Two-Year Outcomes of High Bleeding Risk Patients after Polymer-Free Drug-Coated Stents Philip Urban, Philippe Garot, Damras Tresukosol, Stuart J. Pocock, Ian Meredith, Alex Abizaid, Didier Carrié, Christoph Naber, Andrés Iñiguez, Suneel Talwar, Ian B.A. Menown, Evald H. Christensen, Samuel Copt, John Gregson, Hans-Peter Stoll,Samantha Greene, and Marie-Claude Morice for the LEADERS FREE Investigators
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 2% All-comers HBR
BioFreedom Drug Coated Stent (DCS) Selectively Micro-Structured Surface Holds Drug in Abluminal Surface Structures BA9 TM Drug 1 Times More Lipophilic than Sirolimus 1 1 % 8 6 4 2 Sirolimus Zotarolimus Everolimus Biolimus A9 TM +/- 2.8% (valid for all drugs test) Advantages: Avoid any possible polymer-related adverse effects Rapid drug transfer to vessel wall (98% within one month 2 ) Good fit with short DAPT 1. Data on file at Biosensors Intl;; 2. Tada et al., Circ Cardiovasc Interv 21;;3;;174-183
LEADERS FREE Trial Design Prospective, double-blind randomized (1:1) trial 2466 High bleeding risk (HBR) PCI patients BioFreedom DCS vs. Gazelle BMS DAPT mandated for 1 month only, followed by long-term SAPT 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)
Primary Endpoints at 1 Year Efficacy (cd-tlr) Safety (cardiac death, MI, ST) DCS BMS DCS BMS Cumulative Percentage with Event % 12 9 6 3 p for superiority <.1 HR.5, (95% CI =.37.69) 9.8% 5.1% Cumulative Percentage with Event % 15 12 9 6 3 HR.71, (95% CI =.56.91) p <.1 for non-inferiority p =.5 for superiority 12.9% 9.4% 9 18 27 39 Days 9 18 27 39 Days Urban P et al. N Engl J Med 215;;373:238-47
Two Year Follow-up
Enrollment and Follow-Up 2466 patients randomized 1,239 DCS 1,227 BMS 18 with no PCI performed 16 with no PCI performed 1,221 analyzed (modified ITT) 1,211 analyzed (modified ITT) 28 (2.3%) patients withdrew before 24-month visit or were lost to FU 2 (1.7%) patients withdrew before 24-month visit or were lost to FU 1193 (97.7%) completed 24-month visit or died 1191 (98.3%) completed 24-month visit or died
Antithrombotic Medication at Discharge % 1 96.6 96.9 DCS BMS 8 6 4 36.3 34.6 2 3.1 2.8.4.2 DAPT SAPT no APT OAC ne of the regimens differ at p <.5
% Antithrombotic Medication after 1 month visit* * at day 37 1 88.1 87.2 DCS BMS 8 6 4 35.9 34.9 2 9.2 9.7 2.8 2.9 DAPT SAPT no APT OAC ne of the regimens differ at p <.5
Antithrombotic Medication at 2 years % 1 DCS BMS 8 78.8 76.8 6 4 37.7 38. 2 5.3 7.6 15.8 15.6 DAPT SAPT no APT* OAC p=.3 *82% on OAC
Primary Safety Endpoint (Cardiac Death, MI, ST) at 2 year 2 Patients with Event (%) 15 1 5 12.7% 9.2% HR.8 (95%CI.64-.99) p =.39 15.3% 12.6% Number at Risk 18 365 545 73 Days DCS 1221 114 152 16 62 BMS 1211 167 11 973 587 2 year FU was obtained at 73 days + 6 days
% Components of Safety Endpoint (2 years) 12 1 1.1 DCS BMS 8 6.6 6.9 7.4 6 4 2 2.1 2.3 Cardiac death MI ST (def / prob) p =.69 p =.4 p =.76
% 16 14 12 1 Selected Secondary Safety Endpoints (2 years) 13.8 13.1 DCS BMS 8 6 6.5 6.9 4 2 All death n-card death ST acute / subacute 1. 1.2 1.1 1. ST late.1.1 ST very late ne of these endpoints differ at p <.5
Primary Efficacy Endpoint (Clinically-Driven TLR) at 2 Years 2 Patients with Event (%) 15 1 5 9.3% 12.% 6.8% 4.9% HR.54 (95%CI =.41-.72) P<.1 Number at Risk 18 365 545 73 Days DCS 1221 1129 161 113 626 BMS 1211 174 999 945 561 2 year FU was obtained at 73 days + 6 days
Subgroups at 2 years follow-up Efficacy endpoint (clinically driven TLR) Composite safety endpoint (cardiac death, MI, ST) Category N DCS: Events (%) BMS: Events (%) P-value for interaction Category N DCS: Events (%) BMS: Events (%) P-value for interaction Age >8 162 83 41 (5.5) 36 (9.4) 9 (11.9) 46 (12.1).7 Age >8 162 83 8 (1.3) 67 (16.9) 16 (13.5) 74 (18.7).52 Male 738 1694 21 (6.3) 56 (7.) 42 (12.1) 94 (12.).67 Male 738 1694 43 (12.4) 14 (12.6) 62 (17.) 118 (14.5).42 ACS at admission 1773 659 62 (7.5) 15 (5.) 15 (12.6) 31 (1.4).49 ACS at admission 1773 659 16 (12.4) 41 (13.) 113 (13.) 67 (21.5).5 Diabetes 1622 85 52 (7.1) 25 (6.4) 92 (11.9) 44 (12.2).79 Diabetes 1622 85 87 (11.4) 6 (14.9) 16 (13.2) 74 (19.7).73 Renal failure at admission 1754 466 56 (6.8) 19 (9.5) 1 (12.1) 22 (1.4).14 Renal failure at admission 1754 466 97 (11.3) 39 (18.8) 16 (12.6) 6 (25.5).34 Planned OAC at randomization 1553 879 47 (6.4) 3 (7.5) 92 (12.4) 44 (11.2).43 Planned OAC at randomization 1553 879 85 (11.5) 62 (14.4) 117 (15.4) 63 (15.).26 Crusade score > median (35) 161 962 31 (6.4) 4 (9.2) 65 (12.6) 45 (1.2).4 Crusade score > median (35) 161 962 47 (9.4) 81 (17.9) 58 (11.) 99 (21.2) 1. Anemia, transfusion or bleeding leading to hospitalization 27 425 58 (6.2) 19 (9.8) 114 (12.) 22 (12.3).18 Anemia, transfusion or bleeding leading to hospitalization 27 425 112 (11.6) 35 (17.4) 129 (13.1) 51 (26.3).22 Planned major surgery in following year 2 46 66 (7.1) 9 (4.8) 11 (11.9) 25 (12.5).45 Planned major surgery in following year 2 46 124 (12.7) 2 (1.9) 147 (15.3) 29 (13.9).8 Cancer in last 3 years* 2193 239 73 (7.1) 4 (3.5) 123 (12.) 13 (11.9).3 Cancer in last 3 years* 2193 239 135 (12.7) 12 (1.6) 163 (15.3) 17 (15.4).81 Multi-vessel disease at admission 96 1493 15 (3.5) 61 (8.9) 37 (8.6) 97 (14.1).27 Multi-vessel disease at admission 96 1493 32 (7.5) 111 (15.4) 46 (1.3) 131 (18.2).63 Total stent length > 3 mm 149 999 27 (4.2) 5 (1.3) 64 (9.4) 71 (16.1).27 Total stent length > 3 mm 149 999 72 (11.) 73 (14.4) 87 (12.4) 89 (19.1).35 Minimal stent diameter < 3 mm 1195 1213 31 (5.5) 46 (8.2) 48 (8.5) 87 (15.5).39 Minimal stent diameter < 3 mm 1195 1213 64 (11.2) 81 (13.8) 71 (12.3) 15 (17.8).37.125.25.5 1 2 4 Hazard ratio (95% CI).125.25.5 1 2 4 Hazard ratio (95% CI)
The Balance of Thrombosis and Bleeding
Multivariate Predictors of Primary Safety Endpoint and Major Bleeding (BARC 3-5) Cardiac death/mi/st Major Bleeding Congestive heart failure 1.61 (1.23-2.11) p=.1 Multivessel disease 1.66 (1.27 2.18) p<.1 - Number of stents / patient (per stent) 1.2 (1.9 1.32) p<.1 - BMS (vs. DCS) 1.28 (1.3 1.59) p=.27 - Age > 75 1.56 (1.23 1.97) p<.1 1.52 (1.13 2.6) p=.6 Haemoglobin (per 1 mmol/l lower)* 1.32 (1.19 1.46) p<.1 1.73 (1.52 1.96) p<.1 Serum creatinine > 15 umol/l - 1.58 (1.1 2.27) p=.12 Planned oral anticoagulants - 2.1 (1.51 2.68) p<.1 * Below 9 mmol/l (145 g/l)
Cardiac, Coronary and Major Bleeding events (2 Years Follow-Up) % 2 15 12.9 15.3 DCS BMS 1 8.2 1.6 8.9 9.2 5 cardiac death, MI, ST MI and/or ST BARC 3-5 p=.39 p=.45 All % derived from Kaplan-Meier estimates p=.95
Mortality During the Year Following a Coronary Thrombotic Event (MI and/or ST) or a Major Bleeding event (BARC 3-5) Patients Dead (%) 3 25 2 15 1 27% 26% 5 Major Bleed Thrombotic Event 9 18 27 365 Days Since Event 1-year mortality = 6% for patients with neither thrombotic nor major bleeding events
Conclusions ü At two years, the use of a BA9-DCS remained both significantly safer and more effective than a control BMS in HBR patients treated with a one-month only DAPT course ü subgroup was identified for which use of a BMS was superior to a DCS ü HBR patients suffer from a persistently high incidence of bleeding and thrombotic events, both of which are associated with a high and similar mortality over a one year period ü Identification of predictors of both the composite primary safety event and major bleeding may help design future trials of DAPT duration for HBR patients