Upendra Kaul, MDUpendra Kaul, MD

for the TUXEDO INDIA Investigatorsfor the TUXEDO INDIA Investigators

Paclitaxel Eluting Versus Everolimus Paclitaxel Eluting Versus Everolimus Eluting Stents in Patients with Diabetes Eluting Stents in Patients with Diabetes Mellitus and Coronary Artery DiseaseMellitus and Coronary Artery Disease

One Year Clinical ResultsOne Year Clinical Results

• Upendra Kaul, MDUpendra Kaul, MD

Boston Scientific: Research Grant and Lecture Boston Scientific: Research Grant and Lecture FeeFee

Abbott Vascular: Lecture FeeAbbott Vascular: Lecture Fee

DisclosuresDisclosuresTuxedo India

• More extensive disease, more complex lesionsMore extensive disease, more complex lesions

• Clustering of risk factors and co-morbiditiesClustering of risk factors and co-morbidities

• Profound proliferative vascular responseProfound proliferative vascular response

High risk for restenosis

• Prothrombotic state: Increased platelet activation, Prothrombotic state: Increased platelet activation, increased levels of tissue factor, fibrinogen and PAI-Iincreased levels of tissue factor, fibrinogen and PAI-I

• Endothelial dysfunctionEndothelial dysfunction

High risk for stent thrombosis

PCI in Patients With DiabetesPCI in Patients With Diabetes Why are They at Increased Risk ? Why are They at Increased Risk ?

Tuxedo India

DES have replaced BMS in diabetics because of reduced ISR and need for TVR

• Choice of a DES in diabetic population has been debatableChoice of a DES in diabetic population has been debatable

• Results between Limus analogues and Paclitaxel have Results between Limus analogues and Paclitaxel have been contradictorybeen contradictory

• A meta analysis of Spirit II, III, IV and Compare studies A meta analysis of Spirit II, III, IV and Compare studies showed equivalent results between PES and EES in showed equivalent results between PES and EES in diabetics diabetics ((Stone GW et al. Circulation 2011;124:893-900)Stone GW et al. Circulation 2011;124:893-900)

• On the contrary, in a mixed treatment analysis of 48 On the contrary, in a mixed treatment analysis of 48 randomized trials EES was shown to be the best in diabetics randomized trials EES was shown to be the best in diabetics ((Bangalore S, Bangalore S, et al. BMJ 2012;345:e5170)et al. BMJ 2012;345:e5170)

• In the absence of a dedicated adequately powered In the absence of a dedicated adequately powered randomized study a definitive answer is not possiblerandomized study a definitive answer is not possible

TUXEDO- India BackgroundTUXEDO- India BackgroundTuxedo India

Paclitaxel-eluting TAXUS

Everolimus-eluting XIENCE

1830 patients enrolled at 46 Indian sitesRVD ≥2.25 mm - ≤4 mm; Lesion length ≤34 mm

Upto 3 lesions with a maximum of 2 per epicardial vessel

Pre-rand: ASA Pre-rand: ASA ≥≥300 mg, clopidogrel 300 mg, clopidogrel ≥≥300 300 mg load unless on chronic Rx or Prasugrel mg load unless on chronic Rx or Prasugrel 60 mg or Ticagrelor 180 60 mg or Ticagrelor 180 mgmg

Randomized 1:1 TAXUS ElementTM : XIENCE PrimeTM

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

End PointsEnd Points

Patients with Stable CHD or ACS undergoing PCI1:1 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

Sample Size CalculationSample Size Calculation

• Statistical MethodStatistical Method A two-group Farrington-Manning test was used to test A two-group Farrington-Manning test was used to test

the one-sided hypothesis of non inferiority in the one-sided hypothesis of non inferiority in proportions. proportions.

• Sample Size ParametersSample Size Parameters Expected TAXUS Element™ TVF rate = 8.4% Expected TAXUS Element™ TVF rate = 8.4% Expected XIENCE Prime™ TVF rate = 8.4% (based Expected XIENCE Prime™ TVF rate = 8.4% (based

on data from the SPIRIT trials)on data from the SPIRIT trials) Non-inferiority margin (Δ) = 4.0% (absolute)Non-inferiority margin (Δ) = 4.0% (absolute) Test significance level (Test significance level () = 0.05 (1-sided)) = 0.05 (1-sided) Power (1Power (1) = approximately 0.90) = approximately 0.90 Expected rate of attrition = 10%Expected rate of attrition = 10% N=1,830 patients N=1,830 patients

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Key Eligibility Criteria For EnrolmentKey Eligibility Criteria For EnrolmentTuxedo India

Inclusion Criteria Exclusion Criteria• Patients with diabetes mellitus • Prior 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

RandomizedRandomized(N=1830)(N=1830)

TAXUSTAXUS(N=914)(N=914)

XIENCEXIENCE(N=916)(N=916)

1-Year Follow-up1-Year Follow-up(N=1783; 97.4%)(N=1783; 97.4%)

Withdrawal = 12Lost to f/u = 10

Investigator decision = 5

9 = Withdrawal9 = Lost to f/u 2 = Investigator decision

Tuxedo India Patient Flow

EnrolledEnrolled(N=1851)(N=1851)

21 = Screen Failed

XIENCEXIENCE(N=896)(N=896)

TAXUSTAXUS(N=887)(N=887)

Tuxedo India

ParametersTAXUS n=914

XIENCEn=916

P Value

Age (yr) 58.40±9.21 58.34±9.12 0.87

BMI (kg/m2) 25.77±4.02 25.87±4.25 0.58

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±1.84 8.18±1.66 0.01*

Duration of diabetes (yr) 6.75±7.09 6.14±6.69 0.06

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

ParametersTAXUS n=914

XIENCE n=916

P Value

Previous CABG, n (%) 14 (1.5) 18 (2.0) 0.48

LVEF (%) 54.70±12.27 54.81±11.85 0.84

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 angina 268 (29.3) 253 (27.6) 0.42

- Post STEMI 94 (10.3) 118 (12.9) 0.08

Asymptomatic 57 (6.2) 66 (7.2) 0.41

Target-lesions to be treated, n (%)    

- One 688 (75.3) 656 (71.6) 0.08

- Two 182 (19.9) 209 (22.8) 0.13

- Three 27 (3.0) 39 (4.3) 0.13

Baseline Clinical Data (ITT Analysis) Tuxedo India

ParametersTAXUSn=914

XIENCEn=916

P Value

Target lesions/patient 1.26±0.50 1.32±0.55 0.03*

Total number of target-lesions 1133 1191

Coronary artery (number of lesions, %)    

- LAD 548 (48.4) 555 (46.6) 0.39

- LCX 260 (22.9) 313 (26.3) 0.06

- RCA 325 (28.7) 322 (27.0) 0.38

RVD (mm) 2.90±0.36 2.87±0.36 0.04*

DS (%) 87.26±8.61 87.54±8.43 0.43

Lesion length (mm) 20.13±7.60 20.12±7.71 0.98

Lesion Details (ITT Analysis) Tuxedo India

ProceduresTAXUSn=1133

XIENCEn=1191

P Value

During Procedure      Stents

- Number/patient 1.27±0.55 1.36±0.65 0.003*- Number/lesion 1.00±0.15 1.02±0.21 0.01*

Max. stent diameter/lesion (mm) 2.93±0.38 2.88±0.37 0.008*Max. stent diameter/RVD 1.01±0.06 1.01±0.05 0.08Total stent length/lesion (mm) 25.18±10.21 25.08±9.09 0.82Total stent length/lesion length 1.28±0.32 1.28±0.60 0.71Balloon dilation, lesions/no. (%) 776/1133 (68.5) 787/1191 (66.1) 0.22Max. deployment pressure (atm) 12.05±3.51 12.11±4.28 0.70Glycoprotein IIb/IIIa inhibitors, no. patients/total no. (%)

171/914 (18.7) 169/916 (18.4) 0.89

After procedure      DS (%) 1.87±3.15 1.55±2.93 0.01*TIMI 3 flow 2.98±0.19 2.97±0.21 0.43

Procedural Characteristics (ITT Analysis)Tuxedo India

* Statistically significant

(%)

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

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

Target Vessel Failure Rate at 1 Year

Months

P=0.02 by log-rank testPNI=0.38 by F-M test

PSUP= 0.005

HR [95%CI] = 1.64 [1.09-2.47]PES

EES

*5.9%

*3.2%

Cu

mu

lati

ve In

cid

enc

e (%

)

*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

PES 914 841 818 789 713

EES 916 856 846 820 736

(%)

Components of TVF

TAXUS XIENCE

Tuxedo India

16/91616/914 26/914 5/916 31/914 11/916

P=1.00 P<0.001 P=0.002

Ischemia Driven TLR Rate at 1 Year

Months

P=0.009 by log-rank testHR [95%CI] = 2.18 [1.20-3.95]TAXUS

XIENCEC

um

ula

tive

Inc

iden

ce

(%)

*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

PES 914 845 821 792 716

EES 916 856 846 819 735

ParametersTAXUSn=914

XIENCEn=916

P Value

no. of patients/total no. (%)  

Death, all 23 (2.5) 21 (2.3) 0.75

- Cardiac 16 (1.8) 16 (1.7) 1.00

- Noncardiac 7 (0.8) 5 (0.5) 0.56

MI, all 29 (3.2) 11 (1.2) 0.004

- Q-Wave 8 (0.9) 1 (0.1) 0.02

- Non-Q-Wave 22 (2.4) 10 (1.1) 0.03

All death or MI 47 (5.1) 31 (3.4) 0.06

Cardiac death or MI 40 (4.4) 26 (2.8) 0.08

Death and MI at 1 Year Tuxedo India

Cardiac Death or TV-MI Rate at 1 Year

Months

P=0.03 by log-rank testHR [95%CI] = 1.69 [1.04-2.75]TAXUS

XIENCE

Cu

mu

lati

ve In

cid

enc

e (%

)

*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

PES 914 843 824 798 723

EES 916 857 849 825 739

Stent Thrombosis Rate at 1 Year

Months

P<0.001 by log-rank testHR [95%CI] = 5.08 [1.74-14.87]TAXUS

XIENCE

Cu

mu

lati

ve In

cid

enc

e (%

)

*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

PES 914 845 827 801 726

EES 916 858 848 825 738

TAXUSn=914

XIENCEn=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

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

GroupPES(%)

EES(%)

Relative Risk (95% CI)

Relative Risk (95% CI)

P interaction

All randomized (n=1830) 5.6 2.9 1.89 [1.20-2.99] —

Age < 65 Years (n=1372) 5.3 2.0 2.61 [1.42-4.79]0.08

Age ≥ 65 Years (n=458) 6.4 5.8 1.11 [0.54-2.29]

Male (n=1377) 5.4 2.4 2.22 [1.26-3.91]0.30

Female (n=453) 6.0 4.5 1.32 [0.60-2.91]

Insulin Requirement (n=747) 7.9 3.4 2.33 [1.23-4.42]0.35

No Requirement (n=1083) 4.0 2.6 1..53 [0.79-2.96]

Hb1Ac < 7% (n=419) 4.1 2.7 1.50 [0.53-4.26]0.80

Hb1Ac ≥7 (n=1259) 5.5 3.2 1.74 [1.02-2.98]

eGFR ≤ 60 ml/min (n=347) 7.1 7.3 0.97 [0.46-2.07]0.047*

eGFR > 60 ml/min (n=1474) 5.2 2.0 2.62 [1.45-4.72]

ACS (n=1186) 5.4 3.0 1.80 [1.02-3.17]0.77

Stable angina (n=644) 5.8 2.8 2.07 [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

0.1 1 10

Tuxedo India

GroupEES(%)

PES(%)

Relative Risk (95% CI)

Relative Risk (95% CI)

P interaction

All randomized (n=1830) 5.6 2.9 1.89 [1.20-2.99] —

Lesion Length ≤ 20 mm (n=1186) 6.6 2.7 2.47 [1.40-4.37]0.56

Lesion Length > 20 mm (n=824) 5.8 3.0 1.90 [0.98-3.70]

No. of Treated Lesions = 1 (n=1344) 4.4 2.6 1.68 [0.94-3.02]0.29

No. of Treated Lesions ≥ 2 (n=457) 10.0 3.6 2.77 [1.30-5.91]

Lesion Type A (n=84) 7.7 0 -

0.56Lesion Type B (n=969) 7.4 2.8 2.69 [1.46-4.94]

Lesion Type C (n=987) 5.1 3.0 1.68 [0.89-3.14]

RVD ≤ 2.75 mm 7.4 3.5 2.14 [1.21-3.77]0.97

RVD > 2.75 mm 5.3 2.5 2.12 [1.11-4.05]

LAD 5.9 3.4 1.76 [1.00-3.11]0.53

Non-LAD 6.2 2.7 2.31 [1.24-4.28]

Duration of Diabetes < 5 Years 4.8 3.1 1.59 [0.82-3.08]0.41

Duration of Diabetes ≥ 5 Years 6.9 3.0 2.33 [1.21-4.49]

Tuxedo India Sub group Analysis: TVF at 1 Year

0.1 1 10

PES better EES better

Tuxedo India

In this largest trial of patients with diabetes, paclitaxel-eluting stent compared to everolimus-eluting stent at 1-year follow-up demonstrated:

• Primary endpoint: PES failed to meet non-inferiority as PES failed to meet non-inferiority as compared to EES. Had higher rates of TVF. On superiority compared to EES. Had higher rates of TVF. On superiority testing EES proved superior.testing EES proved superior.

• Major secondary endpoints: Significantly higher rates of MI, Significantly higher rates of MI, stent thrombosis, TVR, TLR, composite of cardiac death or stent thrombosis, TVR, TLR, composite of cardiac death or TV-MI and MACE for PES arm.TV-MI and MACE for PES arm.

• Subgroup Analysis: Insulin requiring diabetics behaved like Insulin requiring diabetics behaved like non insulin requiring with EES superior to PES.non insulin requiring with EES superior to PES.

• The only subgroup where PES and EES had similar results The only subgroup where PES and EES had similar results were patients with an e GFR of <60 ml/min.were patients with an e GFR of <60 ml/min.

Tuxedo India Conclusions Tuxedo India

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

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 OrganizationInvestigator Initiated Study

Tuxedo India

Tuxedo IndiaTUXEDO – Participating Centres (N=46)L.R.G. Naidu Cardiology Research Institute and Clinic, Coimbatore Lisie Hospital, Cochin

SAL Hospital and Medical Institute, Ahmedabad Fortis Flt. Lt. Rajan Dhall Hospital, New Delhi

Fortis Escorts Heart Institute, New Delhi Kasturba Medical College, Manipal

Bankers Heart Institute, Vadodara R. Mehta Kikabai Hospital, Mumbai

Shree B.D. Mehta Mahavir Heart Institute, Surat Sheri Kashmir Institute of Medical Sciences, Srinagar

The Madras Medical Mission, Chennai Niramaya Hospital, Chinchwad

Apex Heart Institute, Ahmedabad Arneja heart Institute, Nagpur

Sir Ganga Ram Hospital, New Delhi Fortis Escorts Hospital, Amritsar

Krishna Institute of Medical Sciences, Secunderabad Amritha Institute of Medical Sciences and Research Centre, Kochi

Ananthapuri Hospitals and Research Institute, Trivandrum Fortis Hospitals, Bangalore

Kamalnayan Bajaj Hospital, Aurangabad CSM Medical University, Lucknow

Holy Family Hospital-Diagnostic Services, Mumbai Jaipur Heart Institute, Jaipur

SGPGI of Medical Sciences, Lucknow St. Johns Medical College Hospital, Bangalore

Wockhardt Heart Hospital, Nagpur Ruby Hall Clinic, Pune

Deenanath Mangeshkar Hospital and Research Centre, Pune Fortis Malar Hospital, Chennai

Medanta- The Medicity, Gurgaon Kovai Medical Center and Hospital, Coimbatore

Zynova Heart Care, Mumbai Fortis Hospital, Bangalore

Crescen Hospital & Heart Centre, Nagpur Jehangir Clinical Development Center Pvt Ltd, Pune

Fortis Escorts Hospital & Research Centre, Faridabad Life Care Institute of Medical Science and Research, Ahemdabad

Baroda Heart Institute and Research Centre, Vadodara Asian Institute of Medical Science, Faridabad

Dayanand Medical College & Hospital, Ludhiana Yashoda Hospital, Secunderabad

Rabindranath Tagore International Institute of Cardiac Science, Kolkata B.M. Birla Heart Research Centre, Kolkata

Fortis Hospital, Mohali

Enrollers Patients

Enrollers Patients

Rajpal K. AbhaychandG. Kuppuswamy Naidu Memorial Hospital, Coimbatore

430 R.K.PremchandKrishna Institute of Medical Sciences, Secunderabad

68

Tejas PatelS A L Hospital and Medical Institute, Ahmedabad, Gujarat

160 C.G.BahuleyanAnanthapuri Hospitals and Research Institute, Trivandrum

65

Upendra KaulFortis Escorts Heart Institute, New Delhi

136 Ajit BhagwatKamalnayan Bajaj Hospital, Aurangabad

58

Darshan BankerBankers Heart Institute, Vadodara, Gujarat

92 Brian PintoHoly Family Hospital-Diagnostic Services, Mumbai

50

Atul AbhyankarShree B.D. Mehta Mahavir Heart Institute, Surat, Gujarat

90 P.K.GoelSGPGI of Medical Sciences, Lucknow

43

Ajit MullasariThe Madras Medical Mission, Chennai, Tamilnadu

77 Prashant JagtapWockhardt Heart Hospital, Nagpur

40

Sanjay ShahApex Heart institute, Ahmedabad, Gujarat

73 Shireesh SatheDeenanath Mangeshkar Hospital and Research Centre, Pune

37

Rajneesh JainSir Ganga Ram Hospital, New Delhi

70

TUXEDO TUXEDO – Top 15 Enrollers Top 15 EnrollersTuxedo India