Endovascular Advancement in the Treatment of Critical Limb Ischemia (CLI) Eric J Dippel, MD FACC

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1 Midwest Cardiovascular Research Foundation Endovascular Advancement in the Treatment of Critical Limb Ischemia (CLI) Eric J Dippel, MD FACC

2 A A man need not have grown old in the practice of medicine to bear witness to its having undergone considerable changes Peter Mere Latham, M.D. ( ) 1875)

3 Catheter Based Peripheral Interventions Rate per Capita Per 100,000 Population National Hospital Discharge Survey 8 Major in-patient vascular categories (ICD-9) Anderson et al. J Vasc Surg.2004;39:

4 If Grandpa walks to the mailbox and has chest pain, we send him to the Emergency Room If Grandpa walks to the mailbox and his legs get tired, we say You re just getting old.

5 Prevalence of PAD The true prevalence of the disease is unknown In many patients the disease progression is begin and the majority will remain asymptomatic Based on epidemiologic studies it is estimated that over 10% of the adult population in the United States has PAD This translates into approximately million people. This is probably a gross under-estimate estimate

6 Prevalence of PAD Rotterdam study Population based study Over 7000 patients Frequency of claudication ranged from 1% for ages yo to >5% over 80 yo However, using ABI <0.90 as a threshold, 16.9% of men and 20.5% of women had PAD Meijer et al. Arterioscler Thromb Vasc Biol. 1998

7 US Adult s s Perception of Illness Severity (SF-36) Intermittent claudication Severe migraine Mild migraine CHF Chronic lung disease Average adult Average well adult Physical Health Component Summary Score Adapted from Understanding Health Outcomes Educational Series (1998).

8 Age-Dependent Prevalence of PAD 25 Men Women PAD Prevalence (%) Age Groups (y) 75 Criqui et al. Circulation.1985;71:

9 Ten-year Mortality Rates Percent (%) Men Women 10 0 Without PVD With PVD Criqui, et al.. New Engl J Med. 1992; 326:

10 Survival of Patients with PAD Survival (%) 100 Control 90 IC 80 CLI Follow Up (years) Norgren, Hiatt, et al. TASC II. Eur J Endovasc Surg

11 Functional Decline in PAD Atherosclerosis is a progressive disorder However, the traditional teaching is that patients with claudication do not progress Prospective, cohort study, >55 yo 676 total patients 417 with PAD 259 without PAD Functional assessment 6 minute walking performance at usual paced and fast paced 4m walking velocity Ankle-brachial index Annual assessment for 2 years Mean annual change McDermott et al. JAMA. July 2004

12 Functional Decline in PAD Findings: Baseline ABI and the nature of leg symptoms predict the degree of functional decline at 2-yr 2 follow up Previously reported lack of worsening in claudication symptoms over time in patients with PAD may be more related to declining functional performance than to lack of disease progression McDermott et al. JAMA. July 2004

13 Physician/Patient Awareness of PVD PARTNERS program PAD Awareness, Risk, and Treatment: New Resources for Survival Multi-center, cross-sectional sectional study 27 sites, 350 primary care practices in US June-October 1999 Hirsch, et al. JAMA. 2001;286:

14 Physician/Patient Awareness of PVD PARTNERS program 6979 patients identified > 70 years old, or years old with h/o tobacco use or diabetes Evaluated by history and ABI PVD defined by: Resting ABI < 0.9, or Documented in medical record, or History of peripheral revascularization Hirsch, et al. JAMA. 2001;286:

15 Physician/Patient Awareness of PVD PARTNERS program 1865/6979 (29%) patients identified with PVD 13% 47% 16% PVD PVD/CAD CAD Neither 24% Hirsch, et al. JAMA. 2001;286:

16 Physician/Patient Awareness of PVD PARTNERS program 457/1865 (55%) patients identified new dx of PVD only 366/1865 (35%) patients identified new dx of PVD and CAD 83% of patients with prior dx of PVD were aware of their diagnosis, but only 49% of their physicians were aware of this diagnosis Hirsch, et al. JAMA. 2001;286:

17 Public Awareness of PAD Cross-sectional, sectional, population-based survey Adults > 50 yo,, n=2501 Awareness of risk factors/disease: HTN 89.7% chol 84.8% Diabetes 77.0% Stroke 73.9% CAD 67.1% CHF 67.3% PAD 25.8% Multiple sclerosis 42.0% ALS (Lou Gehrig s dz) ) 36.3 Cystic fibrosis 29.1% Only 1 in 4 adults were aware of the diagnosis of PAD Hirsch, et al. Circulation.2007;116:online

18 Public Awareness of PAD Perceived causes of PAD in those aware of PAD Overweight 56.2% Smoking 55.6% Lack of exercise 53.0% Only 1 in 2 adults Diabetes 50.0% that were aware of HTN 47.2 the diagnosis of PAD chol 47.0% knew the cause MI or CVA 43.1% Family hx of MI or CVA 37.5% EtOH 30.5% Hirsch, et al. Circulation.2007;116:online

19 Public Awareness of PAD Perceived consequences of PAD in those aware of PAD CVA 27.6% MI 25.3% Death 14.4% Other 6.8% Disability/Inability to walk 6.2% Blood clot 4.2% Less than 1 in 4 adults that were aware of the diagnosis of PAD knew the major consequences of the disease Hirsch, et al. Circulation.2007;116:online

20 Risk Factors Tobacco use High cholesterol High blood pressure Diabetes Obesity Sedentary lifestyle Family history

21 Overlapping Manifestation of Atherosclerosis Coronary Artery Disease 44.6% 4.7% 8.4% Cerebral Artery Disease 1.6% 1.2% 16.6% PAD 4.7% Bhatt, et al. The REACH Registry. JAMA

22 Under Treated Cohort of 1733 patients Known PVD, no known CAD 33% on β-blocker 29% on ACE-inhibitor 31% on statin 56% had SBP > 130 mmhg 62% had screening lipid profile 56% had LDL-chol > 100 mg/dl 21% had LDL-chol > 130 mg/dl In diabetics, 54% had Hg A1C > 7.0% Rehring, et al. J Vasc Surg. 2005;41:

23 Diagnosis - Physical Examination What is the Ankle Brachical Index (ABI)? Ankle Systolic Pressure Brachial Systolic Pressure > 1.0 Normal Lower limit of normal Mild disease Moderate disease < 0.6 Severe disease <0.3 Resting tissue loss

24 All Cause Mortality by Baseline ABI All Cause Mortality by Baseline ABI All-Cause Mortality < < < < < < <1.50 >1.50 Incompressible Norgren, Hiatt, et al. TASC II. Eur J Endovasc Surg Percent (%)

25 Baseline ABI The ABI is a good predictor of non-fatal and fatal cardiovascular events, as well as total mortality, in an unselected general population.* A patient with an ABI of 0.5 has a 4-54 times greater odds of having an MI, CVA, or cardiovascular death than a patient with an ABI of 1.0** *Fowkes, et al. Edinburgh Artery Study. Int J Epidemiol **Mehler, et al. Appropriate Blood Pressure Control in Diabetes Study. Circulation

26 Definition of Critical Limb Ischemia Persistent recurring ischemic rest pain requiring opiate analgesics for at least 14 days Ulceration or gangrene of the foot or toes Ankle-brachial index of <0.40 Toe pressure of < 30 mmhg Systolic ankle pressure < 50 mmhg Flat pulse volume waveform Absent pedal pulse Dormandy, Rutherford et al. TASC-PAD. J Vasc Surg. Jan 2000

27 Critical Limb Ischemia Definition: Critical reduction in blood flow to the foot resulting in: Resting pain (Rutherford 4) Ulceration/Tissue Loss (Rutherford 5) Gangrene (Rutherford 6) Usually due to multi-level level occlusive disease

28 Rutherford Classification Class Clinical symptoms Critical Limb Ischemia Asymptomatic Mild Claudication Moderate Claudication Severe Claudication Ischemic Rest Pain Minor tissue loss Major tissue loss

29 Critical Limb Ischemia Natural history 15-20% of claudicants will progress to CLI 10x higher in diabetics Risk of MI or CVA 10 times higher than the general population Major amputation is a death sentence BKA: <50% regain mobility AKA: <25% regain mobility, 40% dead in 2 years

30 CLI and 5 year Mortality 60 Mortality Breast CA Colon CA PAD/CLI Non-Hodkin's Lymphoma

31 Incidence of CLI There are approx new cases per 1,000,000 people in the US per year Approximately 150, ,000 new cases in the US per year Norgren, Hiatt, et al. TASC II. Eur J Endovasc Surg

32 Diabetes and CLI The rate of non-traumatic traumatic amputations is 10x higher in diabetics than non-diabetics More than 60% of all non-traumatic traumatic amputations occur in diabetics Hispanics are 1.8x as likely, African Americans are 2.7x as likely, and Native Americans are 3-4x 3 as likely to suffer lower limb amputations.

33 Prevalence of PAD & CLI Due to extensive collateral flow in the lower extremities most patients with PAD remain asymptomatic until the burden of disease is significant Approximately 200,000 to 250,000 amputations done in the US per year Patients with CLI typically have multi-level level occlusive disease and are much more likely to have diabetes.

34 Pathophysiology of CLI CLI occurs when blood flow to the affected limb is impaired to such an extent that the nutritive requirements of the tissue cannot be met. This is typically due to multi-level level occlusive arterial disease The hemodynamic consequences of arterial lesions may be influenced by the cardiac output.

35 Progression to CLI The concept of a slow progression through increasingly more severe claudication, to rest pain, ulcers, and ultimately amputation is INCORRECT More than 50% of 713 pts with a BKA for ischemic disease had no symptoms as recently as 6 months previously When the reserve of collaterals suddenly decreases through atherosclerotic plaque rupture, embolization, progression of the disease, etc acute limb ischemia can develop with relatively few preexisting symptoms Dormandy et al. Br J Surg. 1994

36 Fate of Patients Presenting with CLI Initial Therapy 25% 1 yr Later 25% 20% 25% 25% 50% Medical Tx Revascularization Pimary Amputation 30% Dead Alive Amputated CLI Ongoing CLI Resolved Norgren, Hiatt, et al. TASC II. Eur J Endovasc Surg

37 Etiology of Ulcers Above and Below the Ankle Below Ankle Above Ankle Arterial Other Multifactorial Diabetic Venous Venous Arterial Mixed Venous Arterial Other Diabetic Multifactorial Norgren, Hiatt, et al. TASC II. Eur J Endovasc Surg

38 Fate of the Amputee 2-33 times as many BK amputees achieve full mobility compared to AK amputees, and there has been no significant change in over 20 years Rehab can take up to 9 months By 2 years 30% of amputees are not using their prosthesis Elderly patients, women and bilateral amputees have a worse prognosis.

39 Fate of the Below the Knee Amputee 10% Early Results 15% Primary healing Secondary healing AKA Death 15% 60% Dormandy, Rutherford et al. TASC-PAD. J Vasc Surg. Jan 2000

40 Fate of the Below the Knee Amputee After 2 years Full Mobility 30% 40% Contralateral Amputation AKA Death 15% 15% Dormandy, Rutherford et al. TASC-PAD. J Vasc Surg. Jan 2000

41 Treatment of CLI: Pathway to Amputation? In : 2002: 67% of patients had primary amputation (PA) as their first line of therapy for CLI (N=417) 26% had a Cardiology consult 21% had a Vascular Surgery consult ONLY 35% had an ABI before PA ONLY 16% had an angiogram before PA LESS THAN 50% had a vascular evaluation Alli et al. Eurointerventions, May 2005

42 Treatment Goals of CLI Limb preservation Heal ulcers Minimize tissue loss Avoid major amputation Relieve ischemic pain Improve mobility / Quality of Life Maintain vessel patency Reduce cardiac morbidity and mortality

43 Medical Therapy FOR ALL PATIENTS REGARDLESS OF WHETHER OR NOT A REVASCULARIZATION IS DONE AGGRESSIVE RISK FACTOR MODIFICATION HgA1c < 7.0% LDL < 70 mg/dl BP < 120/80 mmhg Smoking cessation Weight loss

44 Surgical Bypass for CLI Viable therapy for limb salvage HOWEVER: Associated with: Prolonged recovery Loss of saphenous vein which may be needed for CABG Chronic lower extremity edema Complications include: 1.3-6% death % MI 10-30% wound complication 1.4% vein infection 5-10% still require amputation Albers et al. J Vasc Surg. 1992, Soong et al. Eur J Vasc Endovasc Surg. 1998, Treiman et al. J Vasc Surg

45 The BASIL Trial Prospective multi-center randomized trial Surgical revascularization vs PTA Pts with CLI N=452 Primary Endpoint: Amputation free survival Mean f/u: : 5.5 years Lancet 2005;366:

46 The BASIL Trial At close f/u: 248 (55%) alive with intact index limb 38 (8%) alive with amputation 36 (8%) dead after amputation 130 (29%) dead without amputation Lancet 2005;366:

47 The BASIL Trial Amputation free survival: After bypass surgery and balloon angioplasty Survival (%) Surgery Angioplasty 0 Years Angioplasty Surgery Number at Risk Lancet 2005;366:

48 BASIL: Take Home Message Early results: Surgery first strategy: Increased morbidity (wound infections) Increased hospital length of stay Increased hospital intensive therapy Increased cost NO difference in 30-day mortality Early results: PTA first strategy: Significantly increased immediate failure Midterm results: Surgery or PTA first strategy Similar outcomes with respect to all cause mortality, amputation free survival, and health related quality of life

49 Endovascular Therapy for CLI CLI patients typically have more co- morbidities Less invasive, lower morbidity and mortality, than surgical therapy Often can recanalize non-bypassable vessels Readily repeatable if there is late failure Need not burn bridges

50 It is easy to be a hero and do a lot of dilatations If you want to be a hero, you better be (a hero) also in the follow-up. up. --Andreas Gruentzig

51 Goals for Endovascular Therapy Re-establish establish in-line flow to the pedal arch of the affected foot Long term vessel patency does not correlate with limb salvage Wound care requires a team approach Aggressive vascular surveillance ABI s/duplex before and after procedure then q 3 months x 2 years, then q 6 months Aggressive risk factor modification

52 Outcomes and Prognostic Factors of Peroneal Artery PTA in CLI Prospective, single center study 58 limbs, 54 patients Clinical and Duplex Doppler follow up at 1, 6, 12,18, 24, 30, and 36 months Stenosis or short (<( 4 cm) occlusion of the peroneal artery Associated with long (> 4 cm) occlusion of the anterior and posterior tibial artery Gargiulo et al. Abstract presented at the International Congress on Endovascular Interventions. Feb 2007.

53 Outcomes and Prognostic Factors of Peroneal Artery PTA in CLI Findings Technical success 100% Mean age 70.3 yo Diabetes 79.6% ESRD 15.5% Stenting in 15.5% 12 mth limb salvage 68.7% 12 mth survival 86.3% Conclusions Patients with infected ulcers, Texas Wound Class IIID, and the absence of straight-line flow to the pedal arch are a high-risk group that has a significantly worse outcome. Gargiulo et al. Abstract presented at the International Congress on Endovascular Interventions. Feb 2007.

54 Revascularization in CLI Some ulcers are entirely ischemic in etiology Other ulcers may be initiated by other causes such as trauma, venous, or neuropathic but will not heal because of the severity of the underlying PAD The healing process requires an inflammatory response and additional perfusion above that required for supporting intact skin and underlying tissue Complete revascularization of the inflow and outflow will allow adequate tissue level perfusion to allow ulcers have a chance to heal. Late loss of a revascularized artery (ie( ie,, restenosis) may still provide adequate tissue level perfusion to maintain tissue integrity once an ulcer is healed. In other words, there may be a disconnect between long term vessel patency and limb salvage.

55 Barriers to Treatment Conservative referral patterns Endovascular tx is considered aggressive Amputation is considered conservative Lack of public knowledge Fear of making things worse Limited number of experienced operators Lack of widespread CLI training Interdisciplinary fighting Limited comparative clinical data

56 Wires and Techniques to Cross Lesions Leading cause of technical failure is inability to cross the lesion with a guidewire Use 0.014in wires Dedicated CTO wires Hydrophilic wires can be helpful, but have a higher perforation risk 90cm contralateral sheath popliteal artery for support Support catheter such a PTA balloon or a Quick Cross catheter Step-by by-step laser technique Front runner catheter FlowCardia The Crosser

57 Step-by by-step Laser Technique for Crossing Chronic Total Occlusions

58 Front Runner Catheter for Crossing Chronic Total Occlusions

59 Endovascular Options Angioplasty POBA Cutting Balloon AngioScore Cryoplasty Drug coated balloon Athrectomy Laser Excisional Orbital Stenting Bare metal Drug Eluting Bio-absorbable

60 What is the Best Therapy for CLI?

61 CLI and POBA Dorros et al treated 284 patients with critical limb ischemia with standard PTA 95% procedural success 5 year follow up Limb salvage in survivors was 91% Significant amputation in 9% Surgical bypass required in 8% Dorros, Jaff et al. Circulation. 2001

62 CLI and Cutting Balloon Ansel et al successfully treated 73 patients with CLI using cutting balloon Adjunctive stenting was required in 20% No patients required surgical bypass Limb salvage at 1 year was 89% Ansel et al. Catheter Cardiovasc Interv. 2004

63 CLI and Angioscore Balloon 31 patients, 36 lesions with CLI and infrapopliteal disease Lesion length 32.4mm Procedure success 100% Dissection: 9.7% Limb salvage 87.4% Limb Salvage No core labs 0 6 months Peeters, Bosiers. et al. CRT 2007

64 CLI and Cryoplasty BTK CHILL was a prospective, multi- center registry of 111 patients CLI patients treated with cryoplasty 67% diabetics 35% occlusions Procedural success was 97% Limb salvage at 6 months was 93% MacNamara, Das, Gray, et al. SIR. 2006

65 Thunder Trial- 6 month TLR Paclitaxel coated balloon 135 patients randomized Interim analysis after 6 months Coated Uncoated 2/43 12/52 Teppe et al. EuroPCR 2007

66 CLI and Laser Athrectomy LACI trial was a prospective, multi-center registry of laser assisted angioplasty in 145 patients with CLI Poor surgical candidates 66% Diabetics 92% Occlusions Procedural success was 86% Limb salvage at 6 months was 92% Laird, Zeller, Gray, et al. J Endovasc Ther. 2006

67 Case Study Left trifurcation

68 Case Study Distal PT Delayed filling of AT

69 Case Study Through CTO with Miracle 6 wire and Quick Cross catheter Grand Slam wire 1.4 mm Laser

70 Case Study Before Following tx with: 1.4 mm Laser 2.5x120 Amphirion

71 Case Study Before Following tx with: 1.4 mm Laser 2.0x20 Savvy

72 CLI and Excisional Athrectomy Kandzari et al. treated 76 limbs in 69 patients with Rutherford class 5 and 6 using excisional athrectomy Procedural success was 99% Limb salvage at 6 months was 82% Kandzari, Keisz, Allie, et al. J Endovasc Ther. 2006

73 CLI and Stents Motarjamee successfully treated 82 vessels in 75 CLI patients with early generation stents Procedural success was >90% Limb salvage rate at 1 year was >80% Vessel patency at 1 year was <30%

74 VIVA I: XCELL Trial Xpert Nitinol Stenting for Critically Ischemic Lower Limbs VIVA physician-sponsored sponsored IDE Prospective, multi-centered registry of 140 patients with Rutherford class CLI First study of self-expanding expanding nitinol, small vessel stenting in tibial arteries

75 XCELL Endpoints Primary endpoint is amputation-free survival at 12 months Major unplanned amputation Secondary endpoints include Major adverse event rates Wound healing Angiographic patency at 6 months TLR at 12 months Stent integrity at 12 months Hemodynamic and QOL improvement

76 BTK Cypher DES 6 month Data Author R N TLR 1 Endpoint Scheinert EuroInterv 2006;2: Y 60 0 vs 23% 0 vs 56% Restenosis Siablis N % 4 vs 55% J Endovasc Ther 2005;12: Limb Salvage Restenosis Bosiers J Cardiov Surg Apr;47(2):171-6 N 18 94% Limb Salvage 0.38 Late Lumen Loss 0% Restenosis Comeau EuroPCR 2006 N % Limb Salvage 97% 1 Patency

77 Bioabsorbable Stents: The Landscape Company Picture Polymer/Drug Features Igaki-Tamai PLLA; Transilast Zig-zag design balloon expandable sheathed delvery Abbott (BVS) Biosensors REVA Medical Biotronik (AMS) All biodegradable polymers (PLLA) with everolimus Poly (L or DL) lactide with BA9 Poly (DTE carbonate) with Iodine for radiopacity Absorbable magnesium alloy Balloon expandable and self expanding designs Self expanding stent with a retractable sheath delivery catheter Balloon expandable design has ratchet locks for radial strength Balloon expandable design

78 FIM AMS Trial Results BEST-BTK First in Man experience with the Biotronik absorbable metal StenT Below The Knee 12 month follow-up results with the Absorbable Metal Stent (AMS) in below-the-knee indications P. Peeters M. Bosiers. EuroPCR 2005

79 BEST-BTK Trial design 20 CLI patients (Rutherford 4-5) 4 due to BTK- pathology Improving inflow limiting ATK lesions AMS implant if short (max 30mm) BTK stenoses Suboptimal angiographic result after PTA ( 50% stenosis) Flow-limiting limiting dissection Threatened or acute closure Inclusion period : December 03 January 04 Peeters P et al J Endovasc Ther 2005; 12:1-5

80 Magnesium Stent Immediate success pre post Acute angiographic result AMS is invisible on fluoroscopy IVUS assessment of stent expansion EuroPCR 2005

81 AMS Stent performance Kaplan Meier Estimation EuroPCR 2005

82 AMS Clinical Outcomes Kaplan Meier Estimation EuroPCR 2005

83 Conclusions Device 6mo Limb Salvage (%) CoreLab PTA ** Cutting B. * Angioscore Cryoplasty Laser Y Y Silverhawk DES Surgery vs PTA** no difference Y * One year, ** Five Year results

84 Conclusions Atherosclerosis is low-grade inflammatory, age-dependent, life-time disease PVD is a very prevalent, under- recognized, under-treated disease associated with an increased overall mortality PVD significantly impacts QOL

85 Conclusions No one should ever have an amputation without a vascular evaluation first >90% technical success rate with endovascular tx >90% of limbs can be salvaged with revascularization Must treat the inflow and outflow Devices are complimentary not competitive Become familiar with the whole gamut of available tools and therapies

86 Conclusions Additional research and training is needed to optimally treat the growing number of patients at risk for limb loss Endovascular devices and techniques will continue to evolve Must improve patient and referral physician awareness

87 Conclusion Endovascular therapy should be the first line treatment strategy for PVD revascularization, regardless of the lesion classification The role for surgical revascularization is diminishing and should be reserved as a second line approach Despite the revascularization strategy, aggressive medical therapy and risk factor modification is mandatory to reduce long-term morbidity and mortality

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