1. Upendra Kaul, MD for the TUXEDO INDIA Investigators Paclitaxel Eluting Versus Everolimus Eluting Stents in Patients with Diabetes Mellitus and Coronary Artery Disease One Year Clinical Results

2. Upendra Kaul, MD Upendra Kaul, MD  Boston Scientific: Research Grant and Lecture Fee  Abbott Vascular: Lecture Fee Disclosures Tuxedo India

3. More extensive disease, more complex lesions More extensive disease, more complex lesions Clustering of risk factors and co-morbidities Clustering of risk factors and co-morbidities Profound proliferative vascular response Profound proliferative vascular response High risk for restenosis Prothrombotic state: Increased platelet activation, increased levels of tissue factor, fibrinogen and PAI-I Prothrombotic state: Increased platelet activation, increased levels of tissue factor, fibrinogen and PAI-I Endothelial dysfunction Endothelial dysfunction High risk for stent thrombosis PCI in Patients With Diabetes Why are They at Increased Risk ? Tuxedo India DES have replaced BMS in diabetics because of reduced ISR and need for TVR

4. Choice of a DES in diabetic population has been debatable Choice of a DES in diabetic population has been debatable Results between Limus analogues and Paclitaxel have been contradictory Results between Limus analogues and Paclitaxel have been contradictory A meta analysis of Spirit II, III, IV and Compare studies showed equivalent results between PES and EES in diabetics (Stone GW et al. Circulation 2011;124:893-900) A meta analysis of Spirit II, III, IV and Compare studies showed equivalent results between PES and EES in diabetics (Stone GW et al. Circulation 2011;124:893-900) On the contrary, in a mixed treatment analysis of 48 randomized trials EES was shown to be the best in diabetics (Bangalore S, et al. BMJ 2012;345:e5170) On the contrary, in a mixed treatment analysis of 48 randomized trials EES was shown to be the best in diabetics (Bangalore S, et al. BMJ 2012;345:e5170) In the absence of a dedicated adequately powered randomized study a definitive answer is not possible In the absence of a dedicated adequately powered randomized study a definitive answer is not possible TUXEDO- India Background Tuxedo India

5. Paclitaxel-eluting TAXUS Everolimus-eluting XIENCE 1830 patients enrolled at 46 Indian sites RVD ≥2.25 mm - ≤4 mm; Lesion length ≤34 mm Upto 3 lesions with a maximum of 2 per epicardial vessel Pre-rand: ASA ≥300 mg, clopidogrel ≥300 mg load unless on chronic Rx or Prasugrel 60 mg or Ticagrelor 180 mg Randomized 1:1 TAXUS Element TM : XIENCE Prime TM Pre-dilatation mandatory Clinical f/u only: 1, 6 months, 1 year and 2 years Aspirin ≥75 mg QD for long term; clopidogrel 75mg QD for at least 12 months or Ticagralor 90 mg BD or Prasugrel 10 mg OD (if not at high risk for bleeding) Tuxedo India Study Algorithm Tuxedo India

6. End Points Patients with Stable CHD or ACS undergoing PCI 1:1 Randomization Paclitaxel-eluting stent (TAXUS ) Everolimus-eluting stent (XIENCE) Primary Endpoint: TVF: Composite of Cardiac Death, Target vessel MI or Ischemia-Driven TVR at 1-Year Secondary Endpoints: Death, Cardiac Death, MI, TLR, TVR, MACE, Definite and Probable ST Tuxedo India

7. Sample Size Calculation Statistical Method Statistical Method  A two-group Farrington-Manning test was used to test the one-sided hypothesis of non inferiority in proportions. Sample Size Parameters Sample Size Parameters  Expected TAXUS Element™ TVF rate = 8.4%  Expected XIENCE Prime™ TVF rate = 8.4% (based on data from the SPIRIT trials)  Non-inferiority margin (Δ) = 4.0% (absolute)  Test significance level (  ) = 0.05 (1-sided)  Power (1  ) = approximately 0.90  Expected rate of attrition = 10%  N=1,830 patients Tuxedo India

8. Key Eligibility Criteria For Enrolment Tuxedo India Inclusion CriteriaExclusion Criteria Patients with diabetes mellitusPrior PCI Procedure within 9 months -Known diabetes mellitus on pharmacological treatment or -ACS NSTEMI with HbA1c >7 Left main Disease, SVG graft disease, severe calcification, total occlusions and Heavy thrombus Symptomatic, stable or unstable coronary artery disease or documented silent ischemia LVEF <30%, Serum Creatinine >2.0 mg/dl Target Lesion -Major coronary artery -Visual estimated stenosis ≥50% -TIMI Flow ≥1 Intolerance to aspirin, clopidogrel or contrast material

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

10. Parameters TAXUS n=914 XIENCE n=916 P Value Age (yr) 58.40±9.2158.34±9.12 0.87 BMI (kg/m 2 )25.77±4.0225.87±4.250.58 Male gender, n (%) 681 (74.5)696 (76.0) 0.46 Hypertension, n (%) 613 (67.1)604 (65.9) 0.61 Hypercholesterolemia, n (%) 702 (76.8)710 (77.5) 0.72 Current smokers, n (%) 128 (14.0)145 (15.8)0.27 Insulin requiring diabetics, n (%) 365 (39.9)382 (41.7) 0.44 HbA1c (%)8.40±1.848.18±1.660.01* Duration of diabetes (yr) 6.75±7.096.14±6.690.06 Previous MI, n (%) 376 (41.1 )366 (40.0 )0.61 Previous PCI, n (%) 77 (8.4 )68 (7.4 )0.43 Baseline Demographics (ITT Analysis) Tuxedo India

11. Parameters TAXUS n=914 XIENCE n=916 P Value Previous CABG, n (%)14 (1.5)18 (2.0)0.48 LVEF (%)54.70±12.2754.81±11.850.84 LVEF <40%, n (%)87 (9.5)80 (8.7)0.56 Clinical presentation at admission, n (%) - ACS (unstable angina or non- STEMI)495 (54.2)479 (52.3)0.42 - Chronic stable angina268 (29.3)253 (27.6)0.42 - Post STEMI94 (10.3)118 (12.9)0.08 Asymptomatic57 (6.2)66 (7.2)0.41 Target-lesions to be treated, n (%) - One688 (75.3)656 (71.6)0.08 - Two182 (19.9)209 (22.8)0.13 - Three27 (3.0)39 (4.3)0.13 Baseline Clinical Data (ITT Analysis) Tuxedo India

12. Parameters TAXUS n=914 XIENCE n=916 P Value Target lesions/patient1.26±0.501.32±0.550.03* Total number of target-lesions11331191 Coronary artery (number of lesions, %) - LAD548 (48.4)555 (46.6)0.39 - LCX260 (22.9)313 (26.3)0.06 - RCA325 (28.7)322 (27.0)0.38 RVD (mm)2.90±0.362.87±0.360.04* DS (%)87.26±8.6187.54±8.430.43 Lesion length (mm)20.13±7.6020.12±7.710.98 Lesion Details (ITT Analysis) Tuxedo India

13. Procedures TAXUS n=1133 XIENCE n=1191 P Value During Procedure Stents - Number/patient1.27±0.551.36±0.650.003* - Number/lesion1.00±0.151.02±0.210.01* Max. stent diameter/lesion (mm)2.93±0.382.88±0.370.008* Max. stent diameter/RVD1.01±0.061.01±0.050.08 Total stent length/lesion (mm)25.18±10.2125.08±9.090.82 Total stent length/lesion length1.28±0.321.28±0.600.71 Balloon dilation, lesions/no. (%)776/1133 (68.5)787/1191 (66.1)0.22 Max. deployment pressure (atm)12.05±3.5112.11±4.280.70 Glycoprotein IIb/IIIa inhibitors, no. patients/total no. (%) 171/914 (18.7)169/916 (18.4)0.89 After procedure DS (%)1.87±3.151.55±2.930.01* TIMI 3 flow2.98±0.192.97±0.210.43 Procedural Characteristics (ITT Analysis) Tuxedo India * Statistically significant

14. (%) Aspirin + Clopidogrel Aspirin + Ticagrelor/Prasugrel Antiplatelet Agent Used P=0.04 647/914 688/916 TAXUS XIENCE P=0.04 647/914 688/916 Aspirin + Ticagrelor/Prasugrel or Clopidogrel 914/914 916/916 NA Tuxedo India

15. TAXUS 5.6% vs. XIENCE 2.9% P non-inferiority = 0.38 Difference: 2.7% Upper one-sided 95% CI: 4.48% −1.0% 0%1.0% 2.0% 3.0% 4.0% 5.0% Non-inferiority margin Non-inferiority Assessment for the Primary Efficacy Endpoint Target Vessel Failure Tuxedo India

16. Target Vessel Failure Rate at 1 Year Months P=0.02 by log-rank test P NI =0.38 by F-M test P SUP = 0.005 HR [95%CI] = 1.64 [1.09-2.47] PES EES *5.9% *3.2% Cumulative Incidence (%) *Events calculated with Kaplan-Meier methods and compared with the use of the log-rank test. Differs slightly from graph which were calculated as categorical variables and compared with use of Chi-Square test. Tuxedo India Number at risk PES914 841818789 713 EES916 856846820 736

17. (%) Components of TVF TAXUS XIENCE Tuxedo India 16/916 16/914 26/914 5/916 31/914 11/916 P=1.00 P<0.001 P=0.002

18. Ischemia Driven TLR Rate at 1 Year Months P=0.009 by log-rank test HR [95%CI] = 2.18 [1.20-3.95] TAXUS XIENCE Cumulative Incidence (%) *Events calculated with Kaplan-Meier methods and compared with the use of the log-rank test. Differs slightly from graph which were calculated as categorical variables and compared with use of Chi-Square test. Number at risk PES914 845821792 716 EES916 856846819 735

19. Parameters TAXUS n=914 XIENCE n=916 P Value no. of patients/total no. (%) Death, all23 (2.5)21 (2.3)0.75 - Cardiac16 (1.8)16 (1.7)1.00 - Noncardiac7 (0.8)5 (0.5)0.56 MI, all29 (3.2)11 (1.2)0.004 - Q-Wave8 (0.9)1 (0.1)0.02 - Non-Q-Wave22 (2.4)10 (1.1)0.03 All death or MI47 (5.1)31 (3.4)0.06 Cardiac death or MI40 (4.4)26 (2.8)0.08 Death and MI at 1 Year Tuxedo India

20. Cardiac Death or TV-MI Rate at 1 Year Months P=0.03 by log-rank test HR [95%CI] = 1.69 [1.04-2.75] TAXUS XIENCE Cumulative Incidence (%) *Events calculated with Kaplan-Meier methods and compared with the use of the log-rank test. Differs slightly from graph which were calculated as categorical variables and compared with use of Chi-Square test. Tuxedo India Number at risk PES914 843824798 723 EES916 857849825 739

21. Stent Thrombosis Rate at 1 Year Months P<0.001 by log-rank test HR [95%CI] = 5.08 [1.74-14.87] TAXUS XIENCE Cumulative Incidence (%) *Events calculated with Kaplan-Meier methods and compared with the use of the log-rank test. Differs slightly from graph which were calculated as categorical variables and compared with use of Chi-Square test. Tuxedo India Number at risk PES914 845827801 726 EES916 858848825 738

22. TAXUS n=914 XIENCE n=916 Stent thrombosis (%) Stent Thrombosis Acute (<24 hours)Subacute (24 hours – 30 days)Late (>30 days – 1 year) Tuxedo India 2.1% 0.4% P=0.002

23. Tuxedo India: 12 Subgroups Examined Non-LAD (n=1027) Target Vessel LAD (n=1056) No. of Treated Lesions = 1 (n=1344) No. of Lesion Treated Lesion ≥ 2 (n=457) RVD ≤ 2.75 mm (n=949) RVD > 2.75 mm (n=1048) Age < 65 (n=1372) Age ≥ 65 (n=458) Lesion Length ≤ 20 mm (n=1186) Lesion Length > 20 mm (n=824) Insulin Therapy Requirement (n=747) No requirement (n=1083) Hb1Ac < 7% (n=419) Hb1Ac ≥ 7% (n=1259) eGFR ≤ 60 ml/min (n=347) eGFR > 60 ml/min (n=1474) ACS (n=1186) Stable angina (n=644) Male (n=1377) Female (n=453) Lesion Type A (n=84) Lesion Type B (n=969) Lesion Type C (n=987) Duration of Diabetes < 5 Years (n=893) Duration of Diabetes ≥ 5 Years (n=837) Tuxedo India

24. Group PES (%) EES (%) Relative Risk (95% CI) Relative Risk (95% CI) P interaction All randomized (n=1830)5.62.91.89 [1.20-2.99]— Age < 65 Years (n=1372)5.32.02.61 [1.42-4.79] 0.08 Age ≥ 65 Years (n=458)6.45.81.11 [0.54-2.29] Male (n=1377)5.42.42.22 [1.26-3.91] 0.30 Female (n=453)6.04.51.32 [0.60-2.91] Insulin Requirement (n=747)7.93.42.33 [1.23-4.42] 0.35 No Requirement (n=1083)4.02.61..53 [0.79-2.96] Hb1Ac < 7% (n=419)4.12.71.50 [0.53-4.26] 0.80 Hb1Ac ≥7 (n=1259)5.53.21.74 [1.02-2.98] eGFR ≤ 60 ml/min (n=347)7.17.30.97 [0.46-2.07] 0.047* eGFR > 60 ml/min (n=1474)5.22.02.62 [1.45-4.72] ACS (n=1186)5.43.01.80 [1.02-3.17] 0.77 Stable angina (n=644)5.82.82.07 [0.95-4.51] Tuxedo India Sub group Analysis: TVF at 1 Year TVF = cardiac death, target vessel MI, or ischemia-driven TVR PES better EES better Tuxedo India

25. Group EES (%) PES (%) Relative Risk (95% CI) Relative Risk (95% CI) P interaction All randomized (n=1830)5.62.91.89 [1.20-2.99]— Lesion Length ≤ 20 mm (n=1186)6.62.72.47 [1.40-4.37] 0.56 Lesion Length > 20 mm (n=824)5.83.01.90 [0.98-3.70] No. of Treated Lesions = 1 (n=1344)4.42.61.68 [0.94-3.02] 0.29 No. of Treated Lesions ≥ 2 (n=457)10.03.62.77 [1.30-5.91] Lesion Type A (n=84)7.70- 0.56 Lesion Type B (n=969)7.42.82.69 [1.46-4.94] Lesion Type C (n=987)5.13.01.68 [0.89-3.14] RVD ≤ 2.75 mm7.43.52.14 [1.21-3.77] 0.97 RVD > 2.75 mm5.32.52.12 [1.11-4.05] LAD5.93.41.76 [1.00-3.11] 0.53 Non-LAD6.22.72.31 [1.24-4.28] Duration of Diabetes < 5 Years4.83.11.59 [0.82-3.08] 0.41 Duration of Diabetes ≥ 5 Years6.93.02.33 [1.21-4.49] Tuxedo India Sub group Analysis: TVF at 1 Year PES better EES better Tuxedo India

26. In this largest trial of patients with diabetes, paclitaxel-eluting stent compared to everolimus-eluting stent at 1-year follow-up demonstrated: PES failed to meet non-inferiority as compared to EES. Had higher rates of TVF. On superiority testing EES proved superior. Primary endpoint: PES failed to meet non-inferiority as compared to EES. Had higher rates of TVF. On superiority testing EES proved superior. Significantly higher rates of MI, stent thrombosis, TVR, TLR, composite of cardiac death or TV-MI and MACE for PES arm. Major secondary endpoints: Significantly higher rates of MI, stent thrombosis, TVR, TLR, composite of cardiac death or TV-MI and MACE for PES arm. Insulin requiring diabetics behaved like non insulin requiring with EES superior to PES. Subgroup Analysis: Insulin requiring diabetics behaved like non insulin requiring with EES superior to PES. The only subgroup where PES and EES had similar results were patients with an e GFR of <60 ml/min. The only subgroup where PES and EES had similar results were patients with an e GFR of <60 ml/min. Tuxedo India Conclusions Tuxedo India

27. Clinical Implications The study supports the current worldwide practice of use of new generation limus stents even in patients with insulin requiring diabetes mellitus. This may have important implications for PES. The results question the outcomes of FREEDOM and BARI-2D showing superiority of CABG since Ist generation stents which are inferior to EES were used as comparators. Tuxedo India

28. Principal Investigator : Upendra Kaul Operations Committee : Priyadarshini Arambam (Head) Steering Committee : Ashok Seth (Chair) CEC : Sanjay Tyagi MD (Chair) DSMB : Rajendra Tandon MD (Chair) Randomization Service : Max Neeman International Data Management : Max Neeman International Funded by : Boston Scientific Corp TUXEDO – Study Organization Investigator Initiated Study Tuxedo India

29. TUXEDO – Participating Centres (N=46) L.R.G. Naidu Cardiology Research Institute and Clinic, CoimbatoreLisie Hospital, Cochin SAL Hospital and Medical Institute, AhmedabadFortis Flt. Lt. Rajan Dhall Hospital, New Delhi Fortis Escorts Heart Institute, New DelhiKasturba Medical College, Manipal Bankers Heart Institute, VadodaraR. Mehta Kikabai Hospital, Mumbai Shree B.D. Mehta Mahavir Heart Institute, SuratSheri Kashmir Institute of Medical Sciences, Srinagar The Madras Medical Mission, ChennaiNiramaya Hospital, Chinchwad Apex Heart Institute, AhmedabadArneja heart Institute, Nagpur Sir Ganga Ram Hospital, New DelhiFortis Escorts Hospital, Amritsar Krishna Institute of Medical Sciences, SecunderabadAmritha Institute of Medical Sciences and Research Centre, Kochi Ananthapuri Hospitals and Research Institute, TrivandrumFortis Hospitals, Bangalore Kamalnayan Bajaj Hospital, AurangabadCSM Medical University, Lucknow Holy Family Hospital-Diagnostic Services, MumbaiJaipur Heart Institute, Jaipur SGPGI of Medical Sciences, LucknowSt. Johns Medical College Hospital, Bangalore Wockhardt Heart Hospital, NagpurRuby Hall Clinic, Pune Deenanath Mangeshkar Hospital and Research Centre, PuneFortis Malar Hospital, Chennai Medanta- The Medicity, GurgaonKovai Medical Center and Hospital, Coimbatore Zynova Heart Care, MumbaiFortis Hospital, Bangalore Crescen Hospital & Heart Centre, NagpurJehangir Clinical Development Center Pvt Ltd, Pune Fortis Escorts Hospital & Research Centre, FaridabadLife Care Institute of Medical Science and Research, Ahemdabad Baroda Heart Institute and Research Centre, VadodaraAsian Institute of Medical Science, Faridabad Dayanand Medical College & Hospital, LudhianaYashoda Hospital, Secunderabad Rabindranath Tagore International Institute of Cardiac Science, KolkataB.M. Birla Heart Research Centre, Kolkata Fortis Hospital, Mohali

30. Enrollers Patients Rajpal K. Abhaychand G. Kuppuswamy Naidu Memorial Hospital, Coimbatore 430R.K.Premchand Krishna Institute of Medical Sciences, Secunderabad 68 Tejas Patel S A L Hospital and Medical Institute, Ahmedabad, Gujarat 160C.G.Bahuleyan Ananthapuri Hospitals and Research Institute, Trivandrum 65 Upendra Kaul Fortis Escorts Heart Institute, New Delhi 136Ajit Bhagwat Kamalnayan Bajaj Hospital, Aurangabad 58 Darshan Banker Bankers Heart Institute, Vadodara, Gujarat 92Brian Pinto Holy Family Hospital-Diagnostic Services, Mumbai 50 Atul Abhyankar Shree B.D. Mehta Mahavir Heart Institute, Surat, Gujarat 90P.K.Goel SGPGI of Medical Sciences, Lucknow 43 Ajit Mullasari The Madras Medical Mission, Chennai, Tamilnadu 77Prashant Jagtap Wockhardt Heart Hospital, Nagpur 40 Sanjay Shah Apex Heart institute, Ahmedabad, Gujarat 73Shireesh Sathe Deenanath Mangeshkar Hospital and Research Centre, Pune 37 Rajneesh Jain Sir Ganga Ram Hospital, New Delhi 70 TUXEDO Top 15 Enrollers TUXEDO – Top 15 Enrollers Tuxedo India