ΑΓΓΕΙΟΠΛΑΣΤΙΚΗ ΣΤΟ ΔΙΑΒΗΤΙΚΟ ΑΣΘΕΝΗ

ΑΓΓΕΙΟΠΛΑΣΤΙΚΗ ΣΤΟ ΔΙΑΒΗΤΙΚΟ ΑΣΘΕΝΗ Νίκος Μεζίλης MD, FESC Κλινική Άγιος Λουκάς

Why diabetes is associated with restenosis endothelial dysfunction metabolic alterations accelerated platelet deposition propensity to growth factors known to promote the restenosis. advanced glycosylation promotes inflammatory cell recruitment smooth muscle cell proliferation

5-Year Outcomes of the SYNTAX Trial Mohr FW et al. Lancet 2013; 381:629-38 MACCE: Death, MI, Stroke, or Repeat Revasc

MACCE to 5 Years by SYNTAX Score Mohr FW et al. Lancet 2013; 381:629-38 Low Scores (0-22) PCI CABG Death 8.9 10.1 P=0.64 MI 7.8 4.2 P=0.11 Intermediate Scores (23-32) Death 13.8 12.7 P=0.68 MI 11.2 3.6 P=0.0009 High Score 33 Death 19.2 11.4 P=0.005 MI 10.1 3.9 P=0.004

Revascularisation strategies in diabetic patients with CAD Trial MVD EF (%) (%) 2368 31 763 1605 N Primary Endpoint FU (y) Trial Results 57 Death 5 No differences in death and MACE 52 57 Death 5 20 57 Death 5 510 93 93 Death, MI or stroke 1 1900 100 100 Death, MI or stroke 3.8 207 - - Death or MI 2 Revascularisation vs. medical therapy BARI-2Dw60 (2009) CABG stratum BARI-2Dw60 (2009) Lower rates of MI with CABG PCI stratum BARI-2Dw60 (2009) No differences in death and MACE PCI vs. CABG CARDiaw61 (2010) FREEDOM (2012)55 VA-CARDSw62 (2013) SYNTAX (2013)54 452 100 Favours CABG - Death, MI, stroke or repeat revascularisation 1 Failure to demonstrate noninferiority of PCI Lower rates of death, MI or stroke with CABG No differences in death or MI Lower rates of death, MI, stroke or repeat revascularisation with CABG

FREEDOM Design (1) Eligibility: DM patients with MV-CAD eligible for stent or surgery Exclude: Patients with acute STEMI, Prior CABG, PCI/ Stent within 6 months Randomized 1:1 MV-Stenting With Drug-eluting CABG With or Without CPB All concomitant Meds shown to be beneficial were encouraged, including: clopidogrel, ACE inhib., ARBs, b-blockers, statins Farkouh ME et al N Engl J Med; 367:2375-2384

FREEDOM Baseline Features Total subjects Two vessel disease Three vessel disease LAD involved SYNTAX score # stents/patient SES/PES 1900 314 1573 1737 26 4.3 51%/43%

PRIMARY OUTCOME DEATH / STROKE / MI CABG PCI/DES Logrank P=0.005 30 PCI/DES 20 CABG Death/Stroke/MI, % 10 5-Year Event Rates: 26.6% vs. 18.7% 0 0 1 2 3 4 5 6 Years post-randomization PCI/DES N 953 848 788 625 416 219 40 CABG N 943 814 758 613 422 221 44

PRIMARY ENDPOINT DEATH / STROKE / MI TREATMENT / SYNTAX INTERACTION - p=0.58 100 90 80 70 60 SYNTAX Score 22 (N=669) 100 90 80 70 60 5-Year Event Rates: 23.2% 17.2% 50 40 30 20 Freedom 10 0 0.0 CABG 1.0 2.0 3.0 4.0 5-Year Event Rates: 50 40 30 20 Freedom 10 0 PCI/DES from Event (%) SYNTAX Score 23-32 (N=844) 5.0 PCI/DES from Event (%) CABG 0.0 1.0 Years post-randomization 2.0 3.0 4.0 Years post-randomization SYNTAX Score 33 (N=374) 100 90 80 70 60 50 40 30 20 Freedom 10 0 5-Year Event Rates: 0.0 27.2% 17.7% 30.6% 22.8% PCI/DES from Event (%) 1.0 2.0 CABG 3.0 4.0 Years post-randomization 5.0 5.0

MYOCARDIAL INFARCTION PCI/DES CABG 30 Logrank P<0.0001 20 13.9 % Myocardial Infarction, % PCI/DES 6.0% 10 CABG 0 0 1 2 3 4 5 Years post-randomization PCI/DES N 953 853 798 636 422 220 CABG N 947 824 772 629 432 229

STROKE Severely Disabling Scale CABG PCI/DES 30 20 NIH > 4 55% Rankin >1 70% 27% 60% CABG PCI/DES Stroke, % Logrank P=0.034 10 5.2% CABG 2.4% PCI/DES 0 0 1 2 3 4 5 Years post-randomization PCI/DES N 953 891 833 673 460 241 CABG N 947 844 791 640 439 230

Quality of Life After PCI vs CABG Among Patients With Diabetes and Multi-vessel Coronary Artery Disease: A Randomized Clinical Trial: FREEDOM Figure Legend: Frequency of Angina by Treatment Group Frequency of angina by treatment group according to the Seattle Angina Questionnaire (SAQ) angina frequency scale. Categories (with scores by increments of 10) were defined as no angina (score, 100), monthly angina (score,70-90), weekly angina (score, 40-60), or daily angina (score, <40). JAMA. 2013;310(15):1581-1590. doi:10.1001/jama.2013.279208

Meta-analysis: DES vs CABG in Diabetic Patients Hakeem A et al. J Am Heart Assoc 2013 1 EP MACE: Death, MI, or Stroke @ 4 Years Sensitivity Analysis According to SYNTAX score

Verma S., et al. Lancet Diabetes Endocrinol 2013

2014ACC/AHAStable Ischemic Heart Disease Focused Update

CABG in Patients with Diabetes in NY 3500 3000 FREEDOM 2500 2000 1500 1000 500 0 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

Issues with FREEDOM 1. Selection Bias 2. Diabetes is not important for decision making for PCI versus CABG 3. PCI arm would have done better if later generation DES and newer stents were available 4. An ischemia guided approach would have shown a different outcome 5. Higher rates of Stroke in the CABG arm

CABG vs. PCI

Do Contemporary DES Change the Equation for PCI vs CABG in the Diabetic Patient?

Gap between PCI and CABG Non-stent Related Events Stent Related Events Restenosis Stent Thrombosis Neoatherosclerosis Death and MI

Drug Eluting Stents CYPHER Strut Thickness: 140 mm Polymer Thickness: 13.7 mm TAXUS Liberté Strut Thickness: ENDEAVOR XIENCE V Strut Thickness: Strut Thickness 97 mm 91 mm 81 mm Polymer Thickness Polymer Thickness Polymer Thickness 17.8 mm 4.8 mm 7.8 mm

DES Polymer Changes 1st Gen 2nd Gen Non uniform polymer coating Uniform polymer coating Webbing and bonding No webbing and bonding Delamination No delamination

14 Day Endothelialization: Rabbit Iliac Model XIENCE V CYPHER TAXUS Joner and Virmani, JACC 2008 ENDEAVOR

Inflammation Rabbit double-injury iliac artery model at 28 days follow-up P = 0.0005 P = 0.0001 18 16 14 12 10 8 6 4 Inflammatory Cells/strut (N) 7 2 0 XIENCE N=16 17 15 ResoluteTM N=16 Van Dyck CJ. et al, Catheter Cardiovasc Interv. 2012 Aug 6. BMS* N=16

In vitro pulsatile Chandler loop model with porcine blood 2 49% ; P<0.001 1.8 1.6 1.4 1.2 µm) 1.0 24% ; P=0.002 0.8 LDH Adsorbance Stentadhesion formulation / 0.6 forcell Relative platelet LDH Adsorbance for MULTI-LINK VISION (81 0.4 0.2 TS = thick strut 0.0 Conclusions: MULTI-LINK VISION (81 µm) TS VISION (162 µm) XIENCE V (96.6 µm) Contrary to popular perception, drug/polymer coatings do not inherently increase acute stent clotting; they reduce thrombosis Kolandaivelu et al. Circulation. 2011;123:1400-1409

Kaul U, Bangalore et al. N Engl J Med. 2015

Tuxedo India Patient Flow Enrolled (N=1851) 21 = Screen Failed Randomized (N=1830) TAXUS (N=914) XIENCE (N=916) Withdrawal = 12 Lost to f/u = 10 Investigator decision = 5 9 = Withdrawal 9 = Lost to f/u 2 = Investigator decision 1-Year Follow-up (N=1783; 97.4%) TAXUS (N=887) Kaul U, Bangalore et al. N Engl J Med. 2015 XIENCE (N=896) Tuxedo India

Tuxedo India Primary End Point: Target Vessel Failure Rate at 1 Year HR [95%CI] = 1.64 [1.09-2.47] P=0.02 by log-rank test PNI=0.38 by F-M test PSUP= 0.005 TAXUS *5.9% *3.2% Cumulative Incidence (%) XIENCE Months Number at risk PES 914 841 818 789 713 EES 916 856 846 820 736 Kaul U, Bangalore et al. N Engl J Med. 2015

Tuxedo India Cardiac Death or TV-MI Rate at 1 Year HR [95%CI] = 1.69 [1.04-2.75] P=0.03 by log-rank test TAXUS Cumulative Incidence (%) XIENCE Months Number at risk PES 914 843 824 798 723 EES 916 857 849 825 739 Kaul U, Bangalore et al. N Engl J Med. 2015

Stent Thrombosis Rate at 1 Year Tuxedo India HR [95%CI] = 5.08 [1.74-14.87] P<0.001 by log-rank test TAXUS Cumulative Incidence (%) XIENCE Months Number at risk PES 914 845 827 801 726 EES 916 858 848 825 738 Kaul U, Bangalore et al. N Engl J Med. 2015

94 384 consecutive stent implantations Conclusions: PCI with n-des is associated with a 38% lower risk of restenosis, 43% lower definite ST, and a 23% lower risk of death compared with o-des Sarno et al. European Heart Journal (2012) 33, 606 613

Bangalore et al. BMJ 2012; 345:e1510

EES vs CABG for Patients With Diabetes and Multivessel Disease Analysis of 8,096 propensity-matched patients from New York State registries, 2008-2011 Mortality rates favored the EES group at 30 days (0.57% vs 1.11%; P =.04), though long-term data showed similar mortality between the EES and CABG arms (10.50% vs 10.23%; P =.16) MI risk was higher with EES vs CABG, but not in the subset of patients who had complete revascularization (P =.30) EES were linked with less stroke but more revascularization Conclusion: With similar long-term survival, second-generation DES and CABG may be reasonable options for diabetics with multivessel disease. Bangalore S, et al. Circ Cardiovasc Interv. 2015;Epub ahead of print.

Conclusions Data from multiple sources suggest consistent superiority of newer generation DES over 1st generation DES for efficacy and safety It is not clear if CABG would have a mortality benefit when compared with newer generation DES The decision about CABG vs. PCI should be based on: Ability to completely revascularize Weighing short term risk of death and stroke with CABG with long term benefit of reducing the risk of repeat revasc Patient preference

Diminishing Mortality Gap between PCI and CABG: NY State Registry (JACC 1999) POBA (NEJM 2005) (NEJM 2008) BMS 1st Gen DES (NEJM 2015) 2nd Gen DES NS 20-29% 24-36% 40-50% Favors PCI Favors CABG

Specific recommendations for diabetic patients. The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) Eur J Cardiothorac Surg 2010 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved. 2010;38:S1-S52

Recommendations for prevention of contrast-induced nephropathy. The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) Eur J Cardiothorac Surg 2010 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved. 2010;38:S1-S52

Specific Recommendations For Revascularization in Patients With Diabetes. Windecker S et al. Eur Heart J 2014;35:2541-2619

Choosing wisely between PCI and CABG Patient Preference Matters!!!!!! Risk of shortterm death and stroke Risk of long-term repeat revascularization* CABG * Risk of MI in patients with incomplete revascularization PCI

Definite Stent Thrombosis: Probability Best % Probability of Lowest ST Rate PtCr-EES, 18 ZES-R,0 ZES,0 PES,0 BP-DES,0 BMS,0 PES/SES 0% Probability CoCr-EES,82 126 randomized trials and 258 544 patient-years of follow-up Bangalore et al. BMJ 2013; 347:f6625

All-Cause Mortality: Probability Best % Probability of Lowest Death Rate PES,0 SES,0 BP-DES,6CoCrEES,18 BMS,0 ZES-R,40 0% Probability PES/SES PtCr EES, 31 ZES-E,2 126 RCTs and >258,000 patient-years of follow-up Bangalore et al. BMJ 2013; 347:f6625

Myocardial infarction: Probability Best % Probability of Lowest MI Rate BMS,0 PES,0 ZES-R,26.36 SES,0.08 EES,46.9 ZES,26.66 76 RCTs with >117, 000 PY of follow up Bangalore et al. Circulation. 2012;125:2873-2891

Definite Stent Thrombosis 126 RCTs and >258,000 patient-years of follow-up BMS DES RR (95% CrI) SES vs. BMS 1.01 (0.76-1.33) PES vs. BMS 1.17 (0.91-1.59) CoCr EES vs. BMS 0.35 (0.21-0.53) PtCr EES vs. BMS 0.50 (0.21-1.13) ZES-E vs. BMS 0.79 (0.51-1.32) ZES-R vs. BMS 0.88 (0.37-1.91) 0.71 (0.48-1.05) BP-DES vs. BMS 0 1 Risk Ratio (95% Crl) Bangalore et al. BMJ 2013; 347:f6625 10

Bangalore et al. Circ Cardiovasc Interv. 2014 Aug;7(4):518-25

Outcome: Mortality CABG vs. PCI in Diabetics Bangalore et al. Circ Cardiovasc Interv. 2014 Aug;7(4):518-25

In patients with DM and MV CAD, CABG was superior to PCI by reducing rates of death and myocardial infarction with a higher rate of stroke Primary Outcome: Death, Stroke, MI The Trial was Heavily Criticized because not all 3VDs are similar 3VD + DM 3VD + DM 3VD + DM

Role of Diabetes The FREEDOM Trial 1900 diabetics with MVD randomized to DES vs CABG; mean SYNTAX score = 26 NEJM 2012;367:2375-2384

Strategies for Multivessel Revascularization in Patients with Diabetes the FREEDOM Trial Farkouh ME et al. N Engl J Med 2012; 367:2375-84 Death, MI, or Stroke Through 5 Years Median SYNTAX-Score = 26 26.6% 13.0% 11.9% 18.7%

Meta-analysis: DES vs CABG in Diabetic Patients Hakeem A et al. J Am Heart Assoc 2013 1 EP MACE: Death, MI, or Stroke @ 4 Years Sensitivity Analysis According to SYNTAX score

What s next?

FAME III PCI vs CABG using FFR in the PCI patients and stenting only the positive lesions 1500 patients randomized About 500 diabetic patients may be too few to have adequate power

What is the current equation for CABG vs. PCI? CABG reduces need for repeat revascularization CABG reduces myocardial infarction (longterm) Protection from future plaque rupture in the bypassed segments CABG reduces risk of death (long-term)