Ticagrelor monotherapy beyond one month vs. standard dual - - PowerPoint PPT Presentation
Ticagrelor monotherapy beyond one month vs. standard dual antiplatelet therapy following drug eluting stent implantation: A randomised multicentre superiority trial. Patrick W. Serruys MD PhD Erasmus University, Rotterdam, Netherlands Pascal
Patrick W. Serruys MD PhD Erasmus University, Rotterdam, Netherlands
Pascal Vranckx, Marco Valgimigli, Stephan Windecker (PIs) Christian W. Hamm, Peter Jüni, P. Gabriel Steg, GerritAnne van Es (SC)
8/27/2018
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better foundation as monotherapy for long term antiplatelet therapy compared to ASA in at-risk patients
ASA (even low dose) to Ticagrelor
beyond the initial period of high stent thrombosis risk (30 days)
single foundation therapy
Experimental strategy
0 30 d 90 d 120 d 1 year 1.5 years 2 years ECG discharge ECG 90D ECG 2Y
Reference strategy
ACS + Stable CAD Stable CAD
ASA 75-100 mg/d Ticagrelor 90 mg bid
ACS:
UA+NSTEMI+STEMI
Clopidogrel 75 mg/d “All-comers” PCI population N = 15,991
1:1 Randomisation,
130 centers worldwide
Ticagrelor 90 mg bid ASA 75-100 mg/d ASA 75-100 mg/d
Bivalirudin-supported BioMatrix DES by default
Any type of lesions: Left main, SVG, CTO bifurcation, ISR, etc. Unrestricted use of DES (number, length)
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Allcause death and nonfatal new Q wave MI at 2 years
Superiority of the experimental arm vs. reference arm.
5% for primary endpoint
2 x 8000 patients
92% to detect a 22.5% relative risk reduction (RRR) 84% to detect a 20% RRR
*Klauss V, Serruys PW, Pilgrim T, Buszman P, Linke A, Ischinger T, et al. 2year clinical followup from the randomized comparison of biolimuseluting stents with biodegradable polymer and sirolimuseluting stents with durable polymer in routine clinical practice. JACC Cardiovascular interventions. 2011;4(8):88795
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– AstraZeneca (Ticagrelor) – Biosensors International (Biomatrix DES) – The Medicines Company (Bivalirudin)
– Jan G.P.Tijssen (Academic Research Center, Amsterdam, The Netherlands) – Laura Mauri (Harvard Clinical Research Institute, Boston, MA, U.S.A.) – Freek W.A. Verheugt (Chairman, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands)
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up to 2 years post randomization (15,991 randomized)
q ECG centrally adjudicated q New Q-waves detected according to the Minnesota Code
(Major criteria 111 to 128)
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q 15,991 pts randomized 23 pts : Data deletion requested No search for vital status q 8 pts with unknown vital status q 15,960 pts with known vital status 15,259 pts : Site reported 701 pts : From public domain q 99.95% with known vital status q 183 new Q waves diagnosed q 3 new LBBB (Q wave equivalent)
Experimental Treatment Strategy Reference Treatment Strategy Total number of patients N = 7980 N = 7988 Age (years) 10.3 ± 64.5 10.3 ± 64.6 Females 23.4 % 23.1 % Body Mass Index (kg/m²) 4.6 ± 28.2 4.6 ± 28.2 Medical history/comorbidities Diabetes mellitus 25.7 % 24.9 % Insulindependent diabetes mellitus 7.6 % 7.7 % Hypertension 74.0 % .733 % Hypercholesterolemia 69.3 % 70.0 % Current smoker 25.9 % 26.3 % Peripheral Vascular Disease .60 % .67 % Chronic obstructive pulmonary disease 5.1 % 5.2 % Previous Major bleeding 0.6 % 0.7 % Impaired renal function (eGFR < 60 ml/min/1.73m2) .139 % .135 % Previous stroke 2.6 % 2.6 % Previous myocardial infarction 23.0 % .236 % Previous PCI 32.7 % 32.7 % Previous CABG 5.6 % 6.2 %
Baseline characteristics
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Experimental Treatment Strategy Reference Treatment Strategy Total number of patients N = 7980 N = 7988 Clinical presentation
53.0 % 53.2 %
47.0 % 46.8 % Unstable Angina 12.6 % 12.7 % Non-STEMI 21.1 % 21.1 % STEMI 13.3 % 12.9 % Procedural characteristics PCI performed 99.5 % 99.4 % Radial artery access 73.9 % 74.2 % BioMatrix DES 94.8 % 94.4 % Bivalirudin-assisted PCI 87.4 % 87.2 % Number of lesions treated per patient One lesion 74.6 % 74.7 % Two lesions 20.5 % 19.8 % Three or more lesions 5.0 % 5.5 %
Baseline characteristics
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Primary and secondary outcomes at 12 months (Intention to treat) Adherence to treatment strategies
Experimental group Reference group Risk Ratio (95% CI)
p-value
Number of pts.
N=7980 N=7988 All-cause mortality or new Q-wave MI*
1.95 %,
(156)
2.47 %, (197) 0.79
(0.640.98)
0.028
All-cause mortality
1.35 %
(108)
1.64 %
(131)
0.82
(0.641.06)
0.138
New Q-wave MI
0.60 %
(48)
0.86 %
(69)
0.70
(0.481.00)
0.052
BARC 3 or 5 Bleeding**
1.47 % 1.70 % 0.86
(0.671.11)
0.243
BARC 5 Bleeding
0.18 % 0.20 % 0.88
(0.431.80)
0.722
BARC 3 Bleeding
1.34 % 1.60 % 0.84
(0.651.08)
0.179
98 % 97 % 96 % 96 %
Percentage
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Experimental arm Reference arm
Discharge Ticagrelor mono in ACS and SA In ACS: Ticagrelor + ASA In SA: Clopidogrel + ASA
86 % 94 % 85 % 92 % 82 % 89 %
Experimental arm Reference arm
Follow-up 1 M
Experimental arm Reference arm
Follow-up 3 M
Experimental arm Reference arm
Follow-up 6 M
Experimental arm Reference arm
Follow-up 12 M
Experimental arm Reference arm
Follow-up 18 M
Experimental arm Reference arm
Follow-up 24 M
0% 25% 50% 75% 100%
*MantelCox method based on time of death or diagnosis of new Q wave MI **MantelCox logrank method for secondary safety endpoints
Primary and secondary outcomes at 24 months (Intention to treat) Adherence to treatment strategies
Experimental group Reference group Risk Ratio (95% CI)
p-value
Number of pts.
N=7980 N=7988 All-cause mortality or new Q-wave MI
3.81 %,
(304)
4.37 %, (349) 0.87
(0.751.01)
0.073
All-cause mortality
2.81 %
(224)
3.17 %
(253)
0.88
(0.741.06)
0.18
New Q-wave MI
1.04 %
(83)
1.29 %
(103)
0.80
(0.601.07)
0.14
BARC 3 or 5 Bleeding
2.04 % 2.12 % 0.97
(0.781.20) 0.77 BARC 5 Bleeding
0.28 % 0.30 % 0.92
(0.521.64) 0.78 BARC 3 Bleeding
1.88 % 1.99 % 0.95
(0.761.18) 0.63
98 % 97 % 96 % 96 %
Percentage
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Experimental arm Reference arm
Discharge
86 % 94 % 85 % 92 % 82 % 89 %
Experimental arm Reference arm
Follow-up 1 M
Experimental arm Reference arm
Follow-up 3 M
Experimental arm Reference arm
Follow-up 6 M
Experimental arm Reference arm
Follow-up 12 M
Ticagrelor monotherapy in ACS and SA ASA monotherapy in ACS and SA
Experimental arm Reference arm
Follow-up 18 M
Experimental arm Reference arm
Follow-up 24 M
79 % 92 % 78 % 93 %
0% 25% 50% 75% 100%
Kaplan Meier estimate of mortality and safety outcome at 2 years
Days since index procedure All-cause death (%) 2.81 % 3.17 % Days since index procedure BARC 3 or 5 bleeding (%) RR (95%CI)=0.97 (0.78-1.20) P=0.766 2.04 % 2.12 % 2.81 % RR (95%CI)=0.88 (0.74-1.06) P=0.182 Reference arm Experimental arm (Ticagrelor monotherapy)
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Tica Mono DAPT (Tica/Clop) DAPT Exp. Ref. ASA mono Tica Mono DAPT (Tica/Clop) ASA mono
3.17 %
Landmark analysis
All-cause death BARC 3 or 5 bleeding Reference arm Experimental arm (Ticagrelor monotherapy)
DAPT Exp. Ref.
Landmark analysis
Experimental Treatment Strategy Reference Treatment Strategy Risk Ratio [Exp/Reference] p-value for interaction Pre-specified subgroups (95% CI) Overall 304/7980 349/7988
(0.75-1.01) 0.87
Indication 0.926 ACS 147/3750 169/3737 (0.691.08) 0.86 Stable CAD 157/4230 180/4251 (0.711.08) 0.87 Age 0.231 >75 years 93/1292 120/1273 (0.58-0.99) 0.75 ≤75 years 211/6688 229/6715 (0.771.11) 0.92 Diabetes mellitus 0.326 diabetics 102/2049 126/1989 (0.601.01) 0.78 nondiabetics 202/5925 222/5994 (0.761.11) 0.92 Renal failure 0.680 Yes 79/1099 93/1072 (0.611.11) 0.82 No 225/6881 256/6916 (0.741.05) 0.88 PVD 0.521 Yes 40/476 44/529 (0.661.56) 1.02 No 260/7428 295/7389 (0.741.03) 0.87 Left main treated 0.950 Yes 13/197 14/190 (0.421.90) 0.89 No 291/7783 335/7798 (0.741.02) 0.87 Geographic area 0.488 Western Europe 226/6156 273/6167 (0.69-0.99) 0.83 Eastern Europe* 68/1502 65/1500 (0.741.47) 1.04 Rest of the world 10/322 11/321 (0.382.14) 0.91
Number of first events and percentages are reported. Risk ratios RR (95% CI) are estimated using the Mantel-Cox method with two-sided p-values from log-rank test. All events were censored beyond 730 days. P-values for interactions were obtained with approximate χ2 tests for unequal RRs in the subgroups (df=1, except geographic area df=4). Renal failure =creatinine-estimated GFR of less than 60 ml/min using the MDRD formula. Assumed no risk in case of missing data: diabetes (n=11), renal failure (n=85), peripheral vascular disease (n=146).
Primary endpoint at 2 years
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*Eastern Europe included Poland, Bulgaria, Hungary
superiority of an antiplatelet regimen consisting of one month of ticagrelor in combination with low dose aspirin followed by 23 months of ticagrelor alone in reducing the 2year rate of allcause mortality and nonfatal, new Qwave MI when compared with the reference treatment (DAPT 12 months, ASA monotherapy 12 months).
treatment adherence between the reference arm and the experimental arm.
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Edouard Benit Virga Jesse 920 patients Helge Möllmann Kerckhoff Heart Center 653 patients Luc Janssens Imelda 535 patients Robert Jan van Geuns Erasmus MC 432 patients Marcello Dominici Azienda Ospedaliera S. Maria 405 patients Kurt Huber Wilhelminenspital 309 patients Ton Slagboom OLVG 304 patients Maurizio Ferrario
479 patients Aleksander Zurakowski PAKS Chrzanów 462 patients
Top investigators in the Global Leaders
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Cardialysis/ECRI team
Project manager Cokky van Meijeren Corelab Marteen Witsenburg (ECG Corelab supervisor) Lali Sikarulidze Martin Muurling Esther Velthuizen Tone de Vreede Addy ter Weele Annemarie Hugense (angios) Clinical research associate department Judith de Bot Dorien Hillen Pieter Heijke Data management Judith Jonk Sanne Palsrok Marco Bressers (Head DM&STAT) Safety Yoshinobu Onuma Osama Soliman Ernest Spitzer Rick Andreae Eva Teurlings Statistics Tessa RademakerHavinga Art Ghandilyan Wietze Lindeboom QA Jako Pranger Yoshinobu Onuma Ernest Spitzer Ply Chichareon Rodrigo Modolo Yuki Katagiri Kuniaki Takahashi Norihiro Kogame ChunChin Chang Mariusz Tomaniak Dik Heg Peter Jüni
Academic Research Team, Rotterdam
Marco Valgimigli Stephan Windecker Sergio Leonardi Anna Franzone Medical monitor Yoshinobu Onuma Ana Guimarães (Protocol)
CTU Bern GLASSY team
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Experimental Treatment Strategy Reference Treatment Strategy p-value Total number of patients N = 7980 N = 7988 Lesions treated in vessel(s) n = 10403 n = 10438 0.611 Left main coronary artery 1.9 % 1.8 % Left anterior descending artery 41.2 % 42.0 % Left circumflex artery 24.3 % 24.5 % Right coronary artery 31.6 % 30.7 % Bypass graft 1.1 % 1.0 % Index PCI No of stents per lesion 1.2 ± 0.5 1.2 ± 0.5 0.820 Type of stent Biolimuseluting stent 94.8 % 94.4 % 0.602 Other stent 6.4 % 6.7 % Total stent length per lesion (mm) 24.8 ± 13.9 24.8 ± 14.0 0.932
Depicted are sample size (n); and counts (%) or means±standard deviations.
aN = 85 patients did not receive PCI: medical treatment only (n=33 reference arm, n=31 experimental arm), transferred to urgent surgery (n=15 reference
arm, n=6 experimental arm), died before PCI (n=0). *Calculated per lesion and analysed using general or generalized linear mixed effects models with a random effect of the patient to account for multiple lesions treated within patients. **Per-protocol BioMatrix family stent used. In n=147 lesions both BioMatrix family stent(s) and Other stent(s) were implanted (n=68 reference arm lesions, n=79 experimental arm lesions). ***Grafts counted as one separate vessel (n=221).
Procedural characteristics
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Days since index procedure All-cause death or New Q-wave MI
RR (95%CI)=0.87 (0.75-1.01) P=0.073
Kaplan Meier estimate of all-cause death or New Q-wave MI or equivalent LBBB at 2 years
3.81 % 4.37 % Reference arm Experimental arm
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Days since index procedure RR (95%CI)=1.00 (0.88-1.12) P=0.962 6.63 % 6.66 % 0 60 120 180 240 300 360 420 480 540 600 660 730 10 9 8 7 6 5 4 3 2 1 BARC 2, 3 or 5 bleeding (%)
Kaplan Meier estimate of BARC 2, 3 or 5 bleeding at 2 years
Reference arm Experimental arm
Depicted are the first event per event type for each patient only (disregards multiple events of the same type within the same patient and censoring at 730 days since index PCI). Percentage of all patients.
bSecondary safety endpoint. cPrimary efficacy endpoint. dExact censoring days used at each follow-up, i.e. events occurring up to n days are used for the First events: 2 years = 730 days. eNew Q-wave or equivalent LBBB (n=3) as adjudicated by the BIMR.
Experimental Treatment Strategy Reference Treatment Strategy Risk Ratio (95% CI) p-value Total number of patients N=7980 N=7988 Composite of allcause mortality, stroke or new Qwave MI 4.54 % 5.21 % (0.761.00) 0.87 0.056 Stroke 1.00 % 1.03% (0.721.33) 0.98 0.90 Ischemic stroke 0.79 %
(N=63)
0.85 %
(N=68)
(0.661.31) 0.93 0.68 Haemorrhagic stroke 0.16 %
(N=13)
0.11 %
(N=9)
(0.623.39) 1.45 0.39 Undetermined stroke 0.08% 0.06 % (0.373.95) 1.21 0.76 Revascularisation 9.26% 9.93 % (0.841.03) 0.93 0.17 Target Vessel Revascularization 4.87% 5.53% (0.771.01) 0.88 0.07 Definite stent thrombosis 0.80 % 0.80 % (0.711.42) 1.00 0.98
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Depicted are the first event per event type for each patient only (disregards multiple events of the same type within the same patient and censoring at 730 days since index PCI). Percentage of all patients.
bSecondary safety endpoint. cPrimary efficacy endpoint. dExact censoring days used at each follow-up, i.e. events occurring up to n days are used for the First events: 2 years = 730 days. eNew Q-wave or equivalent LBBB (n=3) as adjudicated by the BIMR.
Experimental Treatment Strategy Reference Treatment Strategy Risk Ratio (95% CI) p-value Total number of patients N=7980 N=7988 Composite of all-cause mortality, stroke or new Q- wave MI 4.54 % 5.21 % (0.76-1.00) 0.87 0.056 Stroke 1.00 % 1.03% (0.72-1.33) 0.98 0.90 Ischemic stroke 0.79 % 0.85 % (0.66-1.31) 0.93 0.68 Haemorrhagic stroke 0.16 % 0.11 % (0.62-3.39) 1.45 0.39 Revascularisation 9.26% 9.93 % (0.84-1.03) 0.93 0.17 Definite stent thrombosis 0.80 % 0.80 % (0.71-1.42) 1.00 0.98
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Depicted are the first event per event type for each patient only (disregards multiple events of the same type within the same patient and censoring at 730 days since index PCI). Percentage of all patients.
bSecondary safety endpoint. cPrimary efficacy endpoint. dExact censoring days used at each follow-up, i.e. events occurring up to n days are used for the First events: 2 years = 730 days. eNew Q-wave or equivalent LBBB (n=3) as adjudicated by the BIMR.
Experimental Treatment Strategy Reference Treatment Strategy Risk Ratio (95% CI) p-value Total number of patients N=7980 N=7988 All-cause mortality or new Q-wave MIc 304 (3.81) (4.37) 349 (0.75-1.01) 0.87 0.073 All-cause mortality 224 (2.81) (3.17) 253 (0.74-1.06) 0.88 0.18 New Q-wave MIe 83 (1.04) (1.29) 103 (0.60-1.07) 0.80 0.14 Composite of all-cause mortality, stroke or new Q-wave MI (4.54) 362 (5.21) 416 (0.76-1.00) 0.87 0.056 Myocardial infarction 248 (3.11) (3.13) 250 (0.84-1.19) 1.00 0.98 Stroke (1.00) 80 (1.03) 82 (0.72-1.33) 0.98 0.90 Ischemic stroke 63 (0.79) (0.85) 68 (0.66-1.31) 0.93 0.68 Haemorrhagic stroke (0.16) 13 (0.11) 9 (0.62-3.39) 1.45 0.39 Undetermined stroke (0.08) 6 (0.06) 5 (0.37-3.95) 1.21 0.76 Revascularisation (9.26) 739 793 (9.93) (0.84-1.03) 0.93 0.17 Target Vessel Revascularization (4.87) 389 (5.53) 442 (0.77-1.01) 0.88 0.068 Definite stent thrombosis (0.80) 64 (0.80) 64 (0.71-1.42) 1.00 0.98 BARC 3 or 5 Bleedingb 163 (2.04) 169 (2.12) (0.78-1.20) 0.97 0.77 BARC 5 Bleeding (0.28) 22 (0.30) 24 (0.52-1.64) 0.92 0.78 BARC 5b Bleeding (0.19) 15 18 (0.23) (0.42-1.66) 0.84 0.61 BARC 5a Bleeding (0.09) 7 (0.08) 6 (0.39-3.49) 1.17 0.78 BARC 3 Bleeding 150 (1.88) 159 (1.99) (0.76-1.18) 0.95 0.63 BARC 3c Bleeding (0.44) 35 (0.31) 25 (0.84-2.35) 1.41 0.19 BARC 3b Bleeding 53 (0.66) 74 (0.93) (0.51-1.02) 0.72 0.065 BARC 3a Bleeding (0.96) 77 (0.88) 70 (0.80-1.53) 1.10 0.55
Depicted are the first event per event type for each patient only (disregards multiple events of the same type within the same patient and censoring at 730 days since index PCI). Percentage of all patients.
bSecondary safety endpoint. cPrimary efficacy endpoint. dExact censoring days used at each follow-up, i.e. events occurring up to n days are used for the First events: 2 years = 730 days. eNew Q-wave or equivalent LBBB (n=3) as adjudicated by the BIMR.
Experimental Treatment Strategy Reference Treatment Strategy Risk Ratio (95% CI) p-value Total number of patients N=7980 N=7988 BARC 3 or 5 Bleeding 163 (2.04) 169 (2.12) (0.781.20) 0.97 0.77 BARC 5 Bleeding (0.28) 22 (0.30) 24 (0.521.64) 0.92 0.78 BARC 5b Bleeding (0.19) 15 18 (0.23) (0.421.66) 0.84 0.61 BARC 5a Bleeding (0.09) 7 (0.08) 6 (0.393.49) 1.17 0.78 BARC 3 Bleeding 150 (1.88) 159 (1.99) (0.761.18) 0.95 0.63 BARC 3c Bleeding (0.44) 35 (0.31) 25 (0.842.35) 1.41 0.19 BARC 3b Bleeding 53 (0.66) 74 (0.93) (0.511.02) 0.72 0.065 BARC 3a Bleeding (0.96) 77 (0.88) 70 (0.801.53) 1.10 0.55 BARC 3 or 5 Bleeding 163 (2.04) 169 (2.12) (0.781.20) 0.97 0.77
Primary and secondary outcomes from 30 days to 2 years (landmark) Adherence to treatment strategies
Experimental group Reference group Risk Ratio (95% CI)
p-value
Number of pts.
N=7980 N=7988 Allcause mortality or new Qwave MI
3.40 % 3.87 % 0.88
.0)74.103(
0.115
Allcause mortality
2.42 % 2.74 % 0.88
(0.721.07)
0.196
New Qwave MI
1.02 % 1.20 % 0.85
(0.631.15)
0.286
BARC 3 or 5 Bleeding
1.43 % 1.54 % 0.93
(0.721.20)
0.576
BARC 5 Bleeding
0.15 % 0.20 % 0.75
(0.361.59)
0.458
BARC 3 Bleeding
1.36 % 1.47 % 0.93
(0.711.20)
0.567
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Ticagrelor monotherapy in ACS and SA
Ticagrelor + ASA in ACS, Clopidogrel + ASA in SA from 30 days to 1 year ASA monotherapy after 1 year 97.6% 97.2% 96.4% 96.3% 86.0% 93.6% 85.0% 91.8% 81.7% 89.2%
Percentage
78.7% 92.0% 72.6% 93.1%
Primary and secondary outcomes from 1 year to 2 years (landmark) Adherence to treatment strategies
Experimental group Reference group Risk Ratio (95% CI)
p-value
Number of pts.
N=7980 N=7988 Allcause mortality or new Qwave MI
1.89 % 1.95 % 0.97
(0.771.22)
0.790
Allcause mortality
1.47 % 1.55 % 0.95
(0.741.22)
0.687
New Qwave MI
0.45 % 0.44 % 1.03
(0.641.65)
0.913
BARC 3 or 5 Bleeding
0.60 % 0.43 % 1.40
(0.892.19)
0.140
BARC 5 Bleeding
0.10 % .010 % 1.00
(0.382.68)
0.992
BARC 3 Bleeding
0.56 % 0.40 % 1.39
(0.882.21)
0.159
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Ticagrelor monotherapy in ACS and SA ASA monotherapy after 1 year Percentage
97.6% 97.2% 96.4% 96.3% 86.0% 93.6% 85.0% 91.8% 81.7% 89.2% 78.7% 92.0% 72.6% 93.1%
ACS vs stable CAD Age 75 years vs age less than 75 years Female gender vs male gender Diabetic patients vs nondiabetic patients Geographic Region : West Europe vs Eastern Europe* vs Asia vs Canada vs South America Renal function: Creatinine Clearance > 60 ml/1.73m2/min vs 60 ml/1.73m2/min (based on the MDRD formula) History of PVD (symptoms, confirmed stenosis of 50%, or treatment) Angiographic characteristics (preprocedural): Logistic Syntax Score, Left Main
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*Eastern Europe included Poland, Bulgaria, Hungary
Experimental Treatment Strategy Reference Treatment Strategy Risk Ratio [Exp/Reference] Rate ratio (95% CI) p-value for interaction Subgroups (95% CI) Overall 304/7980 349/7988 (0.75-1.01) 0.87 Indication 0.926 ACS 147/3750 169/3737 (0.691.08) 0.86 Stable CAD 157/4230 180/4251 (0.711.08) 0.87 Age 0.231 >75 years 93/1292 120/1273 (0.58-0.99) 0.75 ≤75 years 211/6688 229/6715 (0.771.11) 0.92 Diabetes mellitus 0.326 diabetics 102/2049 126/1989 (0.601.01) 0.78 nondiabetics 202/5925 222/5994 (0.761.11) 0.92 Renal failure 0.680 Yes 79/1099 93/1072 (0.611.11) 0.82 No 225/6881 256/6916 (0.741.05) 0.88 PVD 0.521 Yes 40/476 44/529 (0.661.56) 1.02 No 260/7428 295/7389 (0.741.03) 0.87 Left main treated 0.950 Yes 13/197 14/190 (0.421.90) 0.89 No 291/7783 335/7798 (0.741.02) 0.87 Geographic area 0.488 Western Europe 226/6156 273/6167 (0.69-0.99) 0.83 Eastern Europe* 68/1502 65/1500 (0.741.47) 1.04 Rest of the world 10/322 11/321 (0.382.14) 0.91 Type of reference treatment 0.95 Use of ticagrelor 163/4179 186/4146 (701·07·0) 86·0 Use of clopidogrel 141/3801 163/3842 (701·09·0) 87·0 Number of first events and percentages are reported. Risk ratios RR (95% CI) are estimated using the Mantel-Cox method with two-sided p-values from log-rank test. All events were censored beyond 730 days. P-values for interactions were obtained with approximate χ2 tests for unequal RRs in the subgroups (df=1, except geographic area df=4). Renal failure =creatinine-estimated GFR of less than 60 ml/min using the MDRD formula. Assumed no risk in case of missing data: diabetes (n=11), renal failure (n=85), peripheral vascular disease (n=146).
Primary endpoint at 2 years
19 *Eastern Europe included Poland, Bulgaria, Hungary
Experimental Treatment Strategy Reference Treatment Strategy Risk Ratio [Exp/Reference] p-value for interaction Post-hoc subgroups (95% CI) Overall 1637980/ 1697988/ .090.7) 78.1-20( Indication 0.0068 ACS 733750/ 100/3737 .073.0) 54-0.9(8 Stable CAD 904230/ 694251/ 1.32.0) 971.81( Age 0.057 >75 years 651292/ 50/1273 1.290.8) 91.86( ≤75 years 986688/ 119/6715 .083.0) 63.108( Diabetes mellitus 0.53 diabetics 52/2049 471989/ 1.07.0) 72.159( nondiabetics 111/5925 122/5994 0.7) 0.9211.19( Renal failure 0.48 Yes 431099/ 381072/ 1.10.0) 711.7(1 No 1206881/ 1316916/ 0.7) 0.882.118( PVD 0.99 Yes 15476/ 17529/ 0.98.0) 49.197( No 1487428/ 1507389/ .0980.7) 8.124( Left main treated 0.44 Yes 9197/ 6190/ 1.43 .0)514.03( No 1547783/ 163/7798 .095 0.7)61.18( Geographic area 0.20 Western Europe 1436156/ 141/6167 1.02.0) 811.2(9 Eastern Europe* 171502/ 271500/ 0.63.0) 341.15( Rest of the world 3322/ 1/321 3.000.3) 128.8(4
Number of first events and percentages are reported. Risk ratios RR (95% CI) are estimated using the Mantel-Cox method with two-sided p-values from log-rank test. All events were censored beyond 730 days. P-values for interactions were obtained with approximate χ2 tests for unequal RRs in the subgroups (df=1, except geographic area df=4). Renal failure =creatinine-estimated GFR of less than 60 ml/min using the MDRD formula. Assumed no risk in case of missing data: diabetes (n=11), renal failure (n=85), peripheral vascular disease (n=146).
BARC 3 or 5 bleeding at 2 years
19
*Eastern Europe included Poland, Bulgaria, Hungary
This slide shows a forest plot of 7 prespecified
interaction in other word there was no evidence for a difference in treatment effects for the primary endpoint across prespecified subgroups listed on this slide (ACS or stable CAD, Age, DM, Renal failure, PVD, Left main treated, Geographic area). However, the patients older than 75 years had significant 25% risk reduction in the experimental arm and in western Europe there was also a significant risk reduction of 17% for the primary endpoint in the experimental arm.
0.25 0.5 1.0 2.0 4.0
Experimental Treatment Strategy Reference Treatment Strategy Risk Ratio [Exp/Reference] p-value for interaction Post-hoc subgroups (95% CI) Overall 1637980/ 1697988/ .090.7) 78.1-20( Indication 0.0068 ACS 733750/ 100/3737 .073.0) 54-0.9(8 Stable CAD 904230/ 694251/ 1.32.0) 971.81( Age 0.057 >75 years 651292/ 50/1273 1.290.8) 91.86( ≤75 years 986688/ 119/6715 .083.0) 63.108( Diabetes mellitus 0.53 diabetics 52/2049 471989/ 1.07.0) 72.159( nondiabetics 111/5925 122/5994 0.7) 0.9211.19( Renal failure 0.48 Yes 431099/ 381072/ 1.10.0) 711.7(1 No 1206881/ 1316916/ 0.7) 0.882.118( PVD 0.99 Yes 15476/ 17529/ 0.98.0) 49.197( No 1487428/ 1507389/ .0980.7) 8.124( Left main treated 0.44 Yes 9197/ 6190/ 1.43 .0)514.03( No 1547783/ 163/7798 .095 0.7)61.18( Geographic area 0.20 Western Europe 1436156/ 141/6167 1.02.0) 811.2(9 Eastern Europe* 171502/ 271500/ 0.63.0) 341.15( Rest of the world 3322/ 1/321 3.000.3) 128.8(4 Type of reference treatment strategy 0.016 Use of ticagrelor 84/4179 108/4146 0.77 (0.581.02) Use of clopidogrel 79/3801 61/3842 1.32 (0.951.84) Number of first events and percentages are reported. Risk ratios RR (95% CI) are estimated using the Mantel-Cox method with two-sided p-values from log-rank test. All events were censored beyond 730 days. P-values for interactions were obtained with approximate χ2 tests for unequal RRs in the subgroups (df=1, except geographic area df=4). Renal failure =creatinine-estimated GFR of less than 60 ml/min using the MDRD formula. Assumed no risk in case of missing data: diabetes (n=11), renal failure (n=85), peripheral vascular disease (n=146).
BARC 3 or 5 bleeding at 2 years
19
*Eastern Europe included Poland, Bulgaria, Hungary
This slide shows a forest plot of 7 prespecified
interaction in other word there was no evidence for a difference in treatment effects for the primary endpoint across prespecified subgroups listed on this slide (ACS or stable CAD, Age, DM, Renal failure, PVD, Left main treated, Geographic area). However, the patients older than 75 years had significant 25% risk reduction in the experimental arm and in western Europe there was also a significant risk reduction of 17% for the primary endpoint in the experimental arm.
0.25 0.5 1.0 2.0 4.0
MI according to the major criteria of Minnesota code (serial analysis of 44,741 ECGs at discharge, 3mth and 24mth)
(13 studies, 96389 pts, 1.32%)
20
ECG received and analysis possible D/C = 15647 3M = 14844 24M = 14250 Backup
20 vs. 22.5????
Klauss V, Serruys PW, et al. JACC Cardiovascular
*Klauss V, Serruys PW, Pilgrim T, Buszman P, Linke A, Ischinger T, et al. 2year clinical followup from the randomized comparison of biolimuseluting stents with biodegradable polymer and sirolimuseluting stents with durable polymer in routine clinical practice. JACC Cardiovascular interventions. 2011;4(8):88795
Klauss V, Serruys PW, Pilgrim T, Buszman P, Linke A, Ischinger T, et al. 2-year clinical follow-up from the randomized comparison of biolimus-eluting stents with biodegradable polymer and sirolimus-eluting stents with durable polymer in routine clinical practice. JACC Cardiovascular interventions. 2011;4(8):887-95.
4.5% for death 0.5% for new Q wave? Allcause death at 2 years in BES arm = 4.7% Q wave MI at 2 years in BES arm = 0.5%
12/31/1899 12:00:00... 1/1/1900 12:00:00 AM 1/2/1900 12:00:00 AM 1/3/1900 12:00:00 AM 1/4/1900 12:00:00 AM 1/5/1900 12:00:00 AM 1/6/1900 12:00:00 AM 1/7/1900 12:00:00 AM 1/8/1900 12:00:00 AM 1/9/1900 12:00:00 AM 1/10/1900 12:00:00 ... 1/11/1900 12:00:00 ... 1/12/1900 12:00:00 ... 1/13/1900 12:00:00 ... 1/14/1900 12:00:00 ... 1/15/1900 12:00:00 ... 1/16/1900 12:00:00 ... 1/17/1900 12:00:00 ... 1/18/1900 12:00:00 ... 1/19/1900 12:00:00 ... 1/20/1900 12:00:00 ... 1/21/1900 12:00:00 ... 1/22/1900 12:00:00 ... 1/23/1900 12:00:00 ... 1/24/1900 12:00:00 ...
100 90 80 70 60 50 40 30 20 10
97.5 72.6 6.4 4.4 4.6 3.4 6.8 0.1 23.2 85.7 84.6 81.8 78.4 72.6 2.3 11.2 13.5 Ticagrelor and Aspirin Ticagrelor monotherapy Aspirin monotherapy
Ticagrelor monotherapy
Percentage
ASA + Tica grelor
Allocated Regimen
Adherence to the allocated antiplatelet regimen in the experimental treatment arm
Discharge 1 month 3 months 6 months 1 year 1.5 year 2 years
12/31/1899 12:00:... 1/1/1900 12:00:00 ... 1/2/1900 12:00:00 ... 1/3/1900 12:00:00 ... 1/4/1900 12:00:00 ... 1/5/1900 12:00:00 ... 1/6/1900 12:00:00 ... 1/7/1900 12:00:00 ... 1/8/1900 12:00:00 ... 1/9/1900 12:00:00 ... 1/10/1900 12:00:0... 1/11/1900 12:00:0... 1/12/1900 12:00:0... 1/13/1900 12:00:0... 1/14/1900 12:00:0... 1/15/1900 12:00:0... 1/16/1900 12:00:0... 1/17/1900 12:00:0... 1/18/1900 12:00:0... 1/19/1900 12:00:0... 1/20/1900 12:00:0... 1/21/1900 12:00:0... 1/22/1900 12:00:0... 1/23/1900 12:00:0... 1/24/1900 12:00:0...
100 90 80 70 60 50 40 30 20 10
96.3 [VALUE].0 90.6 87.7 85.0 3.8 1.7
3.2
89.9 91.6 2.7 5.1 6.5 7.4 3 3 Ticagrelor and Aspirin Aspirin monotherapy Clopidogrel and Aspirin
Percentage
Adherence to the allocated antiplatelet regimen in the reference treatment arm (ACS)
ASA monotherapy ASA + Ticagrelor Allocated Regimen
Discharge 1 month 3 months 6 months 1 year 1.5 year 2 years
12/31/1899 12:00:00... 1/1/1900 12:00:00 AM 1/2/1900 12:00:00 AM 1/3/1900 12:00:00 AM 1/4/1900 12:00:00 AM 1/5/1900 12:00:00 AM 1/6/1900 12:00:00 AM 1/7/1900 12:00:00 AM 1/8/1900 12:00:00 AM 1/9/1900 12:00:00 AM 1/10/1900 12:00:00 ... 1/11/1900 12:00:00 ... 1/12/1900 12:00:00 ... 1/13/1900 12:00:00 ... 1/14/1900 12:00:00 ... 1/15/1900 12:00:00 ... 1/16/1900 12:00:00 ... 1/17/1900 12:00:00 ... 1/18/1900 12:00:00 ... 1/19/1900 12:00:00 ... 1/20/1900 12:00:00 ... 1/21/1900 12:00:00 ... 1/22/1900 12:00:00 ... 1/23/1900 12:00:00 ... 1/24/1900 12:00:00 ...
10 20 30 40 50 60 70 80 90 100
88.8 88.6 87.8 87.4 85 9.5 7.6 0.7 0.6 0.9 1 3.1 86.4 87.6 9.8 10.2 10.1 9.7 9.4 0.8
0.8
Clopidogrel and Aspirin Aspirin monotherapy Ticagrelor and Aspirin
Percentage
Adherence to the allocated antiplatelet regimen in the reference treatment arm (stable CAD)
ASA monotherapy ASA + Clopidogrel* Allocated Regimen
*Ticagrelor or Prasugrel in case with pretreated Ticagrelor or Prasugrel
ASA + Clopidogrel ASA monotherapy Ticagrelor and ASA
Discharge 1 month 3 months 6 months 1 year 1.5 year 2 years
100
Experimental strategy Reference strategy p value 24 months Followup N=4254 N=4291 Adherent to treatment strategy n=4043, n=4049, Yes (78%) 3145 (93%) 3776 No 898 (22%) (7%) 273 Reason of nonadherence Dyspnea 233 (26%) (3%) 8 001·0> Bleeding (21%) 191 (16%) 44 0·070 Percutaneous Coronary Intervention (14%) 128 (18%) 50 0·102 Oral anticoagulation 77 )9(% 4) 717(% 001·0> Medical decision 24 (3%) 14 (5%) Surgery 35 (4%) 4 (1%) Others 94 (10%) 28(11%) Reason unclear (13%) 116 (29%) 78 001·0>
Reasons of non-adherence to the allocated strategy at 2 years
* Patients included in the adherence substudy (n=8545) were those who were assessed using the new version of the eCRF at 1 month Followup and later, so reasons for non adherence could be entered into the system. Percentages and twosided Pvalues from Fisher's exact test for reasons of nonadherence refer to the denominator of nonadherent patients at 24 months. Reasons of nonadherence were classified in accordance with the Nonadherence Academic Research Consortium document.
Experimental strategy Reference strategy p value 24 months Followup N=4254 N=4291
Adherent to treatment strategy n=4043, n=4049, Yes (78%) 3145 (93%) 3776 No 898 (22%) (7%) 273 Reason of nonadherence Allergic Reaction (1%) 10 (1%) 2 0·743 Bleeding (21%) 191 (16%) 44 0·070 Cerebrovascular Accident (1%) 6 (1%) 3 0·442 Diarrhea (1%) 8 (0%) 0 0·210 Dizziness (1%) 6 (0%) 0 0·346 Dyspnea 233 (26%) (3%) 8 001·0> Interference With Other Drugs (0%) 4 (1%) 3 0·208 Logistical Issues (0%) 4 (0%) 0 0·579 Medical Decision (3%) 24 (5%) 14 0·051 Myocardial Infarction (0%) 3 (1%) 3 0·142 New Medical Condition (1%) 6 (1%) 3 0·442 Oral anticoagulant (OAC) 77 )9(% 4) 717(% 001·0> Other Signs (1%) 5 (1%) 2 0·667 Other Symptoms (1%) 12 (1%) 2 0·541 Patient Unwilling To Take Medication (1%) 9 (1%) 3 1·000 Percutaneous Coronary Intervention (14%) 128 (18%) 50 0·102 Skin Reaction (1%) 9 (0%) 1 0·469 Surgery (4%) 35 (1%) 4 0·054 Trauma (1%) 5 (0%) 0 0·596 Upper GI Complaints (1%) 7 (2%) 6 0·089 Reason unclear (13%) 116 (29%) 78 001·0>
Cross sectional analysis/mutually exclusive
How do you make the mutually exclusive of the number? In case of the patients had more than 1 possible reason how did you select?
Study Experimental Treatment Group Reference treatment Group Follow up Global Leaders 27.40% 6.90% 2 years Plato 23.40% 23.10% 1 year Plato invasive 23.10% 21.80% 1 year Pegasus (32.0% (90mg (28.7% (60mg 21.40% 36 months Socrates 17.50% 14.70% 90 days Euclid 30.10% 25.90% 30 months
Study drug/strategy non-adherence in published ticagrelor trials
Plato denotes the Study of Platelet Inhibition and Patient Outcomes; Pegasus: the Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin trial; Socrates: The Acute Stroke or Transient Ischaemic Attack Treated with Aspirin or Ticagrelor and Patient Outcomes trial; Euclid: the Examining Use of Ticagrelor in Peripheral Artery Disease (EUCLID) trial.
Randomized (n=15991) Analysed on primary endpoint (n=7980) Censored at time point of last available follow-up information (n=5) Allocated to Reference Treatment Strategy (n=7988) Received allocated reference strategy (n=7767)
Did not receive reference strategy as allocated (n=221)
Ticagrelor & Aspirin DAPT, not in accordance with protocol (n=20) Other P2Y12 & Aspirin DAPT (n=142) Ticagrelor SAPT (n=2) Clopidogrel SAPT (n=2) Aspirin SAPT (n=54) No APT (n=1)
Analysed on primary endpoint (n=7988) Censored at time point of last available follow-up information (n=3) Allocation Follow-Up at 2 years Excluded Withdrew consent, objected to further use of the data (n=23) Allocated to Experimental Treatment (n=12) Allocated to Reference Treatment (n=11) Analysis Included (n=15968) Information on vital status complete (n=7975) Information on vital status incomplete (n=5) ECG information complete, or death at 24 months (n=7446) ECG information incomplete (n=534) ECG unavailable (n=429)*
ECG analysis not possible (n=105)
Completed experimental strategy (n=5551) Discontinued experimental strategy (n=2177)
Ticagrelor & Aspirin DAPT (n=576) Other P2Y12 & Aspirin DAPT (n=212) Other P2Y12 SAPT (n=157) Aspirin SAPT (n=1033) No APT (n=199)
Medication at 2 years unknown (n=252) Allocated to Experimental Treatment Strategy (n=7980) Received allocated experimental strategy (n=7782)
Did not receive experimental strategy as allocated (n=198)
Other P2Y12 & Aspirin DAPT (n=149)
Ticagrelor SAPT (n=1) Other P2Y12 SAP (n = 3) Aspirin SAPT (n=41) No APT (n=4) Figure 1. Flowchart of the Global LEADERS randomized clinical trial. *Includes: Experimental strategy (n=429): n=195, 2 years visit performed but no ECG, n=165, no 2 year visit but vital status known, n=69, lost to follow-up but vital status known. Reference strategy (n=491): n=295, 2 years visit performed but no ECG, n=111, no 2 year visit but vital status known, n=85, lost to follow-up but vital status known.
Information on vital status complete (n=7985) Information on vital status incomplete (n=3) ECG information complete, or death at 24 months (n=7383) ECG information incomplete (n=605)
ECG unavailable (n=491)* ECG analysis not possible (n=114)
Completed experimental strategy (n=7054) Discontinued experimental strategy (n=712) Ticagrelor & Aspirin DAPT (n=149)
Clopidogrel & Aspirin DAPT (n=297) Other P2Y12 & Aspirin DAPT (n=7) Ticagrelor SAPT (n=10) Clopidogrel SAPT (n=116) No APT (n=133)
Medication at 2 years unknown (n=222)
Flowchart of the Global LEADERS randomized clinical trial
10
up to 2 years post randomization (15,991 patients)
q Blind ECGs analysis by core lab q New Qwaves detected according to the Minnesota Code
(Major criteria 111 to 128)
8
Total = 183 new Q waves + 3 new LBBB equivalent to new Q wave
q ECG unavailable in experimental arm (N=534)
q ECG unavailable in reference arm (N=605)
Back up Clinical correlate 38/183 = 20.77%
Total = 186* new Q waves
*3 LBBB equivalent Q wave MI (likely ischemia event identified by symptoms, biomarkers or imaging)
111 112
1 (0.5%) 2
(1.1%)
3 (1.6%)
Not evaluable for Minnesota code
New Left Bundle Branch Block (LBBB) may be considered equivalent to a new Q-wave MI by the BIMR if a likely ischaemic event can be identified during which a patient experienced symptoms compatible with an acute coronary syndrome, or an extensive release of biochemical markers of myocardial necrosis (preferably CK-MB) was documented or there was evidence from imaging for a new regional loss of viable myocardium that is thinned and fails to contract, in the absence of a non- ischaemic cause.
11
Total 183 new Q waves N = 38 (20.8%) N = 145 (79.2%)
Study Study Sample size (n) Total MI (n) Unrecognized MI of total MI patients(%) Unrecognized MI (n) Unrecognized MI of total patients (%) 1.Framingham study 5070 363 30% 109 2.15%
3524 73 37% 27 0.77%
9509 427 40% 171 1.80%
7331 135 22% 30 0.41%
9141 237 35% 83 0.91%
13000 641 33% 212 1.63%
12866 460 25% 115 0.89%
12843 508 20% 102 0.79%
5888 901 22% 198 3.37%
3272 141 36% 51 1.55%
Replacement Study Trail 2763 256 4% 10 0.37%
1387 99 14% 14 1.00%
Lowering in Diabetes Study 9795 406 37% 150 1.53% Total 96389 4647 27% 1271 1.32%
Prevalence of unrecognized MI reported in literature GL 187/15968 = 1.17%
Resting 12-lead electrocardiograms at hospital discharge, 3-months follow-up, and the 24- months end-of-trial visit and any available intercurrent electrocardiograms, related to suspected ischemic events, were inspected for quality and technical errors and analyzed by an independent electrocardiographycore laboratory (Cardialysis, Rotterdam, The Netherlands). Serial comparison of sequential tracings was performed to identify patients with new appearance of Q waves (major QQS wave abnormalities 111 to 128 according to the Minnesota Code 2009).(4) Where new Qwaves, with respect to the immediately preceding electrocardiogram (first reference electrocardiogram is at discharge), were identified an independent cardiologist confirmed or rejected the myocardial as a new Q wave myocardial infarction, and if confirmed also assigned a date, based on review of the reported adverse events to the new Qwave myocardial infarction.(1) Where no clinical correlate was identified, the date of the new silent Qwave myocardial infarction was arbitrarily assigned to the date of the qualifying electrocardiogram. In case electrocardiograms remained missing after review of all documentation (e.g. death before 2 years of followup) it will be assumed no new Qwave myocardial infarction occurred since the last obtained electrocardiogram. The electrocardiogramcore laboratory also identified new left bundle branch block on serial electrocardiograms. Where a new left bundle branch block was identified, the independent cardiologist determined, from electronic clinical record form extracts supplemented where necessary with additional source documents, whether a likely ischemic event (prolonged ischemic chest pain, significant rise in cardiac biomarkers or imaging evidence of loss of viable myocardium) occurred. A new left bundle branch block counted as a new Qwave myocardial infarction only where a qualifying ischemic event was identified. The new Qwave myocardial infarction was assigned to the date of the qualifying ischemic event. Core laboratory staff and the independent cardiologist were unaware of the study group assignments.
(first reference ECG is at discharge), were identified an independent cardiologist confirmed or rejected the myocardial as a new Q wave MI, and if confirmed also assigned a date, based on review of the reported adverse events to the new Qwave MI.
wave MI was arbitrarily assigned to the date of the qualifying ECG.
documentation (e.g. death before 2 years of followup) it will be assumed no new Qwave MI occurred since the last obtained electrocardiogram
Appendix E: Endpoint definition – Q wave MI ascertainment and definition p.33
electronic clinical record form extracts supplemented where necessary with additional source documents, whether a likely ischemic event (prolonged ischemic chest pain, significant rise in cardiac biomarkers or imaging evidence of loss of viable myocardium) occurred.
was identified.
ischemic event.
group assignments.
Appendix E: Endpoint definition – Q wave MI ascertainment and definition p.33
Cardiac events in patients without 2-year ECG in both arms
Experimental group without 2 year-ECG (N = 534) Number of patients Reference group without 2-year ECG (N = 605) Number of patients No adverse cardiac event within 2 years 438 No adverse cardiac event within 2 years 505 Adverse events within 2 years 96 Adverse events within 2 years 100 Investigator reported myocardial infarction 10 Investigator reported myocardial infarction 10 Intercurrent ECG after MI available 7 Intercurrent ECG after MI available 6 Intercurrent ECG after MI not available 3 Intercurrent ECG after MI not available 4 Unstable angina 16 Unstable angina 21 Stable angina 11 Stable angina 6 Ischemic heart disease (other than MI and other than unstable angina) 7 Ischemic heart disease (other than MI and other than unstable angina) 19 Chest pain, noncardiac 6 Chest pain, noncardiac 3 Congestive Heart Failure 8 Congestive Heart Failure 7 Cardiac valve disease 2 Cardiac valve disease 2 Atrial fibrillation/Atrial flutter 10 Atrial fibrillation/Atrial flutter 6 Conduction abnormality (including AV block, BBB) 4 Conduction abnormality (including AV block, BBB) 3 Other arrhythmia 4 Other arrhythmia 2 Ventricular tachycardia 1 Ventricular tachycardia 2 Others 17 Ventricular fibrillation 1 Others 18
the eCRF, angiographies and ECGs)
Summary (N = 2059) Number of patient No clear reason for changing antiplatelet therapy (Ticagrelor adverse effect, ischemic
1047 Ticagrelor adverse effect Dyspnea 391 Allergy (ex. rash, urticaria) and other side effect 72 Ischemic or bleeding event Definite stent thrombosis, STEMI or repeat revascularization 52 Bleeding 267 Start of chronic oral anticoagulant during the study 230 *When there were greater than 1 event to change the allocated regimen (eg. oral anticoagulant and bleeding), the preceding event closest to the ticagrelor stop date was considered as the reason.
Reasons for premature interruption of Ticagrelor in the experimental treatment group, cross-sectional view at 2 years
Treatment strategy Number of patients ASA monotherapy 1015 Clopidogrel and ASA 175 Clopidogrel monotherapy 125 No antiplatelet therapy 194 Other antiplatelet and Aspirin 11 Other antiplatelet monotherapy 21 Ticagrelor and ASA 518
Treatment strategies in 2059 patients who were not adherent to the experimental strategy at 2 years (cross-sectional view)
OF PATIENT ADHERENCE TO THE ALLOCATED ANTIPLATELET TREATMENT STRATEGIES OVER THE 2-YEAR TRIAL PERIOD.
The drug counts at the 1 month, 1 year and 2- year time points reflect patient adherence before the protocol mandated change in antiplatelet regimen. Revascularizations and per
and aspirin for 30 days in the experimental treatment strategy group, ii) dual antiplatelet therapy with ticagrelor and aspirin (acute coronary syndrome, stable coronary artery disease patients already on ticagrelor or prasugrel), clopidogrel and aspirin (stable coronary artery patients) for 365 days in the standard treatment strategy group.
Type of reference treatment strategy was a post
first events and percentages are reported. Rate ratios (95% confidence interval) are estimated using the Mantel-Cox method with two-sided p- values from log-rank test. All events were censored beyond 730 days. P-values for interactions were obtained with approximate χ2 tests for unequal Rate Ratio’s in the subgroups (df=1, except geographic area df=4). Renal failure = estimated creatinine-estimated glomerular filtration ratio (GFR) of less than 60 ml/min using the Modification of Diet in Renal Disease (MDRD) formula. (3) Assumed no risk in case of missing data: diabetes (n=11), renal failure (n=85), peripheral vascular disease (n=146).
ANALYSES OF THE KEY SECONDARY SAFETY ENDPOINT OF BLEEDING ACADEMIC RESEARCH CONSORTIUM GRADE 3 OR 5 EVENTS