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PARIS RegistryPatterns of Non-Adherence to
Anti-Platelet Regimens In Stented Patients: An Observational
Single Arm Study
Roxana Mehran, MDon behalf of PARIS Investigators
PARIS Registry
Background and Rationale• Anti-platelet agents are the cornerstone of therapy in pts
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.)
• 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 non-adherence to DAPT has not been previously studied.
• Whether or not discontinuation of DAPT secondary to bleeding or other events (ie: non-cardiac 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
PARIS Registry
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.
PARIS Registry
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
PARIS Registry
Eligibility for Enrollment (2)
Exclusion Criteria
• Evidence of stent thrombosis during baseline procedure
• Subject is participating in an investigational device or drug study
PARIS Registry
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 non-adherence
• To examine the relationship of major & minor bleeding to stent thrombosis & MACE
PARIS Registry
Study OrganizationStudy Organization
• Principal Investigators:Principal Investigators: Roxana Mehran, MDRoxana Mehran, MD
Antonio Colombo, MDAntonio Colombo, MD
• Steering Committee:Steering Committee: Roxana Mehran, MD (Chair); Roxana Mehran, MD (Chair);
Antonio Antonio Colombo, MD (Co-Chair); Colombo, MD (Co-Chair);
Alaide Alaide Chieffo, MD; David J. Chieffo, MD; David J.
Cohen, MD, MSc; Cohen, MD, MSc; C. Michael Gibson, C. Michael Gibson,
MD; Mitchell W. MD; Mitchell W. Krucoff, MD; David J. Krucoff, MD; David J.
Moliterno, MD; Moliterno, MD; Ph. Gabriel Steg, MD; Ph. Gabriel Steg, MD;
Giora Weisz, Giora Weisz, MD; Bernhard MD; Bernhard
Witzenbichler, MDWitzenbichler, MD
PARIS Registry
Study OrganizationStudy Organization
• Sponsor:Sponsor: Mount Sinai School of MedicineMount Sinai School of Medicine
• Grant Support:: Sanofi-Aventis and Bristol-Myers Sanofi-Aventis and Bristol-Myers
SquibbSquibb
• Data Coordinating Center:Data Coordinating Center: Mount Sinai School of MedicineMount Sinai School of Medicine
• Clinical Event Committee:Clinical Event Committee: Dr. Steven Marx (Chair)Dr. Steven Marx (Chair)
• Site and Data Monitoring:Site and Data Monitoring: Medical Devices Consultancy Medical Devices Consultancy
LtdLtd
• EDC:EDC: Study ManagerStudy Manager
PARIS Registry
PARIS Registry
Investigators and Site NameInvestigators and Site Name
PI NamePI Name Site nameSite name
1 James Hermiller, MDJames Hermiller, MD Heart Center of Indiana, IN
2 Annapoorna Kini, MDAnnapoorna Kini, MD Mount Sinai Medical Center, NY
3 Fayaz Shawl, MDFayaz Shawl, MD Washington Adventist Hospital, MD
4 Giora Weisz, MDGiora Weisz, MD Columbia University Medical Center, NY
5 Bernhard Witzenbichler, MDBernhard Witzenbichler, MD Charité, Germany
6Antonio Colombo, MDAntonio Colombo, MDAlaide Chieffo, MDAlaide Chieffo, MD San Raffaele Hospital, Italy
7 David J. Cohen, MD, MScDavid J. Cohen, MD, MSc Saint Luke's Mid-America Heart Institute, MO
8 David J. Moliterno, MDDavid J. Moliterno, MD University of Kentucky, KY
PARIS Registry
Investigators and Site NameInvestigators and Site Name(cont.)(cont.)
PI NamePI Name Site nameSite 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 Registry
Paris Enrollment - PatientsParis Enrollment - Patients 5,033 pts enrolled at 15 centers in 5 countries
USA [10]USA [10]n=3,666, 72,9%n=3,666, 72,9%
July 1st, 2009 and October 29th, 2010
• Columbia University Medical Center (n=927, 18,5%)Columbia University Medical Center (n=927, 18,5%)• Minneapolis Heart Institute Foundation (n=704, 14%)Minneapolis Heart Institute Foundation (n=704, 14%)• Mount Sinai Medical Center (n=555, 11%)Mount Sinai Medical Center (n=555, 11%)• LeBauer Cardiovascular Research Foundation/ Moses Cone Heart and LeBauer Cardiovascular Research Foundation/ Moses Cone Heart and
Vascular Center (n=344, 6,8%) Vascular Center (n=344, 6,8%) • St. Luke's Hospital/ Mid-America Heart Institute (n=318 , 6,3%) St. Luke's Hospital/ Mid-America Heart Institute (n=318 , 6,3%) • Geisinger Medical Center (n=276, 5,5%) Geisinger Medical Center (n=276, 5,5%) • Washington Adventist Hospital (n=199, 4%)Washington Adventist Hospital (n=199, 4%)• University of Kentucky (n=143, 2,8%) University of Kentucky (n=143, 2,8%) • Heart Center of Indiana/ St. Vincent's/ The Care Group (n= 125, 2,5% ) Heart Center of Indiana/ St. Vincent's/ The Care Group (n= 125, 2,5% ) • Washington Hospital Center (n=75, 1,5%)Washington Hospital Center (n=75, 1,5%)
PARIS Registry
Paris Enrollment - PatientsParis Enrollment - Patients 5,033 pts enrolled at 15 centers in 5 countries
July 1st, 2009 and October 29th, 2010
Germany [1] Germany [1]
n=720, 14,3%n=720, 14,3%
Italy [2] Italy [2] n=307, 6%n=307, 6%
France [1] France [1] n=160, 3,2%n=160, 3,2%
Greece [1] Greece [1]
n=180, 3,6%n=180, 3,6%
EUROPE [5]EUROPE [5]n=1,367, 27,1%n=1,367, 27,1%
• Charité Hospital, Germany (n=720, 14,3%)Charité Hospital, Germany (n=720, 14,3%)• San Raffaele Hospital, Italy (n=221 , 4,4%)San Raffaele Hospital, Italy (n=221 , 4,4%)• Onassis Cardiac Surgery Center, Greece (n= 180, 3,5%)Onassis Cardiac Surgery Center, Greece (n= 180, 3,5%)• Hospital Bichat, France (n=160, 3,2%)Hospital Bichat, France (n=160, 3,2%)• Careggi Hospital, Italy (n=86, 1,7%)Careggi Hospital, Italy (n=86, 1,7%)
Enrollment Over TimeEnrollment Over Time
PARIS Registry
Baseline Characteristics
Variable Patients (n=5033)
Age, years 63.96 ± 11.32
Body mass index, kg/m2 29.26 ± 5.63
Male, n (%) 3750 (74.5)
Acute coronary syndrome, n (%) 2047 (40.9)
Current smoker, n (%) 984 (19.6)
Diabetes Mellitus, n (%) 1663 (33.0)
Insulin-requiring DM, n (%) 547 (10.9)
Dyslipidemia, n (%) 3810 (75.7)
Hypertension, n (%) 4020 (79.9)
Peripheral Vascular Disease, n (%) 396 (7.9)
Prior coronary artery disease, n (%) 1613 (32.1)
Prior MI, n (%) 1220 (24.2)
Prior PCI with stenting, n (%) 1853 (36.8)
Prior CABG, n (%) 691 (13.7)
Prior stroke, n (%) 174 (3.5)
PARIS RegistryEnrolled: n= 5033Complete 30 Day Follow-Up Available: 5023 (99.3%)
Medication UsageMedication Usage
AspirinThienopyridi
ne
Proton-Pump
InhibitorDAPT
Triple Therapy
Pre-Procedure 3582 2014 991 1894 47At Discharge 5012 5031 1177 5012 311
0
1000
2000
3000
4000
5000
6000
Pat
ient
s
PARIS Registry
3582 (71.1%) 2014 (40.0%) 991 (19.7%) 1894 (37.6%) 47 (0.9%)
5012 (99.6%) 5031 (100%) 1177 (23.4%) 5012 (99.6%) 311 (6.2%)
Procedural InformationProcedural Information
56%28%
16%
Number of Stents
One (n = 2792)
Two (n = 1417)
> Two (n = 824)
16%
82%
2%
Stent Type
BMS alone (n = 817)
DES alone (n = 4141)
BMS & DES (n = 70)
PARIS Registry
Stents by Type
• Total # of stents used: 8434 (1.68 stents/pt)
15%
8%3%
11%62%
1%
Stents by Type
BMS (n = 1258)
PES (n = 662)
SES (n = 289)
ZES (n = 920)
EES (n = 5226)
Other DES (n = 79)
PARIS Registry
Thienopyridine at DischargeThienopyridine at Discharge
92%
6%
2%
Clopidogrel (n = 4647)
Prasugrel (n = 315)
Ticlopidine (n = 69)
PARIS Registry
Rates of Non-Adherence (Patient-level)
98%
2%
Incidence of Non-Adherence
Adherent (4929)
Non-Adherent (104)
69%
19%
12%
Non-Adherence by Mode
Disruption (72)
Interruption (20)
Discontinuation (12)
PARIS Registry
PARIS Registry
Any Non-AdherenceAny Non-Adherence
Variable Variable Patients Patients Episodes Episodes
Any Non-adherence 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
Non Adherence to Thienopyridine:Non Adherence to Thienopyridine:
Variable Variable Patients Patients Episodes 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.)
PARIS Registry
Non Adherence to Aspirin:Non Adherence to Aspirin:
Variable Variable Patients Patients Episodes 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)
Incidence of Non-Adherence(Cont.)
PARIS Registry
Bleeding Non-Compliance Other
ASA 18 34 4Thienopyridine 14 30 2
Bleeding32%
Non-Compliance
61%
Other7%
Aspirin
Bleeding31%
Non-compliance
65%
Other4%
Thienopyridine
Reasons for Disruption
PARIS Registry
Surgery
Other Medical Procedure
(epidural, catheter removal, GI Scope) GI Upset Allergy Coumadin
ASA 5 2 3 3 2
Thienopyridine 5 3 0 4 0
Surgery34%
Other Medical
Procedure13%
GI Upset20%
Allergy20%
Coumadin13%
Aspirin
Surgery42%
Other Medical
Procedure25%
Allergy33%
Thienopyridine
Reasons for Interruption
PARIS Registry
Non-Adherence guided by healthcare professionals Non-Adherence guided by healthcare professionals
38%
18%
13%
5%
10%
16%
Recommended By
Cardiologist (n = 31)
Primary Care Physician (n = 15)
ER Physician (n = 11)
GI Specialist (n = 4)
Other (n = 8)
Unknown (n = 13)
PARIS Registry
Total episodes of “Recommended” DAPT non-adherence: 82
PARIS Registry
Baseline Characteristics
VariableAdherentn=4929
Non-adherentn=104
p-value
Age, years 63.94 [11.33] 64.83 [11.31] 0.42
Male, n (%) 3676 (74.6) 74 (71.2) 0.43
Acute coronary syndrome, n (%) 1987 (40.5) 60 (58.3) <0.0001
Diabetes Mellitus, n (%) 1627 (33.0) 36 (34.6) 0.73
Dyslipidemia, n (%) 3744 (76.0) 66 (63.5) 0.003
Hypertension, n (%) 3944 (80.0) 76 (73.1) 0.08
Peripheral Vascular Disease, n (%) 387 (7.9) 9 (8.7) 0.76
Prior coronary artery disease, n (%) 1987 (40.5) 60 (58.3) <0.0001
Prior MI, n (%) 1201 (24.4) 19 (18.3) 0.15
Rates of 30-Day non-adherenceRates of 30-Day non-adherence in Similar Registries in Similar Registries
Study 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%
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.
PARIS Registry
PARIS Registry
Adverse Event RatesAdverse Event Rates
TotalTotalAdherent Adherent (n=4929)(n=4929)
Non-adherentNon-adherent(n=104)(n=104)
Ischemic
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)
Bleeding
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)
BARC Bleeding Scale1
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
PARIS RegistryStent Thrombosis Stent Thrombosis
(n=26)(n=26)
Probable (n=9)Probable (n=9) Definite (n=17)Definite (n=17)
Adherent (n=14)Adherent (n=14) Non-adherent (n=3)Non-adherent (n=3)
Disrupted ASA Disrupted ASA (n=2)(n=2)
Disrupted Disrupted Clopidogrel (n=1)Clopidogrel (n=1)
Odds Ratio (95% CI) for stent thrombosis associated with non-adherence: 6.3 (1.9-21.4)
PARIS Registry
Relative Risk of Non-Adherence on Relative Risk of Non-Adherence on 30 Day Stent Thrombosis in 30 Day Stent Thrombosis in
Contemporary RegistriesContemporary 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.
