comparison of ischemic and bleeding events after drug ......lee, daniel simon, adrian corneliu...

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

1

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

2

Randomized treatment period 12-30 m

Observation period 30-33m off treatment

3

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 mStratified 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

12 m DAPT

ArmAspirin + blinded

placebo

30 m DAPT

ArmAspirin + blinded

thienopyridine

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)Total 33 month follow-up

Mauri, Kereiakes et al AHJ 2010;160:1038-1041

Total 33 month follow-up

18

mos

DAPT: Study Design

9,961

5,020 Receive Thienopyridine + Aspirin

Subject Flow:

452 Sites / 11 Countries

Index Stent

Procedure

DESTreated Subjects22,866

BMSTreated Subjects

2,816

1,687

At Month 12: 1:1

Randomization Occurs

12-30 Months: Blinded

Treatment Occurs

4,941 ReceivePlacebo + Aspirin

845 ReceivePlacebo + Aspirin

Follow-Up

9,499 (95.4%)

1,580(93.7%)

9,390(94.3%)

1,565(92.8%)

30 Months: Primary End Point

33Months

4

0-12 Months: All Subjects on

Open-Label DAPT

842 Receive Thienopyridine + Aspirin

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.

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 2:1

9500 evaluable DES matched with 1965 evaluable BMS subjects provides

>80% power to reject null hypothesis using 1-sided test of non-inferiority at

0.025 significance for each endpoint

2) BMS randomized 30 vs 12 months DAPT therapy (ITT)

6

Prespecified Key Secondary Analysis

Propensity Analysis Cohort

Baseline Characteristics After Match

7

After Match (weighted for match ratio)

MeasureDES

N=8308BMS

N=1718Standardized Difference

Clinical CharacteristicAge (years) 60.6 60.3 0.035

Female 26.4% 26.4% 0.000

Race – Non-White 9.0% 8.6% 0.014

Hispanic or Latino 4.8% 4.7% 0.005

Weight (kg) 89.5 88.7 0.054

BMI 29.8 29.8 -0.004

Diabetes mellitus 25.8% 25.6% 0.005

Hypertension 69.7% 69.6% 0.002

Cigarette smoker (within past year) 36.5% 38.7% -0.045

Stroke / TIA 4.4% 5.0% -0.028

Congestive heart failure 5.2% 5.0% 0.009

Peripheral arterial disease 6.5% 6.4% 0.004

Prior PCI 23.2% 22.7% 0.012

Prior CABG 8.3% 8.3% 0.000

Previous MI 21.0% 21.6% -0.015

Indication for PCISTEMI 27.6% 27.6% 0.000

NSTEMI 20.6% 21.9% -0.032

Stable angina 28.1% 27.8% 0.007

Unstable Angina 11.3% 11.4% -0.003

Other 12.4% 11.3% 0.034


Procedure Characteristics After Match

8

After Match (weighted for match ratio)

MeasureDES

N=8308BMS

N=1718Standardized

Difference

Procedure Characteristics

Number of treated lesions (per subject) 1.20 1.18 0.047

Number of treated vessels (per subject) 1.06 1.05 0.028

Treated vessels

Native coronary 96.4% 96.3% 0.005

Left main 0.8% 0.3% 0.057

LAD 33.2% 31.8% 0.030

RCA 39.2% 42.9% -0.075

Circumflex 23.3% 21.3% 0.048

Venous graft 3.1% 3.7% -0.033

Arterial graft 0.6% 0.1% 0.100

Modified ACC/AHA lesion class B2 or C 48.7% 48.7% 0.000

Number of stents (per subject) 1.36 1.33 0.051

Minimum stent diameter (per subject)

<3 30.3% 28.9% 0.031

=3 32.0% 32.7% -0.015

>3 37.7% 38.5% -0.016

Total stent length (mm, per subject) 24.57 24.16 0.038

Prasugrel at discharge 16.6% 15.0% 0.044

Clopidogrel at discharge 83.4% 85.0% -0.044


Baseline Stent Thrombosis Risk Factors

9

Before Match After Match (weighted for match ratio)

MeasureDES

N=13257BMS

N=2056DES

N=8308BMS

N=1718Standardized

Difference

Any Clinical 32.1% 62.4% 54.8% 55.7% -0.018

Enzyme positive ACS (STEMI or NSTEMI) 25.6% 56.9% 48.2% 49.5% -0.026

Renal insufficiency / failure 4.8% 4.0% 4.0% 3.9% 0.005

LVEF < 30% 1.9% 4.2% 3.5% 3.5% 0.000

Any Lesion-Related 33.3% 37.9% 33.7% 33.7% 0.000

>2 vessels stented 0.5% 0.0% 0.1% 0.1% 0.000

>2 lesions per vessel 2.3% 1.2% 1.4% 1.3% 0.009

Lesion length ≥ 30 mm* 11.1% 6.6% 7.0% 6.7% 0.012

Bifurcation lesion with sidebranch ≥ 2.5mm 6.0% 4.4% 4.9% 4.7% 0.009

In-stent restenosis of a DES 4.5% 0.8% 1.1% 0.9% 0.020

Vein bypass graft stented 3.4% 3.6% 3.4% 3.8% -0.021

Unprotected left main stented 0.6% 0.1% 0.2% 0.2% 0.000

Thrombus-containing lesion 10.5% 25.6% 20.1% 20.1% 0.000

Prior brachytherapy 0.3% 0.1% 0.1% 0.1% 0.000

Any Risk Factor 51.8% 69.3% 64.0% 63.9% 0.002

10

Drug-Eluting Stent Types Implanted at

Index Procedure

11

0

10

20

30

40

50

60

70

80

90

100

Por onofmatchsubjects

randomized

Studydrugcompliance

Studydruginterrup on>14

days

Aspirininterrup on

61.4

96.6

0.6

13.2

76.0

96.5

0.5

12.0

%Pa

ents

N=8308 N=1718

Randomized

DES(n=5100)

BMS(n=1305)

Study Drug and Aspirin Compliance

Post-Randomization

Propensity-Matched DES + BMS Subjects

12

OutcomeDES

N=8308BMS

N=1718Weighted risk

difference1-sided 97.5%

upper CL1-sided P value non-inferiority

P value for difference

ST ARC definite / probable 1.7% 2.6% -1.05% -0.27% <0.001 0.01

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% <0.001 0.053

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

Primary Outcomes: Stent Thrombosis and MACCE,

0-33 Months Propensity-Matched DES + BMS Subjects

0-12 Months:RD -1.00%0.70% vs. 1.68%P=0.002 (Difference)

DES

BMS

20%

15%

10%

5%

0%Cu

mu

lative

In

cid

en

ce

of S

ten

t T

hro

mb

osis

*

0 15 18 21 24 27 30 33

Months After Enrollment

0-33 Months:

RD -1.05%

1.70% vs. 2.61%

P<0.001 (Non-inferiority)

P=0.01 (Difference)

No. At Risk

DES 8308 8233 8181 8125 8066 8008 7948 7896 7843 7804 7702 5013

BMS 1718 1691 1666 1648 1631 1620 1611 1598 1589 1578 1563 922

126 93

Stent Thrombosis


13

*Weighted Kaplan-Meier and risk differences (RD) are presented.

0-12 Months:RD -1.76%5.07% vs. 6.83%P=0.01 (Difference)

DES

BMS

20%

15%

10%

5%

0%

Cu

mu

lative

In

cid

en

ce

of

De

ath

, M

yo

ca

rdia

l In

farc

tion

or

Str

oke

*

0 15 18 21 24 27 30 33

Months After Enrollment

0-33 Months:

RD -1.83%

11.37% vs. 13.24%

P<0.001 (Non-inferiority)

P=0.053 (Difference)

No. At Risk

DES 8308 8155 8051 7976 7895 7800 7719 7644 7559 7497 7372 4780

BMS 1718 1670 1639 1613 1597 1579 1562 1547 1535 1518 1500 884

126 93

MACCE


14


15

Abbreviations: EES, everolimus-eluting stent; SES, sirolimus-eluting stent; PES, paclitaxel-eluting stent;

ZES, zotarolimus-eluting stent (Endeavor).

Primary Outcomes by DES Type (Propensity Matched Weighted RD vs. BMS), 0-33 Months

Weighted RD 0.49%

4.04% vs. 3.67%

P=0.321

DES

BMS

5%

4%

3%

2%

0%

Cu

mu

lative

In

cid

en

ce

of M

od

era

te o

r

Se

ve

re B

lee

din

g (

GU

ST

O)

0 15 18 21 24 27 30 33

Months After Procedure

No. At Risk

DES 8308 8197 8110 8037 7954 7883 7819 7756 7688 7636 7527 4910

BMS 1718 1695 1670 1646 1627 1611 1599 1585 1567 1555 1543 914

126 93

1%

Moderate or Severe Bleeding


16


1,687 BMS-Treated Randomized at 12 Months

845 Randomized to Aspirin + Blinded Placebo

796 (94.5%) Clinical Follow-up Available at 30 Months

20 Withdrew Consent

37 Lost to Follow-Up

842 Randomized to Aspirin + Blinded Thienopyridine

13 Withdrew Consent


2 Withdrew Consent


0 Withdrew Consent

3 Lost to Follow-Up

3 Not Available for Follow-Up*

4 Not Available for Follow-Up*




*Subjects were prematurely exited from the study or incarcerated.

Randomization and Follow-up

BMS-Treated Subjects

17

18

Measure ThienopyridineN=842

PlaceboN=845 P value

Clinical Characteristics

Age (years) 58.9 59.2 0.55

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) 88.0 88.5 0.55

BMI 29.5 29.6 0.66

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

Baseline Characteristics

Randomized BMS-Treated Subjects

19

MeasureThienopyridine

N=842PlaceboN=845

P value


Number of treated lesions (per subject) 1.16 1.17 0.49

Number of treated vessels (per subject) 1.03 1.05 0.046

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) 1.32 1.32 0.97

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) 24.0 23.9 0.86

Clopidogrel at discharge 87.2% 87.7% 0.77

Prasugrel at discharge 12.8% 12.3% 0.77



20

Outcome

Thienopyridine

N=842

Placebo

N=845

Stratified

HR, 95% CI

Stratified

Log-rank

P-Value

Stent Thrombosis ARC

Definite/Probable

0.5% 1.1% 0.49 (0.15-1.64) 0.24

ARC Definite 0.5% 1.1% 0.49 (0.15-1.64) 0.24

ARC Probable 0.0% 0.0% -- (--, --)

MACCE (Death, MI, Stroke) 4.0% 4.7% 0.92 (0.57-1.47) 0.72

Death 1.0% 1.2% 0.90 (0.35-2.33) 0.83

Cardiac 0.5% 0.6% 1.03 (0.26-4.12) 0.97

Vascular 0.0% 0.0% -- (--, --)

Non-Cardiovascular 0.5% 0.6% 0.79 (0.21-2.96) 0.73

MI 2.7% 3.1% 0.91 (0.51-1.62) 0.74

Stroke (total) 0.7% 0.6% 1.22 (0.37-4.01) 0.74

Ischemic stroke 0.5% 0.6% 0.82 (0.22-3.05) 0.77

Hemorrhagic stroke 0.1% 0.0% -- (--, --) 0.32

Type Uncertain 0.1% 0.0% -- (--, --) 0.32

ST and MACCE, 12-30 Months


21

Bleeding ComplicationsThienopyridine

N=790

Placebo

N=776Risk 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 5 4.56% 1.80% 2.75% 0.002

BARC Type 2 2.78% 0.90% 1.88% 0.01

BARC Type 3 2.03% 0.77% 1.25% 0.04

BARC Type 5 0.00% 0.13% -0.13% 0.31

Bleeding Outcomes, 12-30 Months


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)

P Value

Interaction

DES (N=9961) 19 (0.4%) 65 (1.4%) 0.29 (0.17-0.48)0.42

BMS (N=1687) 4 (0.5%) 9 (1.1%) 0.49 (0.15-1.65)

MACCE

Stent Type

30 Month DAPT

N (%)

12 Month DAPT

N (%) HR (95% CI)

P Value

Interaction

DES (N=9961) 211 (4.3%) 285 (5.9%) 0.71 (0.59-0.85)0.32

BMS (N=1687) 33 (4.0%) 38 (4.7%) 0.92 (0.57-1.47)

Conclusions

• 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 follow-

up 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

23

DES vs BMS Propensity Matched Comparison

• 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.

24

BMS 12 vs 30 months Randomized ITT

Conclusions (2)

ACS (STEMI / NSTEMI) subgroup analysis

ST and MACCE BMS ITT; 12-30 Months F/U

25

30 Month

DAPT

N (%)

12 Month

DAPT

N (%) HR (95% CI)

P Value for

Interaction

ARC Definite/Probable ST

No ACS Within 72

Hours (N=699)

2 (0.6%) 1 (0.3%) 2.04 (0.18-22.47)

0.14ACS Within 72 Hours

(N=988)

2 (0.4%) 8 (1.7%) 0.24 (0.05-1.14)

MACCE

No ACS Within 72

Hours (N=699)

17 (5.0%) 17 (5.0%) 1.02 (0.52-2.00)

0.50ACS Within 72 Hours

(N=988)

16 (3.3%) 21 (4.5%) 0.74 (0.39-1.42)

Dot Plot

26

comparison of ischemic and bleeding events after drug ......lee, daniel simon, adrian corneliu...

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