1. Whether the risks of stent thrombosis (ST) and major adverse cardiovascular and cerebrovascular events (MACCE) differ from BMS and DES

Transcription

1 1 Comparison of Ischemic and Bleeding Events After Drug- Eluting Stents or Bare Metal Stents in Subjects Receiving Dual Antiplatelet Therapy: Results from the Randomized Dual Antiplatelet Therapy (DAPT) Study Dean J. Kereiakes, Robert Yeh, Joseph M. Massaro, Priscilla-Driscoll-Shempp, Donald E. Cutlip, Sharon-Lise T. Normand, P. Gabriel Steg, Anthony Gershlick, Jean Francois Tanguay, Stephan Windecker, Kirk Garratt, David Kandzari, David Lee, Daniel Simon, Adrian Corneliu Iancu, Jaroslaw Trebacz, Laura Mauri, on behalf of he Dual Antiplatelet Therapy (DAPT) Study Investigators

2 2 DAPT Trial Secondary Analysis: Bare metal stents are a commonly used alternative to drug eluting stents (DES) particularly for patients presenting with acute coronary syndromes or in whom dual antiplatelet therapy (DAPT) has perceived increased bleeding risk. We aimed to determine: 1. Whether the risks of stent thrombosis (ST) and major adverse cardiovascular and cerebrovascular events (MACCE) differ from BMS and DES 2. Whether the optimal duration of DAPT therapy differs for BMS and DES

3 DAPT: Study Design Eligible for Enrollment after PCI Any PCI with FDA approved DES or BMS >18 years of age No contraindications to dual antiplatelet therapy Able and willing to provide written informed consent Eligible for Randomization at 12 m Stratified by DES v BMS, drug type, study site, complexity (ACS or lesion-based) Not Eligible for Randomization at 12 m Death MI or repeat PCI at > 6 weeks CABG Stroke Major Bleed Poor Compliance Total 33 month follow-up 18 mos 12 m DAPT Arm Aspirin + blinded placebo 30 m DAPT Arm Aspirin + blinded thienopyridine Randomized treatment period m Observation period 30-33m off treatment Total 33 month follow-up Primary analysis Randomized DES treated subjects, 12-30m Secondary analysis 1.propensity matched BMS to DES 0-33m 2. BMS randomized 12 vs 30m ITT 2 co-primary endpoints: stent thrombosis (ST) and MACCE (death, myocardial infarction or stroke) Powered safety endpoint: moderate/severe bleeding (GUSTO) Mauri, Kereiakes et al AHJ 2010;160:

4 Subject Flow: 452 Sites / 11 Countries 4 Index Stent Procedure 0-12 Months: All Subjects on Open-Label DAPT At Month 12: 1:1 Randomization Occurs Months: Blinded Treatment Occurs Follow-Up 30 Months: Primary End Point 33 Months DES Treated Subjects 22,866 9,961 5,020 Receive Thienopyridine + Aspirin 4,941 Receive Placebo + Aspirin 9,499 (95.4%) 9,390 (94.3%) BMS Treated Subjects 2,816 1, Receive Thienopyridine + Aspirin 845 Receive Placebo + Aspirin 1,580 (93.7%) 1,565 (92.8%)

5 Prespecified Key Secondary Analysis 1) Propensity matched BMS to DES 0-33 months comparison Hypothesis: DES are non-inferior to BMS for ST and/or MACCE using risk difference (RD) approach Analysis population: Enrolled subjects with 29 months follow-up or ST / MACCE event. BMS to DES match (1: 1-8 ratio) exactly on STEMI and remaining (total 55) variables via propensity score using caliper of 0.10.

6 6 Prespecified Key Secondary Analysis Propensity match sample size assumptions: True ST and MACCE rates for DES + BMS 0-33 months 1.67%, 9.5% respectively NI margins 0.97% (ST); 2.28% (MACCE) Minimum matched DES:BMS ratio 2: evaluable DES matched with 1965 evaluable BMS subjects provides >80% power to reject null hypothesis using 1-sided test of non-inferiority at significance for each endpoint 2) BMS randomized 30 vs 12 months DAPT therapy (ITT)

7 Propensity Analysis Cohort Baseline Characteristics After Match After Match (weighted for match ratio) Measure DES N=8308 BMS N=1718 Standardized Difference Clinical Characteristic Age (years) Female 26.4% 26.4% Race Non-White 9.0% 8.6% Hispanic or Latino 4.8% 4.7% Weight (kg) BMI Diabetes mellitus 25.8% 25.6% Hypertension 69.7% 69.6% Cigarette smoker (within past year) 36.5% 38.7% Stroke / TIA 4.4% 5.0% Congestive heart failure 5.2% 5.0% Peripheral arterial disease 6.5% 6.4% Prior PCI 23.2% 22.7% Prior CABG 8.3% 8.3% Previous MI 21.0% 21.6% Indication for PCI STEMI 27.6% 27.6% NSTEMI 20.6% 21.9% Stable angina 28.1% 27.8% Unstable Angina 11.3% 11.4% Other 12.4% 11.3%

8 8 Propensity Analysis Cohort Procedure Characteristics After Match After Match (weighted for match ratio) Measure DES N=8308 BMS N=1718 Standardized Difference Procedure Characteristics Number of treated lesions (per subject) Number of treated vessels (per subject) Treated vessels Native coronary 96.4% 96.3% Left main 0.8% 0.3% LAD 33.2% 31.8% RCA 39.2% 42.9% Circumflex 23.3% 21.3% Venous graft 3.1% 3.7% Arterial graft 0.6% 0.1% Modified ACC/AHA lesion class B2 or C 48.7% 48.7% Number of stents (per subject) Minimum stent diameter (per subject) <3 30.3% 28.9% =3 32.0% 32.7% >3 37.7% 38.5% Total stent length (mm, per subject) Prasugrel at discharge 16.6% 15.0% Clopidogrel at discharge 83.4% 85.0%

9 Propensity Analysis Cohort Baseline Stent Thrombosis Risk Factors 9 Before Match After Match (weighted for match ratio) Measure DES N=13257 BMS N=2056 DES N=8308 BMS N=1718 Standardized Difference Any Clinical 32.1% 62.4% 54.8% 55.7% Enzyme positive ACS (STEMI or NSTEMI) 25.6% 56.9% 48.2% 49.5% Renal insufficiency / failure 4.8% 4.0% 4.0% 3.9% LVEF < 30% 1.9% 4.2% 3.5% 3.5% Any Lesion-Related 33.3% 37.9% 33.7% 33.7% >2 vessels stented 0.5% 0.0% 0.1% 0.1% >2 lesions per vessel 2.3% 1.2% 1.4% 1.3% Lesion length 30 mm* 11.1% 6.6% 7.0% 6.7% Bifurcation lesion with sidebranch 2.5mm 6.0% 4.4% 4.9% 4.7% In-stent restenosis of a DES 4.5% 0.8% 1.1% 0.9% Vein bypass graft stented 3.4% 3.6% 3.4% 3.8% Unprotected left main stented 0.6% 0.1% 0.2% 0.2% Thrombus-containing lesion 10.5% 25.6% 20.1% 20.1% Prior brachytherapy 0.3% 0.1% 0.1% 0.1% Any Risk Factor 51.8% 69.3% 64.0% 63.9% 0.002

10 Drug-Eluting Stent Types Implanted at Index Procedure 10

11 11 Study Drug and Aspirin Compliance Post-Randomization Propensity-Matched DES + BMS Subjects % Pa ents N=8308 N=1718 Por on of match subjects randomized Study drug compliance Study drug interrup on >14 days Randomized DES (n=5100) BMS (n=1305) Aspirin interrup on

12 12 Primary Outcomes: Stent Thrombosis and MACCE, 0-33 Months Propensity-Matched DES + BMS Subjects Outcome DES N=8308 BMS N=1718 Weighted risk difference 1-sided 97.5% upper CL 1-sided P value non-inferiority P value for difference ST ARC definite / probable 1.7% 2.6% -1.05% -0.27% < ARC definite 1.4% 2.5% -1.08% 0.01 ARC probable 0.3%) 0.1% 0.05% 0.56 MACCE (Death, MI, Stroke) 11.4% 13.4% -1.83% 0.03% < Death 4.2% 5.1% -0.83% 0.16 Cardiac 2.4% 2.9% -0.59% 0.19 Vascular 0.3% 0.3% 0.07% 0.64 Non-cardiovascular 1.6% 2.0% -0.30% 0.39 MI 7.2% 8.1% -0.80% 0.27 Stroke (total) 1.8% 2.1% -0.24% 0.49 Ischemic 1.5% 1.6% -0.13% 0.67 Hemorrhagic 0.4% 0.4% 0.05% 0.75

13 Cumulative Incidence of Stent Thrombosis* Stent Thrombosis Propensity-Matched DES + BMS Subjects 20% DES BMS 15% 10% 0-12 Months: RD -1.00% 0.70% vs. 1.68% P=0.002 (Difference) 0-33 Months: RD -1.05% 1.70% vs. 2.61% P<0.001 (Non-inferiority) P=0.01 (Difference) 5% 0% Months After Enrollment No. At Risk DES BMS *Weighted Kaplan-Meier and risk differences (RD) are presented. 13

14 Cumulative Incidence of Death, Myocardial Infarction or Stroke* MACCE Propensity-Matched DES + BMS Subjects 20% 15% DES BMS 0-12 Months: RD -1.76% 5.07% vs. 6.83% P=0.01 (Difference) 0-33 Months: RD -1.83% 11.37% vs % P<0.001 (Non-inferiority) P=0.053 (Difference) 10% 5% 0% Months After Enrollment No. At Risk DES BMS *Weighted Kaplan-Meier and risk differences (RD) are presented. 14

15 15 Primary Outcomes by DES Type (Propensity Matched Weighted RD vs. BMS), 0-33 Months Abbreviations: EES, everolimus-eluting stent; SES, sirolimus-eluting stent; PES, paclitaxel-eluting stent; ZES, zotarolimus-eluting stent (Endeavor).

16 Cumulative Incidence of Moderate or Severe Bleeding (GUSTO) Moderate or Severe Bleeding Propensity-Matched DES + BMS Subjects 5% 4% DES BMS Weighted RD 0.49% 4.04% vs. 3.67% P= % 2% 1% 0% Months After Procedure No. At Risk DES BMS *Weighted Kaplan-Meier and risk differences (RD) are presented. 16

17 Randomization and Follow-up BMS-Treated Subjects 17 1,687 BMS-Treated Randomized at 12 Months 13 Withdrew Consent 30 Lost to Follow-Up 3 Not Available for Follow-Up* 2 Withdrew Consent 10 Lost to Follow-Up 842 Randomized to Aspirin + Blinded Thienopyridine 796 (94.5%) Clinical Follow-up Available at 30 Months 784 (93.1%) Clinical Follow-up Available at 33 Months 845 Randomized to Aspirin + Blinded Placebo 20 Withdrew Consent 37 Lost to Follow-Up 4 Not Available for Follow-Up* 784 (92.8%) Clinical Follow-up Available at 30 Months 781 (92.4%) Clinical Follow-up Available at 33 Months 0 Withdrew Consent 3 Lost to Follow-Up *Subjects were prematurely exited from the study or incarcerated.

18 Baseline Characteristics Randomized BMS-Treated Subjects 18 Measure Thienopyridine N=842 Placebo N=845 P value Clinical Characteristics Age (years) Female 25.5% 21.8% 0.08 Race Non-White 7.5% 7.3% 0.93 Hispanic or Latino 4.8% 5.8% 0.44 Weight (kg) BMI Diabetes mellitus 21.7% 20.7% 0.63 Hypertension 64.0% 64.6% 0.80 Cigarette smoker (current or within past year) 44.3% 43.3% 0.69 Stroke / TIA 5.1% 4.0% 0.30 Congestive heart failure 4.2% 3.3% 0.37 Peripheral arterial disease 4.2% 5.5% 0.26 Prior PCI 17.9% 20.3% 0.22 Prior CABG 6.0% 5.9% 1.00 Prior MI 19.4% 21.5% 0.33 Indication for PCI STEMI 36.9% 38.3% 0.58 NSTEMI 21.9% 20.0% 0.37 Unstable angina 9.1% 9.6% 0.80 Stable angina 23.6% 23.4% 0.95

19 Procedure Characteristics Randomized BMS-Treated Subjects 19 Measure Thienopyridine N=842 Placebo N=845 P value Procedure Characteristics Number of treated lesions (per subject) Number of treated vessels (per subject) Treated vessel(s) Native coronary 97.5% 97.5% 1.00 Left main 0.00% 0.1% 1.00 LAD 31.6% 30.9% 0.77 RCA 44.8% 45.6% 0.75 Circumflex 21.1% 20.9% 0.91 Venous graft 2.5% 2.5% 1.00 Arterial graft 0.0% 0.0% - Modified ACC/AHA lesion class B2 or C 47.6% 47.8% 0.93 Number of stents (per subject) Minimum stent diameter (per subject) 0.50 <3 23.9% 24.4% =3 31.5% 32.9% >3 44.7% 42.7% Total stent length (mm, per subject) Clopidogrel at discharge 87.2% 87.7% 0.77 Prasugrel at discharge 12.8% 12.3% 0.77

20 ST and MACCE, Months Randomized BMS-Treated Subjects 20 Outcome Stent Thrombosis ARC Definite/Probable Thienopyridine N=842 Placebo N=845 Stratified HR, 95% CI Stratified Log-rank P-Value 0.5% 1.1% 0.49 ( ) 0.24 ARC Definite 0.5% 1.1% 0.49 ( ) 0.24 ARC Probable 0.0% 0.0% -- (--, --) MACCE (Death, MI, Stroke) 4.0% 4.7% 0.92 ( ) 0.72 Death 1.0% 1.2% 0.90 ( ) 0.83 Cardiac 0.5% 0.6% 1.03 ( ) 0.97 Vascular 0.0% 0.0% -- (--, --) Non-Cardiovascular 0.5% 0.6% 0.79 ( ) 0.73 MI 2.7% 3.1% 0.91 ( ) 0.74 Stroke (total) 0.7% 0.6% 1.22 ( ) 0.74 Ischemic stroke 0.5% 0.6% 0.82 ( ) 0.77 Hemorrhagic stroke 0.1% 0.0% -- (--, --) 0.32 Type Uncertain 0.1% 0.0% -- (--, --) 0.32

21 Bleeding Outcomes, Months Randomized BMS-Treated Subjects 21 Bleeding Complications Thienopyridine N=790 Placebo N=776 Risk Difference 2-Sided P Value Difference GUSTO Severe/Moderate 2.03% 0.90% 1.12% 0.07 GUSTO Severe 0.76% 0.39% 0.37% 0.33 GUSTO Moderate 1.27% 0.52% 0.75% 0.12 BARC Types 2, 3, or % 1.80% 2.75% BARC Type % 0.90% 1.88% 0.01 BARC Type % 0.77% 1.25% 0.04 BARC Type % 0.13% -0.13% 0.31

22 Treatment Duration by Stent Type Interaction on Stent Thrombosis/MACCE 22 ARC Definite/Probable ST Stent Type 30 Month DAPT N (%) 12 Month DAPT N (%) HR (95% CI) DES (N=9961) 19 (0.4%) 65 (1.4%) 0.29 ( ) BMS (N=1687) 4 (0.5%) 9 (1.1%) 0.49 ( ) P Value Interaction 0.42 MACCE Stent Type 30 Month DAPT N (%) 12 Month DAPT N (%) HR (95% CI) DES (N=9961) 211 (4.3%) 285 (5.9%) 0.71 ( ) BMS (N=1687) 33 (4.0%) 38 (4.7%) 0.92 ( ) P Value Interaction 0.32

23 23 Conclusions DES vs BMS Propensity Matched Comparison DES not inferior to BMS for ST and MACCE over the 0-33 month follow-up period DES superior to BMS for ST over the 0-33 month followup period (for MACCE 0-12 month) Greatest portion of risk difference between stent platforms accrues within the first 12 months for both ST and MACCE

24 24 Conclusions (2) BMS 12 vs 30 months Randomized ITT Magnitude of reduction in ST risk with longer (30 months) duration thienopyridine therapy appears consistent for both BMS and DES, based on lack of interaction (P int=0.42) and hazard ratios < 1.0 (DES HR 0.29, BMS HR 0.49) In BMS treated patients, prolonged thienopyridine therapy (30 months or longer) may provide durable ischemic benefit in addition to increased bleeding risk, and requires further study.

25 ACS (STEMI / NSTEMI) subgroup analysis ST and MACCE BMS ITT; Months F/U Month DAPT N (%) 12 Month DAPT N (%) HR (95% CI) P Value for Interaction No ACS Within 72 Hours (N=699) ACS Within 72 Hours (N=988) ARC Definite/Probable ST 2 (0.6%) 1 (0.3%) 2.04 ( ) 2 (0.4%) 8 (1.7%) 0.24 ( ) 0.14 No ACS Within 72 Hours (N=699) ACS Within 72 Hours (N=988) MACCE 17 (5.0%) 17 (5.0%) 1.02 ( ) 16 (3.3%) 21 (4.5%) 0.74 ( ) 0.50

26 Dot Plot 26