3% 3.3% 2.2% 2.1% 6.7% NA but not 0.45 (P for noninferiority) NA but not 0.06 tion. 9, 11) Therefore, dedicated prospective randomized trials are necessary to address whether PCI could be a viable option in 3-vessels CAD patients with low/intermediate SYNTAX score. V. Future perspectives in the treatment of multivessel CAD Most previous studies showed the benefit of over PCI in 8, 10, 12, 13, 17) long-term cardiovascular outcomes even in DES era. However, newer adjunctive medical therapies such as novel P2Y12 receptor inhibitors and PCSK9 inhibitors, as well as newer device including newer generation DES and bioresorbable scaffolds might expect to improve clinical outcomes of multivessel CAD patients treated with PCI ) PCI guided by fractional flow reserve (FFR), furthermore, was reported to provide improved clinical outcomes as compared with conventional angiography-guided PCI in multivessel CAD. 22) The currently ongoing FAME 3 trial, in which 1,500 patients with multivessel CAD randomly assign to PCI guided by FFR or, would provide further guidance for treatment for multivessel CAD. VI. Left main coronary artery disease In the LM-CAD stratum (N=705) of the SYNTAX trial, the cumulative 5-year incidences of (36.9% versus 31.0%, P=0.12), all-cause death (12.8% versus 14.6%, P=0.53), and MI (8.2% versus 4.8%, P=0.10) in the PCI group was not ly different with those in the group. 23) The risk of PCI relative to for was ly lower (1.5% versus 4.3%, P=0.03), while the risk for repeat revascularization was ly higher in PCI than (26.7% versus 15.5%, P<0.01). Favorable long-term mortality of LM-CAD patients after PCI was consistently observed in several clinical studies despite of higher risk of PCI relative to for repeat revascularization (Table 2). 17, 23-25) In Japan, The CREDO-Kyoto registry cohort-2 reported longterm clinical outcomes after PCI and in patients with LM CAD in DES era. 17) In the CREDO-Kyoto registry cohort-2, the cumulative 5-year incidences of a composite of death/mi/ (34.5% versus 24.1%, log-rank P) and all-cause death (25.3% versus 18.0%, log-rank P=0.001) were ly higher in the PCI group than in the group. After adjusting for confounders, the risk of PCI relative to for all-cause death was not ly different (HR: 1.32, 95%CI: , P=0.16), although that for death/mi/ was still signifi- 269

4 cantly higher (HR: 1.48, 95%CI: , P=). VII. Treatment selection according to anatomical complexity Consistent with the SYNTAX trial, the CREDO-Kyoto registry cohort-2 showed the utility of SYNTAX score for risk stratification and selection of mode of revascularization procedure in LM-CAD. 17, 23) In the CREDO-Kyoto registry cohort-2, the adjusted risk for death/mi/ was not ly different between PCI and in low (HR: 1.76, 95%CI: , P=0.0504), or intermediate (HR: 1.53, 95%CI: , P=0.14) SYNTAX scores, whereas it was ly higher in PCI than for patients with high SYNTAX score (HR: 2.09, 95%CI: , P=0.004). The current clinical guidelines updated the recommendations of PCI for LM CAD 15, 16) according to SYNTAX score. VIII. Future perspectives in the treatment of LM CAD The previous studies reporting favorable long-term clinical outcomes after PCI using DES suggest that further shifting to PCI could be possible without impairing long-term outcome in selected patients with LM CAD. The currently ongoing EXCEL trial, in which 2,600 LM CAD patients with SYNTAX score<33 randomly assign to PCI with EES or, would provide further guidance for treatment for LM CAD. IX. Conclusion After the introduction of DES in daily clinical practice, the selection of mode of coronary revascularization has dramatically changed over time in Japan. 2) The currently available evidence based on the of clinical studies comparing PCI with in DES era suggest that is still standard treatment for advanced multivessel CAD, while PCI can be a reasonable alternative to in selected patients with LM CAD. More appropriate indication for coronary revascularization and selection of revascularization procedure as well as stringent adherence to evidence-based medicines might lead further improvement of outcome in patients with severe CAD. All authors declare no conflict of interest. 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