New-generation drug-eluting stents and dual antiplatelet
therapy: overview
Giuseppe Biondi Zoccai, MDDepartment of Medico-Surgical Sciences and Biotechnologies
Sapienza University of Rome, Rome, [email protected]
Choice of aspirin was empirical from the beginning…
In the first reported case of PTCA by Andreas Gruentzig, 3 days of aspirin was empirically added to heparin therapy
Gruentzig et al. NEJM 1979
Addition of ticlopidine after stentingwas empiric at first and then
confirmed by more sound data
Serruys Roubin Schatz Fishman Colombo Leon0
5
10
15
20
25
30
24
7.66
3.51.4 0.5
30-d
ay s
tent
th
rom
bosi
s ra
te (%
)
ASA
ASA plus OAC
DAPT
The CREDO RCT of 1- vs 12-month* DAPT:1-year death, MI and stroke
Steinhubl et al. JAMA 2002*1-month regimen did not include clopidogrel front-loading
The TRITON RCT of 6- to 15-month* DAPT with clopidogrel vs prasugrel: stent thrombosis†
Wiviott et al. Lancet 2008*median 14.5 months; †definite or probable
The PLATO RCT of 6- to 12-month* DAPT with clopidogrel vs ticagrelor: stent thrombosis†
Cannon et al. Lancet 2010*median 9.3 months; †definite, probable or possible
Cannon et al. Lancet 2010*median 14.5 months
The PLATO RCT of 6- to 12-month* DAPT with clopidogrel vs ticagrelor: all cause death
The VA observational study with CYPHER and TAXUS: events after discontinuing DAPT
Ho et al. JAMA 2008
The PRODIGY RCT of 6- vs 24-month DAPT:2-year death, MI and stroke
Valgimigli et al. Circulation 2012
The PRODIGY RCT of 6- vs 24-month DAPT:2-year type II, III, or V BARC bleeding
Valgimigli et al. Circulation 2012
Study Sample Size
DAPT (months)
Stent type
ITALIC 3,750 0 (ASA only) vs 6
EES
OPTIMIZE 3,120 3 vs 12 ZESISAR-SAFE 6,000 6 vs 12 DESDAPT 20,645 12 vs 30 DES (n=15,245) /
BMS (n=5,400)DES Late 5,000 12 vs >12 DESSCORE 280 12 vs 24 DESOPTIDUAL 1,966 12 vs 36 DES
Uncertainty will persist for some time: ongoing studies on DAPT
The XIENCE V USA study including 5,054 unselected real-world patients
Hermiller, PCR 2010
AMI 18.1%
ACS 37.5%
Renal Insufficiency 11.1%
Multivessel Disease 40.8%
EF < 30% 3.4%
Multivessel Treated 13.8%
Left Main 1.6%
Graft Lesion 4.8%
CTO Lesion 2.5%
Direct Stenting 38.7%
Restenosis Lesion 9.5%
Ostial 11.9%
Bifurcation 9.0%
Diabetes 35.6%
A Real-World Population
The XIENCE USA study: DAPT details
Hermiller, PCR 2010
Temporary Interruption % (N) 5.6% (N = 243)
Number of Interruptions 1.1 ± 0.5 (N = 243)
Days to First Interruption (days) 134.3 ± 121.4 (N = 243)
Duration of Interruption (days) 20.3 ± 46.9 (N = 243)
Top 3 Reasons for Interruption Surgical Procedure = 35.4%Adverse Event** = 30.5%Patient Non-compliance = 9.5%
Permanent Discontinuation % (N) 8.5% (N = 366)
Days to Discontinuation (days) 239.2 ± 140.4 (N = 366)
Top 3 Reasons for Discontinuation Adverse Event** = 21.9%Surgical Procedure = 10.7%Increased Bleeding Risk = 9.6%
Study Patients Design SettingSPIRIT II 223 RCT On-labelSPIRIT III 669 RCT On-labelSPIRIT IV 2458 RCT On-labelSPIRIT V 1662 Non-RCT Real-world settingSPIRIT Women 1506 Non-RCT Real-world settingXIENCE V USA 3770 Non-RCT Real-world settingXIENCE V India 931 Non-RCT Real-world setting
Stone, TCT 2011
The SPIRIT/XIENCE pooled analysis on 11,219 patients: included studies
The SPIRIT/XIENCE pooled analysis on 11,219 patients: stent thrombosis according to DAPT
Stone, TCT 2011
0.0
1.0
2.0
3.0
4.0
5.0ST
thro
ugh
2 ye
ars
(%)
No DAPT Interruption
DAPT Interruption within 90 Days
DAPT Interruption after 90 Days
0.66% 0.69%
2.61%
44/6648 16/613 23/3314
Timing of First DAPT Interruption and ALL Stent Thrombosis (ARC Definite/Probable)
Through 2 Years
No DAPT interruption
DAPT interruption
within 90 days
DAPT interruption after 90 days
The SPIRIT/XIENCE pooled analysis on 11,219 patients: stent thrombosis according to DAPT
Stone, TCT 2011
The SPIRIT/COMPARE pooled analysis on 6,789 patients: included studies
Kedhi, ACC 2011
Study Patients Design SettingSPIRIT II 223 RCT On-labelSPIRIT III 669 RCT On-labelSPIRIT IV 2458 RCT On-labelCOMPARE 1800 RCT Real-world setting
Kedhi, ACC 2011
1-6 mo DAPT
>24 moDAPT
6-12 moDAPT
12-24 moDAPT
The SPIRIT/COMPARE pooled analysis on 6,789 patients: stent thrombosis according to DAPT
The SPIRIT/XIENCE meta-analysis on 10,615 patients: included studies
Palmerini, PCR 2012
Study Patients Design SettingSPIRIT V 1662 Non-RCT Real-world settingSPIRIT Women 1506 Non-RCT Real-world settingXIENCE V USA 3770 Non-RCT Real-world settingXIENCE V India 931 Non-RCT Real-world setting
The SPIRIT/XIENCE meta-analysis on 10,615 patients: stent thrombosis according to DAPT
Palmerini, PCR 2012
CE mark indication for XIENCE 3-month DAPT
Language from CE IFU Section 8.1 for XIENCE:XIENCE demonstrated low stent thrombosis rates in patients who either discontinued or interrupted Dual Antiplatelet Therapy (DAPT) after 3 months post stent implantation. It is therefore recommended that patients treated with XIENCE stents remain on DAPT for at least 3 months after stent implantation.
New indication underlines the XIENCE safety outcomes even when patients interrupt DAPT
after 3 months
Mega-Meta AnalysisST & DAPT Interruption
at 3 Months2
7 XIENCE Trials (n=13,259)
ST rate after DAPT interruption beyond 3 months was low and numerically similar to no DAPT interruption
through 2 years
Real World Pooled Analysis:
3 Months DAPT Analysis3
All Comer Population 4 XIENCE Trials
(n=10,615)
XIENCE shows 0% ST after DAPT interruption
from 3 to 12 months
3 Months DAPT CE Submission Data
Source: 1. Based on data from the XIENCE V USA trial (Hermiller PCR 2012). 2. Based on data from the Mega-Meta Analysis of 7 XIENCE trials (Stone, TCT 2011). 3. Based on data from SPIRIT/XIENCE analysis (Palmerini PCR 2012).
XIENCE V USAST and DAPT Interruption at 3 Months1
All Comer Population (n=5,054)
ST rate after DAPT interruption beyond 3 months was low and
numerically similar to no DAPT
interruption through 1 year
PCR 2012
CE mark indication for XIENCE 3-month DAPT
Additional insights from a comprehensive network meta-analysis
Palmerini, Biondi-Zoccai et al, Lancet 2012
Evidence network9 studies PESBMS
SESEnd-ZES
Res-ZES PtCr-EES
CoCr-EES1 study
8 studies1 stu
dy4 stu
dies 9 studies
6 studies
6 studies
2 studies
2 studies 5 st
udie
s
Palmerini, Biondi-Zoccai et al, Lancet 2012
Additional insights from a comprehensive network meta-analysis
Odds Ratio[95%]
CoCr-EES vs BMS
CoCr-EES vs PES
CoCr-EES vs SES
CoCr-EES vs Res-ZES
CoCr-EES vs End-ZES
SES vs BMS
End-ZES vs SES
0.23 (0.13-0.41)
0.28 (0.16-0.48)
0.41 (0.24-0.70)
0.14 (0.03-0.47)
0.21 (0.10-0.44)
0.57 (0.36-0.88)
1.92 (1.07-3.90)
Favors Stent 1 Favors Stent 2
1010.10.01
Palmerini, Biondi-Zoccai et al, Lancet 2012
1-Year Definite Stent Thrombosis
Statistical consistency
IV = inverse varianceSE = standard error
Odds Ratio IVRandom, 95% CI
1010.10.001
Favors CoCr-EES Favors BMS
WeightSELog (odds ratio)
Definite stent thrombosisDirect estimateIndirect estimateTotal (95% CI)Test for overall effect Z=4.82 (p<0.00001)
Definite or probable thrombosisDirect estimateIndirect estimateTotal (95% CI)Test for overall effect Z=4.48 (p<0.00001)
-1.427-1.421
-0.968-1.122
0.5190.359
0.3770.304
32.4%67.6%
100.00%
39.4%60.6%
100.00%
0.24 (0.09-0.66)0.24 (0.12-0.49)0.24 (0.14-0.43)
0.38 (0.18-0.80)0.33 (0.18-0.53)0.35 (0.22-0.55)
Statistical inconsistency (I2): 0% for both comparisons
Palmerini, Biondi-Zoccai et al, Lancet 2012
• Statistical consistency or homogeneity is a measure of how similar are the estimates stemming from head-to-head RCTs and the indirect comparison
The Good: ↓ risk of TLRand↓ risk of bleeding with long-term DAPT
46-year-old with effort angina: RCA as culprit♂
The Bad: ↑risk of TLR but↓ risk of bleeding with long-term DAPT
61-year-old ♀ with STEMI: LAD as culprit
The Ugly: ↑risk of TLR and ↑ risk of bleeding with long-term DAPT
74-year-old with NSTEMI & AF requiring oral ♂anticoagulants: LM-LAD as culprit
Take home messages• DAPT aims to prevent two different events: stent
thrombosis and non-target lesion thrombosis.• Long-term DAPT reduces the risk of non-target
lesion events.• However, there is mounting uncertainty on the
impact of long-term DAPT on stent thrombosis.• EES have a unique safety profile among coronary
stents:– After 3 months, patients with EES discontinuing DAPT
have a risk of stent thrombosis similar to those not discontinuing;
Take home messages– Accordingly, 3-month DAPT appears adequate to reduce the
risk of stent thrombosis in patients receiving EES;– Favorable yet much less thorough results have also been
reported for BES.• I personally do not recommend 3-month DAPT in all
patients, but surely do in carefully selected ones.• Moreover, I can be truly confident that any of my
patients who has received a EES and discontinue DAPT ≥3 months is not put at a higher risk of stent thrombosis.
• This property cannot so far be inferred for any other DES, and thus makes EES a unique treatment opportunity to maximize efficacy and safety.
Thank you for your attention
For any correspondence: [email protected]
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Meta-analysis and Evidence-based medicine Training in Cardiology