venous hypertension secondary to reflux ucsf vascular

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UCSF Vascular Symposium 204

Aggressive assessment and management are the keys to

healing

Peter J. Pappas, M.DProfessor of Surgery

Chariman, Department of SurgeryThe Brooklyn Hospital

Venous Hypertension Secondary to Reflux

Leukocytes with TGF-ß1 Granules Leukocyte Diapedesis

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TGF-ß1 Release TGF-ß1 Release

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TGF-ß1 stimulated fibroblasts differentiate into myofibroblasts.

Injury Stimulus causes cytokine releaseAnd RAS activation with possible

Senescence development and MMPSynthesis

RAS Activation RAS Activation

Normal wound healing process

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Impaired venous ulcer healing process

Treatment Options for Venous UlcersAnd Levels of Evidence

• Compression Therapy

• Vein Surgery

– Superficial

– Deep

– Perforator

• Skin Grafting

Compression modalities

Unna BootMulti layer Bandage

Circaid

CompressionStocking

Compression Rx: Evidence of Efficacy

• Cochrane library review

– Meta-analysis

• Reviewed over 200 studies of Rx of VSU

• Conclusions

– Overall dataset is relatively poor

– Appears clear that compression is better than no compression in healing VSU

– Sustained compression of high strength is better than non-sustained compression

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Recent Trials of Compression Methods

Primary author

Journal ref # pts % healed group A

% healed group B

P val

Nelson J Vasc Surg 2007;45:134

245; 4 layer vs single layer

67% 4 layer at 24 wks

49% single layer at 24 wks

.009

Nelson Br J Surg 2004 91:1292

387; 4 layer vs short str

92 days median for 4 layer

126 days median for SS

< .05

Partsch Vasa 2001;30:108

112; 4 layer vs short str


73% SS at 16 wks

NS

Franks Wound Rep Regen 2004;12:157

156; 4 layer vs SS


73% SS at 24 wks

NS

Polignano J Wd Care 2004;13:21

68; 4 layer vs Unna


66% Unna at 24 wks

NS

Percent healed at:

6 weeks 29%10 weeks 57%16 weeks 75%52 weeks 93%

1 amputation required (0.4%)

Weeks of Treatment

01020304050

60708090

100

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56

Healing Rate for 252 Ulcers: UNC experience

J Vasc Surg Sept 1999

Weeks of Treatment

Percent healed at 10 weeks

of Rx:< 5 cm2 77%5 to 20 cm2 61%> 20 cm2 22% All curves significant difference (P < .01)

0

10

20

30

40

50

60

70

80

90

100

2 6 10 14 18 22 26 34 42 52

< 5 cm2 n = 91

5 - 20 cm2 n = 94

> 20 cm2 n = 67

Healing Rate by Initial Ulcer Size

Compression and Compliance

Mayberry et al. Surgery 1991; 81:575-581.

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Wrong Diagnosis: Venous Mimics

• Basal or squamous cell carcinoma.

• Rheumatoid, lupus, scleroderma and other collagen vascular disorders.

• Tuberculosis and syphilis.

• Pyoderma gangrenosum.

• AIDS.

• Arteriovenous malformations.

• Cryoglobulinemia and macroglobulinemia.

• Burns and insect bites.

Level of Evidence for Venous Ulcer SurgeryVersus Compression

Summation Data for Studies Prior to 2000

Howard et al. The role of superficial venous surgery in the management ofVenous ulcers: A systematic review. Eur J Vasc Endovasc Surg. 2008;36: 458-465.

Randomized Clinical Trials For Venous Ulcer Surgery

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C5-6 Disease - The ESCHAR Trial Barwell JR, Lancet 2004

• Prospective randomized trial

– High ligation, stripping, phlebectomy and

Compression versus

– Multilayer compression bandaging

• 500 patients with CEAP 5 and 6 disease

– Isolated superficial reflux - 300 (60%)

– Mixed superficial / deep reflux - 200 (40%)

• Endpoints

– 24 week ulcer healing

– 12 month ulcer recurrence

Barwell et al. Eschar Trial.Lancet 2004; 363: 1854-1859

ESCHAR Trial - Ulcer Healing Barwell JR, Lancet 2004

• 24 week ulcer healing - 65% in both groups

0%10%20%30%40%50%60%70%80%90%

100%

0 3 6 9 12

Months

% H

eale

d

SurgeryCompression

ESCHAR Trial - Ulcer Recurrence Barwell JR, Lancet 2004

• 12 month freedom from recurrence (p < 0.0001)– Surgery + Compression -

12%– Compression alone

- 28%

• Four year freedom fromRecurrence (p<0.01)– Surgery + compression

31%– Compression alone

56%0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 3 6 9 12

Months

Fre

edo

m f

rom

Rec

urre

nce

Surgery

Compression

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Ulcer Healing With Surgery

24 weeks

Gloviczki et al. J Vasc Surg 1999;29:489-502.

Effect Of Outflow Obstruction On Ulcer Healing:NASEPS Registry Data


Recurrence Rate With Outflow Obstruction:NASEPS Registry Data


Inadequate Surgical Correction• LSV not ligated flush at

saphenofemoral junction.

• LSV tributaries left intact.

• LSV ligated and not stripped. Recurrence at thigh due to Hunterian perforator.

• Pelvic vein varicosity.

• Neovascularization.

Stonebridge et al. Br J Surg 1995; 82: 60-62.

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Calf Muscle Pump Dysfunction

• Always consider calf muscle pump dysfunction in patients with venous ulcer and no evidence of reflux on duplex examination.

• Important cause of pump dysfunction is poor ankle range of motion.

• Role of physical therapy?

Back et al. J Vasc Surg, 1995;22:519-523.

Clinical Trials Data For Varicose Veins, Not Ulcer Healing: Stripping and compression versus Endovenous

Technologies

CEAP Class 2 and 3 Disease:Primary Varicose Veins

History of Venous Surgery

• Trendelenburg (1890) GSV ligation upper/mid 1/3

• Homans (1916) - Flush Saphenofemoral ligation

• Mayo (1906) - Extraluminal stripper

• Babcock (1907) - Rigid intraluminal stripper

• Myers (1947) - Flexible intraluminal stripper

• 2006 - Endovenous Ablation (Laser / RF)

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Mechanism of Action

Randomized Controlled Trials

• RF versus SurgeryRautio 2002Lurie 2005Hinchcliff 2006Stötter 2006

• Laser versus Surgeryde Medeiros 2005Rasmussen 2007Kalteis 2008Ogawa 2008Darwood 2008

• RF versus LaserMorrison 2005Almeida 2008Goode 2008

• Varisolve Foam vs Surgery/ScleroWright 2006

* Foam sclero combined with sapheno-femoral ligation vs surgeryBountouroglou 2006,

2008

Stripping vs Endovenous RF AblationLurie et al, J Vasc Surg 2003

Eur J Vasc Endovasc Surg 2005

• Prospective, multicenter randomized trial

Stripping

n = 36

RF Ablation

n = 44

p

Ablation @ 1 wk 100% 90.5%

Ablation @ 2 yrs 100% 92%

Return to nl activity 3.89 days 1.15 days .02

Return to work 12.4 days 4.7 days < .05

Global QOL @ 1 wk + 3.7 - 9.2 .001

Global QOL @ 4 mo NS

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Evolves TrialVenous Clinical Severity Scores


Global Quality of Life Scores


QoL scores: Immediate and Long-Term


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Stripping vs Endovenous Laser AblationRasmussen et al; J Vasc Surg 2007

• Randomized trial of

– High ligation & stripping (HL/S) - 68 legs

– Endovenous laser (EVL) - 69 legs

• Office based procedures

– U/S guided tumescent anesthesia

– Simultaneous miniphlebectomy

• Treatment failure at 6 months

– HL/S - 2

– EVL - 3

Stripping vs Endovenous Laser AblationRasmussen et al; J Vasc Surg 2007

7.7 7.6

12

3.948

6.9 7

12.9

4.347

0

2

4

6

8

10

12

14

Normal Activity Work Pain Medication Cost X 1000 (euro)

HL/SEVL

No significant difference in VCSS, AVVSS, or SF-36 at 3 months

p < 0.05

What Endovenous Critics IgnoreRasmussen et al; J Vasc Surg 2007

• Highly selected population

– 1135 patients screened

– 121 (11%) patients enrolled

• Office-based stripping is not standard in North America

• Although QoL not different at 3 months, early reduction of bodily

pain is important to the patient

• Return to work longer than in other series

– Cost benefit of € 312 based upon return to work in 7 days

– Costs equivalent at return to work of 5.2 days

REACTIV TrialMichaels et al, Heath Technol Assess 2006

• 246 patients extensive vv and saphenous reflux randomized to

– Conservative measures (n = 122)

– Saphenous stripping / phlebectomy (n = 124)

• HRQoL (SF-6D) at 1 yr significantly better with surgery

• Fewer symptoms at 1 year with surgery

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

Aching Heaviness Itching Swelling Cosmesis

Symptoms Improved or Absent

ConservativeSurgery

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The Economics of Venous Ablation

4.7

12.4

7 7.6

20

14

4

17

8.9

11.5

0

2

4

6

8

10

12

14

16

18

20

Ret

urn

to

Wo

rk (

Day

s)

Lurie Rasmussen Kalteis Darwood WeightedAverage

EndovenousStripping

• Return to work variable with• Healthcare system• Social expectations• Adjunct procedures (high ligation, phlebectomy)

Cost-Effectiveness of SurgeryRatcliffe et al; Br J Surg 2006

• Randomized trial of conservative tx vs surgery

• 24 mo cost effectiveness of £4682 per QALY gained

• Below NHS threshold of £20,000 per QALY

Conservative Surgery Mean Difference

Mean NHS Cost £344.53 £733.10 £388.57

AUC SF-6D 1.42 1.50 0.083

ICER * £4682

* Incremental cost effectiveness ratio

Results of Valvular Repair Techniques

Kistner, Surgical Management of Venous Disease, ed Raju, Villavicencio, 1997

Combined Arterial And Venous Insufficiency

• Treiman et al. studied patients with combined arterial and venous disease*.– Group 1:

• Patent arterial graft, venous stripping for superficial reflux, no DVT.

• 95% of ulcers healed

– Group 2: • Patent arterial graft, superficial and deep venous

reflux, no DVT.• Four ulcers healed, three remained unhealed.

Treiman et al. J Vasc Surg 2001;33:1158-1164.

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Combined Arterial And Venous Insufficiency

• Group 3: Patent arterial graft and prior proximal DVT.

– 41% healed their ulcers, 36% remained unhealed and 13% required BKA.

• Group 4: Occluded arterial grafts

– 0% ulcer healing.

Future Directions

Bioengineered Skin Bioengineered Skin

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BiofilmDiagnosis and Treatment Algorithm

For Poor Ulcer Healing

HemodynamicAssessment

Correct arterialInsufficiency

ControlLocal woundenvironment

Infection

Compression

RevascularizationFollowed by

Venous surgery

ArterialInsufficiency

LigationStrippingSEPSValve RepairEndovascular

CorrectiveSurgery

Compression

PhysicalTherapy

Calf pumpDysfunction

Other Causes

APG

Reflux+/- Obstruction

ImagingDuplex

Venography

VenousHemodynamic

Assessment

RecurrentDisease

History andPhysical

yes no

yes no

Conclusions

• Surgery for Venous ulcers heals ulcers at same rate as compression but is better at preventing recurrences.

• Endovenous ablation appears better than stripping in terms of pain and QoL.

• Registry data provides useful information that hasn’t been addressed in clinical trials: AVR

Conclusions

• High Venous Ulcer recurrence rates, despite best medical care indicates an enormous need for better wound care products.

– Smart dermal substitutes.

– Smart stockings that provide clinicians information.• Computer chips that can be interrogated.

• Compliance chips.

– Better therapies for wound colonization.

venous hypertension secondary to reflux ucsf vascular

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