Leg Ischaemia Management Collaboration (LIMb)

Single-centre prospective cohort study of patients presenting with severe limb ischaemia (SLI). The primary outcome measure will be 12 month major amputation rate. A historical cohort of patients identified retrospectively will be the comparitor group used to assess the impact of a newly-established rapid-access limb salvage clinic.

Primary aim:

- Determine the proportion of patients with SLI undergoing major lower limb amputation within 12 months of presentation.

Secondary aims:

• Assess clinically important short-, medium- and long-term outcomes in those undergoing and not undergoing amputation
• Prevalence and degree of frailty and cognitive impairment
• Pevalence and degree of cardiac disease (detected by stress MRI)
• Establish a biobank for future biomarker analysis
• Investigate the role of frailty and cognitive assessments, cardiac MRI and biomarkers in risk-stratification of patients with SLI

Study Overview

• Status: Recruiting
• Conditions: Coronary Artery Disease; Peripheral Arterial Disease; Cognitive Impairment; Frailty; Critical Limb Ischemia

Detailed Description

Severe limb ischaemia (SLI) is the end-stage of peripheral arterial occlusive disease (PAOD) whereby the viability of the limb is threatened due to the degree of arterial disease and subsequent ischaemia in the peripheral tissues. It is defined as ischaemic rest pain (or night pain) and/or ulceration or gangrene in the affected limb(s) for a minimum of two weeks attributed to confirmed PAOD. Treatment includes open surgical and endovascular revascularisation, with or without surgical debridement of affected tissues, amputation of toes and drainage of sepsis. In some patients revascularisation is not possible or fails resulting in the person requiring a major lower limb amputation.

Over 4000 major lower limb amputations per year were undertaken in England alone between 2003 and 2013 and a diabetes-related major lower limb amputation is performed every 30 seconds world-wide. As many as 25% of people with SLI will undergo a major lower limb amputation in the first year after presentation. Amputation negatively affects quality of life due to its negative impact on mobility, independence and ability to carry out activities of daily living.

This single-centre prospective cohort study will investigate the amputation rate at one year in patients presenting with SLI and compare this to a retrospectively identified historical cohort. This study will also investigate the prevelance and degree of frailty, cognitive impairment, and cardiac disease (detected by cardiac magnetic resonance imaging (MRI)), as well as establish a biobank for future biomarker analyses. The role of frailty and cognitive assessments, cardiac MRI and biomarker analysis in risk-stratifying patients with SLI will also be investigated.

• Study Type: Observational
• Enrollment (Anticipated): 420

Contacts and Locations

• Study Contact: Name: Rob D Sayers, MD; Phone Number: +44 (0)116 252 3141; Email: rs152@le.ac.uk
• Study Contact Backup: Name: Tanya J Payne, BSc; Phone Number: +44 (0)116 258 3867; Email: tjp28@le.ac.uk

Study Locations

• United Kingdom
  • Leicestershire
    • Leicester, Leicestershire, United Kingdom, LE3 9QP
      • Recruiting
      • Glenfield Hospital Leicester
      • Sub-Investigator: Gerry P McCann, MD
      • Contact: Tanya J Payne; Phone Number: +44 (0)116 358 3867; Email: tjp28@le.ac.uk
      • Principal Investigator: Rob D Sayers, MD
      • Sub-Investigator: Matt J Bown, MD
      • Sub-Investigator: Thompson G Robinson, MD
      • Sub-Investigator: Victoria J Haunton, MD
      • Sub-Investigator: Sally J Singh, PhD
      • Principal Investigator: Robert SM Davies, MD
      • Sub-Investigator: Tanya J Payne, BSc
      • Sub-Investigator: Laura J Gray, PhD
      • Sub-Investigator: Harjeet S Rayt, MD
      • Sub-Investigator: Gregory S McMahon, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 110 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

As representative a sample of patients presenting to the Leicester Vascular Institute with SLI during the study period as possible. All patients presenting with SLI within the age criteria will be eligible and personal consultee consent will allow recruitment even of those patients lacking capacity to consent.

Description

PRIMARY COHORT

Inclusion Criteria:

• All patients presenting to the Leicester Vascular Institute with SLI

Exclusion Criteria:

• SLI not caused by PAOD
• Patients undergoing intervention during their index presentation prior to recruitment
• Patients lacking capacity to consent with no accompanying next of kin, relative, partner or friend who can act as a personal consulted
• Patients who cannot read, write or understand English
• Any significant disease or disorder which may either put the patient at risk because of participation in the study, or may influence the results of the study or the patient's ability to participate in the study

FRAILTY & COGNITIVE ADDITIONAL ASSESSMENTS

Inclusion criteria:

• Patients recruited to the primary cohort in whom a decision has been made to undergo an intervention for SLI
• Patients aged ≥65 years

Exclusion criteria:

• Nil additional

CARDIAC MRI ADDITIONAL ASSESSMENTS

Inclusion criteria:

• Patients recruited to the primary cohort in whom a decision has been made to undergo an intervention

Exclusion criteria:

• Absolute contraindications to cardiac MRI (Pregnancy, Non-MR safe permanent pacemaker, implanted cardiac defibrillator, intra-auricular implant or intra-cranial clips, severe claustrophobia, unstable angina)
• Contraindication to gadolinium contrast agent (Known adverse reaction, chronic renal failure (eGFR <30mL/min/1.73m^2))
• Patients lacking capacity to consent for cardiac MRI

BIOMARKERS ADDITIONAL ASSESSMENTS

• Patients recruited to the primary cohort in whom a decision has been made to undergo an intervention

Exclusion criteria:

• Nil additional

Study Plan

How is the study designed?

Number of groups / cohorts

5

Cohorts and Interventions

Group / Cohort
Primary cohort; Any patient presenting to the Leicester Vascular Institute with SLI during the 2 year recruitment period (minimum 420 patients).
Frailty & cognitive additional assessments; Any patient recruited to the primary cohort aged ≥65 years and undergoing an intervention for SLI (minimum 150 patients, target 210 patients).
Cardiac MRI additional assessments; Any patient recruited to the primary cohort, with capacity to consent and undergoing an intervention for SLI (minimum 100 patients).
Biomarkers additional assessments; Any patient recruited to the primary cohort and undergoing an intervention for SLI (no target recruitment set).
Historical cohort; Retrospectively identified cohort of patients presenting to the study site with SLI between 2013 -15 (target 420).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
12 month amputation rate	Proportion of patients undergoing major lower limb amputation	12 months post recruitment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Amputation free survival	Composite outcome measure of death or amputation	≥12 months post recruitment
All-cause mortality	Death from any cause	≥12 months
Quality of life	Quality of life as measured by the Vascular Quality of Life questionnaire (VascuQoL); 25 item questionnaire, score 1-7 for each item, higher score = better quality of life; Domains: activities (8 items), symptoms (4 items), pain (4 items), social (2 items) and emotional (7 items); each scored 1-7 (total of domain item scores/number of items); Overall score 1-7 (total item score/25)	12 and 24 months post recruitment
Disability	Level of disability as measured by the Barthel Index - Score 0-20; higher score = greater degree of functional independence/lower level of disability	12 and 24 months post recruitment
Clinical Frailty Scale	Prevalence and degree of frailty as measured by the Clinical Frailty Scale (CFS); Score 1-9, higher score = greater degree of frailty; Results will also be reported dichotomised to frail (score ≥5) and non-frail (score ≤4)	Baseline, 12 and 24 months
Anxiety & Depression	Prevalence and degree of anxiety and depression as measured by the Hospital Anxiety and Depression Scale (HADS); 14 item questionnaire; score 0-3 for each item, higher score = more severe anxiety/depression; Domains: Depression (7 items), Anxiety (7 items); each scored 0-21; 0-7 = normal, 8-10 = bordeline, 11-21 = abnormal (case).	Baseline, 12 and 24 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cognitive impairment (Frailty & Cognitive additional assessments only)	Prevalence of cognitive impairment as detected by the Montreal Cognitive Assessment (MoCA); Score 0-30; highger score = greater level of cognitive function; Results will also be reported dichotomised to normal (score ≥24) and cognitive impairment (score ≤23)	Baseline, 3 and 12 months
Post-operative delirium (Frailty & Cognitive additional assessments only)	Incidence of post-operative delirium as detected by the Single Question in Delirium (SQiD) +/- 4 A's Test for delirium (4AT)	24 and 72 hours post intervention
Prevalence of coronary artery disease (Cardiac MR additional assessments only)	Prevalence of coronary artery disease as detected by stress cardiac MRI	Baseline
Incidence of peri-operative myocardial infarction (Cardiac MR additional assessments only)	Incidence of peri-operative myocardial infarction as detected by cardiac MRI	2-4 months post intervention
Edmonton Frail Scale (Frailty & Cognitive additional assessments only)	Prevalence and degree of frailty as measured by the Edmonton Frail Scale (EFS); Score 0-17, 0-5 = not frail, 6-7 = vulnerable, 8-9 = mild frailty, 10-11 = moderate frailty, 12-17 = severe frailty; Results will also be reported dichotomised to frail (score ≥8) and non-frail (score ≤7)	Baseline, 3 and 12 months

Collaborators and Investigators

• Sponsor: University of Leicester
• Collaborators: University Hospitals, Leicester; National Institute for Health Research, United Kingdom; The George Davies Charitable Trust
• Investigators: Study Chair: Rob D Sayers, MD, University of Leicester

Publications and helpful links

General Publications

• Houghton JSM, Nduwayo S, Nickinson ATO, Payne TJ, Sterland S, Nath M, Gray LJ, McMahon GS, Rayt HS, Singh SJ, Robinson TG, Conroy SP, Haunton VJ, McCann GP, Bown MJ, Davies RSM, Sayers RD. Leg ischaemia management collaboration (LIMb): study protocol for a prospective cohort study at a single UK centre. BMJ Open. 2019 Sep 3;9(9):e031257. doi: 10.1136/bmjopen-2019-031257.

Study record dates

Study Major Dates

• Study Start (Actual): May 10, 2019
• Primary Completion (Anticipated): May 9, 2022
• Study Completion (Anticipated): May 9, 2031

Study Registration Dates

• First Submitted: July 11, 2019
• First Submitted That Met QC Criteria: July 18, 2019
• First Posted (Actual): July 19, 2019

Study Record Updates

• Last Update Posted (Actual): November 4, 2020
• Last Update Submitted That Met QC Criteria: November 3, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: Peripheral arterial disease; Biomarkers; Frailty; Cognitive dysfunction; Limb salvage; Myocardial perfusion imaging
• Additional Relevant MeSH Terms: Pathologic Processes; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Atherosclerosis; Coronary Disease; Coronary Artery Disease; Ischemia; Peripheral Arterial Disease; Peripheral Vascular Diseases; Frailty
• Other Study ID Numbers: 0686

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Anonymised dataset will be available on request to the Chief Investigator (Prof Rob Sayers). The study protocol will be published in an open-access journal prior to completion of recruitment.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No