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Philip Urban, Alexandre Abizaid, Ian T. Meredith, Stuart J. Pocock, Didier Carrié, Christoph Naber, John Gregson, Samantha Greene, Hans Peter Stoll and Marie-Claude Morice for the LEADERS FREE Investigators Biolimus-Coated vs. Bare-Metal Coronary Stents in High Bleeding Risk Patients
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Disclosure Statement of Financial Interest Affiliation / Financial Relationship Grant / Research Support Consulting Fees / Honoraria Company Biosensors Europe Edwards Lifesciences Terumo Abbott Vascular Within the past 12 months, I, Philip Urban, have had a financial interest / arrangement or affiliation with the organization(s) listed below.
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High Bleeding Risk Patients (HBR) Mostly excluded from device and APT trials Never specifically studied Current guideline recommendations: BMS + one month DAPT DES + “shortened” DAPT
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BioFreedom™ Drug Coated Stent (DCS) Selectively Micro-Structured Surface Holds Drug in Abluminal Surface Structures Potential Advantages: Avoid any possible polymer-related adverse effects Rapid drug transfer to vessel wall (98% within one month 2 ) Safe to shorten DAPT? BA9 TM Drug 10 Times More Lipophilic than Sirolimus 1 SirolimusZotarolimusEverolimusBiolimus A9 TM 0 20 40 60 80 100 % +/- 2.8% (valid for all drugs test) 1. Data on file at Biosensors Intl; 2. Tada et al., Circ Cardiovasc Interv 2010;3;174-183
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Median In-Stent LLL at 12-month Follow-up 2 nd Cohort – Primary Endpoint N = 31 N = 35 p = 0.001 (non-inferiority) Costa R et al. JACC interv (published online October 11, 2015 – DOI 10.1016/j.jcin.2015.09.008)
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For patients with a high bleeding risk, using one month DAPT, can the BioFreedom DCS be shown to be as safe and more effective than a Gazelle BMS? Hypothesis
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LEADERS FREE Trial Design Prospective, double-blind randomized (1:1) trial 2466 High bleeding risk (HBR) PCI patients vs. DAPT mandated for 1 month only, followed by long-term SAPT BioFreedom™ DCS Gazelle™ BMS Primary safety endpoint: Composite of cardiac death, MI, definite / probable stent thrombosis at 1 year (non-inferiority then superiority) Primary efficacy endpoint: Clinically-driven TLR at 1 year (superiority)
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Inclusion Criteria (One or More) Age ≥ 75 years OAC planned after PCI Baseline Hb < 11g / dl or transfusion during prior 4 weeks Planned major surgery (within next year) Cancer diagnosed or treated ≤ 3 years Creatinine clearance < 40 ml / min Hospital admission for bleeding during past year Thrombocytopenia (< 100.000 / mm3) Any prior intra-cerebral bleed Any stroke during the past year Severe liver disease NSAID or steroids planned after PCI Anticipated poor DAPT compliance for other medical reason
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Trial Organization
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Determination of Trial Size Predicted event rates in BMS control arm Composite safety endpoint (cardiac death, MI and ST) 8% Efficacy endpoint (clinically-driven TLR) 10% Patients per group: 1228 Both with one-sided alpha 0.025 Endpoints Safety: > 80% power to demonstrate non-inferiority with margin 3.2% Efficacy: > 80% power to detect a 3.3% reduction in c-TLR
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Enrollment and Follow-Up 2466 patients randomized 16 with no PCI performed 18 with no PCI performed 22 (1.8%) patients withdrew before 12-month visit or Were lost to FU 25 (2.0%) patients withdrew before 12-month visit or were lost to FU 1189 (98.2%) completed 12-month visit or died 1196 (98.0%) completed 12-month visit or died 1,227 BMS1,239 DCS 1,211 analyzed (modified ITT) 1,221 analyzed (modified ITT)
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Inclusion Criteria Applied (1.7 criteria / patient)
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Baseline Characteristics None of the baseline characteristics differ at p < 0.05
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Index Procedure None of the procedure characteristics differ at p < 0.05
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Index Procedure (Continued) None of the procedure characteristics differ at p < 0.05
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Antithrombotic Medication at Discharge % None of the regimens differ at p < 0.05 * Any oral anticoagulant + DAPT
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Primary Efficacy Endpoint (Clinically-Driven TLR) 0 90180270390 Cumulative Percentage with Event 3 6 9 12 Days 0 9.8% 5.1% p for superiority < 0.001 Number at Risk DCS12211167113010981053 BMS1211113110721034984 390 days chosen for assessing primary EP to capture potential evens driven by the 360 day FU contact %
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Primary Efficacy Endpoint Difference: -4.8% (95% CI = -6.9% to -2.6%) HR 0.50, (95% CI = 0.37 – 0.69) p<0.001 for superiority
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Secondary Efficacy Endpoints % p = 0.004p < 0.001 p < 0.005
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Primary Safety Endpoint (Cardiac Death, MI, ST) 0 90180270390 Cumulative Percentage with Event 3 6 9 12 Days0 12.9% 9.4% Number at Risk DCS12211146110510811045 BMS12111115106610371000 p = 0.005 for superiority 15 390 days chosen for assessing primary EP to capture potential events driven by the 360 day FU contact %
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Primary Safety Endpoint Risk difference: -3.6% (95% CI -6.1% to -1.0%) HR 0.71, (95% CI = 0.56 – 0.91) p < 0.0001 for non-inferiority p = 0.005 for superiority * 3rd Universal definition of MI, Thygesen K et al Circulation 2012;126:2020 –2035 ARC definition, Cutlip D et al. Circulation 2007; 115: 2344-51
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Components of Safety Endpoint % p = 0.01 p = 0.70 p = 0.19
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Selected Secondary Safety Endpoints % None of these endpoints differ at p < 0.05
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Subgroups Composite safety endpoint (cardiac death, MI, ST) 1.125.25.5124 Hazard Ratio (95% CI)
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Efficacy endpoint (clinically driven TLR) Subgroups (continued) 1.125.25.524 Hazard Ratio (95% CI)
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DAPT During Follow-Up 03090180270390 0 20 40 60 80 100 Day Since Randomization SAPT DAPT 94.9% 9.5% DAPT= dual antiplatelet treatment or clopidogrel alone + vitamin K antagonist during first 30 days %
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Bleeding During 12 Months Follow-Up % p = 0.55p = 0.68p = 0.96
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Conclusions LEADERS FREE is the first randomized clinical trial dedicated to HBR patients Such patients are often excluded from stent and drug trials, constitute a rapidly growing proportion of PCI candidates and suffer high event rates Together with a one-month only DAPT course, the use of a BA9-DCS was both significantly safer and more effective than a control BMS in HBR patients
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LEADERS FREE published online October 14, 2015
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Leaders Free
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