Incidence and Impact of Dual Antiplatelet Therapy (DAPT) Cessation on Adverse

Events following Percutaneous Coronary Intervention (PCI):

Results from the Real-World PARIS Registry

Roxana Mehran, MDProfessor of Medicine (Cardiology) and Health Evidence Policy

Director of Interventional Cardiovascular Research and Clinical TrialsThe Icahn School of Medicine at Mount Sinai, New York, NY

on behalf of PARIS Investigators

PARIS Registry

Conflict of Interest:

Institutional Grant/Research

Support:

Bristol-Myers Squibb/ Sanofi

Lilly/ DSI

The Medicines Company

BG Medicine

Consulting Fees/Honoraria

Sanofi

Abbott Vascular

Astra Zeneca

Merck

Regado Biosciences

Janssen (J+J)

BSC

Covidien

CSL Behring

Background and Rationale

• Antiplatelet agents are the cornerstone of therapy in patients with ACS and in those undergoing PCI

• Current ACC/AHA guidelines1 recommend 30 days DAPT following placement of a BMS and 1 year following placement of a DES.

• In patients with ACS 12 months of DAPT is recommended regardless of stent type

1. Wright et al. JACC. 10 May.2011.

PARIS Registry

DAPT Cessation and PCI: Existing Evidence

• Premature cessation of DAPT, within the first 6 months after PCI, has been associated with an increased risk of stent thrombosis.1

• Sustained DAPT (one year or longer) has been associated with lower risk for adverse events in observational studies.2,3

• Most studies involved select cohorts and limited by pre-specified or standard criteria to define DAPT status

PARIS Registry

1Schulz et al., EHJ 2009; 2Ho et al., AHJ 2007; 3Park et al., AJC 2006

DAPT Cessation and PCI: Unresolved Questions

• Does risk after DAPT cessation depend on the underlying context or clinical circumstances in which antiplatelet therapy is stopped (surgery vs. bleeding vs. physician-guidance)?

• How long does risk persist after antiplatelet therapy is withdrawn?

• What is the overall contribution of DAPT cessation on adverse events in the contemporary PCI era?

PARIS Registry

PARIS – Objectives

• Determine the incidence of different modes of DAPT cessation after PCI.

• Evaluate the associations between DAPT cessation and adverse events following PCI by the underlying clinical context in which antiplatelet therapy was withdrawn.

PARIS Registry

Study Design

• Multicenter, multinational, observational study

• 5,031 subjects were followed for approximately 24 months post stent implantation

• Included bare metal and drug-eluting stents

• All events, including all occurrences of DAPT cessation, were adjudicated by a blinded external clinical events committee

PARIS Registry

Enrollment Eligibility (1)

Inclusion Criteria

• Successful stent placement in one or more lesions in native coronary arteries using an approved coronary stent, and discharged on DAPT

• Diagnosis of acute coronary syndrome, stable angina, or documented silent ischemia

• Patient was over 18 years old, provided consent, and agreed to follow-up

PARIS Registry

Eligibility for Enrollment (2)

Exclusion Criteria

• Evidence of stent thrombosis during baseline procedure

• Patient was already participating in an investigational device or drug study

PARIS Registry

Modes of DAPT Cessation

• Discontinuation patients had discontinued DAPT as per recommendation

of their physician who felt the patient no longer needed therapy

• Interruption patients had interrupted DAPT use on a voluntary basis

and as guided by a physician due to (e.g. surgery) DAPT was then reinstituted within 14 days

• Disruption patients had disrupted DAPT use due to bleeding or non-

compliance.

PARIS Registry

PARIS Registry

Paris Enrollment - Patients

5,031 patients enrolled at 15 centers in 5 countries

USA [10]n=3,666, 72,9%

July 1st, 2009 to Dec 2nd, 2010

Columbia University Medical Center (n=927, 18,5%)Minneapolis Heart Institute Foundation (n=704, 14%)Mount Sinai Medical Center (n=555, 11%)LeBauer Cardiovascular Research Foundation/ Moses Cone Heart and Vascular Center (n=344, 6,8%) St. Luke's Hospital/ Mid-America Heart Institute (n=318 , 6,3%) Geisinger Medical Center (n=276, 5,5%) Washington Adventist Hospital (n=199, 4%)University of Kentucky (n=143, 2,8%) Heart Center of Indiana/ St. Vincent's/ The Care Group (n= 125, 2,5% ) Washington Hospital Center (n=75, 1,5%)

PARIS Registry

Paris Enrollment - Patients

Germany [1]

n=720, 14,3%

Italy [2] n=307, 6%

France [1] n=160, 3,2%

Greece [1]

n=180, 3,6%

EUROPE [5]n=1,367, 27,1%

Charité Hospital, Germany (n=720, 14,3%)San Raffaele Hospital, Italy (n=221 , 4,4%)Onassis Cardiac Surgery Center, Greece (n= 180, 3,5%)Hospital Bichat, France (n=160, 3,2%)Careggi Hospital, Italy (n=86, 1,7%)

5,031 patients enrolled at 15 centers in 5 countries

July 1st, 2009 to Dec 2nd, 2010

Site Principal Investigator Total # EnrolledColumbia University, USA Dr. Giora Weisz 927

Charité, Germany Dr. Bernhard Witzenbichler 720

Minneapolis Heart, USA Dr. Tim Henry 704

Mount Sinai, USA Dr. Annapoorna Kini 553

LeBauer/Moses Cone, USA Dr. Thomas Stuckey/Dr. Bruce Brodie 344

St. Luke's /Mid-America Heart, USA Dr. David Cohen 318

Geisinger Medical, USA Dr. Peter Berger 276

San Raffaele, Italy Dr. Antonio Colombo 221

Washington Adventist, USA Dr. Fayaz Shawl 199

Onassis, Greece Dr. George Dangas/Dr. Ioannis Iakovou 180

Hospital Bichat, France Dr. Gabriel Steg 160

University of Kentucky, USA Dr. David Moliterno 143

Heart Center of Indiana/St. Vincent's, USA

Dr. James Hermiller 125

Careggi, Italy Dr. David Antonucci 86

Washington Hospital Center, USA Dr. Ron Waksman 75

Participating Sites, Principal Investigators and Patients Enrolled

PARIS: Study Organization

• Data Management and Monitoring • Medical Devices Consultancy, Ltd. New Zealand

• Statistical Analysis• London School of Tropical Health and Hygiene: Stuart Pocock,

Cono Ariti• Mount Sinai School of Medicine: Usman Baber, Samantha

Sartori

• Project Management/Clinical Coordinating Center• Mount Sinai School of Medicine: Kristin Falciglia, Maria Alu

• Funding (Investigator-Initiated)• Bristol Myers Squib/Sanofi-Aventis

PARIS Registry

Executive Committee Members*Dr. Roxana Mehran, USA and **Dr. Antonio Colombo, Italy

Dr. Alaide Chieffo, Italy

Dr. David Cohen, USA

Dr. David Moliterno, USA

Dr. Gabriel Steg, France

Dr. Michael Gibson, USA

Dr. Mitch Krucoff, USA

Dr. Bernhard Witzenbichler, USA

Dr. Giora Weisz, USA

Executive Committee and CEC

Clinical Events Committee

*Dr. Steven Marx, Columbia University, NY

Dr. Jason C. Kovacic, Mount Sinai, NY

Dr. Mun Hong, St. Luke’s Roosevelt Hospital, NY

Dr. S. Chiu Wong, NYP Cornell, NY

Dr. Bruce Darrow, Mount Sinai, NY

* Chair, ** Co-chair

Sequence of ResultsPARIS Registry

• Baseline characteristics compared between subjects by presence or absence of any DAPT cessation over 2 years.

• Incidence of major ischemic and bleeding adverse events calculated in overall population.

• Association between modes of DAPT cessation on adverse events examined using Cox proportional hazards regression with DAPT cessation entered as time updated covariate.

• Time updated covariates were generated using hierarchy of ‘worst’ DAPT status defined as Recommended Discontinuation -> Interruption -> Disruption

5,031 Patients with successful PCI with stenting enrolled at 15 sites in the US and Europe

Final Study Population – 5018 Patients

13 Patients excluded from analysis (1 died prior to discharge and 12 not discharged on DAPT)

Lost to follow-up (n=340)

Within 2 years Available Follow-up: 4678/5018 (93.2%)

Lost to follow-up (n=133)

Within 365 days Available Follow-up: 4885/5018 (97.3%)

Within 30 days Available Follow-up: 4972/5018 (99.1%)

Lost to follow-up (n=46)

2-Year Kaplan-Meier Plot of Any DAPT Cessation

60

0 6 12 18 24

Time From PCI, Months

50

Cum

ulat

ive

Inci

denc

e, %

40

30

20

10

30 Days (2.9%)

One Year (23.3%)

Two Years (57.3%)

Incidence rates calculated over entire study population. Patients censored at last known contact, death or study end.

2-Year Kaplan-Meier Plots of Any Discontinuation, Interruption and Disruption

60

0 6 12 18 24

Time From PCI, Months

50

Cum

ulat

ive

Inci

denc

e, %

40

30

20

10

DiscontinuationDisruptionInterruption

40.8%

14.4%

10.5%

Incidence rates calculated over entire study population. Patients censored at last known contact, death or study end.

*SD = standard deviation; PVD = peripheral vascular disease; MI = myocardial infarction; CABG = coronary artery bypass graft; DAPT=dual antiplatelet therapy. BMI= body mass index. P-value is for each DAPT status versus the No DAPT cessation category.

Baseline Characteristics by Any DAPT Cessation Over 2 Years

No DAPT Cessation (n= 2304)

Recommended Discontinuation

(n = 1611)

Interruption (n = 412)

Disruption (n = 691)

Age (years) 62.9 ± 11.4 64.7 ± 10.85 65.3 ± 10.74 64.8 ± 12.26

Female Gender, n (%) 559 (24.3) 404 (25.1) 103 (25) 213 (30.8)

BMI (kg/m2) 29.5 ± 5.7 28.7 ± 5.3 30.0 ± 5.5 29.3 ± 6.2

Hypertension, n (%) 1860 (80.7) 1258 (78.1) 355 (86.2) 536 (77.6)

Previous MI, n (%) 637 (27.6) 329 (20.4) 109 (26.5) 139 (20.1)

Previous CABG, n (%) 374 (16.2) 169 (10.5) 67 (16.3) 75 (10.9)

Stroke, n (%) 79 (3.4) 52 (3.2) 17 (4.1) 25 (3.6)

PVD, n (%) 188 (8.2) 120 (7.4) 33 (8) 51 (7.4)

Current smoker, n (%) 445 (34.7) 315 (41.1) 62 (27.7) 159 (40.3)

Diabetes, n (%) 829 (36) 456 (28.3) 150 (36.4) 219 (31.7)

Acute Coronary Syndrome, n (%) 938 (40.7) 640 (39.7) 140 (34) 338 (48.9)

BMS, n (%) 255 (11.1) 325 (20.2) 68 (16.5) 163 (23.6)

1st generation DES, n (%) 347 (15.1) 194 (12.0) 58 (14.1) 75 (10.9)

2nd generation DES, n (%) 1702 (73.9) 1092 (67.8) 286 (69.4) 453 (65.6)

0%

5%

10%

15%

1.0%0.5% 0.6% 0.5% 0.3%

7.4%

2.2%

1.2%

5.1%

1.7%

11.6%

3.8%

1.5%

7.5%

3.1%

30 Days One Year Two Years

Overall Event Rates Over 2 YearsC

umul

ativ

e In

cide

nce,

%

Incidence calculated as cumulative incidence from a Kaplan-Meier estimate of the time to the first occurrence of the adverse event.

TIMI ACUITY/HORIZONS BARC > 30%

2%

4%

6%

0.3%

0.8%0.6%

1.4%

2.9%

2.6%

2.1%

4.2%4.0%

30 Days One Year Two Years

Major Bleeding Rates Over 2 Years C

umul

ativ

e In

cide

nce,

%

Incidence calculated as cumulative incidence from a Kaplan-Meier estimate of the time to the first occurrence of the adverse event.

Impact of DAPT Cessation on Adverse Events

1.00 (Ref)

0.63 (0.46, 0.86)

1.41 (0.94, 2.12)

1.50 (1.14, 1.97)

On-DAPT

Discontinuation

Interruption

Disruption

0.004

0.101

0.004

413

52

26

67

7.04 (3.31, 14.95)

2.17 (0.97, 4.88)

1.30 (0.97, 1.76)

0-7 Days

8-30 days

31+ days

<0.001

0.06

0.083

7

6

54

HR (95% CI) P Events (n)

0.25 0.5 1 2 4 8 16

DAPT Cessation and MACE*

Hazard Ratio*Cardiac Death, Def/Prob ST, Spontaneous MI, Clinically Driven TLR. All Cox Models adjusted for age, gender, region, ACS presentation, type of stent, number of stents implanted.

DAPT Cessation and Cardiac Death, Def/Prob ST, Spontaneous MI

1.00 (Ref)

0.76 (0.50, 1.14)

1.05 (0.58, 1.92)

2.06 (1.49, 2.83)

On-DAPT

Discontinuation

Interruption

Disruption

0.181

0.864

<0.001

218

31

12

54

9.82 (4.57, 21.12)

2.96 (1.21, 7.24)

1.71 (1.20, 2.44)

0-7 Days

8-30 days

31+ days

<0.001

0.017

0.003

7

5

42

HR (95% CI) P

0.25 0.5 1 2 4 8 16 32

Hazard RatioAll Cox Models adjusted for age, gender, region, ACS presentation, type of stent, number of stents implanted.

Events (n)

DAPT Cessation and Spontaneous MI

1.00 (Ref)

0.92 (0.53, 1.58)

1.20 (0.55, 2.63)

2.95 (1.99, 4.38)

On-DAPT

Discontinuation

Interruption

Disruption

0.748

0.647

<0.001

116

18

7

39

0-7 Days

8-30 days

31+ days

18.25 (8.34, 39.95)

4.69 (1.71, 12.83)

2.22 (1.42, 3.46)

<0.001

0.003

<0.001

7

4

28

0.25 0.5 1 2 4 8 16 32 64

Hazard Ratio

HR (95% CI) P

All Cox Models adjusted for age, gender, region, ACS presentation, type of stent, number of stents implanted.

Events (n)

1.00 (Ref)

0.39 (0.11, 1.35)

0.64 (0.09, 4.82)

2.58 (1.22, 5.46)

On-DAPT

Discontinuation

Interruption

Disruption

0.137

0.664

0.013

57

3

1

10

0-7 Days

8-30 days

31+ days

15.94 (5.57, 45.58)

2.68 (0.36, 19.68)

1.35 (0.50, 3.64)

<0.001

0.334

0.551

4

1

5

0.25 0.5 1 2 4 8 16 32 64

Hazard Ratio

HR (95% CI) P

DAPT Cessation and Def/Prob Stent Thrombosis

All Cox Models adjusted for age, gender, region, ACS presentation, type of stent, number of stents implanted.

Events (n)

1.00 (Ref)

0.64 (0.36, 1.16)

1.06 (0.48, 2.34)

On-DAPT

Discontinuation

Interruption

Disruption

0.141

0.885

100

15

7

1.68 (1.05, 2.67) 0.029 26

5.73 (1.39, 23.62)

3.44 (1.08, 10.98)

1.44 (0.87, 2.38)

0-7 Days

8-30 days

31+ days

0.016

0.037

0.161

2

3

21

HR (95% CI) P

0.25 0.5 1 2 4 8 16 32

Hazard Ratio

DAPT Cessation and Cardiac Death

All Cox Models adjusted for age, gender, region, ACS presentation, type of stent, number of stents implanted.

Events (n)

Overall Contribution of DAPT Cessation on Adverse Events

Number (%) of Spontaneous MI events by DAPT Status*

ON DAPT Recommended Discontinuation

Interruption Disruption0

20

40

60

80

100

120

140

116 (64.4%)

18 (10.0%)

7 (3.9%)

39 (21.7%)

*Out of 180 spontaneous MI events at 2 years, 116 (64.4%) occurred while patients were ON DAPT. Spontaneous MI defined according to Universal Definition.

Num

ber

of E

vent

s

Number (%) of Def/Prob ST events by DAPT Status*

ON DAPT Recommended Discontinuation

Interruption Disruption0

20

40

60

80

57 (80.3%)

3 (4.2%) 1 (1.4%)

10 (14.1%)

*Out of 71 ST events at 2 years, 57 (80.3%) occurred while patients were ON DAPT. ST defined by the Academic Research Consortium (ARC) Critera.

Num

ber

of E

vent

s

Number (%) of Cardiac Death events by DAPT Status*

ON DAPT Recommended Discontinuation

Interruption Disruption0

20

40

60

80

100

120

100 (67.6%)

15 (10.1%)

7 (4.7%)

26 (17.6%)

*Out of 148 Cardiac Death events at 2 years, 100 (67.6%) occurred while patients were ON DAPT. Cardiac Death defined using ARC criteria.

Num

ber

of E

vent

s

Number (%) of Major (BARC ≥ 3) Bleeding Events by DAPT Status*

ON DAPT Recommended Discontinuation

Interruption Disruption0

20

40

60

80

100

120

140 131 (66.8%)

26 (13.3%)

14 (7.1%)

25 (12.8%)

*Out of 196 Bleeding events at 2 years, 131 (66.8%) occurred while patients were ON DAPT. Major Bleeding defined as BARC ≥ 3).

Num

ber

of E

vent

s

Proportion of Ischemic Adverse Events Attributable to DAPT Disruption or Interruption

Spontaneous MI Def/Prob ST TLR Cardiac Death0.0%

5.0%

10.0%

15.0%

20.0%

15.0%

7.7%

4.5%

7.4%

Attr

ibut

able

Ris

k, %

Limitations• Observational design precludes causal inferences

• Follow-up phone calls to ascertain DAPT status can introduce recall bias

• Small number of events (n=7) occurring early (days 1-7) after disruption led to imprecise risk estimates with wide CI. Findings merit confirmation in larger studies.

Conclusions• The impact of DAPT cessation on cardiac risk after PCI is not

uniform but varies substantially by underlying mode, a novel finding with important implications for future study design and clinical practice.

• Relative risk for MACE due to disruption is substantial, albeit short-lived, compared to those on DAPT.

• The overall impact of DAPT cessation on adverse events is modest and may have been mitigated with the introduction of safer stent platforms.

• Findings highlight the need for uniform approaches in classifying DAPT cessation, analogous to those currently used for bleeding and MI.