First-in-man experience with the DES Orsiro in the treatment of patients with single de novo coronary

artery lesions (BIOFLOW-I)

Martial Hamon, MD, FESCUniversity Hospital of Caen

Normandy, France

ClinicalTrials.gov Identifier: NCT01214148

Speaker’s name: Martial Hamon

I have the following potential conflicts of interest to report: Research contracts Consulting for BIOTRONIK AG Employment in industry Stockholder of a healthcare company Owner of a healthcare company Other(s)

I do not have any potential conflict of interest

Potential conflicts of interest

Background

• Early generations of DES have reduced restenosis, but have been associated with an increased risk of late events

• Efforts to resolve these problems have been made including improvements in stent platforms, polymer carriers as well as drug selection

• A hybrid combination of active and passive coatings on a DES aim to optimize effectiveness of results and also mediate the threat of late events

• The aim of the BIOFLOW-I study was to evaluate the safety and efficacy of the Orsiro Hybrid Drug Eluting Stent with a bioabsorbable polymer, in patients with a single de novo lesion in a native coronary artery

The device: Orsiro Hybrid Drug Eluting Stent

• PROBIO® passive coating encapsulates the stent and minimizes interaction between the metal stent and the surrounding tissue

• BIOlute® active coating contains a highly biocompatible polymer which delivers a Limus drug via a biodegradable matrix

• PRO-Kinetic Energy Stent System brings good deliverability for reaching complex lesions

BIOlute® achieves acontrolled drug release

The BIOlute® polymer matrix gently degrades into CO2 and H2O

Only a PROBIO® sealed stent is left in the arterial wall

Quick facts

Passive coating PROBIO® amorphous silicon carbide coating

Active coating BIOlute® bioabsorbable PLLA eluting Sirolimus

Drug dose 1.4 µg/mm2

Stent material Cobalt chromium L-605

Strut thickness 60 µm (3.00 mm stent)

Approval status CE approved

Investigational centers & core lab

Principal investigatorRodica Niculescu, MD, PhD, FESCSpitalul Clinic de Urgenţă Bucureşti, Romania

15 Subjects enrolled 100% Angio & IVUS FUP @ 4month100% Angio & IVUS FUP @ 9month

Angiography CorelabRon Waksman MDMedStar Health Research Institute, Washington DC, USA

Principal investigatorDan Deleanu, MD, FESCInstitutul de Urgenţă pentru Boli Cardiovasculare, Romania

15 Subjects enrolled100% Angio FUP @ 4month100% Angio FUP @ 9month

IVUS CorelabNeil J. Weissman MDMedStar Health Research Institute, Washington DC, USA

BIOFLOW-I trial design

Clinical endpoint assessment

Angiographic & IVUS endpoint assessment

30 d 4 mo 9 mo 12 mo 2 yr 3 yr

• Design: Prospective, multi-centre, first in man trial • Patient Number: 30• Patents with angiographic follow-up: 30• Patients with IVUS follow-up: 15• Follow-up rate: 100%• Enrollment time: Between 02 – 23 July 2009

Study endpoints

Primary Endpoint• In-stent late lumen loss at 9 months by QCA

Secondary Endpoints • In-stent and in-segment binary restenosis rate at 4 and 9 months post procedure• Clinically driven target lesion revascularization (TLR) at 1, 4 and 9 months and at 1,

2 and 3 years post-procedure• Composite of cardiac death, MI attributed to the target vessel and clinically driven

target lesion revascularization at 1, 4 and 9 month post-procedure, and yearly up to 3 years

• Stent thrombosis at 1, 4 and 9 months, and at 1, 2 and 3 years post-procedure.Definitions• Lesion Treatment Success is defined as the attainment of <30% residual stenosis

by offline QCA using any percutaneous method• Device Success defined as achievement of a final residual diameter stenosis of

<30% by offline QCA, using the assigned device only

Patient eligibility

Inclusion Criteria• Patient is ≥18 years old• Clinical evidence of ischemic heart disease

and / or a positive functional study. Documented stable angina pectoris, or documented silent ischemia

• Single de novo lesion with ≥50% and <90% stenosis in 1 coronary artery

Exclusion Criteria• Documented left ventricular ejection

fraction (LVEF) ≤ 30%• ACS (NSTE-MI or STEMI)• Three-vessel coronary artery disease• Evidence of myocardial infarction

within 72 hours prior to the index procedure

• Total occlusion (TIMI 0 or 1)• Target lesion is located in or supplied

by an arterial or venous bypass graft• Target lesion involves a side branch

>2.0mm in diameter• Unprotected Left main coronary

artery disease (stenosis >50%)

Baseline clinical characteristics

N=30

Age, years 58.10 yrs ± 9.80

Male sex 60.0% 18/30

Hyperlipidemia 93.3% 28/30

History of MI 73.3% 22/30

Hypertension 66.6% 20/30

Smoker 53.3% 16/30

Diabetes 23.3% 7/30

CHF 20.0% 6/30

Baseline lesion characteristics

Pre-Procedure N=30

RVD (mm) 2.75 ± 0.34

MLD (mm) 0.95 ± 0.29

% Diameter stenosis 65.52 ± 9.47

Mean Lesion length (mm) 11.71 ± 4.40

Procedural N=30

Stent length per lesion (mm) 19.93 ± 5.33

Stent diameter per lesion (mm) 3.08 ± 0.37

Direct stenting 20.0%

Device success* 100.0%* Defined as In-Stent < 30% residual stenosis by offline QCA

Angiographic follow-up results4-month FUP 9-month FUP

RVD (mm) 2.81 ± 0.28 2.81 ± 0.30

Minimal Lumen Diameter In-stent (mm) 2.50 ± 0.36 2.56 ± 0.38

In-segment (mm) 2.20 ± 0.35 2.21 ± 0.31

Diameter Stenosis In-stent (%) 15.19 ± 4.55 13.60 ± 4.27

In-segment (%) 23.66 ± 9.80 23.55 ± 8.06

Late Loss In-stent (mm) 0.12 ± 0.19 0.05 ± 0.22

In-segment (mm) 0.06 ± 0.23 0.05 ± 0.26

Binary Restenosis In-stent (mm) 0% 0%

In-segment (mm) 0% 0%

Cumulative frequency of Diameter Stenosis

Cumulative Frequency of Minimum Lumen Diameter

Cumulative Frequency of In-Stent Late Lumen Loss

Mean In-Stent LLL:4 Months 0.12 ± 0.219 Months 0.05 ± 0.22

9-month clinical results N %Death 0 0.0

Stent thrombosis 0 0.0

MI 0 0.0

TLR (clinically driven) 2 6.7

MACE 2 6.7

Clinical outcomes at 9 months

BIOFLOW-I results in perspective

Overview of in stent late lumen loss in FIM trials

* Randomized trial. Only number of patients in device arm displayed

1 Serruys et al. A randomized comparison of a durable polymer Everolimus-eluting stent with a bare metal coronary stent: The SPIRIT first trial; Eurointervention2 Ormiston et al. Six-month results of the NEVO Res-Elution I (NEVO RES-I) trial: a randomized, multicenter comparison of the NEVO sirolimus-eluting coronary stent with the TAXUS Liberte paclitaxel-eluting stent in de novo native coronary artery lesions; Circ.Cardiovasc.Interv.3 Sousa et al. Lack of neointimal proliferation after implantation of sirolimus-coated stents in human coronary arteries: a quantitative coronary angiography and three-dimensional intravascular ultrasound study; Circulation4 Meredith et al. The next-generation Endeavor Resolute stent: 4-month clinical and angiographic results from the Endeavor Resolute first-in-man trial; EuroIntervention5 Meredith et al. Clinical and angiographic results with the next-generation resolute stent system: a prospective, multicenter, first-in-human trial; JACC.Cardiovasc.Interv.

FIM SR3

4 mn=15

NevoNevo Res-I2*

6 mn=186

XienceVSPIRIT First1

6 m n=28

Endeavor Resolute OrsiroBIOFLOW-I9 mn=30

FIM FR3

4 mn=15

FIM4

4 mn=30

FIM5

9 mn=92

Cypher

± 0.21

± 0.31

± 0.30

± 0.26

± 0.27

± 0.22

(mm)

0.10

0.13

0.09

-0.01

0.12

0.22

0.05

BIOFLOW-I Case report Pre-procedural angiography

Medical history & risk factors• Male, 53 yrs• MI (April-2009), smoker,

hyperlipidemia, DM (insulin)

Procedure 09 JUL 2009RCA midLesion length 16 mm

Source: BIOFLOW-i case, patient ROM001-009

BIOFLOW-I Case report Post-procedural angiography

Medical history & risk factors• Male, 53 yrs• MI (April-2009), smoker,

hyperlipidemia, DM (insulin)

Procedure 09 JUL 2009RCA midLesion length 16 mmPost-dilatationStent size 3.5 x 18 mmMax pressure 21 atm

Source: BIOFLOW-i case, patient ROM001-009

BIOFLOW-I Case report Four-month follow-up angiography

Medical history & risk factors• Male, 53 yrs• MI (April-2009), smoker,

hyperlipidemia, DM (insulin)

Procedure 09 JUL 2009RCA midLesion length 16 mmPost-dilatationStent size 3.5 x 18 mmMax pressure 21 atm

Source: BIOFLOW-i case, patient ROM001-009

BIOFLOW-I Case report Nine-month follow-up angiography

Medical history & risk factors• Male, 53 yrs• MI (April-2009), smoker,

hyperlipidemia, DM (insulin)

Procedure 09 JUL 2009RCA midLesion length 16 mmPost-dilatationStent size 3.5 x 18 mmMax pressure 21 atm

Source: BIOFLOW-i case, patient ROM001-009

Study design

– A prospective, multi-centre, single treatment clinical trial

– Endpoint: LLL 9 months, N=30

– A prospective, multi-center, non-inferiority, randomized study, Orsiro vs. Xience Prime

– Endpoint: LLL at 9 months, N=440

– A prospective, multi-centre, single treatment clinical study

– Endpoint: LLL at 9 months, N=120

– A prospective, multi-centre, single treatment clinical registry

– Endpoint: TLF at 9 months, with long term follow-up, N=1000+

– Comparative, non-inferiority trial evaluating safety and efficacy

– Study to evaluate safety and efficacy in a complex patient population

– Post marketing surveillance to demonstrate long term outcomes

– First-in-man study evaluating safety and efficacy, data submitted during CE approval (TÜV)

Clinical strategy

Study design

Clinical strategy

BIOFLOW Clinical Program for Orsiro Hybrid Drug Eluting Stent

Conclusions

• In this FIM study with a primary angiographic endpoint, the Orsiro Hybrid DES showed excellent results in terms of late lumen loss in the overall patient population

• This mixed population of patients is atypical for a FIM study, with its high rate of diabetic patients and complex lesions

• At 9 months follow-up, no late catch-up was seen in the LLL values and a narrow standard deviation suggests that these study results are quite robust

• A larger randomized, comparative study is currently running to prove the safety and effectiveness of this promising device