Disclosure William Marston, M.D.

I disclose the following financial relationship(s):

•Consultant/Advisory Board: Advanced BioHealing, BSN Jobst

Venous leg ulcers:

Wound preparation and adjuvants to healing

Bill Marston, MD

Professor of Surgery

Director, Wound Management

Center

University of North Carolina

Medical School

Rx protocol for VLU

• Compression

• Wound debridement/elimination of bacteria

• Exudate control

• Adjuvant therapies to accelerate closure

• Prevention of recurrence

Adjuvant therapies

• Skin grafting

• Bioengineered dermal equivalents

– Apligraf

– Orcel

– Dermagraft

• Non-living dermal substitutes

– Oasis

• Growth factors

– nil

Growth factors for VLU healing

• Becaplermin (Regranex):

– Recombinant platelet-derived growth factor

– No evidence of benefit in limited studies

• Keratinocyte growth factor

– No significant difference in trial of over 300 patients

• Is there a growth factor deficit in VLU?

Venous leg ulcer biopsy before

and after compression treatment

0

20

40

60

80

100

120

140

160

pg/ml

EGF GM CSF VEGF TNF-a

Normal

before Rx

after Rx

UNC data unpublished

N=8

STSG for VLU: Results

Author # Pts Method Initial rate

of ulcer

healing

Long term

results

Kirsner et al

Derm Surg 1995

50 STSG in

hospital

70% 52% at

one year

Millard et al

Br J Derm 1997

41 STSG 74% NA

Schmeller et al

JAAD 1998

13 Debride to

fascia

STSG

80% 88% at

one year

Living human dermal substitutes

Apligraf: Structure

• Bilayered human skin equivalent

• Source neonatal foreskin

• Dermal layer composed of living fibroblasts

interspersed within a bovine-derived

collagen matrix

• Overlying epidermal layer composed of

living human keratinocytes

FGF = fibroblast growth factor; ECGF = endothelial cell growth factor; IGF = insulin-like

growth factor; PDGF = platelet-derived growth factor; TGF = transforming growth factor;

IL = interleukin; VEGF = vascular endothelial growth factor.

FGF-1

FGF-2

FGF-7

ECGF

IGF-1

IGF-2

PDGF-AB

TGF-

IL-1

IL-6

IL-8

IL-11

TGF-1

TGF-3

VEGF

+

–

–

–

–

–

+

+

+

–

–

–

–

–

+

+

+

+

+

–

+

+

–

–

+

–

+

+

+

–

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

Human Keratinocytes

Human Dermal Fibroblasts

Apligraf

Human Skin

CYTOKINE EXPRESSION IN

APLIGRAF AND HUMAN SKIN

Apligraf: Method of application

• Wound bed

preparation

– good granulation

– edema control

– bacterial balance

• Debride wound to

healthy, bleeding base

Apligraf: method of application

• Must use compression if venous leg ulcer

– Multi-layered elastic compression

• Management of wound drainage critical

– Foam dressings optimal for exudate

• Do not debride wound for 2-3 weeks after application

– Avoid temptation to remove yellow slough

Apligraf: venous leg ulcer pivotal

trial

• 240 patients

• Ulcers present > 1 month

• Average 3.3 applications

• Applied with compression

• Percent closed at 24 weeks compared to compression alone

0

10

20

30

40

50

60

24 weeks

Apligraf

control

57%

40%

P=0.02

Apligraf: venous leg ulcer pivotal

trial

0

5

10

15

20

25

30

35

40

45

50

24 weeks

Apligraf

control

0

10

20

30

40

50

60

70

80

90

100

24 weeks

Apligraf

control

Ulcer duration > 1 year

P = 0.002 N=120

P = NS

Ulcer duration < 1 year

47%

19%

66 73%

N=120

Apligraf - cost

• Approx $1200 per piece (7.5 cm diameter)

• May require multiple applications for

results to match those in clinical trials

– Avg 3.4 applications per patient in venous

study

• Reimbursed by most insurers including

medicare

Cost-efficacy of Apligraf for VLU

Comparison to Clopidogrel

Caprie trial: Clopidogrel vs Aspirin

for patients at risk for ischemic

events

Ischemic event

• Asymptomatic MI

• Symptomatic non-

fatal MI

• Fatal MI

• Stroke

Caprie trial specifics: Use of RRR

• Nearly 20,000 patients enrolled

• Incidence of ischemic event at 2 yrs

– Aspirin 9.6%

– Clopidogrel 7.9%

• Absolute reduction in event incidence 1.7%

• Relative risk reduction 18%

• Cost – Aspirin $2-3/month

– Clopidogrel $60-80/month

Apply RRR to wound healing

• Apligraf VLU pivotal trial – 40% healed SOC

– 57% healed with SOC plus AG

– 42% relative increase in healed wounds

Number needed to treat

• To prevent an ischemic event

– Need to treat 59 patients with clopidogrel instead of ASA

– Cost for each prevented event $85,000

• To heal one additional wound

– Need to treat 6 patients with AG

– Cost for each additional healed wound

– $15,000 - 25,000 depending on # used per pt

What is the difference between treating CAD and healing a chronic wound?

Treatments reported in case series to

assist in VLU healing but no

randomized studies testing benefit

• Intermittent pneumatic

compression

• Therapeutic Ultrasound

• Electromagnetic therapy

• Hyperbaric oxygen

• Negative pressure wound

therapy

• Cochrane Review

Library

– no strong evidence to

support use of these

treatments for venous

leg ulcers

Currently in clinical trials

• 2nd generation living dermal equivalents

– Dermagraft

– HP-802

• Dermal matrix implants

– Integra

• Stem cell delivery

– Early phase results promising

• Protease inhibitors

• Anti-inflammatory

agents

Reimbursement for applying

biologics

• Apligraf

– VSU > 3 month duration failing to respond to 1-2 months of conservative Rx

– 15340 and 15341 codes

– Medicare allowable $250 - 300

– 10 day global

Conclusions

• Compression methods provide baseline treatment modality

• Bacterial control is critical

• Assess progress at 3-6 weeks

• For slow responders/large ulcers, consider addition of active modalities

– Apligraf

• Get to know your local wound centers