Incidence and Impact of Dual Antiplatelet Therapy (DAPT) Cessation on Adverse Events following...
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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• How long does risk persist after antiplatelet therapy is withdrawn?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DAPT cessation and adverse events following PCI by the underlying clinical context in which antiplatelet therapy was withdrawn.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.