Olive registry: 3-years outcome of BTK intervention in Japan. Osamu Iida, MD Kansai Rosai Hospital Amagasaki, Hyogo, Japan

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1 Olive registry: 3-years outcome of BTK intervention in Japan Osamu Iida, MD Kansai Rosai Hospital Amagasaki, Hyogo, Japan

2 What is the optimal treatment for the patient with critical limb ischemia (CLI)? Transmetatarsal Amputation Recommendation 24. Optimal treatment for patients with CLI Revascularization is the optimal treatment for patients with CLI.

3 % of patients without major amputation Medical intervention for CLI patients who were not candidates for revascularization (Learn from Circulase trial) Placebo Lipo-ecraprost Log-rank test p = Event Placebo Lipo-ecraprost P value (n =177) (%) (n = 179) (%) Major amputation 23 (13.0) 29 (16.2) N.S 60 Death 10 (5.6) 18 (10.1) N.S Composite (amputation or death) 31 (17.5) 43 (24.0) N.S Pain free at 6 months 44 (24.3%) 40 (22.1%) N.S Ulcer free at 6 months 25 (24.5%) 25 (23.2%) N.S Days from the first dose Conclusion Intensive treatment with lipo-ecraprost failed to modify the 6-month amputation rate in patients with CLI who were not candidates for revascularization. Brass EP, et al. J Vasc Surg. 2006;43:752-9.

4 Revascularization for patients with critical limb ischemia Bypass therapy (BSX) Endovascular therapy (EVT)

5 Surgery vs. Endovascular Therapy (EVT) Bypass vs. Angioplasty in Severe Ischemia of the Leg (BASIL) Amputation-free survival All-cause mortality Conclusion A bypass-surgery-first and a balloon-angioplasty-first strategy are associated with broadly similar outcomes in terms of amputation-free survival, and in the short-term, surgery is more expensive than angioplasty. Adam DJ, et al. Lancet. 2005;36:

6 Analysis of AFS and Overall Survival by Treatment Received Bypass vs. Angioplasty in Severe Ischemia of the Leg (BASIL) AFS (amputation-free survival) for patients undergoing bypass therapy (SVG vs. PTFE) and angioplasty (Sub vs. Intra) AFS: Bypass (SVG) > Angioplasty (Sub=Intra)> Bypass (PTFE) Bradbury AW, et al. J Vasc Surg 2010;51:18S-31S.

7 Analysis of AFS and Overall Survival by Treatment Received Bypass vs. Angioplasty in Severe Ischemia of the Leg (BASIL) Amputation-free survival Overall survival Results of BSX after failed BAP. The 37 patients who underwent BSX after first attempted failed angioplasty had poorer AFS (P=0.006, log-rank test) and somewhat poorer OS (P=0.06, log-rank test) than the 184 patients who underwent BSX as first treatment. Bradbury AW, et al. J Vasc Surg 2010;51:18S-31S.

8 Decision making for CLI treatment based on current AHA guidelines Life expectancy of >2 years with a usable autogenous vein Bypass therapy first Life expectancy of <2 years without an adequate vein Endovascular therapy first The predictors of 2-year mortality for patients with CLI have not been examined well. Andrew WB, et al. J Vasc Surg. 2010;51:18S-31S. Anderson JL, et al. Circulation. 2013;127:

9 Predictive scoring model of mortality after surgical or endovascular revascularization in patients with CLI: multivariate analysis for 2-year mortality Factors Univariate analysis Multivariate analysis Hazard ratio [95%CI] P-value Hazard ratio[95%ci] P-value Age > [ ] * [ ] *0.015 Male 1.01 [ ] [ ] Rutherford classification Nonambulatory status 1.67 [ ] * [ ] [ ] *< [ ] *<0.001 BMI < [ ] * [ ] Regular dialysis 2.58 [ ] *< [ ] *0.003 Ejection fraction <50 % 3.25 [ ] *< [ ] *0.001 CI, Confidence interval; BMI, Body mass index *: P <0.05 Shiraki T, Iida O, et al. J Vasc Surg. 2014;60:383-9.

10 Predictive scoring model of mortality after surgical or endovascular revascularization in patients with CLI: receiver operating characteristic curve 2 risks 1 risk SCORE for critical limb ischemia 3 risks 4 risks AUC = 0.81 (95% CI: ) POINTS Age >75 1 Nonambulatory status 1 Regular dialysis 1 LVEF <50% 1 LVEF: Left ventricular ejection fraction AUC: Area under the curve Shiraki T, Iida O, et al. J Vasc Surg. 2014;60:383-9.

11 OLIVE (endovascular treatment for Infrapopliteal Vessel): 1-year results Primary Endpoint: Amputation-free survival Independent predictors for AFS Variables HR (95%CI) P value BMI < ( ) Statin administration 0.59( ) 0.11 Anemia 1.80( ) 0.06 Heat failure 1.73( ) 0.04 Wound infection 1.89( ) 0.02 AFS were 86±2%, 81±2%, 77±3%, and 74±3% at 3, 6, 9, and 12 months, respectively. BMI <18.5 Heat failure Wound infection Iida O, et al. Circ Cardiovasc Interv. 2013;6:68-76.

12 OLIVE (endovascular treatment for Infrapopliteal Vessel): 1-year results Secondary Endpoint: Time to wound healing Independent predictors for Time to wound healing Variables HR (95%CI) P value BMI < ( ) 0.03 Hemodialysis 0.79( ) 0.15 Wound infection 0.60( ) 0.04 The proportion of not-healed patients was 54±3%, 29±3%, 18±3%, and 14±3% at 3, 6, 9, and 12 months, respectively. Median value was 97±10 days. BMI <18.5 Wound infection 75% Rutherford 5 25% Rutherford 6 Iida O, et al. Circ Cardiovasc Interv. 2013;6:68-76.

13 Amputation-free survival (%) OLIVE (endovascular treatment for Infrapopliteal Vessel): 1-year and 3-year results Primary Endpoint: Amputation-free survival Factors BMI <18.5 Heat Age failure Wound Chronic infection Dialysis Rutherford Follow-up period (months) No. at risk Rate (%)

14 Risk factors for amputation-free survival in patients with critical limb ischemia in short period Heat failure Wound infection BMI <18.5 in short and long period Age Chronic Dialysis Rutherford 6 BMI <18.5

15 OLIVE (endovascular treatment for Infrapopliteal Vessel): 3-year results Secondary Endpoint: Wound recurrence and its predictors Stepwise analysis for recurrence of wound ALL OR 95%CI Wald Lower Upper p-value Male Gender Serum albumin<3.0g.dl Diabetes mellitus Hemodialysis Isolated below-the knee lesions <.0001 STEPWISE Diabetes mellitus Isolated below-the knee lesions < Recurrence of wound until 3 years: 43.9 %

16 OLIVE (endovascular treatment for Infrapopliteal Vessel): 3-year results Secondary Endpoint: Time to wound healing 0% 20% 40% 60% 80% 100% EVT after 1 year 18,7% 7,6% 14,7% 58,9% EVT after 2 years 28,5% 7,3% 9,4% 54,8% EVT after 3 years 37,0% 7,8% 5,6% 49,6% Death Survive with wounds Major amputation Survive without wounds

17 WIFI Classification System: Risk Stratification Based on Wound, Ischemia, and Foot Infection Wound: extent and depth Ischemia: perfusion/flow Foot Infection: presence and extent Based on existing validated systems or best available data with 4 point scales where: 0 = none, 1 = mild-moderate, 2 = moderate-severe, 3 = severe or advanced Estimate risk of amputation at 1 year for each combination Very low = VL, Low = L, Moderate = M, High = H Mills JL Sr, et al. J Vasc Surg. 2014;59:

18 Case: Risk factor: Labo data: Representative case of CLI with concurrent R6 and wound infection 65 yrs, Male, Ambulatory status DM, hemodialysis Alb 2.6 g/dl, CRP 37.4 mg/dl

19 Endovascular Therapy (EVT) Distal puncture and subintimal angioplasty

20 Final angiogram Proximal Distal

21 Emergent debridement and minor amputation

22 Time course of wound healing 5 months Re-EVT: 3 times

23 Secondary infection due to limb wound infection during healing process 1 months late Post-sternotomy osteomyelitis Sternal resection and wire exclusion 5 months later Pacemaker lead infection

24 Differential impact of WIfI classification on wound healing rate after EVT for CLI with and without malnutrition status WIfI classification was clinically useful in predicting wound healing rate after endovascular therapy. Differential impact of WIfI classification on wound healing rate after EVT for CLI with and without malnutrition status was observed.

25 3-Month Outcomes in J-BEAT Angio Registry 100% 80% 3 months 12 months 73% 82% 60% 40% 32% 40% 48% 20% 5% 13% 15% 0% Mortality Without complete healing or recurrence of rest pain Reintervention Restenosis per lesion Iida O, et al. Eur J Vasc Endovasc Surg. 2012;44:

26 1-year results from the ACHILLES trial: Comparison of balloon angioplasty and infrapopliteal stenting with the sirolimus-eluting stent in patients with ischemic peripheral arterial disease Study design: Multicenter, randomized trial Study subjects: SES (n=99) vs angioplasty (n=101) Lesion length: 27±21mm vs 27±21mm Stent: CYPHER SELECT stents (J&J) Primary endpoint: Angiographic binary restenosis Outcomes: Restenosis rate: 22% vs 42% Freedom from death, TLR, bypass amputation, and R 4: 70% vs 50% BTK lesion Angioplasty VS. Cypher stent SES implantation may offer a promising therapeutic alternative to PTA for treatment of infrapopliteal peripheral arterial disease. Scheinert D, et al. J Am Coll Cardiol. 2012;60:

27 Drug-eluting balloon in peripheral intervention for below the knee angioplasty evaluation (DEBATE-BTK): A randomized trial in diabetic patients with critical limb ischemia Device: IN.PACT Amphirion, Medtronic Average lesion length: 129±83mm (DCB) vs 131±79mm (PTA) * Time to wound healing 4.4±1.5 vs 5.2±1.6 months 12m DEB compared with PTA strikingly reduces 1-year restenosis, target lesion revascularization, and target vessel occlusion in the treatment of BTK lesions in diabetic patients with CLI. Liistro F, et al. Circulation. 2013;128:

28 Randomized trial of IN.PACT Amphirion DEB vs. PTA for infrapopliteal revascularization in CLI: 12-month results Prospective, multicenter, RCT, Independent, angiographic and wound core lab 358 patients randomized 2:1 DEB:PTA (lesion length: 10.2±9.1 vs. 12.9±9.5 cm) Primary Outcomes Primary Efficacy DEB PTA p 12-month LLL (mm) 0.61 ± ± month CD-TLR 9.2% (18/196) 13.1% (14/107) Primary Safety DEB PTA p 6-month death, major amputation or CD-TLR 17.7% (41/232) 15.8% (18/114) (noninferiority) (superiority) IN.PACT DEEP did not meet either 1⁰ efficacy endpoint. IN.PACT DEEP Trial met the noninferiority primary safety endpoint. Zeller T, et al. J Am Coll Cardiol. 2014;64:

29 Take-Home Messages Revascularization is the optimal treatment for patients with CLI. BASIL finally concluded that beyond 2 years after revascularization there appeared to be a benefit for open bypass therapy (BSX). Long-term clinical outcomes were acceptable after EVT for patients with CLI due to infrainguinal lesions. DEBATE-BTK shows that DEB compared with PTA strikingly reduces 1-year restenosis in the treatment of BTK lesions in diabetic patients with CLI, whereas IN.PACT DEEP did not meet 1⁰ efficacy endpoint.

30 Olive registry: 3-years outcome of BTK intervention in Japan Osamu Iida, MD Kansai Rosai Hospital Amagasaki, Hyogo, Japan