New-generation drug-eluting stents and dual antiplatelet therapy: overview Giuseppe Biondi Zoccai, MD Department of Medico-Surgical Sciences and Biotechnologies Sapienza University of Rome, Rome, Italy

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 stenting was empiric at first and then confirmed by more sound data 30-day stent thrombosis rate (%) 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

StudySample Size DAPT (months) Stent type ITALIC3,7500 (ASA only) vs 6 EES OPTIMIZE3,1203 vs 12ZES ISAR-SAFE6,0006 vs 12DES DAPT20,64512 vs 30DES (n=15,245) / BMS (n=5,400) DES Late5,00012 vs >12DES SCORE28012 vs 24DES OPTIDUAL1,96612 vs 36DES 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 Interruptions1.1 ± 0.5 (N = 243) Days to First Interruption (days)134.3 ± (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 ± (N = 366) Top 3 Reasons for DiscontinuationAdverse 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

StudyPatientsDesignSetting SPIRIT II223RCTOn-label SPIRIT III669RCTOn-label SPIRIT IV2458RCTOn-label SPIRIT V1662Non-RCTReal-world setting SPIRIT Women1506Non-RCTReal-world setting XIENCE V USA3770Non-RCTReal-world setting XIENCE V India931Non-RCTReal-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 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 StudyPatientsDesignSetting SPIRIT II223RCTOn-label SPIRIT III669RCTOn-label SPIRIT IV2458RCTOn-label COMPARE1800RCTReal-world setting

Kedhi, ACC mo DAPT >24 mo DAPT 6-12 mo DAPT mo DAPT 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 StudyPatientsDesignSetting SPIRIT V1662Non-RCTReal-world setting SPIRIT Women1506Non-RCTReal-world setting XIENCE V USA3770Non-RCTReal-world setting XIENCE V India931Non-RCTReal-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 Analysis ST & DAPT Interruption at 3 Months 2 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 Analysis 3 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 USA ST and DAPT Interruption at 3 Months 1 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 network 9 studies PES BMS SES End-ZES Res-ZESPtCr-EES CoCr-EES 1 study 8 studies 1 study 4 studies 9 studies 6 studies 2 studies 5 studies 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 ( ) 0.28 ( ) 0.41 ( ) 0.14 ( ) 0.21 ( ) 0.57 ( ) 1.92 ( ) Favors Stent 1Favors Stent Palmerini, Biondi-Zoccai et al, Lancet Year Definite Stent Thrombosis

Statistical consistency IV = inverse variance SE = standard error Odds Ratio IV Random, 95% CI Favors CoCr-EESFavors BMS Weight SE Log (odds ratio) Definite stent thrombosis Direct estimate Indirect estimate Total (95% CI) Test for overall effect Z=4.82 (p< ) Definite or probable thrombosis Direct estimate Indirect estimate Total (95% CI) Test for overall effect Z=4.48 (p< ) % 67.6% % 39.4% 60.6% % 0.24 ( ) 0.24 ( ) 0.24 ( ) 0.38 ( ) 0.33 ( ) 0.35 ( ) Statistical inconsistency (I 2 ): 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 TLR and↓ 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: For these and further slides on these topics feel free to visit the metcardio.org website: Meta-analysis and Evidence-based medicine Training in Cardiology