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