Transcript PARIS Registry Patterns of Non-Adherence to Anti-Platelet Regimens In Stented Patients: An Observational Single Arm Study Roxana Mehran, MD on behalf of PARIS Investigators.

PARIS Registry
Patterns of Non-Adherence to
Anti-Platelet Regimens In Stented
Patients: An Observational
Single Arm Study
Roxana Mehran, MD
on behalf of PARIS Investigators
Background and Rationale
• Anti-platelet agents are the cornerstone of
therapy in pts with ACS and in those undergoing
PCI.
• Current ACC/AHA guidelines recommend 30
1
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.)
• Premature discontinuation of DAPT (within the
first 6 months after DES) has been associated
with an increased risk of stent thrombosis, but
the optimal duration of DAPT has not yet been
precisely determined, especially with regard to
second generation DES.
1. Wright et al. JACC 10 May 2011
Background and Rationale
• The mode and circumstances around nonadherence to DAPT has not been previously
studied.
• Whether or not discontinuation of DAPT
secondary to bleeding or other events (ie: noncardiac surgery) may lead to subsequent
ischemic events has not been systematically
studied.
• Previous studies have only addressed patients
“on” or “off” DAPT at specific follow-up points or
at the time of events.
Study Design
• Multicenter, multinational, observational study
• 5033 subjects to be followed for approximately
24 months post stent implantation
• Includes bare metal and drug eluting stents
Modes of Non-adherence
• Discontinuation: subjects have discontinued
use of DAPT as per recommendation of their
physician who felt subject no longer needed
therapy.
• Interruption: subjects have interrupted DAPT
use on a voluntary basis and under guidance
and recommendation of their physician due to
need for surgery. DAPT will be reinstituted
within 14 days.
• Disruption: subjects have disrupted DAPT use
due to bleeding or non-compliance. Includes
use of DAPT at lower dose levels than
prescribed.
Eligibility for Enrollment (1)
Inclusion Criteria
• Successful stent placement in one or more
lesions in native coronary arteries using an
approved coronary stent, and intent to
discharge on DAPT
• Diagnosis of Acute Coronary Syndrome,
Stable Angina, or Documented Silent
Ischemia
• Subject is over 18 years old, provides
consent, and agrees to follow-up
Eligibility for Enrollment (2)
Exclusion Criteria
• Evidence of stent thrombosis during
baseline procedure
• Subject is participating in an
investigational device or drug study
Objectives
Primary Objectives
• To examine the modes of non-adherence to
dual anti-platelet therapy (DAPT) following
stenting
• To evaluate subsequent clinical outcomes and
the relation to non-adherence to DAPT
Secondary Objectives
• To examine factors associated with nonadherence
• To examine the relationship of major & minor
bleeding to stent thrombosis & MACE
Study Organization
•
Principal Investigators:
Roxana Mehran, MD
Antonio Colombo, MD
•
Steering Committee:
Roxana Mehran, MD (Chair); Antonio
Colombo, MD (Co-Chair); Alaide
Chieffo, MD; David J. Cohen, MD, MSc;
C. Michael Gibson, MD; Mitchell W.
Krucoff, MD; David J. Moliterno, MD;
Ph. Gabriel Steg, MD; Giora Weisz,
MD; Bernhard Witzenbichler, MD
Study Organization
• Sponsor:
Mount Sinai School of Medicine
• Grant Support:
Sanofi-Aventis and Bristol-Myers
Squibb
• Data Coordinating Center: Mount Sinai School of Medicine
• Clinical Event Committee: Dr. Steven Marx (Chair)
• Site and Data Monitoring: Medical Devices Consultancy Ltd
• EDC:
Study Manager
Investigators and Site Name
PI Name
Site name
1
James Hermiller, MD
Heart Center of Indiana, IN
2
Annapoorna Kini, MD
Mount Sinai Medical Center, NY
3
Fayaz Shawl, MD
Washington Adventist Hospital, MD
4
Giora Weisz, MD
Columbia University Medical Center, NY
5
Bernhard Witzenbichler, MD
Charité, Germany
6
Antonio Colombo, MD
Alaide Chieffo, MD
San Raffaele Hospital, Italy
7
David J. Cohen, MD, MSc
Saint Luke's Mid-America Heart Institute, MO
8
David J. Moliterno, MD
University of Kentucky, KY
Investigators and Site Name
(cont.)
PI Name
Site name
9
David Antoniucci, MD
Careggi Hospital, Italy
10
Ph. Gabriel Steg, MD
Hopital Bichat, France
11
Peter B. Berger, MD
Geisinger Medical Center, PA
12
Thomas Stuckey, MD
LeBauer Cardiovascular Research Foundation, NC
13
Ron Waksman, MD
Washington Hospital Center, DC
14
Timothy D. Henry, MD
Minneapolis Heart Institute Foundation, MN
15
Ioannis Iakovou, MD, PhD
Onassis Cardiac Surgery Center, Greece
Paris Enrollment - Patients
5,033 pts 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, 2009 and October 29th, 2010
Paris Enrollment - Patients
5,033 pts enrolled at 15 centers in 5 countries
EUROPE [5]
n=1,367, 27,1%
France [1]
n=160, 3,2%
Germany [1]
n=720, 14,3%
Greece [1]
n=180, 3,6%
Italy [2]
n=307, 6%
•
•
•
•
•
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, 2009 and October 29th, 2010
Enrollment Over Time
6000
5000
4000
3000
2000
1000
0
Jul-09
Aug-09
Sep-09
Oct-09
Nov-09
Dec-09
Jan-10
Feb-10
Mar-10
Apr-10
May-10
Jun-10
Jul-10
Aug-10
Sep-10
Oct-10
Baseline Characteristics
Enrolled: n= 5033
Complete 30 Day Follow-Up Available: 5023 (99.3%)
Variable
Age, years
Body mass index, kg/m2
Male, n (%)
Acute coronary syndrome, n (%)
Current smoker, n (%)
Diabetes Mellitus, n (%)
Insulin-requiring DM, n (%)
Dyslipidemia, n (%)
Hypertension, n (%)
Peripheral Vascular Disease, n (%)
Prior coronary artery disease, n (%)
Prior MI, n (%)
Prior PCI with stenting, n (%)
Prior CABG, n (%)
Prior stroke, n (%)
Patients (n=5033)
63.96 ± 11.32
29.26 ± 5.63
3750 (74.5)
2047 (40.9)
984 (19.6)
1663 (33.0)
547 (10.9)
3810 (75.7)
4020 (79.9)
396 (7.9)
1613 (32.1)
1220 (24.2)
1853 (36.8)
691 (13.7)
174 (3.5)
Medication Usage
6000
Patients
5000
4000
3000
2000
1000
0
Aspirin
(71.1%)
Pre-Procedure 35823582
(99.6%)
At Discharge 50125012
Thienopyridi
ne
2014 2014
(40.0%)
5031 5031
(100%)
ProtonPump
Inhibitor
991 (19.7%)
991
1177 1177
(23.4%)
DAPT
Triple
Therapy
1894 1894
(37.6%)
47 (0.9%)
47
5012 5012
(99.6%)
311 (6.2%)
311
Procedural Information
Stent Type
Number of Stents
2%
16%
16%
BMS alone
(n = 817)
One (n = 2792)
28%
56%
Two (n = 1417)
> Two (n = 824)
DES alone
(n = 4141)
82%
BMS & DES
(n = 70)
Stents by Type
• Total # of stents used: 8434 (1.68 stents/pt)
Stents by Type
BMS (n = 1258)
1%
PES (n = 662)
15%
8%
3%
62%
11%
SES (n = 289)
ZES (n = 920)
EES (n = 5226)
Other DES (n = 79)
Thienopyridine at Discharge
2%
6%
Clopidogrel (n = 4647)
Prasugrel (n = 315)
Ticlopidine (n = 69)
92%
Rates of Non-Adherence
(Patient-level)
Incidence of Non-Adherence
2%
Adherent (4929)
Non-Adherence by Mode
12%
Disruption (72)
19%
98%
Non-Adherent
(104)
Interruption (20)
69%
Discontinuation
(12)
Incidence of Non-Adherence
Any Non-Adherence
Variable
Any Non-adherence
Patients Episodes
104 (2.1)
147
Disruption, n (%)
72 (69)
102 (70)
Interruption, n (%)
20 (19)
27 (18)
Discontinuation, n (%)
12 (12)
18 (12)
Incidence of Non-Adherence
(Cont.)
Non Adherence to Thienopyridine:
Variable
Patients Episodes
Any Non-adherence, n (%) 66 (1.3)
69
Disruption, n (%)
43 (65)
46 (67)
Interruption, n (%)
12 (18)
12 (17)
Discontinuation, n (%)
11 (17)
11 (16)
Incidence of Non-Adherence
(Cont.)
Non Adherence to Aspirin:
Variable
Patients Episodes
Any Non-adherence, n (%) 70 (1.4)
78
Disruption, n (%)
51 (73)
56 (72)
Interruption, n (%)
12 (17)
15 (19)
Discontinuation, n (%)
7 (10)
7 (9)
Reasons for Disruption
Thienopyridine
Aspirin
Other
4%
Other
7%
Bleeding
31%
Bleeding
32%
Noncompliance
65%
NonCompliance
61%
ASA
Thienopyridine
Bleeding
18
14
Non-Compliance
34
30
Other
4
2
Reasons for Interruption
Aspirin
Thienopyridine
Coumadin
13%
Surgery
34%
Allergy
20%
GI Upset
20%
ASA
Thienopyridine
Allergy
33%
Other
Medical
Procedure
13%
Surgery
5
5
Surgery
42%
Other
Medical
Procedure
25%
Other Medical
Procedure
2
GI Upset
3
Allergy
3
Coumadin
2
3
0
4
0
(epidural, catheter removal, GI Scope)
Non-Adherence guided by healthcare professionals
Recommended By
Cardiologist (n = 31)
16%
38%
10%
5%
Primary Care Physician (n = 15)
ER Physician (n = 11)
13%
GI Specialist (n = 4)
18%
Other (n = 8)
Unknown (n = 13)
Total episodes of “Recommended” DAPT non-adherence: 82
Baseline Characteristics
Variable
Age, years
Male, n (%)
Acute coronary syndrome, n (%)
Diabetes Mellitus, n (%)
Dyslipidemia, n (%)
Hypertension, n (%)
Peripheral Vascular Disease, n (%)
Prior coronary artery disease, n (%)
Prior MI, n (%)
Adherent
n=4929
Non-adherent
n=104
p-value
63.94 [11.33]
3676 (74.6)
1987 (40.5)
1627 (33.0)
3744 (76.0)
3944 (80.0)
387 (7.9)
1987 (40.5)
1201 (24.4)
64.83 [11.31]
74 (71.2)
60 (58.3)
36 (34.6)
66 (63.5)
76 (73.1)
9 (8.7)
60 (58.3)
19 (18.3)
0.42
0.43
<0.0001
0.73
0.003
0.08
0.76
<0.0001
0.15
Rates of 30-Day non-adherence
in Similar Registries
Timeframe
Population
N
DAPT
Discontinuation at 30
days (%)
Airoldi et al1
2002 – 2004
PCI with DES
3021
2.4%
PREMIER
Registry2
2003 – 2004
DES for MI
500
13.6%
MATRIX Registry3
2004-2006
PCI with SES
1504
5.8%
E-Five Registry4
2005-2007
PCI with ZES
7988
2.1%
E-SELECT
Registry5
2006-2008
PCI with SES
14,365
2%
Study
1. Airoldi F et al. Circulation. 2007 Aug 14;116(7):745-54.
2. Spertus J et al. Circulation 2006 June 20; 113(24):2803-9.
3. Claessen B et al. Am J Cardiol 2011;107:528-534.
4. Lotan C et al. J Am Coll Cardiol Interv 2009; 2(12), 1227-1235.
5. Urban P et al J Am Coll Cardiol 2011;57:1445-54.
Adverse Event Rates
Total
Adherent
(n=4929)
Non-adherent
(n=104)
MACE, n (%)
78 (1.5)
67 (1.4)
11 (10.6)
Death, all-cause, n(%)
17 (0.3)
15 (0.3)
2 (1.9)
Cardiac Death, n (%)
15 (0.3)
14 (0.3)
1 (1.0)
Myocardial Infarction, n (%)
54 (1.1)
46 (0.9)
8 (7.7)
Stent Thrombosis, n (%)
26 (0.5)
23 (0.5)
3 (2.9)
TVR, n (%)
30 (0.6)
25 (0.5)
5 (4.8)
TLR, n (%)
23 (0.5)
19 (0.4)
4 (3.8)
TIMI major, n (%)
9 (0.2)
6 (0.1)
3 (2.9)
ACUITY Major, n (%)
35 (0.7)
23 (0.5)
12 (11.5)
BARC ≥ 3, n (%)
30 (0.6)
18 (0.4)
12 (11.5)
Ischemic
Bleeding
BARC Bleeding Scale
1
BARC Classification
N (% of total population)
Type 1 (not actionable)
26 (0.5)
Type 2 (requiring medical attention)
37 (0.7)
Type 3
30 (0.6)
3a
15 (0.3)
3b
15 (0.3)
3c
0
Type 4 (CABG related)
0
BARC Type 5 (Fatal)
0
1. Mehran et al. Circulation 2011 Jun 14;123(23):2736-47.
Stent Thrombosis
Stent Thrombosis
(n=26)
Probable (n=9)
Definite (n=17)
Adherent (n=14)
Non-adherent (n=3)
Disrupted ASA
(n=2)
Disrupted
Clopidogrel (n=1)
Odds Ratio (95% CI) for stent thrombosis associated with
non-adherence: 6.3 (1.9-21.4)
Relative Risk of Non-Adherence on
30 Day Stent Thrombosis in
Contemporary Registries
Adherent
Non-Adherent
RR
PARIS Registry
0.5%
2.9%
5.8
Airoldi et al1
0.9%
4.2%
4.7
eSELECT Registry2
0.5%
4.6%
9.2
1. Airoldi F et al. Circulation. 2007 Aug 14;116(7):745-54.
2. Urban P et al. J Am Coll Cardiol 2011;57:1445-54.