Philip Urban

Meyrin - Geneva

June 15, 2016

High bleeding risk? No longer a contraindication for DES

Coronary stenting & bleeding risk

• Early days & the DAPT duration debate

• HBR patients & the LEADERS FREE trial

• Other data from randomized trials

• Bleeding vs. thrombosis

Gladys Desmeules 1936 12 Juin, 1986

2006

1988

Angiographic follow-up after placement of a self-expanding coronary artery stent

Serruys PW et al New Eng J Med 1991;324:13-17

67%

5%

3%2%

23%

Scan of fig 1

patent

occluded

March 86-January 88

117 wallstents in 105 patients

Angio FU in 95 patients at 5.7 mths

23%

6.2

2.4

8.6

11

1.6

0.6

5.7 5.6

3.6

0

2

4

6

8

10

12

ISAR STARS FANTASTIC MATTIS

ASA + OAC

ASA + TIC

ASA

Death/MI/Re-intervention at 30-day

Antithrombotic treatment

after bare metal stent implantation

ISAR: Schoemig A et al, NEJM 1996;334:1084

STARS: Leon M et al, NEJM 1998;339:1665

FANTASTIC: Bertrand ME et al, Circulation 1998;98:1597

MATTIS: Urban P et al, Circulation 1998;98:2126

%

RAVEL - Marie-Claude Morice et al.N Engl J Med 2002;346:1773-80

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

OPTIDUAL (1799)

DES LATE (2701)

DAPT DES (9961)

ITALIC (1850)

PRODIGY (2014)

ARCTIC INTER. (1259)

SECURITY (1399)

ISAR SAFE (4000)

EXCELLENT (1443)

OPTIMIZE (3120)

RESET (2117)

MACCE ST

months

DAPT duration after DES

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

OPTIDUAL (1799)

DES LATE (2701)

DAPT DES (9961)

ITALIC (1850)

PRODIGY (2014)

ARCTIC INTER. (1259)

SECURITY (1399)

ISAR SAFE (4000)

EXCELLENT (1443)

OPTIMIZE (3120)

RESET (2117)

BLEEDING

DAPT duration after DES

months

«For every complex problem there is an answer that is clear, simple and wrong»

H.L.Menken

Optimal DAPT duration after coronary stenting?

Ndrepepa G et al J Am Coll Cardiol 2008;51:690–7

4 ISAR trials (5384 patients)

DAPT duration

Stent

Lesion & Procedure

Patient

Coronary stenting & bleeding risk

• Early days & the DAPT duration debate

• HBR patients & the LEADERS FREE trial

• Other data from randomized trials

• Bleeding vs. thrombosis

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

Ventes

All-comers HBR

Planned surgeryNeed for anticoagulants

Anemia/bleeding

Cancer

Recent

stroke

Advanced age

BioFreedom™ Drug Coated Stent (DCS)

Potential Advantages:

Avoid any possible polymer-related adverse effects

Rapid drug transfer to vessel wall (98% within one month2)

Safe to shorten DAPT?

BA9TM Drug 10 Times More

Lipophilic than Sirolimus1

Sirolimus Zotarolimus Everolimus Biolimus A9TM

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

Selectively Micro-Structured Surface Holds

Drug in Abluminal Surface Structures

Median In-Stent LLL at 12-month Follow-up2nd Cohort – Primary Endpoint

0.17

0.22

0.35

0

0.1

0.2

0.3

0.4

0.5

BioFreedom BioFreedom low-dose Taxus

N = 31 N = 31N = 35

p = 0.001 (non-inferiority)

Costa R et al. J Am Coll Cardiol Intv. 2016; 9: 51-64

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)

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

Leaders Free

Switzerland

Participating Center Principal Investigator Enrollment

Triemli Hospital, CH Franz Eberli 47

University Hospital Zurich, CH Oliver Gamperli 23

Centre Hospitalier Universitaire Vaudois (CHUV), CH Eric Eeckhout 23

Cardiocentro Ticino, CH Tiziano Moccetti 19

La Tour Hospital, CH Philip Urban 10

Franz Eberli MD

• 74 year old man, 5 weeks crescendo angina (August 2013).

• First episode during a mountain hike, now with minimal exertion

•

• 2010 Prostate cancer:

• Radical prostatectomy & radiation therapy

• Radiation proctitis complicated by infrequent bleeding

• 2013 Bladder cancer: partial surgical resection of bladder

PCI August 14, 2013

Stenosis mid LAD Stent 2.75x14mm Result post Stent

Stopped Clopidogrel mid-September 2013

May 2014: macrohematuria + reintervention (on ASA) for bladder ca.

August 2015 (2 year FU): doing well, no angina, no further bleeding.

Christoph Dubois MD

• 84 years old man

• NIDD, high BP, hyperlipidemia

• Hx gastric ulcer

• AF on Pradaxa (110 mg BD)

• Creatinine clearance 52 ml/min

• Hb 10.7 g/dl

• Admitted for CHF, preserved LVEF, inferior

hypokinesia, biopsies negative for amyloidosis

Diagnostic angiogram

PCI - April 2014

Antithrombotic regimen:

1 mth triple Rx

11 mths NOAC + ASA

Then NOAC aloneClinical events:

June 2014: fall + haematoma requiring hospital

admission (Hb 8.4 g/dl) – adjudicated as BARC 2

Nov 2014: Readmitted for CHF + renal failure

April 2016: stable, no angina.

Study stent 28 x 3.5 mm

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

Inclusion Criteria Applied (1.7 criteria / patient)

1.1

0.9

1.2

1.6

3.1

3.4

3.8

9.7

15.2

15.3

17.9

36.7

64.5

1.6

0.8

2

1.5

2.8

3.9

2.7

9.9

16

17.4

20.2

35.6

64.1

0 10 20 30 40 50 60 70

Prior intracerebral bleed

Severe liver disease

Stroke < 1 year

Thrombocytopenia

NSAID or steroids

DAPT compliance

Hospital for bleeding

Cancer

Anemia or recent TF

Surgery soon

Renal failure

Oral anticoagulants

Age ≥ 75

BMS

DCS

Urban P et al, NEJM 2015; 373: 2038-47

Baseline Characteristics

DCS (%) BMS (%)

Mean age 75.7 + 9.4 75.7+9.3

Female gender 29.8 30.9

BMI 27.5 ± 4.8 27.2 ± 4.6

Diabetes 34.0 32.3

NSTEMI presentation 22.4 23.2

STEMI presentation 4.7 4.0

Prior MI 19.6 21.4

Prior PCI 22.2 21.9

Prior CABG 9.4 10.1

Multivessel CAD 62.9 61.6

Congestive heart failure 14.4 12.4

Atrial fibrillation 34.9 34.6

Peripheral vascular disease 15.7 15.8

Chronic obstructive lung disease 10.9 11.7

None of the baseline characteristics differ at p < 0.05

Urban P et al, NEJM 2015; 373: 2038-47

Index Procedure

DCS (%) BMS (%)

Radial access 60.7 58.7

Staged procedure 4.5 5.9

Multi-lesion procedure 37.8 35.3

Multi-vessel procedure 21.8 21.4

Number of treated lesions / patient 1.6 ± 0.8 1.6 ± 0.9

LMS 3.0 3.9

SVG 1.4 1.8

Bifurcation 14.9 16.0

ISR 2.4 2.6

CTO 5.0 4.4

None of the procedure characteristics differ at p < 0.05

Urban P et al, NEJM 2015; 373: 2038-47

Index Procedure (Continued)

DCS BMS

Mean stent diameter 3.0 ± 0.4 3.0 ± 0.4

Mean total implanted

stent length / patient34.5 ± 23.1 33.4 ± 23.4

Mean number of stents

implanted / patient1.9 ± 1.1 1.8 ± 1.2

Lesion success 97.7 98.0

Device success 97.7 97.6

Procedure success 94.4 93.7

UFH during procedure 90.5 89.4

LMWH during procedure 8.4 8.8

Bivalirudin during procedure 1.1 1.8

2b3a blocker during procedure 2.0 1.2

None of the procedure characteristics differ at p < 0.05

Urban P et al, NEJM 2015; 373: 2038-47

Primary Endpoints

LEADERS FREE

Efficacy (cd-TLR) Safety (cardiac death, MI, ST)

DCS BMS BMSDCS

Primary Efficacy and Safety Endpoints

Urban P et al, NEJM 2015; 373: 2038-47

Components of Safety Endpoint

4.2

6.1

2.0

5.3

8.9

2.2

0

1

2

3

4

5

6

7

8

9

10

Cardiac death MI ST (def / prob)

DCS BMS

%

p = 0.01 p = 0.70p = 0.19

Urban P et al, NEJM 2015; 373: 2038-47

Bleeding During 12 Months Follow-Up

18.1

13.9

7.2

19.1

14.7

7.3

0

5

10

15

20

25

BARC 1-5 BARC 2-5 BARC 3-5

DCS BMS

%

p = 0.55 p = 0.68 p = 0.96

Urban P et al, NEJM 2015; 373: 2038-47

Major bleeding in DES DAPT trials (first 12 months on DAPT after PCI)

7.2

2.8 2.7

0.6 0.6 0.4

0

1

2

3

4

5

6

7

8

LEADERSFREE

ARCTIC(2440)

DAPT DES(22866)

EXCELLENT(721)

RESET(1058)

OPTIMIZE(1556)

%

LEADERS FREE BARC 3-5

ARCTIC STEEPLE major

DAPT DES GUSTO moderate or severe

EXCELLENT TIMI major

RESET TIMI major

OPTIMIZE trial specific

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✗ ✗ ✗ ✗ ✓

DAPT trials exclusion criteria (✗)

vs. LEADERS FREE inclusion criteria (✓)

There now is a choice…

PCI candidate

not HBR HBR

DCS & short DAPTDES & guidelines

Coronary stenting & bleeding risk

• Early days & the DAPT duration debate

• HBR patients & the LEADERS FREE trial

• Other data from randomized trials

• Bleeding vs. thrombosis

DES & very short DAPT - two very different questions:

Is it safe to stop early

for selected patients?how do DES/DCS compare

with a BMS standard, combined

with systematic ultra-short DAPT ?

RESET (E-ZES 3 mo)

OPTIMIZE (E-ZES 3 mo)

LEADERS FREE (BA9 DCS 1 mo)

ZEUS HBR (E-ZES 32 days)

All comers High risk for bleeding

• 2117 patients

• 1ary EP: CV death, MI, ST, TVR

or bleeding

E-ZES + 3 mo DAPT

vs.

SES, EES or R-ZES + 12 mo DAPT

JACC 2012; 60: 1340-8

Major bleeding

E-ZES: 0.2%

Control: 0.6%

Primary EP Stent thrombosis

E-ZES vs. a thin-strut BMS

+ 30 days DAPT

• 828 HBR patients

• 1ary EP: death, MI, TVR

JACC intv 2016; 9: 426-36

Completed randomized trials (clinical endpoints)

of very short DAPT (3 months or less)

Trial stent typelimus

kineticspatients

experimental

arm DAPTcomparator outcome

RESET (1)Endeavor

ZES

1st G

perm polyfast

2117

Low/med risk3 months

R-ZES, SES or

EES & 12

months DAPT

achieved

non-inferiority

OPTIMIZE (2)Endeavor

ZES

1st G

perm polyfast

3119

Low/med risk3 months

E-ZES & 12

months DAPT

achieved

non-inferiority

ZEUS (3)Endeavor

ZES

1st G

perm polyfast

1606

Doubtful DES

candidates

variable

(median

32 days)

BMS &

same DAPT

Achieved

superiority

LEADERS

FREE (4)

BioFreedom

BESpolymer-free fast

2466 High Bleeding Risk

(HBR)1 month

BMS &

same DAPT

achieved

superiority for

safety & efficacy

1) Kim B-K et al. JACC 2012; 60: 1340-8

2) Feres F et al. JAMA 2013; 310: 2510-22

3) Valgimigli M et al. JACC 2015;65:805-15

4) Urban P et al. NEJM 2015; 373: 2038-47

Coronary stenting & bleeding risk

• Early days & the DAPT duration debate

• HBR patients & the LEADERS FREE trial

• Other data from randomized trials

• Bleeding vs. thrombosis

A delicate balance

bleedingthrombosis

DAPT SAPT

Major Bleeding and Thrombotic Eventsin the DCS and BMS Arms

8.6%

7.3%

7.2%

5.7%

p=0.006

BMS - Bleeding

BMS - Thrombotic Events

DCS - Bleeding

DCS - Thrombotic Events

0

2

4

6

8

10

0 90 180 270 360

Cu

mu

lati

ve

Pe

rce

nta

ge

(%

)

Days since procedure

Independent Predictors of Bleeding and Thrombosis

(Hazard Ratio % 95% CI)

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

Model C-statistic 0.66 0.71

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

Predicted Individual Patient Risks of Major Bleeding & Thrombotic Events

1.2

52

.55

10

20

40

Pre

dic

ted

1-y

ea

r M

I/S

T r

isk (

%)

1.25 2.5 5 10 20 40Predicted 1-year bleeding risk (%)

DCS BMS

Thrombotic risk > 2x bleeding risk

Bleeding risk > 2x thrombotic risk

Example #1 from LEADERS FREE

• 75 years old lady

• Recurrent GI bleeding

• Presents with NSTEMI

Hemoglobin = 9.7 g/dl

Colonic angiodysplasia LM stenosis (Medina 1-1-1)

Femoral access

LM bifurcation target

Multivessel disease

• Culotte to LM (2 BMS)

September 2013

• Day 14 after PCI:

GI bleeding, & Hb drop to 7.9 g/dl

NSTEMI (type 2 MI)

Transfused 2 units (BARC 3a)

Continued on DAPT

• Clopidogrel alone after day 29

• No further events during 2 year FU

Courtesy of Keith Oldroyd, Glasgow, Scotland

Trial stent typelimus

kineticspatients

experimental arm DAPT

control armStatus

(clinicaltrials.gov) Spring 2016

SENIORSynergy

EES2nd G

biodeg polyslow

1200 elderly (>75)

SCAD 1 month ACS 6 months

BMSenrolment completed

YONSEIUNIVERSITY

BioFreedom

DCSpolymer-free fast

3020 low risk SCAD

1 monthBiomatrix & 6-12 mths

DAPT enrolling

ISAR DAPT Coroflex ISARpolymer-free

matrixslow

906low risk SCAD

3 months 6 months DAPT enrolling

REDUCECombo

SESEPC capture &

biodeg polyslow

1500 low risk ACS after

successful PCI3 months 1 year DAPT enrolling

ReCre8 Cre8SES

polymer-free slow1532

all-comersSCAD 1 month ACS 12 months

R-ZES same DAPT

enrolling

MASTER DAPTUltimaster

SES2nd G

biodeg polyslow

4300HBR

1 month guidelines planned

HOST-IDEAOrsiro SES

Coroflex ISAR

2ndG biodegPoly-free

matrix

slow

slow

2132SCAD

(no OAC)3 months 1 year DAPT planned

STOPDAPT-2Xience

EES2nd G

perm polyslow

3000low/med risksuccessful PCI

1 month 1 year DAPT planned

COBRA-REDUCE

Cobra PzFPolyzene-F

nanocoatingna

840 on AVK or NOAC

2 weeksEES or R-ZES &

6mths DAPTplanned

Ongoing/planned RCT (clinical endpoints)

of short DAPT (3 months or less)

Conclusions (I)

HBR patients have until now often been excluded from

stent and drug trials. They constitute a rapidly growing

proportion of PCI candidates and suffer high event

rates

LEADERS FREE is the first randomized clinical trial

dedicated to such patients

Together with an ultra-short (1 month) DAPT course,

the use of a BA9-DCS was both significantly safer and

more effective than a control BMS in HBR patients

Conclusions (II)

An increased bleeding risk often goes together with an

increased risk of thrombotic events

The BioFreedom DCS with 1 month DAPT should be

considered as the current default therapy for HBR

patients

Several other DES (with degradable or permanent

polymers) are currently beeing evaluated with short

DAPT in HBR patients, but no results are yet

available.

BMS should no longer be used

Thank you