The Balance of Thrombosis vs. Bleeding for

PCI In HBR Patients :

insight into Patients Safety from the

LEADERS FREE Trial

Yuejin Yang MD, PhD, FACC, FESC

Fu-Wai Hospital, CAMS & PUMC, NCCD

OCC 2016, Advances in interventional Cardiology at ACC 2016 & EuroPCR 2016

0

2

4

6

8

10

All-

cau

sed

eath

(%)

BMS Early DES New DES

20

18

16

14

12

10

8

6

4

2

0

#M

yoca

rdia

lIn

farc

tio

n(%

)

BMS Early DES New DES

26

24

2220

1816

14

1210

86

4

20

Targ

et-l

esio

nre

vasc

ula

riza

tio

n(%

)

BMS Early DES New DES0

1

2

3

4

5

6

Def

init

est

ent

thro

mb

osi

s(%

)

BMS Early DES New DES

Death MI

TLR Definite ST

1. DES ARE SUPERIOR TO BMSESC-EAPCI Stent Task Force | Eur Heart J 2015

0 1 2

Years after PCI

3 4

0

1

2

3

5 (%)

4

Incidence density1.0 / 100 pt years

3.3%

2. VERY LATE ST WITH EARLY DES

ST With Early DES

Daemen J et al. Lancet 2007; 369:667-78

2010 ESC MR Guidelines

6-12 months post PCI

2011 ACC/AHA PCI Guidelines

12 months post PCI

Recommended DAPT

3. EXTENDED DAPT AND BLEEDING RISK

A Network Meta-Analysis of

10 RCTs including 31,666 Patients

Treated With DES

Impact of Bleeding

on 1 Year Mortality

Ndrepepa G et al. Circulation 2012

Increased Bleeding Risk

With Long-Term DAPT

Palmerini T et al. Lancet 2015

P<0.001

BARC type 3-5 Bleeding

0

1

AR

C D

efin

ite

ST (

%)

3

Paclitaxel Stent 2.4%

2

4

Räber L et al. Circulation 2012; 125:1110-21

5

0 6 12

*from Cox proportional hazards model

18 24 30Months after index PCI

36 42 48

EES vs. SES HR* = 0.33, 95% CI 0.15 – 0.72,P=0.006

EES vs. PES HR* = 0.24, 95% CI 0.13-0.47,P <0.0001

Sirolimus Stent 1.6%

Everolimus Stent 0.6%

4. ST IS NOT AN ISSUE WITH NEW DES

WITH NEW GENERATION DES

Significant interaction between treatment effect of

DAPT duration on ST and type of DES !

Giustino G et al. J Am Coll Cardiol 2015;65:1298-310

Meta-analysis

of 10 RCT

(n =32,135)

First-generation DES:

SES and PES

Second-generation DES:

EES and ZES

5. LONG-TERM DAPT MAY NOT BE NEEDED

• Patients at high-bleeding risk were not included in all-comer DES trials due to the recommended duration of DAPT in these trials

6. LIMITED AVAILABLE EVIDENCE ON

DES IN HIGH-BLEEDING RISK PATIENTS

7. AVAILABLE EVIDENCE: ZEUS TRIAL

Need for CCS or NSAIDRx: 1:1, Sx: inclusion criteria

1,606 pts, 20 sites in Italy, Switzerland, Portugal and Hungary from June 2011 to September 2012

Valgimigli et al. J. Am. Coll. Cardiol 2015; 65(8):805-15

Urgent or emergent coronary stenting in pts fulfilling ≥1 of the below:

Endeavor Sprint Zotarolimus-eluting Stent

Thin-strut Bare Metal Stent

Personalised DAPT duration, i.e. modelled according to the patient clinical risk profile and not by stent type

High Bleeding Risk High Thrombotic Risk Low Restenosis RiskNeed for OACs Intolerance to ASA Planned stent ≥3.0 mm,Previous Relevant BleedingAge > 80 y/o

Intolerance to any P2Y12

Planned surgery w/in 1 yearapart from LMCA andSVG intervention or for

Bleeding diathesis Cancer-life expectancy >1 Y ISR lesionsKnown Anemia (Hb<10 gr/dl) Pro-thrombotic diathesis

Valgimigli et al. J. Am. Coll. Cardiol 2015; 65(8):805-15

Urgent or emergent coronary stenting in pts fulfilling ≥1 of the below:

DAPT:30 days

DAPT:Stable CAD 30 days

ACS ≥ 6 mos

DAPT:None if ASA/P2Y12i intol.Up to surgery if planned

≥ 6 mos in others

7. AVAILABLE EVIDENCE: ZEUS TRIAL

High Bleeding Risk High Thrombotic Risk Low Restenosis RiskNeed for OACs Intolerance to ASA Planned stent ≥3.0 mm,Previous Relevant Bleeding Age > 80 y/o

Intolerance to any P2Y12

Planned surgery w/in 1 yearapart from LMCA and SVG intervention or for

Bleeding diathesis Cancer-life expectancy >1 Y ISR lesionsKnown Anemia (Hb<10 gr/dl) Pro-thrombotic diathesisNeed for CCS or NSAID

Ariotti S et al. JACC Intv 2016; 9(5):426-36

Primary EP: Major Adverse Cardiovascular Events(Death for any cause, myocardial infarction or target vessel revascularization)

BMS: 29.0%E-ZES: 22.6%

HR 0.74 p: 0.039

26%

7. AVAILABLE EVIDENCE: ZEUS TRIAL

Myocardial Infarction Target Vessel Revascularization

Definite or Probable Stent Thrombosis Death for all causes

BMS: 6.2%E-ZES: 2.6%

HR 0.41 p: 0.016

BMS: 17.3%E-ZES: 15.8%

HR 0.91 p: 0.57

BMS: 10.4%E-ZES: 3.5%

HR 0.33 p < 0.001

BMS: 11.4%E-ZES: 5.9%

HR 0.49 p: 0.006

7. AVAILABLE EVIDENCE: ZEUS TRIALAriotti S et al. JACC Intv 2016; 9(5):426-36

1. DES are superior to BMS

2. Long-term DAPT was implemented to prevent very late ST afterearly generation DES implantation

3. Extended DAPT is associated to higher bleeding risk, which has anegative impact on prognosis

4. Very late ST is not an issue with new generation DES

5. Short term DAPT is safe after new generation DES

6. Limited available evidence in high-bleeding risk patients

7. ZEUS, the only available RCT, showed superiority of Endeavor ZES over BMS in high bleeding risk patients

8. ESC GL 2014 considered <6 months DAPT after DES in HBR patients

9. High bleeding risk remains the most frequent reason for BMS implantation in current clinical practice

WHAT WAS KNOWN

BEFORE LEADERS FREE?

Study Objectives

For patients with a high bleeding risk, using one monthDAPT, can the BioFreedom DCS be shown to be as safe

and more effective than a Gazelle BMS?

2 Hypotheses : NI for safety; Sup for EfficacyThey had to be tested sequentially, to avoid splitting of the Alpha error

Was this study worth being conducted ? Yes, no data available when the study was designed;This remains today the second study chronologically speaking which focused on HBR pts and the only study fullydedicated to this selected patient population

HBR patients….who are they ?

Multivariable-adjusted, cubic splines

Bleeding Events

Restricted cubic splines with 3 knots of the distribution (10th, 50th, and 90th percentiles) Age ≤30 years is the reference value (HR=1)

PRODIGY: EFFECT OF AGEING ON BLEEDING OUTCOMES

HBR patients….who are they ?

Therefore this study included a combination of trueHBR patients together with pts who did not want orcould not adhere long-term to a DAPT regimen

HBR patients:

• how frequently are these patientsencountered in our practice ?

≈40% among all comer PCI patients in the BERN PCI registry

Only 1% of patients with CRUSADE score > 40 would NOT fulfill these HBR criteria

Unanswered questions

• Is 1 month DAPT the optimal DAPT duration inthis selected patient population ?

• Can we transfer these data to other DES?

– Is the polymer the real reason for prolongingDAPT after DES ?

– Or is it the drug-elution over time?

– If so, how important are the drug release kinetics?

• Both E-ZES and DCS elute close to 100% of the drugwithin 1 month

Drug Coated Stent (DCS)

BioFreedom™

Potential Advantages:

Avoid any possible polymer-related adverse effects

Rapid drug transfer to vessel wall (98% within one month1)

Safe to shorten DAPT?

1. Tada et al., Circ Cardiovasc Interv 2010;3;174-183

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

• 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)

BioFreedom™

DCS

Gazelle™

BMS

Urban P et al. Am Heart J 2013; 165: 704-9

Primary Endpoints

LEADERS FREE

Efficacy (cd-TLR)

DCS BMS

Safety (cardiac death, MI, ST)

DCS BMS

Urban P et al. N Engl J Med 2015;373:2038-47

Thrombosis and Bleeding in LEADERS FREE

For the first time in HBR patients, the current pre-specified analysisfocuses on:

1. The location and consequences of major bleeding

2. The incidence and associated mortality of major thrombotic (stentthrombosis and/or MI) and bleeding (BARC 3-5) events.

3. The identification of predictors for both types of events in this population

Location of Major Bleeding

76

24

12 10 8 7 7 6 63

1 2 80

10

30

20

40

60

50

70

80

Nu

mb

er

of

pa

tie

nts

170 first major bleeding events

PPI at discharge

51.9% of all trial patients

64.5% of patients with subsequent GI bleed

Major Bleeding and Thrombotic Events by Main Inclusion Criteria

11

8,1

11,311,6

6,2

6,9

6,5

7,78,1

6,9

17,6

13

10,1

9,1

7,8

4,7

0 5 10 15 20

Hb<11g/dl or recent transfusion (379)

Bleeding in prior 12 months(79)

Renal insufficency (464)

Cancer (239)

Planned OAC use post-PCI(879)

Planned surgery (398)

Age > 75 (1564)

Expected poor compliance (88)

BARC 3-5

MI and/or ST

%

DAPT SAPT

Major Bleeding and Thrombotic Events in the DCS and BMS Arms

8.6%

7.3%

7.2%

5.7%

4

2

0

BMS - Thrombotic Events DCS - Thrombotic Events

p=0.006

BMS - Bleeding DCS - Bleeding

6

8

10

0 90 180 270

Days since procedure

360

Cu

mu

lati

ve

Pe

rce

nta

ge

(%)

BARC 3-5 Bleeding

3

p = 0.957

0

90 180 270 390 Days

Cum

ula

tive

Pe

rce

nta

ge

with

Eve

nt

6

9

%

12

0

SAPTDAPT

Number at risk

DCS 1220 1129 1098 1078 1044

BMS 1211 1116 1085 1058 1021

Mortality Following Bleeding and Thrombotic Events

25,424,4

0

5

10

15

20

25

Died during follow-up

%

30

BARC 3-5 MI and/or ST

n.s.

7,1

13,7

0

5

10

15

20

25

Died within 7 days of event

%

30

BARC 3-5 MI and/or ST

p=0.051

Mortality during FU for patients with neither BARC 3-5 or MI/ST was 6.2%

Prediction of Major Bleeding and

Thrombotic Events

•Development of 2 separate prediction models

→ Major bleeding

→ Major thrombotic events (MI/ST)

•Common set of 33 candidate predictors

→ Baseline or procedural characteristics

•Cox-regression

→ Forward selection of candidate predictors

→ P-value of 0.05 for inclusion

Candidate Predictors (n=33)

Independent Predictors of Bleeding and Thrombosis

(Hazard Ratio % 95% CI)

Model C-statistic 0.66 0.71

* Below 9 mmol/l (145 g/l)

Thrombotic Events Major Bleeding

Plasma creatinine > 150 umol/l 1.80 (1.19-2.72) p=0.005 -

Multivessel disease 1.70 (1.14-2.54) p=0.010 -

Bifurcation target lesion (1 or more) 1.50 (1.03-2.19) p=0.036 -

BMS (vs. DCS) 1.43 (1.04-1.98) p=0.029 -

Age > 75 1.53 (1.08-2.16) p=0.017 1.50 (1.08-2.08) p=0.021

Number of stents/patient (per stent) 1.16 (1.02-1.31) p=0.018 1.14 (1.02-1.27) p=0.025

Haemoglobin (per 1 mmol/l lower)* 1.21 (1.04-1.40) p=0.014 1.74 (1.53-1.99) p<0.001

Femoral access - 1.66 (1.22-2.27) p=0.001

Oral anticoagulants - 1.83 (1.34-2.50) p>0.001

Baseline Haemoglobin: A Very

Powerful Predictor of Bleeding

BARC 3-5MI and/or ST

Predicted Individual Patient Risks of Major Bleeding & Thrombotic Events

1.2

52

.55

10

20

40

Pre

dic

ted

1-y

ea

rM

I/S

Trisk

(%)

1.25 2.5 5 10 20Predicted 1-year bleeding risk (%)

DCS BMS

40

Thrombotic risk > 2x bleeding risk n=286 (13.1%)

Conclusions (I)

These data represent the first attempt to define the balance of bleeding and thrombosis in a population defined by a high bleeding risk and followed for 390 days after PCI with 1 month DAPT only:

Major bleeding (BARC 3-5) was frequent (7.2%)

Mortality rates during follow-up after major bleeding (25.4%) or thrombotic events (24.4%) were high and comparable

Patients at the highest risk for bleeding were generally also thoseat the highest risk of thrombosis

Thrombotic risk (ST and/or MI) was significantly lower with DCS (5.7%) than BMS (8.6%)

Conclusions (II)

9 predictors for thrombosis and/or bleeding were identifiedfor HBR patients. It is a good model for bleeding, but hasmore limited discrimination for thrombosis

Predictors of bleeding: low hemoglobin levels, planneduse of OAC at discharge and femoral access

Predictors of thrombosis: renal insufficency,multivessel disease, bifurcation target lesion, and use of a BMS

Predictors of both: advanced age and use of multiple

stents

With the goal of aiding to define individual priorities, a simplifiedbleeding vs. thrombosis trade-off score is under development,and should be available soon.

LEADERS FREE – Impact on Practice

Conclusions

• LEADERS FREE is an important study: (1) raised awareness of HBR patients who represent a frequent clinical dilemma and have been excluded in most previous clinical trials;(2) introduced an alternative to BMS, asessed usingrigorous study methodology

• Study demonstrated superiority of Biofreedom cw BMS:both safety and efficacy endpoints (as defined)

• Study outcomes raise many qualifying considerations: broaddefinition of HBR, control BMS ↑ ST at 1 year (2.2%), safetyendpoint driven by ↑ MI 2ry ISR, no cw with best-in-class“current” generation DES

LEADERS FREE – Impact on Practice

Conclusions

(my thinking opinion)

Is the 1 month DAPT regimen after PCI safe for HBR patients?

Definitely No ! The 1 week and 1yr mortalities due to bleeding and

thrombotic events are too high ( as high as 7.1% and 13.7% ,and 25.4% and 24.4% !) with DCS !

The 1 yr rates of cardiac death and ST ( 5.3% and 2.2% ) is also too high in the BMS arm

Is the 1 month DAPT regimen after PCI Problematic in ethics

for those patients with low thrombotic events

Yes, sure ! What is the right strategy for those HBR patients?

Medical therapy in most cases PTCA is of choice in some patients if needed

What can we learn from the LEADERS FREE trial? Negative example for lession! Forget the 1 month DAPT regimen for PCI patients no matter the

bleeding risk is !

Thank you for your attention !