1. PARIS Registry
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, MD Professor of Medicine (Cardiology) and Health Evidence Policy Director of Interventional Cardiovascular Research and Clinical Trials The Icahn School of Medicine at Mount Sinai, New York, NY on behalf of PARIS Investigators 1

2. 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

3. Background and Rationale
PARIS Registry
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.

4. DAPT Cessation and PCI: Existing Evidence
PARIS Registry
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
1Schulz et al., EHJ 2009; 2Ho et al., AHJ 2007; 3Park et al., AJC 2006

5. DAPT Cessation and PCI: Unresolved Questions
PARIS Registry
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How long does risk persist after antiplatelet therapy is withdrawn?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?

6. PARIS – Objectives
PARIS Registry
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DAPT cessation and adverse events following PCI by the underlying clinical context in which antiplatelet therapy was withdrawn.

7. Study Design Multicenter, multinational, observational study
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

8. Enrollment Eligibility (1)
PARIS Registry
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

9. Eligibility for Enrollment (2)
PARIS Registry
Exclusion Criteria
Evidence of stent thrombosis during baseline procedure
Patient was already participating in an investigational device or drug study

10. Modes of DAPT Cessation
PARIS Registry
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.

11. Paris Enrollment - Patients
PARIS Registry
5,031 patients enrolled at 15 centers in 5 countries
USA [10]
n=3,666, 72,9%
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%)
July 1st, to Dec 2nd, 2010

12. Paris Enrollment - Patients
PARIS Registry
5,031 patients enrolled at 15 centers in 5 countries
Germany [1]
n=720, 14,3%
EUROPE [5]
n=1,367, 27,1%
Greece [1]
n=180, 3,6%
France [1] n=160, 3,2%
Italy [2] n=307, 6%
Remove animation
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%)
July 1st, to Dec 2nd, 2010

13. Participating Sites, Principal Investigators and Patients Enrolled
Total # Enrolled
Columbia 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

14. PARIS: Study Organization
PARIS Registry
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

15. Executive Committee and CEC
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
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

16. Sequence of Results
PARIS 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

17. 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)
Within 30 days Available Follow-up: 4972/5018 (99.1%)
Lost to follow-up
(n=46)
Lost to follow-up
(n=133)
Within 365 days Available Follow-up: 4885/5018 (97.3%)
Lost to follow-up
(n=340)
Within 2 years Available Follow-up: 4678/5018 (93.2%)

18. 2-Year Kaplan-Meier Plot of Any DAPT Cessation
Two Years
(57.3%) 60 50 40
Cumulative Incidence, % 30
One Year
(23.3%) 20
30 Days
(2.9%) 10 6 12 18 24
Time From PCI, Months
Incidence rates calculated over entire study population. Patients censored at last known contact, death or study end.

19. 2-Year Kaplan-Meier Plots of
Any Discontinuation, Interruption and Disruption 60
Discontinuation
Disruption
Interruption 50
40.8% 40
Cumulative Incidence, % 30 20
14.4%
10.5% 10 6 12 18 24
Time From PCI, Months
Incidence rates calculated over entire study population. Patients censored at last known contact, death or study end.

20. 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)
2nd generation DES, n (%)
1702 (73.9)
1092 (67.8)
286 (69.4)
453 (65.6)
*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.

21. Procedure Characteristics by DAPT Cessation Over 2 Years
No DAPT Cessation
(n= 2304)
Recommended Discontinuation
(n = 1611)
Interruption
(n = 412)
Disruption
(n = 691)
PCI vessel
Left Main, n (%)
77 (3.3)
44 (2.7)
11 (2.7)
26 (3.8)
LAD, n (%)
1066 (46.3)
766 (47.5)
183 (44.4)
309 (44.7)
Proximal LAD, n (%)
498 (21.6)
407 (25.3)
85 (20.6)
127 (18.4)
LCx, n (%)
747 (32.4)
468 (29.1)
130 (31.6)
205 (29.7)
RCA, n (%)
806 (35.0)
549 (34.1)
150 (36.4)
255 (36.9)
Number of vessels treated
1 vessel, n (%)
1941 (84.2)
1406 (87.3)
355 (86.2)
590 (85.4)
2 vessels, n (%)
334 (14.5)
194 (12.0)
52 (12.6)
98 (14.2)
3 vessels, n (%)
29 (1.3)
11 (0.7)
5 (1.2)
3 (0.4)
Bifurcation lesion, n (%)
255 (11.1)
211 (13.1)
36 (8.7)
93 (13.5)
Chronic total occlusion, n (%)
86 (3.7)
66 (4.1)
16 (3.9)
24 (3.5)
Thrombotic lesion, n (%)
156 (6.8)
178 (11.0)
25 (6.1)
56 (8.1)
Stent type
BMS, n (%)
325 (20.2)
68 (16.5)
163 (23.6)
1st generation DES, n (%)
347 (15.1)
58 (14.1)
75 (10.9)
2nd generation DES, n (%)
1702 (73.9)
1092 (67.8)
286 (69.4)
453 (65.6)
Number of stents implanted
1 stent, n (%)
1250 (54.3)
892 (55.4)
247 (60.0)
393 (56.9)
2 stents, n (%)
664 (28.8)
460 (28.6)
94 (22.8)
197 (28.5)
3+ stents, n (%)
390 (16.9)
259 (16.1)
71 (17.2)
101 (14.6)
*SD = standard deviation; PVD = peripheral vascular disease; MI = myocardial infarction; CABG = coronary artery bypass graft; DAPT=dual antiplatelet therapy. BMI= body mass index.

22. Overall Event Rates Over 2 Years
Cumulative Incidence, %
Incidence calculated as cumulative incidence from a Kaplan-Meier estimate of the time to the first occurrence of the adverse event.

23. Major Bleeding Rates Over 2 Years
Cumulative Incidence, %
Incidence calculated as cumulative incidence from a Kaplan-Meier estimate of the time to the first occurrence of the adverse event.

24. Impact of DAPT Cessation on Adverse Events

25. DAPT Cessation and MACE*
HR (95% CI) P
Events (n)
On-DAPT
1.00 (Ref)
413
Discontinuation
0.63 (0.46, 0.86)
0.004 52
Interruption
1.41 (0.94, 2.12)
0.101 26
Disruption
1.50 (1.14, 1.97)
0.004 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
0.25
0.5 1 2 4 8 16
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.

26. DAPT Cessation and Cardiac Death, Def/Prob ST, Spontaneous MI
HR (95% CI) P
Events (n)
On-DAPT
1.00 (Ref)
218
Discontinuation
0.76 (0.50, 1.14)
0.181 31
Interruption
1.05 (0.58, 1.92)
0.864 12
Disruption
2.06 (1.49, 2.83)
<0.001 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
0.25
0.5 1 2 4 8 16 32
Hazard Ratio
All Cox Models adjusted for age, gender, region, ACS presentation, type of stent, number of stents implanted.

27. DAPT Cessation and Spontaneous MI
HR (95% CI) P
Events (n)
On-DAPT
1.00 (Ref)
116
Discontinuation
0.92 (0.53, 1.58)
0.748 18
Interruption
1.20 (0.55, 2.63)
0.647 7
Disruption
2.95 (1.99, 4.38)
<0.001 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 7 4 28
0.25
0.5 1 2 4 8 16 32 64
Hazard Ratio
All Cox Models adjusted for age, gender, region, ACS presentation, type of stent, number of stents implanted.

28. DAPT Cessation and Def/Prob Stent Thrombosis
Events (n)
HR (95% CI) P
1.00 (Ref) 57
On-DAPT
0.39 (0.11, 1.35)
0.137 3
Discontinuation
0.64 (0.09, 4.82)
0.664 1
Interruption
2.58 (1.22, 5.46)
0.013 10
Disruption
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
All Cox Models adjusted for age, gender, region, ACS presentation, type of stent, number of stents implanted.

29. DAPT Cessation and Cardiac Death
HR (95% CI) P
Events (n)
On-DAPT
1.00 (Ref)
100
Discontinuation
0.64 (0.36, 1.16)
0.141 15
Interruption
1.06 (0.48, 2.34)
0.885 7
Disruption
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
0.25
0.5 1 2 4 8 16 32
Hazard Ratio
All Cox Models adjusted for age, gender, region, ACS presentation, type of stent, number of stents implanted.

30. Overall Contribution of DAPT Cessation on Adverse Events

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

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

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

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

35. Proportion of Ischemic Adverse Events Attributable to DAPT Disruption or Interruption
Attributable Risk, %

36. 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.

37. 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.