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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
Tuxedo India
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