outcomes of cli rcts and registries: key take-home points · bypass vs. angioplasty in severe...

Olive registry: 3-years outcome of BTK intervention in Japan

Osamu Iida, MD

Kansai Rosai Hospital

Amagasaki, Hyogo, Japan

What is the optimal treatment for the patient with critical limb ischemia (CLI)?

Recommendation 24. Optimal treatment for patients with CLI Revascularization is the optimal treatment for patients with CLI.

Transmetatarsal Amputation

Medical intervention for CLI patients who were not

candidates for revascularization (Learn from Circulase trial)

Brass EP, et al. J Vasc Surg. 2006;43:752-9.

Conclusion

Intensive treatment with lipo-ecraprost failed to modify the 6-month

amputation rate in patients with CLI who were not candidates for revascularization.

Days from the first dose

0 20 40 60 80 100 120 140 160 180 200 % o

f p

atie

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wit

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50

60

70

80

90

100

Placebo

Lipo-ecraprost

Log-rank test p = 0.308

Event Placebo

(n =177) (%) Lipo-ecraprost (n = 179) (%)

P value

Major amputation 23 (13.0) 29 (16.2) N.S 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

Bypass therapy (BSX) Endovascular therapy (EVT)

Revascularization for patients with critical limb ischemia

Amputation-free survival All-cause mortality

Surgery vs. Endovascular Therapy (EVT) Bypass vs. Angioplasty in Severe Ischemia of the Leg (BASIL)

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;36:1925-34.

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)

Analysis of AFS and Overall Survival by Treatment Received Bypass vs. Angioplasty in Severe Ischemia of the Leg (BASIL)

Bradbury AW, et al. J Vasc Surg 2010;51:18S-31S.

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.

Analysis of AFS and Overall Survival by Treatment Received Bypass vs. Angioplasty in Severe Ischemia of the Leg (BASIL)

Amputation-free survival Overall survival

Bradbury AW, et al. J Vasc Surg 2010;51:18S-31S.

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.

Decision making for CLI treatment based on current AHA guidelines

Andrew WB, et al. J Vasc Surg. 2010;51:18S-31S.

Anderson JL, et al. Circulation. 2013;127:1425-43.

Factors Univariate analysis Multivariate analysis

Hazard ratio [95%CI] P-value Hazard ratio[95%CI] P-value

Age >75 1.63 [1.06-2.51] *0.024 1.74 [1.11-2.74] *0.015

Male 1.01 [0.64-1.58] 0.955 0.91 [0.57-1.44] 0.705

Rutherford classification

1.67 [1.15-2.43] *0.007 1.26 [0.84-1.90] 0.255

Nonambulatory status

7.08 [4.03-12.4] *<0.001 5.34 [3.01-9.46] *<0.001

BMI <18.5 2.04 [1.31-3.20] *0.001 1.41 [0.88-2.25] 0.145

Regular dialysis 2.58 [1.63-4.08] *<0.001 2.11 [1.28-3.49] *0.003

Ejection fraction <50 %

3.25 [2.05-5.15] *<0.001 2.23 [1.37-3.62] *0.001

CI, Confidence interval; BMI, Body mass index *: P <0.05

Predictive scoring model of mortality after surgical or endovascular revascularization in patients with CLI: multivariate analysis for 2-year mortality

Shiraki T, Iida O, et al. J Vasc Surg. 2014;60:383-9.

≥2 risks

≥1 risk

≥3 risks

≥4 risks AUC = 0.81

(95% CI: 0.76 – 0.86)

SCORE for critical limb ischemia

POINTS

Age >75 1

Nonambulatory status 1

Regular dialysis 1

LVEF <50% 1

LVEF: Left ventricular ejection fraction AUC: Area under the curve

Predictive scoring model of mortality after surgical or endovascular revascularization in patients with CLI: receiver operating characteristic curve

Shiraki T, Iida O, et al. J Vasc Surg. 2014;60:383-9.

AFS were 86±2%, 81±2%, 77±3%, and 74±3% at 3, 6, 9, and 12

months, respectively.

OLIVE (endOvascuLar treatment for Infrapopliteal Vessel):

1-year results

Variables HR (95%CI) P value

BMI <18.5 2.22(1.23-4.01) 0.008

Statin administration 0.59(0.30-1.13) 0.11

Anemia 1.80(0.97-3.32) 0.06

Heat failure 1.73(1.02-2.91) 0.04

Wound infection 1.89(1.07-3.32) 0.02

Primary Endpoint: Amputation-free survival

Iida O, et al. Circ Cardiovasc Interv. 2013;6:68-76.

Independent predictors for AFS

BMI <18.5 Wound infection Heat failure

75% Rutherford 5 25% Rutherford 6

Secondary Endpoint: Time to wound healing

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.

OLIVE (endOvascuLar treatment for Infrapopliteal Vessel):

1-year results

Variables HR (95%CI) P value

BMI <18.5 0.54(0.31-0.96) 0.03

Hemodialysis 0.79(0.58-1.09) 0.15

Wound infection 0.60(0.36-0.98) 0.04

Independent predictors for Time to wound healing

Iida O, et al. Circ Cardiovasc Interv. 2013;6:68-76.

BMI <18.5 Wound infection

0

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0 12 24 36

Am

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ival

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)

Follow-up period (months)

0 12 24 36

No. at risk 312 204 165 94

Rate (%) 100 73.6 64.2 55.2

Factors

OLIVE (endOvascuLar treatment for Infrapopliteal Vessel):

1-year and 3-year results

Primary Endpoint: Amputation-free survival

BMI <18.5 Wound infection Heat failure BMI <18.5 Age Chronic Dialysis Rutherford 6

Risk factors for amputation-free survival in patients with critical limb ischemia

in short period

in short and long period

BMI <18.5 Wound infection Heat failure

BMI <18.5 Age Chronic Dialysis Rutherford 6

Stepwise analysis for recurrence of wound OR 95%CI Wald

Lower Upper p-value

ALL

Male Gender 1.61 0.74 3.52 0.23

Serum albumin<3.0g.dL 2.72 0.42 17.61 0.29

Diabetes mellitus 1.75 0.76 4.01 0.19

Hemodialysis 1.52 0.74 3.14 0.26

Isolated below-the knee lesions 4.54 2.20 9.37 <.0001

STEPWISE

Diabetes mellitus 2.05 0.94 4.45 0.07

Isolated below-the knee lesions 4.28 2.15 8.53 < 0.001

Recurrence of wound until 3 years: 43.9 %

OLIVE (endOvascuLar treatment for Infrapopliteal Vessel):

3-year results

Secondary Endpoint: Wound recurrence and its predictors

18,7%

28,5%

37,0%

7,6%

7,3%

7,8%

14,7%

9,4%

5,6%

58,9%

54,8%

49,6%

0% 20% 40% 60% 80% 100%

EVT after 1 year

EVT after 2 years

EVT after 3 years

Death Major amputation

Survive with wounds Survive without wounds

OLIVE (endOvascuLar treatment for Infrapopliteal Vessel):

3-year results

Secondary Endpoint: Time to wound healing

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;59:220-34.

Representative case of CLI with concurrent R6 and wound infection

Case: 65 yrs, Male, Ambulatory status Risk factor: DM, hemodialysis Labo data: Alb 2.6 g/dL, CRP 37.4 mg/dL

Endovascular Therapy (EVT) Distal puncture and subintimal angioplasty

Proximal Distal

Final angiogram

Emergent debridement and minor amputation

Time course of wound healing

5 months Re-EVT: 3 times

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

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.

3-Month Outcomes in J-BEAT Angio Registry

Iida O, et al. Eur J Vasc Endovasc Surg. 2012;44:425-31.

5%

32%

40%

73%

13% 15%

48%

82%

0%

20%

40%

60%

80%

100%

Mortality Without complete healingor recurrence of rest pain

Reintervention Restenosis per lesion

3 months 12 months

BTK lesion

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

Scheinert D, et al. J Am Coll Cardiol. 2012;60:2290-5.

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% Cypher stent

Angioplasty

VS.

SES implantation may offer a promising therapeutic alternative to PTA for treatment of infrapopliteal peripheral arterial disease.

Drug-eluting balloon in peripheral intervention for below the knee angioplasty evaluation (DEBATE-BTK): A randomized trial in diabetic patients with critical limb ischemia

Liistro F, et al. Circulation. 2013;128:615-21.

12m

* Time to wound healing 4.4±1.5 vs 5.2±1.6 months

Device: IN.PACT Amphirion, Medtronic

Average lesion length: 129±83mm (DCB) vs 131±79mm (PTA)

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.

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)

Randomized trial of IN.PACT Amphirion DEB vs. PTA for infrapopliteal revascularization in CLI: 12-month results

Zeller T, et al. J Am Coll Cardiol. 2014;64:1568-76.

Primary Efficacy DEB PTA p

12-month LLL (mm) 0.61 ± 0.78 0.62 ± 0.78 0.95

12-month CD-TLR 9.2% (18/196) 13.1% (14/107) 0.291

Primary Safety DEB PTA p

6-month death, major amputation or CD-TLR

17.7% (41/232)

15.8% (18/114)

0.021 (noninferiority) 0.662 (superiority)

IN.PACT DEEP did not meet either 1⁰ efficacy endpoint.

IN.PACT DEEP Trial met the noninferiority primary safety endpoint.

Primary Outcomes

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.

Olive registry: 3-years outcome of BTK intervention in Japan

Osamu Iida, MD

Kansai Rosai Hospital

Amagasaki, Hyogo, Japan