1. Philip Urban MD La Tour Hospital Geneva, Switzerland
EU experience with 30-day DAPT: Challenges and Execution of Pivotal Trials
Philip Urban MD
La Tour Hospital
Geneva, Switzerland

2. Philip Urban MD Consultant: Biosensors International
Consultant:
Biosensors International  
Honoraria/Speaker’s bureau:
Terumo
Abbott Vascular
Edwards Lifesciences

3. LEADERS FREE Trial Design
Prospective, double-blind randomized (1:1) trial
2466 High bleeding risk (HBR) PCI patients
BioFreedom™
DCS
Gazelle™
BMS
vs.
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)
Urban P et al. Am Heart J 2013; 165:704-9

4. Primary Efficacy Endpoint (Clinically-Driven TLR)% 12
9.8% 9
Cumulative Percentage with Event 6
5.1% 3
p < 0.001
HR 0.50, (95% CI = 0.37 – 0.69) 90
180
270
390
Days
Number at Risk
DCS
1221
1167
1130
1098
1053
BMS
1211
1131
1072
1034
984
390 days chosen for assessing primary EP to capture potential evens driven by the 360 day FU contact
Urban P et al, NEJM 2015; 373: 2038

5. Primary Safety Endpoint (Cardiac Death, MI, ST)% 15
12.9% 12 9
9.4%
Cumulative Percentage with Event 6 3
HR 0.71, (95% CI = 0.56 – 0.91)
p < for non-inferiority
p = for superiority 90
180
270
390
Days
Number at Risk
DCS
1221
1146
1105
1081
1045
BMS
1211
1115
1066
1037
1000
390 days chosen for assessing primary EP to capture potential events driven by the 360 day FU contact
Urban P et al, NEJM 2015; 373: 2038

6. Bleeding During 12 Months Follow-Up%
p = 0.55
p = 0.68
p = 0.96
Urban P et al, NEJM 2015; 373: 2038

7. Trial Structure PIs: P. Urban, A. Abizaid & I. Meredith Executive
Committee
3 PI’s & D.Carrié, S. Greene, M-C Morice,
C. Naber, S. Pocock, H-P Stoll
Statistics:
S. Pocock, J. Gregson, S. Copt, R. Piault
DSMB:
B. Meier (chair), J-P. Bassand, T. Cuisset, E. Vicaut
CEC:
R. Mehran (chair), A. Baumbach, S. Cook, P. Kala,
J. Machecourt, F. Mauri, G. Olivecrona, S. Petronio,
F. Ribichini, L. Thuesen
CRO:
CERC, Massy, France (Project leader U. Windhovel)
e-CRF:
MERGE
Sponsor:
Biosensors Europe, Morges, Switzerland
Urban P et al, NEJM 2015; 373: 2038

8. DSMB Review Timepoints (3 months after each predefined milestone)
2y FU 50
250
500
1000
1500
2000
2466
1y FU

9. 30-day DAPT: Challenges and Execution of Pivotal Trials
Developing awareness of HBR patients
Defining specifics of HBR patients
Predicting the rates of adverse events
Polymer-free & fast BA-9 kinetics
Guidelines for DAPT after stenting
Separate assessment of safety and efficacy endpoints
Importance of a double blinded design
Ensuring compliance with DAPT regimen
patients
device
context
trial design

10. Patients at High Bleeding Risk (HBR)
Need for anticoagulants
Anemia/bleeding
Cancer
Advanced age
Recent
stroke
Planned surgery
BMS

11. 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

12. Inclusion Criteria Applied (1.7 criteria / patient)
Urban P et al, NEJM 2015; 373: 2038

13. DAPT trials exclusion criteria (✗) vs
DAPT trials exclusion criteria (✗) vs. LEADERS FREE inclusion criteria (✓)
EXCELLENT
RESET
ARCTIC
OPTIMIZE
DAPT DES
LEADERS FREE
Low Hb or thrombocytopenia ✗ ✓
Recent bleeding
Anticoagulants
Need for surgery
Renal or hepatic failure
STEMI and/or GP 2b3a blockers
not excluded
Anticipated difficulties with long term DAPT

14. A straight forward case…
66 year old lady with recurrent grade 2 AP in October 2013
Lobectomy March 2013 for bronchial carcinoma
Bilateral hip replacement planned ASAP (pain ++ & walking with difficulty)
Randomized November 5, 2013
Single 3 x 14 mm LF stent
On aspirin and clopidogrel for 30 days, aspirin alone afterwards
Hip operations done January and March 2014: no problems (TF 1 unit)
Seen November 2015: doing well, no angina, no tumor recurrence

15. Event rates in BMS arm predicted vs. observed%

16. 30-day DAPT: Challenges and Execution of Pivotal Trials
Developing awareness of HBR patients
Defining specifics of HBR patients
Predicting the rates of adverse events
Polymer-free & fast BA-9 kinetics
Guidelines for DAPT after stenting
Separate assessment of safety and efficacy endpoints
Importance of a double blinded design
Ensuring compliance with DAPT regimen
device

17. BioFreedom™ Drug Coated Stent (DCS)
BA9TM Drug 10 Times More Lipophilic than Sirolimus1
Sirolimus
Zotarolimus
Everolimus
Biolimus A9TM 20 40 60 80
100 %
+/- 2.8% (valid for all drugs test)
Potential Advantages:
Avoid any possible polymer-related adverse effects
Rapid drug transfer to vessel wall (98% within one month2)
Safe to shorten DAPT?
1. Data on file at Biosensors Intl; 2. Tada et al., Circ Cardiovasc Interv 2010;3;

19. 30-day DAPT: Challenges and Execution of Pivotal Trials
Developing awareness of HBR patients
Defining specifics of HBR patients
Predicting the rates of adverse events
Polymer-free & fast BA-9 kinetics
Guidelines for DAPT after stenting
Separate assessment of safety and efficacy endpoints
Importance of a double blinded design
Ensuring compliance with DAPT regimen
context

20. ESC Myocardial revascularization Guidelines (2010)
Wijns W et al. EHJ 2010; 31:

21. ESC Myocardial revascularization Guidelines (2014)
Windecker S. et al EHJ 2014; 35:

22. 30-day DAPT: Challenges and Execution of Pivotal Trials
Developing awareness of HBR patients
Defining specifics of HBR patients
Predicting the rates of adverse events
Polymer-free & fast BA-9 kinetics
Guidelines for DAPT after stenting
Separate assessment of safety and efficacy endpoints
Importance of a double blinded design
Ensuring compliance with DAPT regimen
trial design

23. LEADERS FREE: measures of outcome%
TLF=Cardiac death or target-vessel MI or clinically-driven TLR
TVF=Cardiac death or target-vessel MI or clinically-driven TVR
MACE=Cardiac death or MI or clinically-driven TLR
efficacy
safety

24. Importance of double blind design
Device success and total length of stent could both have been different without double-blinding

25. Importance of a double blind design: DAPT compliance in DCS and BMS groups%
38 patients in each group stayed on DAPT for the entire 390 days = 76 = 3.1% of 2466
DAPT
SAPT

26. Conclusions
LEADERS FREE documents the efficacy and safety of combining ultra-short DAPT with a polymer-free BA9 eluting DCS for HBR patients
Such patients are often excluded from “all-comer” RCTs, but represent a sizable proportion of PCI candidates
The thrombotic and bleeding event rates that were observed during the 390 days follow-up were high
The double-blind design and the availability of sufficient power to analyze efficacy and safety separately were important features that significantly contribute to the robustness of the results
These data have the potential of modifying current PCI guidelines
Do you agree with “ultra-short”? I think it help to differentiate with 3 month DAPT
SG: I like the idea of differentiating between 3 mo and 1 mo DAPT but not sure how I feel about ultra – I either love it or hate it. I like the exclusivity of ultra but also feel like it makes it seem like a VERY small group. Do you mind if I ask a few folks?

27. Thank you