By: William Marston, M.D. Visit VeinGlobal at http://www.veinglobal.com/ for more presentations and videos on this topic, or for more information on venous disease news, education and research.

1. Disclosure
William Marston, M.D.
I disclose the following financial relationship(s):
•Consultant/Advisory Board: Advanced
BioHealing, BSN Jobst

2. 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

3. Rx protocol for VLU
• Compression
• Wound debridement/elimination of bacteria
• Exudate control
• Adjuvant therapies to accelerate closure
• Prevention of recurrence

4. Adjuvant therapies
• Skin grafting
• Bioengineered dermal equivalents
– Apligraf
– Orcel
– Dermagraft
• Non-living dermal substitutes
– Oasis
• Growth factors
– nil

5. 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?

6. 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UNC data unpublished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

7. 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

8. Living human dermal substitutes

9. 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

11. 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
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Human
Keratinocytes
Human Dermal
Fibroblasts Apligraf
Human
Skin
CYTOKINE EXPRESSION IN
APLIGRAF AND HUMAN SKIN

12. Apligraf: Method of application
• Wound bed
preparation
– good granulation
– edema control
– bacterial balance
• Debride wound to
healthy, bleeding base

13. 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

14. 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

15. 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

16. 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

17. Cost-efficacy of Apligraf for VLU
Comparison to Clopidogrel

18. Caprie trial: Clopidogrel vs Aspirin
for patients at risk for ischemic
events
Ischemic event
• Asymptomatic MI
• Symptomatic non-
fatal MI
• Fatal MI
• Stroke

19. 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

20. Apply RRR to wound healing
• Apligraf VLU pivotal trial
– 40% healed SOC
– 57% healed with SOC plus AG
– 42% relative increase in healed wounds

21. 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?

22. 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

23. 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

24. 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

25. 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