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, Italygiuseppe.biondizoccai@uniroma1.it

Our original sin…

An ongoing challenge after stenting: preventing both…

THROMBOSIS

BLEEDING

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 PCI-CURE RCT of 0- vs 12-month DAPT:1-year CV death or MI

Mehta et al. Lancet 2001

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 Duke observational study with CYPHER and TAXUS: 2-year events

Eisenstein et al. JAMA 2005

The VA observational study with CYPHER and TAXUS: events after discontinuing DAPT

Ho et al. JAMA 2008

The J-CYPHER observational study: 2-year stent thrombosis

Kimura et al. Circulation 2009

The Milan-Naples-Siegburg observational study with TAXUS and CYPHER

Airoldi et al. Circulation 2007

The LATE RCTs of 12- vs 24-month DAPT:2-year death, MI and stroke

Park et al. NEJM 2010

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

The EXCELLENT RCT of 6- vs 12-month DAPT:1-year target vessel failure

Gwon et al. Circulation 2012

The EXCELLENT RCT of 6- vs 12-month DAPT:other 1-year events

Gwon 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 ZES

ISAR-SAFE 6,000 6 vs 12 DES

DAPT 20,645 12 vs 30 DES (n=15,245) / BMS (n=5,400)

DES Late 5,000 12 vs >12 DES

SCORE 280 12 vs 24 DES

OPTIDUAL 1,966 12 vs 36 DES

Uncertainty will persist for some time: ongoing studies on DAPT

2010: ESC Guidelines on PCI/CABG

2011: ESC Guidelines on NSTEACS

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%

The XIENCE USA study: stent thrombosis according to DAPT interruption

Hermiller, PCR 2010

Study Patients Design Setting

SPIRIT II 223 RCT On-label

SPIRIT III 669 RCT On-label

SPIRIT IV 2458 RCT On-label

SPIRIT V 1662 Non-RCT Real-world setting

SPIRIT Women 1506 Non-RCT Real-world setting

XIENCE V USA 3770 Non-RCT Real-world setting

XIENCE V India 931 Non-RCT Real-world setting

Stone, TCT 2011

The SPIRIT/XIENCE pooled analysis on 11,219 patients: included studies

Stone, TCT 2011

The SPIRIT/XIENCE pooled analysis on 11,219 patients: 2-year stent thrombosis

Stone, TCT 2011

The SPIRIT/XIENCE pooled analysis on 11,219 patients: compliance to DAPT

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

5.0

ST th

roug

h 2

year

s (%

)

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: days of DAPT discontinuation

Stone, TCT 2011

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 Setting

SPIRIT II 223 RCT On-label

SPIRIT III 669 RCT On-label

SPIRIT IV 2458 RCT On-label

COMPARE 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 Setting

SPIRIT V 1662 Non-RCT Real-world setting

SPIRIT Women 1506 Non-RCT Real-world setting

XIENCE V USA 3770 Non-RCT Real-world setting

XIENCE 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-EES

1 study

8 studies1 st

udy

4 studies 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

Other new-degeneration DES

Raber et al, JAMA 2012

Other new-degeneration DES

Raber et al, JAMA 2012

Prototypical clinical cases

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: giuseppe.biondizoccai@uniroma1.it

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Meta-analysis and Evidence-based medicine Training in Cardiology