randall w. franz, m.d., f.a.c.s., r.v.t. chief of vascular ... › sites ›...

Randall W. Franz, M.D., F.A.C.S., R.V.T. Chief of Vascular and Endovascular Surgery

OhioHealth/Grant Medical Center Director Grant Vascular and Vein Center

Columbus, Ohio

• Decrease in limb blood flow with potential threat to limb viability

• ABI

• 100,000 limb amputations in US/year

• Cost 13 Billion/year

• Limb amputation quality of life similar to terminal cancer

• Survival after BKA or AKA

70% @ 1 year

35% @ 5 years

• Diabetic patients highest risk

• Medical : • Cilostazol (Pletal): 100 mg po bid

• Clopidogrel bisulfate (Plavix): 75 mg po daily

• Vascular rehab: i.e. walking, lifestyle changes Smoking Cessation

Diabetic Education

Lipid Management

• Endovascular: angioplasty, stents, laser, etc.

• Open Surgery: bypass

• Wound Care Management as needed

• Stem Cells

• Embryonic stem cells Multipotent stem cells

• Multipotent stem cells Hemanigioblasts

• Hemangioblasts Vascular cells

• Angiogenesis: Blood flow increases cells to allow for wound healing • Migration of endothelial cells followed by

neovessel creation

• Vasculogenesis: Progenitor stem cells Vascular Network • Occurs during embryonic development

• Also found in peripheral blood and bone marrow in adults

• 3 Intra-arterial and Intramuscular studies • Only one to Rx complex cases including nonhealing

ulcers

• Used as limb salvage therapy • Prior studies Rx earlier stages

• Heterogenous patient population • Represents all PVD patients

• Included Diabetics

• Autologous Bone Marrow Mononuclear Cell Implantation for Moderate to Severe Peripheral Arterial Disease

• Study NCT00919516 Information provided by The Vascular and Vein Center, Columbus, OH

• First Received: June 11, 2009 Last Updated: December 31, 2012

• December 2007 Estimated Primary Completion Date December 2012 (final data collection date for primary outcome measure) Current Primary Outcome Measures ICMJE (submitted: June 11, 2009) Major limb amputation [ Time Frame: 3,6,12 months ] [ Designated as safety issue: No ] Original Primary Outcome Measures ICMJE Same as current Change History Current Secondary Outcome Measures ICMJE (submitted: June 11, 2009) Improved ABI measurements [ Time Frame: three months ] [ Designated as safety issue: No ]

• Relief of rest pain [ Time Frame: three months ] [ Designated as safety issue: No ]

• Ulceration healing [ Time Frame: three months ] [ Designated as safety issue: No ]

• Original Secondary Outcome Measures ICMJE Same as current

• Prospective study December 2007 – 2012

• IRB approved

• Intramuscular and intra-arterial stem cell implantation

• Evaluate outcomes in patients with severe PVD

• Intra-arterial injection allows stem cells to reach all target vessels • Ischemic muscle regions still perfused receive high

concentration of stem cells

• Intramuscular injection allows muscles to receive high local concentration of stem cells • Local dispersion results in surrounding muscle

• Mononuclear cell types include hematopoetic cells, angioblasts, and mesenchymal cells • Low oxygenated ischemic sites

• Allows multiple means of regeneration

• Severe limb threatening PVD

• ABI

• Evaluations: baseline, 2 weeks and 3months

• Initial : H&P, rest pain, ulcer, ABI, angiogram, classifications

• 2 weeks: procedure related issues

• 3 months: rest pain, ulcerations, ABI, classifications, amputations (digit or limb)

• 6 months: amputations (digit or limb)

• 12 months: amputations (digit or limb)

• Routine Angiogram in all pts • Mac/Local anesthesia • Bone marrow aspiration from anterior

superior iliac spine • 50-60 ml of aspirate • Centrifuge @ 2400 rpm for 12 minutes to

concentrate cells

• Intra-arterial injection - 12ml • Intramuscular injection - 2 ml at each site • 3 medial/lateral – 8 cm apart (Total 12 ml)

• Post Procedure Angiogram

• Four criteria for success • Improvement in ABI

• Relief of rest pain

• Ulcer healing

• Absence of major limb amputation

Gender Overall Group N = 49

Females 18(36.7%)

Males 31(63.3%)

Franz RW et al Unpublished Data

Age Overall Group N = 49

Mean ± SD* 64.8+/- 13.3

Median 64.6

Range (min – max) (26.0-92.0)

*SD = Standard Deviation


Tobacco Use Overall Group N = 49

Absent 25(51.0%)

Present 24(49.0%)


Hypertension

N = 49 Diabetes N = 49

CAD N = 49

Hyperlipidemia N = 49

Kidney Disease N = 49

CVA N = 49

Present 34 (69.4%) 29 (59.2%) 20 (40.8%) 22 (44.9%) 13 (26.5%) 9 (18.4%)

Absent 15 (30.6%) 20 (40.8%) 29 (59.2%) 27 (55.1%) 36 (73.5%) 40 (81.6%)


Prior Major Open Procedure(s)

N = 56

Prior Endovascular Procedure(s)

N = 56

Yes 23 (41.1%) 26 (46.4%)

No 33 (58.9%) 30 (53.6%)


Grade Category Clinical Description

0 0 Asymptomatic

I 1

2

3

Mild claudication

Moderate claudication

Severe claudication

II 4 Ischemic rest pain

III 5

6

Minor tissue loss, non-healing ulcer, focal gangrene with diffuse pedal ischemia

Major tissue loss, extending above transmetatarsal level, functional foot no longer salvageable

Rutherford et al, J Vasc Surg, 1986, 1997

Grade Category N = 56

0 0 0 (0%)

I 1 2 3

0 (0%) 1 (1.8%) 0 (0%)

II 4 4 (7.1%)

III 5 6

41 (73.2%) 10 (17.9%)



Grade Category N = 48

0 0 8 (16.7%)

I 1 2 3

4 (8.3%) 5 (10.4%)

12 (25.0%)

II 4 1 (2.1%)

III 5 6

16 (33.3%) 2 (4.2%)

p = 0.001, Power 1.000

Classification Clinical Description

I Asymptomatic

II Claudication

III Rest Pain

IV Pedal Necrosis

Rutherford et al, J Vasc Surg, 1997 Rutherford et al, J Vasc Surg, 1986

Classification N = 56

I 0 (0.0%)

II 1 (1.8%)

III 5 (8.9%)

IV 50 (89.3%)


Classification N = 49

I 9 (18.4%)

II 21 (42.9%)

III 1 (2.0%)

IV 18 (36.7%)


Fontaine Classification at

3-Month Follow-up Evaluation

p = 0.001, Power 1.000

• Four criteria for success • Improvement in ABI

• Relief of rest pain

• Ulcer healing

• Absence of major limb amputation

Pre-Procedure Dorsalis Pedis Artery

ABI N = 44

Post-Procedure Dorsalis Pedis Artery

ABI N = 33

Mean

SD* 0.44+/- 0.36 0.53+/- 0.34

Median 0.45 0.54

Range (min – max)

(0.0-1.3)

(0.0-1.2)

*SD = Standard Deviation p = 0.402


Pre-Procedure Posterior Tibial Artery

ABI N = 43

Post-Procedure Posterior Tibial Artery

ABI N = 25

Mean

SD* 0.39 +/- 0.37 0.55+/- 0.42

Median 0.37 0.54

Range (min – max)

(0.0-1.8)

(0.0-1.8)

*SD = Standard Deviation p = 0.011, Power = 0.514


Rest Pain Overall Group N = 56

Present 51 (91.1%)

Absent 3 (5.4%)

Unable to Ascertain 2 (3.5%)


Rest Pain Overall Group N = 49

Present 8 (16.3%)

Absent 39 (79.6%)

Unable to Ascertain 2 (4.1%)


Presence of Non-Healing Ulcer(s)

N = 56

Presence of Gangrene N = 56

Yes 51 (91.1%) 29 (51.8%)

No 5 (8.9%) 27 (48.2%)

51 Limbs had 81 Non-Healing Ulcers Present


Ulcer Location N = 81

Toe 54 (66.7%)

Foot 14 (17%)

Digit Amputation Site 1 (1.2%)

TMT Amputation Site 3 (3.7%)

Heel 3 (3.7%)

Ankle 2 (2.5%)

Anterior Tibia 2 (2.5%)

Lower Extremity 2 (2.5%)


Presence of Non-Healing Wound(s)

Overall Group N = 44

Present 18 (40.9%)

Absent 26 (59.1%)


Minor Amputation of Involved Limb

N = 54

Major Amputation of Involved Limb

N = 54

Yes 4 (7.4%) 5 (9.3%)

No 50 (92.6%) 49 (90.7%)


Months N = 49

Years N = 49

Mean+/- SD* 17.3 +/- 12.0 1.4 +/- 1.0

Median 13.2 1.1

Range (min-max) 4.1-52.2 0.3-4.4


*SD = Standard Deviation

Minor Amputation of Involved Limb

N =49

Major Amputation of Involved Limb

N = 49

Yes 6 (12.2%) 7 (14.3%)

No 43 (87.8%) 42 (85.7%)


Four-Pronged Definition of Success


N = 52

Improvement in all 4 criteria • Improvement in ABI measurement(s), absence of rest pain, ulcer healing, and no major limb amputations

19(38.8%)

Improvement in 3 of 4 criteria • Improvement in ABI measurement(s), absence of rest pain, & no major amputations • Improvement in ABI measurement(s), ulcer healing, & no major amputations • Absence of rest pain, ulcer healing, & no major amputations • Absence of rest pain and no major amputations

15 (30.6%)

Improvement in 2 of the 4 criteria • Absence of rest pain and no major amputations

13(26.5%)

Improvement in 1 of the 4 criteria • Improvement in ABI measurement(s)

2 (4.1%)

No improvement in any criteria 3 (6.1%)

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• Stem cell study offers hope for those with peripheral arterial disease

• By The Grand Rapids Press

• February 21, 2010, 2:00PM

• Gazette News Service / Rex Larsen Helen Thomas, shown hugging her husband Mason, says a new stem cell injection procedure saved her leg and her life. HASTINGS — Suffering a painful circulation problem in her right leg, Helen Thomas rarely left home.

• On most days, the 80-year-old was so wiped out by painkillers she didn’t want to get up. Amputation looked to be her only option. Then her physician, Kenneth Merriman of Hastings, started asking around at a medical conference in late 2008. He spoke with Dr. Randall Franz. Franz was studying a new procedure using a patient’s own stem cells, the biological building blocks with potential to develop into different cell types. The stem cells are injected into the leg, causing new blood vessels to grow. A few days later, Thomas left for Grant Medical Center in Columbus, Ohio. “It was a miracle,” she said this week. “I’m walking, and I wouldn’t be walking without the stem cells. I have my leg.” Therein lies hope for millions of people.

• ABI equal to or less than 0.4

• Rest pain or ulcerations

• Non-revascularizable

• Helps avoid major amputation

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5. Cobellis G et al. Long-term effects of repeated autologous transplantation of bone marrow cells in patients affected by peripheral arterial disease. Bone Marrow Transplant. 2008;42:667-672.

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