Team Approach to Critical Limb Ischemia Care and Research

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Team Approach to Critical Limb Ischemia Care and Research Rahul S. Patel MD

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To appear in: Tech Vasc Interventional Rad

Cite this article as: Rahul S. Patel MD, Team Approach to Critical Limb Ischemia Care and Research, Tech Vasc Interventional Rad , http://dx.doi.org/10.1053/j.tvir.2016.04.002 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Team Approach to Critical Limb Ischemia Care and Research

Rahul S. Patel, MD Assistant Professor of Radiology and Surgery Division of Interventional Radiology Department of Radiology The Mount Sinai Medical Center [email protected] 1176 5th Ave, Box 1234 New York, NY 10029-6574

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Abstract

Critical limb ischemia has a high rate of major amputation and mortality due to advance systemic cardiovascular disease. The goals of treating patients with CLI not only include the prevention of limb loss, but also to relieve pain, improve quality of life and prevent death1. A multidisciplinary team approach to treating CLI patients improves limb salvage rates by helping to tailor the best intervention for these patients. Also a multidisciplinary team can help address cardiovascular risk modification and wound management to help in decreasing mortality and increase amputation free survival. This review intends to summarize the current trends and data in the team approach to CLI care. Also, we will review the large multidisciplinary study evaluating surgical and endovascular treatments for critical limb ischemia.

Multidisciplinary Team Approach to CLI Despite the dramatic explosion of novel technologies, techniques, and therapies the treatment of patients with critical limb ischemia remains highly variably and, in many situations, sub-optimal. Amputation free survival at one year is still about 76.5%2. This number though hides a bigger problem; most patients with critical limb ischemia may never actually have any intervention prior to amputation3. A recent study found that only 40% of

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patients with CLI received prompt revascularization.4 This problem is only magnified with the increasing incidence of CLI and the increasing prevalence of atherosclerotic risk factors including diabetes, obesity and advanced age (>65 years).5 To this end many consensus documents have recently been advocating for creation of multidisciplinary care teams to improve the outcomes of critical limb ischemia patients.67 This team approach to CLI has been validated in many retrospective studies. In a retrospective analysis of 146 patients with CLI, Chung et al found that patients who underwent evaluation and management with a multidisciplinary care team had greater than 2 fold increase in amputation free survival versus patients who had not been treated by the team (593.3 +/- 33.2 days vs. 281.0 +/- 38.2 days P=0.2).8

There are three critical points to the team approach: (1) a high level of primary medical team awareness, (2) dedicated foot clinics, and (3) inclusion of multiple disciplines.

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The members of the multidisciplinary team not only consists of specialists who can restore perfusion to the affected limb (vascular surgery, interventional radiology and interventional cardiology) , but also specialists who can perform wound care (vascular surgery, podiatry, and plastic surgery), treat any underlying infection(infection disease) treat underlying comorbidities (cardiology and endocrinology and primary care physicians) and educate the patient.9

In this multidisciplinary team model patients may not always see the same specialist first. A patient may see a podiatrist first or conversely may be seen by an invasive specialist as a referral for revascularization due to rest pain. Whomever the primary contact point, the patient should receive the appropriate care each specialist can offer.

Best Endovascular Versus Best Surgical Therapy in Patients with CLI (BEST-CLI)

With regards to critical limb ischemia there remains clinical equipoise as to what should be the first line “gold-standard” therapy for critical limb ischemia patients.

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On one side of the debate there are the “old school” open surgery proponents who see little evidence to suggest the historic gold standard of surgery is less dependable than newer percutaneous interventions. Conversely there are the operators who are strongly skilled in non-surgical endovascular options and have fully adopted an endovascular-first strategy for critical limb ischemia patients.10

To help settle this debate the BEST-CLI trial was designed. This is a prospective, randomized, multicenter trial comparing best endovascular therapy with best open surgical therapy in patients with CLI. The primary aim is to compare the treatment efficacy, functional outcomes, and costs in patients with CLI who are good candidates for either surgical or endovascular therapeutic approach. This study is being funded by a grant from the National Heart, Lung, and Blood Institute of the National Institutes of Health and is led by Drs. Alik Farber (Boston Medical Center), Matthew Menard (Brigham and Women’s Hospital) and Kenneth Rosenfeld (Massachusetts General Hospital).

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The trial aims to be the first of its kind to use a novel primary endpoint, major adverse limb event (MALE)-free survival. The study designers felt that this aggregate measure best captures the therapeutic goals of treatment of CLI, which are survival with a functional limb and avoidance of reinterventions that effect quality of life (QoL).11 This measure was devised by the Society of Vascular Surgery (SVS) Objective Performance Working Group specifically for use in critical trials involving patients with CLI and has been endorsed by the SVS and Food and Drug Administration.12

The secondary endpoints include freedom from MALE, peri-operative death, myocardial infarction, stroke, reinterventions in index limb, clinical failure, all-cause mortality and hemodynamic failure. Also the number of reinterventions per limb salvaged will be tracked.13

The BEST-CLI trial will have a robust cost-effectiveness component that aims to quantify the financial costs in each arm as well as all relevant functional and QoL outcomes. This will serve a vital secondary endpoint that will allow for an evaluation of the net clinical benefit based on both QoL and the economic value of the observed differences in these outcomes. The cost data collected will include all the resources consumed during each subject’s initial

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hospitalization and all related subsequent inpatient and outpatient contacts with the medical system. The main measures of functional outcome will by the EQ-5D and VascuQoL, both of which are standard validated instruments.14,15

To avoid many of the common pitfalls in conducting research of this kind, the trial incorporates a pragmatic design in which the definition of “best therapy” is left to each participating investigator. All commercially available endovascular therapies (excluding cryoplasty) are allowed, as are all surgical bypass techniques and types of conduits. According to the study protocol as new surgical or endovascular techniques become available they will be evaluated for possible suitability to be used in the trial.

The trial will aim to enroll 2100 patients across 120 sites in North America during the course of 4 years, with each patient having a minimum follow-up 2.25 years. The trial is a two-cohort design, with each cohort being independently powered to evaluate outcomes to in two separate prevailing groups of CLI patients.

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The first cohort will be 1620 patients and will evaluate patients who have adequate single-segment great saphenous vein. The second cohort will be a smaller group of 480 patients and will study those CLI patients who do not have adequate single-segment great saphenous vein. According to the study designers, this is due to the fact that the quality of conduit is critical to the success of infrainguinal bypass.16 The first cohort will answer whether CLI patients with ideal conduit do better with an endovascular first or surgical first strategy. The second cohort will answer how patients with less than ideal conduit (e.g. alternative autogenous vein, cryopreserved vein or prosthetic graft) do better with an endovascular first or surgical first approach.

Within each of these cohorts the patients will be randomized within four strata defined by the clinical presentation and anatomical classification. With regards to clinical presentation, patients will be stratified by ischemic rest pain alone (Rutherford 4) versus tissue loss with or without rest pain

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(Rutherford 5 and 6). With regards to anatomical classification, patients will be stratified by the presence or absence of significant tibial disease. According to the study designers this was chosen because of their perceived potential impact on the therapeutic approach and clinical outcomes of CLI patients.

Also, previous large-scale trials randomizing interventions to surgery or medicine have been heavily criticized for the lack of experience by operators or utilizing dated techniques in the interventional arm. To address this issue the study designers developed processes to ensure best treatment in both arms. First, they have chosen sites for participation that have a record of being vascular centers of excellence. Second they have a credentialing committee, which has created guidelines to credential operators in both the surgical and endovascular arms. Lastly they have created CLI teams at every site that consist of all investigators participating in the trial at that site which at the one year update in the study nearly 80% of the sites have multidisciplinary CLI teams.

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The trial began enrolling in the fall of 2014 and has enrolled over 461 patients. They have started a number of new initiatives to facilitate accrual, including some modification of the protocol exclusion criteria, distribution of additional funds to all participating and enrolling centers, and expansion from 120 to 140 trial sites.

Conclusion The multidisciplinary team approach to the care of patients with critical limb ischemia represents a coordination of many disciplines brought together to not only prevent functional limb loss and wound care but also to optimize the cardiovascular health of these patients. This coordinated approach makes intuitive sense and has been proven to improve amputation free survival and overall survival. The team approach to CLI will remain critical in the BEST-CLI trial to help evaluate which therapies (endovascular or surgical) are most beneficial for patients with CLI. Initial enrollment has been slower than expected; however, with the addition of new sites and protocol changes the study hopes to be finished enrolling in the next few years.

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1

Norgren L, Hiatt WR, Dormandy JA, et al. Inter-Society Consensus for the

Management of Peripheral Arterial Dis- ease (TASC II). J Vasc Surg 007;45(Suppl. S):S5–67. 2

Conte MS, Geraghty PJ, Bradbury AW, Hevelone ND, Lipsitz SR, Moneta GL,

et al. Suggested objective performance goals and clinical trial design for evaluating catheter-based treatment of critical limb ischemia. J Vasc Surg 2009;50:1462-73. 3

Goodney PP, Travis LL, Nallamothu BK, et al. Variation in the Use of Lower

Extremity Vascular Procedures for Critical Limb Ischemia. Circ Cardiovasc Qual Outcomes. 2012 Jan;5(1):94-102. 4

O’Hare AM, Bertenthal D, Sidawy AN, et al. Renal insufficiency and use of

revascularization among a national cohort of men with advanced lower extremity peripheral arterial disease. Clin J Am Soc Nephrol. 2006;1(2):297– 304. 5

Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB, et al.

Heart disease and stroke statistics- 2013 update: a report from the American Heart Association. Circulation 2013;127:e6-245.

11

6

Sumpio BE, Armstrong DG, Lavery LA, Andros G; the SVS/APMA writing

group. The role of interdisciplinary team approach in the management of the diabetic foot. J Vasc Surg 2010;51:1504-6. 7

Driver VR, Fabbi M, Lavery LA, Gibbons G. The costs of diabetic foot: the

economic case for the limb salvage team. J Vasc Surg 2010;52(3 Suppl):1722S. 8

Chung J, Modrall JG, Ahn C et al. Multidisciplinary care improves

amputation-free survival in patients with chronic critical limb ischemia. J Vasc Surg 2015;61(1):162-69. 9

Larsson J, Apelqvist J, Agardh CD, Stenstrom A. Decreasing incidence of

major amputation in diabetic patients: a consequence of a multidisciplinary foot care team approach? Diabet Med. 1995; 12(9):770-776. 10

Menard MT and Farber A. The BEST-CLI trial: a multidisciplinary effort to

assess wherher surgical or endovascular therapy is better for patients with critical limb ischemia. Seminars in Vascular Surgery. 2014; 27:82-84 11

. Conte MS, et al: Suggested objective performance goals and clinical

trial design for evaluating catheter-based treatment of critical limb ischemia. J Vasc Surg 50:1462-1473, 2009 (e1-3) 12

Kumar A, et al: FDA perspective on objective performance goals and

clinical trial design for evaluating catheter-based treatment of critical

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limb ischemia. J Vasc Surg 50:1474-1476, 2009 13

Farber A, Rosenfiled K, and Menard MT: The BEST-CLI trial: a

multidisciplinary effort to assess which therapy is best for patients with critical limb ischemia. Techniques in Vascular and Interventional Radiology. 2014; 17(3):221-224 14

Kumar A, et al: FDA perspective on objective performance goals and

clinical trial design for evaluating catheter-based treatment of critical limb ischemia. J Vasc Surg 50:1474-1476, 2009 15

The EuroQol Group: EuroQol—A new facility for the measurement

of health-related quality of life. Health Policy 16:199-208, 1990 16

Schanzer A, Hevelone N, Owens CD, et al. Technical factors affecting

autogenous vein graft failure: observations from a large multicenter trial. J Vasc Surg 2007;46:1180–90.

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