BEST-CLI Trial

Alik Farber, M.D.Professor and Chief

Division of Vascular and Endovascular SurgeryBoston Medical Center

Boston University School of Medicine

Disclosures

Trial Co-Chair

Supported by NHLBI: 1U01HL107407-01A1

Chronic Limb Threatening Ischemia (CLI)

• a state of arterial insufficiency manifested by chronic, inadequate tissue perfusion at rest

• characterized by ischemic rest pain, ulcers or gangrene in the presence of objective hemodynamic evidence of

arterial insufficiency

Patel MR et al. PARC. J Am Coll Cardiol. 2015;65:931-41

CLI Facts

• Prevalence: 1 - 3% of patients with PAD

• expected to increase due to increasing age, diabetes and metabolic syndrome

• Incidence: 220 - 3,500 cases/million/year

• 5-10% patients with asymptomatic PAD or intermittent claudication will progress to CLI within 5 years

• Economic burden: > $4 billion/year in the US

Norgren L et al. TASC II. J Vasc Surg 2007;45:S5-67. Biancari F. J Cardiovasc Surg (Torino) 2013;54:663-9.Fowkes FG et al. Lancet 2013;382:1329-40.Sachs T et al. J Vasc Surg 2011;54:1021-1031.American Heart Association. Heart Disease and Stroke Statistics—2005 Update. 2005.

>1,500 patients in 13 studies at 1 year f/u--22% mortality--35% worsening tissue loss--22% major amputation rate

Natural History of Critical Limb Ischemia

Goals Of Treatment

• Medical therapy to optimize cardiovascular risk

• Measures to improve limb perfusion (revascularization)

– Relieve pain

– Heal wounds

– Preserve a functional limb

– Maintain ambulatory status

Hirsch AT et al. J Am Coll Cardiol 2006;47:1239-131 Conte MS and Farber A. BJS 2015;102:1007-1009

Current Status of Limb Revascularization to treat CLI?

Current Status of Limb Revascularization to treat CLI?

Lots of under-treatment, variability ... chaos!

10Reinecke H et al. Eur Heart J 2015 (epub)

• Outcomes of 41,882 patients in a German insurance registry (2009-2013) who were admitted with PAD

• 20,685 had CLI

• 4298 patients with CLI underwent amputation during index hospitalization

• 37% of these patients underwent amputation without revascularization (over course of prior 2 years)

Variation in Amputation and Revascularization Rates Among Patients

with CLI

Dartmouth Atlas of Cardiovascular and Thoracic Healthcare Care. Manning Selvage & Lee; 1998

Intensity of Vascular Care Varies Across Regions of the United States

Goodney et al, Circulation CV Q+O 2012 (5) 94-102

Revascularization Options in CLI

Bypass Surgery

Endovascular Therapy

Surgical Bypass

• 1948- 1st successful femoral popliteal bypass

using rGSV in a patient with PAD (Kunlin J. Rev Chir Paris 70:206-236, 1951)

1964

Novel Technology

Trends in PAD Therapy

Goodney et al. JAMA Surg 2015;150(1):84-86

Open Vascular Surgery for CLI

Endarterectomy

Inflow BypassInfrainguinalBypass

Endovascular Therapy for CLI

Comparison of Revascularization Strategies

Surgical Bypass

• Traditional treatment

• Excellent, durable results

• Long follow up periods available

• Invasive

• Mortality and morbidity

• Is associated with blood loss

• Wound complications

Endovascular Therapy

• Minimally invasive• No need for general anesthesia or

incisions• No hospitalization• Lower morbidity and mortality

• Low patency rates in some vascular beds

• Decreased durability• Requires use of nephrotoxic

contrast agents • Expensive• Driven by business interests

Revascularization Options in CLI

Bypass Surgery

Endovascular Therapy

Which is best?

What is current state

of evidence?

Current CLI Literature is not helpful!

• Retrospective• Poorly controlled• Poorly powered• Suboptimal endpoints

o Amputation free survivalo Target lesion revascularizationo Target vessel revascularization

• Sponsor bias• Operator bias• Inclusion of claudicants• Short or incomplete follow up

“…There is paucity of high-quality data available to guideclinical decision making….”

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Critical Limb Ischemia: % Treated by Bypass (vs. PVI)

0% Bypass

100% Bypass

Procedure Selection Variation

VQI Centers

Course of Events

October 2007: Idea for RCT to help guide treatment of patients with CLI

2009: Obama earmarked 1.1 billion for Cost-effectiveness Research

2010: Society for Vascular Surgery prioritizes CLI within top three unmet

challenges

June 2010: Submitted R01 application to National Institutes of Health (NHLBI)

October 2013: Grant approved and funds released

BEST-CLI Trial: Overview

NIH-funded, prospective, randomized, multicenter,

multispecialty, pragmatic, open-label superiority trial

2100 patients at 160 clinical sites

Funded by National Heart Lung and Blood Institute

Goal: to assess clinical outcomes, quality of life, cost

and value in patients who are candidates for both

vascular surgery and endovascular therapy

BEST Trial Organization

Clinical Events

Committee

Executive CommitteeNHLBI, CCC, DCC, C-E Core +

M. Conte, C. White (Co-Chairs)M. Creager, M. Dake, M. Jaff,

J. Kaufman, R. Powell

Subcommittees

Certified Clinical Centers US & Canada

Clinical Coordinating CenterTrial Chairs

Brigham and Women’s Hospital A. Farber, Boston Medical Center

M. Menard, Brigham and Women’s Hospital*K. Rosenfield, Mass General Hospital

* Awarded Institution

Cost-Effectiveness Core

Brigham and Women’s Hospital

J. Avorn, N. Choudhry

Data Coordinating Center

New England Research Institutes, Inc.

S. Assmann, S. Siami

National Heart, Lung, and Blood InstitutesG. Sopko, D. Reid, X. Tian DSMB

BEST-CLI is unique

• Well powered and designed

Real world pragmatic trial

Two cohort design

SSGSV (optimal conduit) – 1620 patients

All conduits are allowed – 480 patients

Stratification by clinical presentation and anatomy

Novel endpoints

MALE-free Survival is optimal endpoint

Death, amputations AND major re-interventions

Hemodynamic success, clinical success

Comprehensive quality & economic analysis planned

• All specialties involved

Planned by a multidisciplinary group of CLI experts

• Provide a treasure trove of relevant data about CLI

and its management

BEST-CLI is positioned

• Define an evidence-based standard of care

• Inform next set of scientific, clinically relevant questions

BEST-CLI is positioned

Current Status

35

Site Activation Status

178 Sites Selected

• 167 Sites Activated

134 Sites Open for enrollment

26 Sites Closed

5 Sites on Temporary Enrollment hold

2 Sites in Non-Enrollment status – follow-up only

• 11 Sites in Start-up

930 Investigators

• 114 Interventional Cardiologists

• 111 Interventional Radiologists

• 3 Vascular Medicine Specialists

• 690 Vascular Surgeons

• 12 Other

2/3 of Sites are Multidisciplinary36

BEST-CLI in North America

North America 130 Active Sites

BEST-CLI Global Footprint

OverseasNew Zealand

• Wellington Hospital• Waikato Hospital• Auckland City Hospital

Finland• Helsinki University Hospital

4 Active Sites

OnboardingGermany

• St. Franziskus Hospital –Muenster

Italy • San Giovanni di Dio

Hospital

Europe

NewZealand

Enrollment

As of 7/12/2018

1,403 subjects randomized – 697 to go!

BIAS

Tough Nut to Crack…

Treatment Bias is the Biggest Obstacle

What have we learned so far…

Patient Characteristics and Trial Compliance

42

Patient Characteristics (as of 4/9/2018 data freeze)

1,266 patients

• Cohort 1: 1004 (79%) – 77% predicted

• Cohort 2: 262

Cohort 1

• Strata

Rest pain, no tibial dz 8%

Rest pain and tibial dz 12%

Tissue loss, no tibial dz 24%

Tissue loss and tibial dz 56%

Cohort 1

• 29% female – 36% predicted

• 30% non-white race – 27% predicted

• 15% Hispanic – 13% predicted

• Median age: 67 years

• Bilateral CLI: 16%

Patient Characteristics (as of 4/9/2018 data freeze)

Cohort 1

• HTN: 87%

• DM: 72%

• CAD: 43%

• COPD: 13%

• CVA: 14%

• ESRD: 12%

• Smoking Hx: 76%

Current smoking: 34%

• Any previous vascular intervention: 12%

Any previous inflow reconstruction: 7%

Patient Characteristics (as of 4/9/2018 data freeze)

Trial compliance

• Randomized procedure initiated first: 96%

Trial Compliance (as of 4/8/2018 data freeze)

Conclusions

• Current management of CLI is marred by

geographic variability, treatment variability and

under-treatment

• Although CLI is treated with both surgical and

endovascular revascularization it is not clear

what procedure should be offered first

• BEST-CLI will provide a treasure trove of

invaluable data on CLI and its management