Freedom to Treat Your High Bleeding Risk Patients. Tim Kinnaird University Hospital of Wales, Cardiff, UK

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1 Freedom to Treat Your High Bleeding Risk Patients Tim Kinnaird University Hospital of Wales, Cardiff, UK

2 Relevant Disclosures Honoraria for lectures from: o Eli Lilly & Co, Daiichi Sankyo, Boehringer, AstraZeneca, Orbus Neich, Biosensors and Bayer Honoraria for Ad-boards from: o Eli Lilly & Co, Daiichi Sankyo, AstraZeneca, Medco Health Solutions, Boston Therapeutics and Correvio Research Grant support from: o Boston Therapeutics

3 Difficult and not infrequent management problem: Complex coronary artery disease High Ischaemia bleeding vs. risk(hbr) Bleeding Warfarin or NOAC Prolonged DAPT undesirable Issues with DAPT Very elderly Bleeding risk Anaemia Conservative estimate ~20% usual PCI practice

4 BMS Registry - April 9 to May 15, European / Asian centres 744 consecutive patients treated with BMS Single main reason for using a BMS large vessel diameter STEMI reimbursmt/regulatory/other advanced age oral anticoagulants bleeding risk/anemia/cancer planned surgery < 12 months anticipated poor DAPT % % directly driven by a concern about bleeding or DAPT compliance % Morice M-C et al. J Am Coll Cardiol. 2013; 61:

5 Dual antiplatelet therapy duration after coronary stenting in clinical practice: results of an EAPCI survey How do you manage a patient who is at very high risk of bleeding requiring coronary stent implantation? 19% 7% BMS & 1 mth DAPT DES & SAPT 11% 3% 61% DES & 1 mth DAPT DES & 3 mths DAPT DES & 6 mths DAPT 946 interventional cardiologists Vaglimigli et al, EuroIntervention 2015;11:68-74

6 Syntax Score Syntax Score High bleeding risk patients undergoing PCI Baseline SYNTAX 1 p= Baseline SYNTAX score 2 p= ± ± ± ± Warfarin No warfarin 0 Old Young 1 Kinnaird et al, American Journal Cardioloy 2015; 2 Kinnaird et al, in review 2015

7 Cumulative Incidence (%) PRODIGY - Short versus Long-Term Duration of Dual- Antiplatelet Therapy After Coronary Stenting A Randomised Multi-Centre Trial 12 Safety bleeding end point 8 24-months 6-months 7.4% 4 3.5% Valgimigli et al, Circulation 2012;125: Days since randomisation No. at risk 24-month clopidogrel month clopidogrel

8 Major Bleeding (%) Bleeding Risk and Excess Bleeding with Prolonged DAPT Insights from the PRODIGY Trial CRUSADE >40 and long DAPT (n=144) CRUSADE >40 and short DAPT (n=163) CRUSADE <40 and long DAPT (n=831) CRUSADE <40 and short DAPT (n=808) HR 2.69 ARD 6% p=0.035 HR 1.50 ARD 0.8% P int = Follow-Up (days) p=0.25 HR - hazard ratio; ARD - absolute risk difference Costa et al, EuroPCR 2015

9 BioFreedom Drug Coated Stent Selectively micro-structured surface holds drug in abluminal surface structures Proprietary Highly Lipophilic Limus drug Potential advantages 1 1 o Avoid long term late adverse effects that might be attributable to the polymer o Improved surface integrity since there is no polymer to be sheared or peeled away from the stent struts o Possible shorter need of dual antiplatelet therapy 1 Data on file at Biosensors Intl

10 (mm) FIM: Median in-stent LLL at 12-month FU 2 nd Cohort P = 0.001* (p=0.11**) 0.5 P = 0.21* (p=0.55**) [0.09, 0.39] 0.22 [0.17, 0.66] 0.35 [0.22, 0.57] BFD SD BFD LD TAXUS N = 31 N = 35 N = 31 *Non-inferiority tests based on the mean. **Superiority tests. All values are presented as median [IQR]. Grube E., oral presentation, TCT 2010

11 LEADERS FREE Trial Design Prospective, multi-center, multi-national, double blinded randomized trial High Bleeding Risk PCI population (ACS + Elective stable patients) PI: P. Urban 2466 HBR patients in 68 centers worldwide BioFreedom DCS 1:1 randomization Gazelle BMS Clinical Follow-up 1 mo 2 mo 4 mo 1 yrs 2 yrs Primary safety endpoint: Primary efficacy endpoint: Composite of cardiac death, MI, definite/probable stent thrombosis at 1 year (non inferiority) Clinically driven TLR at 1 year (Superiority) DAPT mandated for 1 month only, followed by long term SAPT Urban et al., Am Heart J. 2013; 165:

12 Cumulative Percentage with Event (%) LEADERS FREE - Results Primary Efficacy Endpoint (Clinically-Driven TLR) % 6 5.1% Number at risk Days p for superiority <0.001 DCS BMS Urban et al NEJM 2015

13 Percent LEADERS FREE - Results Primary Safety Endpoint DCS (n=1221) BMS (n=1211) Cardiac Death, Myocardial Infarction or Stent Thrombosis at 390 days 112 (9.4%) 154 (12.9%) HR 0.71 (95% CI = ) p< for non-inferiority; p=0.005 for superiority 10 8 p=0.01 DCS BMS p= p= Cardiac death MI ST (def/prob) Urban et al NEJM 2015

14 Percent Preliminary Experience with the BA9 Drug- Coated Stent in three UK PCI Centers University Hospital of Wales (Tim Kinnaird, Richard Anderson) Morriston Cardiac Centre (Dave Smith, Alex Chase) Royal Bournemouth Hospital (Peter O Kane) (Average 1.4 indications per patient) patients treated 21-month period Interventional cardiologists discretion Patients with shock excluded, otherwise consecutive cohort of all Biofreedom patients ~9% total PCI workload Kinnaird et al submitted 2015

15 Baseline Clinical Characteristics Per patient BioFreedom (n=525) Usual DES population (n=1604) p value Age (±SD) 71.6± ±11.6 <0.001 Female (%) <0.001 ACS presentation % <0.001 Diabetes (%) NS CKD (%) Weight (kg) 77.7± ±17.2 <0.001 Hypertension (%) <0.002 Previous CABG (%) NS Previous MI (%) NS Severe LVSD (%) <0.001 OAC (%) <0.001 Kinnaird et al submitted 2015

16 Percent Mehran bleed risk subgroups patient group 50 DCS Usual PCI population p< p< p< Low Medium High Very High Mehran bleed risk score Kinnaird et al submitted 2015

17 Per patient Lesion Characteristics BioFreedom (n=525) Usual DES population p value (n=1604) Femoral (%) CTO (%) Left main (%) NS LAD (%) NS Circumflex (%) NS Right (%) <0.05 Saphenous graft (%) NS No. vessels (±SD) 1.51± ± No. lesions (±SD) 1.81± ± Lesion length mm (±SD) 33.2± ±17.6 <0.001 Multi-lesion PCI (%) Multi vessel (%) Kinnaird et al submitted 2015

18 Per patient Procedural Characteristics BioFreedom (n=525) Usual DES population (n=1604) p value Atherectomy device (%) Number stents used (±SD) 1.96± ± Largest balloon mm (±SD) 3.43± ± Smallest stent mm (±SD) 2.84± ± Longest stent mm (±SD) 27.7± ±8.2 <0.001 Mean stent diam mm (±SD) 2.94± ±0.49 NS Mean stent length mm (±SD) 23.8± ±7.8 <0.001 Total stent length mm (±SD) 37.9± ±20.3 <0.001 GPI used (%) No. lesions successful 1.79± ±0.93 <0.001 Procedural event (%) NS TIMI flow <3 (%) NS

19 DAPT (%) Percent DAPT (%) Anti-platelet treatment Mean DAPT duration: 3.6±4.3 months for BFS vs. 11.3±2.4 months for usual PCI patients (p<0.0001) p< DCS Usual PCI population p< DCS Months 40 Usual PCI population p< p< DAPT duration (months) Kinnaird et al submitted Months

20 Stent Thrombosis through 12-months Definite/Probable/Possible Acute ( 1 day) Subacute (2-30 days) Late (30 days 1 year) Definite N=2 0.8% ST 1 : Day 9, non-compliant with DAPT ST 2 : Day 25, sub-optimal stent deployment Possible N=2 0.8% ST 3 : Sudden death day 82 ST 4 : Sudden death day 132 No definite ST events after completion of prescribed DAPT course Kinnaird et al submitted 2015

21 ID-TLR, death and MACE at Follow-Up Mean follow-up 392±124 days (minimum 180 days) 6 5 BA9-DCS Usual DES 5.2 p=0.19 p= p= ID-TLR Definite ST Death Kinnaird et al submitted 2015

22 Where next with this stent? o RUDI-FREE: Italian Registry enrolling 1000 patients using Biofreedom as a work-horse stent o Formally industry funded prospective post-marketing registry in HBR patients o SORT-OUT IX RRCT THANKS Non-inferiority trial vs. Osiro DES (biodegradable-polymer SES) 3150 (not necessarily HBR) patients with registry-style follow-up Primary end point target lesion failure at 12-months Reporting 2018 o Plans underway for larger informal UK registry with minimum 12- month follow-up (let me know if have decent size cohort and want to be involved)