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 Vranckx, Marco Valgimigli, Stephan Windecker (PIs) Christian W. Hamm, Peter Jüni, P. Gabriel Steg, GerritAnne van Es (SC)
8/27/2018
Background: Global Leaders Vision 1. Ticagrelor, a potent and consistent antiplatelet drug, may be a better foundation as monotherapy for long term antiplatelet therapy compared to ASA in at-risk patients 2. Avoid the higher risk of bleeding potentially associated with adding ASA (even low dose) to Ticagrelor 3. Maintain the clinical benefits of potent platelet inhibition after PCI, beyond the initial period of high stent thrombosis risk (30 days) 4. The trial may pave the way for future studies of Ticagrelor as a single foundation therapy 2
“All-comers” Experimental strategy PCI population N = 15,991 ASA 75-100 mg/d ACS + 1:1 Randomisation, Stable CAD Ticagrelor 90 mg bid open-label design, 130 centers worldwide Reference strategy ASA 75-100 mg/d ACS: Any type of lesions: Left main, SVG, CTO Ticagrelor 90 mg bid UA+NSTEMI+STEMI bifurcation, ISR, etc. ASA 75-100 mg/d Unrestricted use of Stable CAD DES (number, length) Clopidogrel 75 mg/d Bivalirudin-supported 0 30 d 90 d 120 d 1 year 1.5 years 2 years BioMatrix DES by default ECG ECG ECG 2Y discharge 90D 3
• Primary endpoint : Allcause death and Expected risk reduction nonfatal new Q wave MI • Based on PLATO trial at 2 years • • Design : Sample size • Superiority of the experimental 2 x 8000 patients arm vs. reference arm. Power • Expected event rate • 92% to detect a 22.5% relative 5% for primary endpoint risk reduction (RRR) Death 4.5% • 84% to detect a 20% RRR New Q wave MI 0.5% • Attrition rate: 4% • Based on 2year outcome • of LEADERS trial* *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 4
Trial organisation (investigator-initiated trial) Sponsor: European Clinical Research Institute (www. ECRI trials.com) • Grant giver: • AstraZeneca (Ticagrelor) – Biosensors International (Biomatrix DES) – The Medicines Company (Bivalirudin) – Clinical Research Organization: Cardialysis • ECG and angiographic core laboratory: Cardialysis • Statistical analysis: Clinical Trials Unit (CTU), Bern university • Data and Safety Monitoring Board (DSMB) • 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) – 5
Primary endpoint status The composite of all-cause mortality or non-fatal new Q-wave MI • up to 2 years post randomization (15,991 randomized) q 15,991 pts randomized q ECG centrally adjudicated q New Q-waves detected according 23 pts : Data deletion requested to the Minnesota Code No search for vital status (Major criteria 111 to 128) 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) 6
Baseline characteristics Experimental Treatment Reference Treatment Strategy Strategy Baseline clinical 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 .139 % .135 % (eGFR < 60 ml/min/1.73m 2 ) Previous stroke 2.6 % 2.6 % Previous myocardial infarction 23.0 % .236 % Previous PCI 32.7 % 32.7 % Previous CABG 5.6 % 6.2 % 7
Baseline characteristics Experimental Treatment Reference Treatment Strategy Strategy Total number of patients N = 7980 N = 7988 Clinical presentation Stable Coronary Artery Disease • 53.0 % 53.2 % Acute Coronary Syndrome (ACS) • 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 % 8
Adherence to treatment strategies Primary and secondary outcomes at 12 months (Intention to treat) 0% 25% 50% 75% 100% Percentage Discharge Experimental Reference Risk Ratio p-value 98 % group group (95% CI) Experimental arm Reference arm 97 % Number of pts. N=7980 N=7988 Follow-up 1 M 96 % Experimental arm 96 % Reference arm All-cause 1.95 %, 0.79 Follow-up 3 M mortality or new 2.47 %, (197) 0.028 (156) (0.640.98) 86 % Q-wave MI* Experimental arm 94 % Reference arm All-cause 1.35 % 1.64 % 0.82 0.138 Follow-up 6 M mortality (108) (131) (0.641.06) 85 % Experimental arm New Q-wave 0.60 % 0.86 % 0.70 0.052 Reference arm 92 % MI (48) (69) (0.481.00) Follow-up 12 M 0.86 BARC 3 or 5 1.47 % 1.70 % 0.243 82 % Bleeding** (0.671.11) Experimental arm Reference arm 89 % 0.88 0.18 % 0.20 % 0.722 BARC 5 Bleeding Follow-up 18 M (0.431.80) Experimental arm 0.84 1.34 % 1.60 % 0.179 BARC 3 Bleeding Reference arm Ticagrelor mono in ACS and SA (0.651.08) Follow-up 24 M In ACS: Ticagrelor + ASA Experimental arm *MantelCox method based on time of death or diagnosis of new In SA: Clopidogrel + ASA Reference arm Q wave MI **MantelCox logrank method for secondary safety endpoints 9
Adherence to treatment strategies Primary and secondary outcomes at 24 months (Intention to treat) 0% 25% 50% 75% 100% Percentage Discharge Experimental Reference Risk Ratio p-value 98 % group group (95% CI) Experimental arm Reference arm 97 % Number of pts. N=7980 N=7988 Follow-up 1 M 96 % Experimental arm 96 % Reference arm All-cause 3.81 %, 0.87 Follow-up 3 M mortality or new 4.37 %, (349) 0.073 (304) (0.751.01) 86 % Q-wave MI Experimental arm 94 % Reference arm All-cause 2.81 % 3.17 % 0.88 0.18 Follow-up 6 M mortality (224) (253) (0.741.06) 85 % Experimental arm New Q-wave 1.04 % 1.29 % 0.80 0.14 Reference arm 92 % MI (83) (103) (0.601.07) Follow-up 12 M BARC 3 or 5 0.97 2.04 % 2.12 % 0.77 82 % Bleeding Experimental arm (0.781.20) Reference arm 89 % 0.92 0.28 % 0.30 % BARC 5 Bleeding 0.78 Follow-up 18 M (0.521.64) 79 % Experimental arm 0.95 1.88 % 1.99 % BARC 3 Bleeding 0.63 Reference arm 92 % (0.761.18) Follow-up 24 M Ticagrelor monotherapy in ACS and SA 78 % Experimental arm 93 % ASA monotherapy in ACS and SA Reference arm 10
Kaplan Meier estimate of mortality and safety outcome at 2 years All-cause death BARC 3 or 5 bleeding Reference arm Reference arm BARC 3 or 5 bleeding (%) Experimental arm (Ticagrelor monotherapy) Experimental arm (Ticagrelor monotherapy) All-cause death (%) 3.17 % RR (95%CI)=0.88 (0.74-1.06) RR (95%CI)=0.97 (0.78-1.20) 3.17 % P=0.182 P=0.766 2.81 % 2.12 % 2.81 % 2.04 % Landmark analysis Landmark analysis Days since index procedure Days since index procedure Ref. DAPT (Tica/Clop) DAPT (Tica/Clop) ASA mono Ref. ASA mono DAPT DAPT Exp. Exp. Tica Mono Tica Mono 11
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