TRIAL UPDATE 1 ISAR TRIPLE SECURITY Trial Dr Deven Patel Royal Free Hospital
NO CONFLICT OF INTEREST TO DECLARE
ISAR TRIPLE Comparison of 6 weeks vs 6 months Triple Therapy in patients on oral anticoagulation after DE Stenting
ISAR - TRIPLE Prospective, Randomised at time of PCI Inclusion DES in pts requiring Oral Anti Coag Exclusion Stent Thrombosis / LMS Stent Primary Endpoints Death, MI, Stent Thrombosis, Stroke, TIMI Major bleeds Secondary Endpoints Ischaemic Cardiac Death, MI, Stent Thrombosis, Stroke Bleeding - TIMI Major bleeds
ISAR TRIPLE Study Design 614 patients with DES implantation 3 European centers (September 2008 December 2013) Aspirin and VKA 6-week Clopidogrel (n=307) 6-month Clopidogrel (n=307) Clinical follow up at 9 months in 606 patients (98.7%)
Randomization ISAR - TRIPLE PCI Randomization Stop clopidogrel Group A Stop clopidogrel Group B A: 6-week group Clopidogrel Aspirin and oral anticoagulation B: 6-month group Clopidogrel Aspirin and oral anticoagulation 0 6-week Follow-up 6-month Follow-up 9-month Follow-up Time (months)
ISAR TRIPLE - Clinical Characteristics 6 Weeks Gp (n=307) 6 Months gp (n= 307) Age / Female 74 y / 25% 73y / 21% Diabetes 28% 23% ACS 33% 31% Prev MI 29% 25% OAC - AF 83% 85% OAC - Mechanical Valve 5% 9% Clopidogrel usage at 6 mths* 26% 87% Clopidogrel usage at 9 mths* 23% 35% DES 2 nd Generation 49% 50% DES Biodeg Polymer 31% 33% DES 1 st Gen Polymer 7% 4%
Primary Endpoint ISAR - TRIPLE 20 Death, myocardial infarction, stent thrombosis, stroke ortimi major bleeding Cumulative Incidence (%) 15 10 5 0 HR 1.14 (95%, CI 0.68 1.91), p=0.63 9.8 % 8.8 % 6-month group 6-week group 0 1 2 3 4 5 6 7 8 9 Months After Randomization
ISAR - TRIPLE Results 6-week group (n=307) 6-month group (n=307) Hazard ratio (95% CI) p value Death 12 (4.0) 16 (5.2) 0.75 (0.35-1.59) 0.45 Cardiac death 5 (1.7) 9 (3.0) 0.56 (0.19-1.66) 0.29 Myocardial infarction 6 (2.0) 0-0.03 Definite stent thrombosis 2 (0.7) 0-0.50 Stroke 4 (1.3) 6 (2.0) 0.67 (0.14-2.78) 0.75 Ischemic stroke 3 (1.0) 4 (1.3) 0.75 (0.11-4.40) 0.99 Temporal distribution of MIs in 6-week group: 4 within 24h of PCI } Both groups on triple therapy 1 at 2.5 weeks 1 at 7 months } Both groups on aspirin and OAC
ISAR - TRIPLE Any BARC Bleeding (type 1-5) Any BARC Bleeding Post-hoc landmark analysis of any BARC Bleeding before and after 6 weeks (6w) Cumulative Incidence (%) 50 40 30 20 10 0 HR 0.94 (0.73-1.21), p=0.63 40.2 % 37.6 % 0 1 2 3 4 5 6 7 8 9 Months After Randomization 50 40 30 20 10 0 HR 0.68 (0.47 0.98), p=0.04 6w 27.9 % 20.5 % 0 1 2 3 4 5 6 7 8 9 Months After Randomization 6-month group 6-week group
ISAR TRIPLE Conclusions Largest study to date. Logic of Clopidogrel withdrawal were due concerns for non-responders. 6 weeks Triple therapy not superior to 6 mths Shortened triple therapy associated with reduce minor bleeding only, but no there was no increase in ischaemic events
Triple Therapy 5-8% PCI for patient on Oral Anticoagulants DES preferred if bleeding risk is low. WOESt Omission of Aspirin reduced bleeding. Duration of Triple therapy should be tailored individually depending on procedural outcome, thromboembolic risk (CHA 2 DS 2 -Vasc) and bleeding risk (HAS-Bled).
SECURITY Six months versus Twelve months DAPT following Second Generation Drug-Eluting Stent Implantation
SECURITY - Methods Prospectivenon-inferiority design Randomisation at time of PCI Second-generation DES - Endeavor Resolute, Xience, Promus, Nobori, Biomatrix Stable Angina or ACS No prior DES implanted before target procedure No BMS in 3 months before target procedure Exclusions Bypass grafts / in-stent restenosis / Unprotected Left Main STeMI <48 hours prior to procedure Non STeMI previous six months LVEF 30% Chronic renal insufficiency (creatinine >180 µmol/l)
SECURITY Objectives Primary Endpoint at 12 months Composite of cardiac death, MI, stroke, definite or probable stent thrombosis or BARC type 3-5 bleeding. Secondary Endpoints Composite of cardiac death, spontaneous MI, stroke, definite or probable stent thrombosis or BARC type 2-5 bleeding 12, 24 mths MI, Urgent TVR, All-bleeding events and All-cause mortality at 30 days, 6, 12 and 24 months.
SECURITY - Clinical Characteristics Characteristics 6-Month DAPT (682) 12-Month DAPT (717) Age / Females 65 / 22% 66 / 23% Diabetes Mellitus 30% 31% ACS 22% 20% Stable Angina 62% 62% No of Vessels 1 / 2 / 3 56% / 32% / 11% 59% / 29% / 11% AHA Class B 65% 64% DAPT 6mths ASA+clopidogrel 97% 98% DAPT 12mths ASA+clopidogrel 34% 96% ASA only 12 mths 63% 2%
SECURITY - Primary and Secondary Endpoints P = NS P = NS P = NS
SECURITY - Secondary Endpoints Cardiac Mortality 6 Months DAPT BARC 3 or 5 Bleeding 12 Months DAPT 6 Months DAPT 0.9% 0.7% 24 Months 12 Months 2.3% 2.1% 6 Months DAPT 12 Months DAPT 3.1% 0.9% 12 Months DAPT 0.9% 2.6% 0.3% 12 Months 24 Months Stroke Myocardial Infarction 6 Months DAPT 1.1% 0.6% 0.4% 12 Months 1.1% 0.8% 0.7% 12 Months DAPT 24 Months 12 Months 0.4% 24 Months
Stent Thrombosis Events Timeline day 1 6-month Group day 4 0.3% 0.4% day 540 0 7 30 90 180 360 720 days day 1 All on DAPT at the time of ST (Except 1 very late) 12-month Group day 40 0.4% 0.4% day 78 0 7 30 90 180 360 720 days DAPT ASA Only No APT ST
SECURITY - Event Rate after 6 months 6-Month DAPT (N = 682) 12-Month DAPT (N = 717) M12 M24 M12 M24 Cardiac death - 1 (0.2%) 1 (0.2%) 3 (0.5%) Myocardial Infarction 2 (0.3%) 5 (0.9%) 2 (0.3%) 4 (0.7%) Stroke 3 (0.5%) - - 1 (0.2%) Stent Thrombosis - 1 (0.2%) - - BARC 3 or 5 1 (0.2%) 1 (0.2%) 2 (0.3%) -
Time Line of Bleeding Risk P = NS P = NS P = NS P = NS
SECURITY - Primary Endpoint Multivariate Analysis Variables in the Model HR 95% CI p value Age 75 years 2.211 1.234 3.962 0.007 Stent Type 0.019 Endeavor Resolute Vs. Biomatrix / Xience / Promus 2.336 1.051 5.190 Mean Number of Stents (for each unit increase) 1.410 1.128 1.741 0.002 Mean Stents Length (for each 5 units increase) 1.383 1.135 1.685 0.001 Mean Stent Size (for each 2.5 units increase) 1.326 1.106 1.590 0.002 Diabetes Mellitus 0.069 NIDDM Vs. None 0.895 0.464 1.729 IDDM Vs. None 2.349 1.080 5.106 DAPT 6- vs. 12-month 1.272 0.754 2.145 0.367
SECURITY - Conclusions Six months DAPT appeared non-inferior to 12 months with 2 nd -generation DES for primary and secondary endpoints 1/3 of patients in short duration cohort continued DAPT to 12 months Stent thrombosis, bleeding rates low after six mths. Age 75 years, Stent type, number of stents, length and size predictors of adverse outcome.
Duration of Dual Antiplatelet Therapy post DE Stenting Short duration studies not adequately powered. DAPT study showed benefit in reducing stent thrombosis for 30 mths compared to 12 mths at the expense of increased bleeding risk. PCI in ACS should be for minimum 12 months. Selected patients could stop at 6 mths. Duration could be tailored to no, type of stents, complexity and risk of bleeding.