University of Groningen Chronic limb-threatening ischemia Ipema, Jetty

University of Groningen

Chronic limb-threatening ischemia

Ipema, Jetty

DOI:

10.33612/diss.170945328

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Ipema, J. (2021). Chronic limb-threatening ischemia: Optimizing endovascular and medical treatment.

University of Groningen. https://doi.org/10.33612/diss.170945328

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8

Medical adjunctive therapy for

patients with chronic

limb-threatening ischemia:

a systematic review

J Cardiovasc Surg (Torino). 2019;60:642-651

Jetty Ipema

Nicolaas C Roozendaal

Willem A Bax

Gert J de Borst

Jean-Paul PM de Vries

Çagdas Ünlü

Abstract

Introduction: The aim of this article is to systematically review the literature on

medical adjunctive therapy for patients with chronic limb-threatening ischemia

(CLTI).

Evidence acquisition: MEDLINE, EMBASE, and Cochrane Database of Systematic

Reviews were searched for studies published between January 1

_{, 2009, and June}

1

_{, 2019. Articles that studied medical treatment of CLTI patients and reported}

clinical outcomes were eligible. Main exclusion criteria were case reports <20

patients, incorrect publication type, and CLTI caused by Buerger disease. The

primary endpoint was major amputation (above the ankle) in studies with a

follow-up of ≥6 months. Secondary endpoints were other clinical endpoints such

as death and wound healing. Study quality was assessed according to the Downs

and Black checklist.

Evidence synthesis: Included were 42 articles; 4 focused on antiplatelet

therapy, 5 on antihypertensive medication, 6 on lipid-lowering therapy, 16 on

stem cell therapy, 3 on growth factors, 5 on prostanoids, and 1 study each on

cilostazol, glucose-lowering therapy, spinal cord stimulation, sulodexide, and

hemodilution. Calcium channel blockers, iloprost, cilostazol, and hemodilution

showed significant improvement of limb salvage, but data are limited. Stem cell

therapy showed no significant improvement of limb salvage but could potentially

improve wound healing. Antiplatelets, antihypertensives, and statins showed

significantly lower cardiovascular events rates but not evident lower major

amputation rates. The quality of the studies was fair to good.

Conclusion: Certain medical therapies serve to improve limb salvage next to

revascularization in CLTI patients, whereas others are important in secondary

prevention. Because high quality evidence is limited, further research is needed.

Introduction

Chronic limb-threatening ischemia (CLTI), characterized by chronic ischemic

rest pain, ischemic ulcers, and/or gangrene, is the most severe form of peripheral

arterial disease (PAD).

_{The incidence of CLTI is 1% to 3% and is highest among}

elderly, smokers, and diabetic patients.

_{It is associated with high rates of limb}

amputation, cardiovascular events, impaired quality of life, and death. The

current first choice of invasive treatment is endovascular intervention (EVT)

rather than open surgical repair (OR).

_{For a long time, studies have been focused}

on invasive techniques rather than on adjunctive therapy. However, any type

of revascularization should always be accompanied with optimal medication

support.

_{Conservative treatment also includes smoking cessation, dietary}

advice, and wound care.

In CLTI patients, medical adjunctive therapy serves two goals: improvement

of limb salvage and wound healing and the secondary prevention of cardiovascular

events and death. Secondary prevention, consisting of a combination of aspirin,

statin, angiotensin-converting enzyme inhibitor prescription, treatment of

obesity and smoking cessation, has shown significant reductions in the risk of

cardiovascular, cerebrovascular, and major adverse limb events.

_{More recent}

treatment options, such as gene therapy and stem cell therapy, have been

developed to stimulate angiogenesis to improve limb salvage and wound healing.

The current systematic review was performed to give an update on the medical

adjunctive treatment options in CLTI patients, with limb salvage as the main

focus.

This article was written according to the Preferred Reporting Items for Systematic

Reviews and Meta-Analyses (PRISMA) guidelines.

Literature search

A search was performed in MEDLINE, EMBASE, and the Cochrane Database of

Systematic Reviews for eligible articles published between January 1

_{, 2009, and}

June 1

_{, 2019. Keywords of the search were medical therapy, medicine therapy,}

critical limb ischemia, CLI, CLTI, and chronic limb-threatening ischemia. A

flowchart of the literature search is shown in Figure 8.1, and the full search

strategy is summarized in Appendix A.

Inclusion and exclusion criteria and data collection

Articles including medical adjunctive treatment for CLTI patients studying

clinical endpoints were eligible. Studies had to be published in English, German,

French, Spanish, or Dutch, with a full text available, and had to include human

subjects. CLTI patients included patients with chronic ischemic rest pain, tissue

loss, and/or gangrene, classified as Fontaine stage 3 or 4 or Rutherford category

4, 5, or 6. Patients undergoing revascularization and patients unsuitable for

revascularization were included.

Exclusion criteria were case reports of studies with <20 patients, reviews,

guidelines, letters to the editor, comments, conference abstracts; studies about

dietary habits, smoking cessation, hyperbaric oxygen therapy, acute limb

ischemia, nonsystemic (local) therapy, or pain medication; studies with

radiologic, laboratory, physiological, or other nonclinical endpoints; and

studies including patients with CLTI caused by Buerger disease.

After removal of duplicates, two authors (J.I., N.R.) screened the titles and

abstracts of the articles found by the search according to the inclusion and

exclusion criteria. The full texts of the remaining articles were read by two authors

(J.I., N.R.), and all articles that met the inclusion criteria were included. A final

selection of the included studies was made based on the primary endpoint,

which was major amputation in studies with a follow-up of at least 6

months. Secondary endpoints were other clinical endpoints, such as death,

amputation-free survival (AFS), wound healing, major adverse limb events

(MALEs), major adverse cardiac events (MACEs), and pain improvement. In case

of discrepancy between the two authors, a third author (C.U.) was consulted.

Data analysis and quality assessment

The final included studies were sorted by type of medication (Table 8.1) and

presented in tables with results (Appendix B). The studies excluded based on the

final selection are presented in Appendix C. Two authors (J.I., N.R.) independently

performed data extraction. Data extracted included year of publication, study

design, study population, sample size, type of medical therapy, and clinical

outcomes such as mortality, major amputation, AFS, wound healing, MALEs,

MACEs, and pain improvement. Mortality was defined as all-cause death.

Major amputation was defined as amputation above the ankle. AFS was defined

as avoidance of major amputation and/or death. Wound healing was defined as

full epithelization of the wound. MALEs were defined as major amputation or

repeat revascularization. MACEs were defined as myocardial infarction, stroke, or

cardiovascular death. If other definitions were maintained, this was mentioned

in the tables.

The quality of all included studies was assessed according to the Downs and

Black checklist for measuring study quality.

_{The total score of each study}

corresponds to quality levels as follows: 26 to 28, excellent; 20 to 25, good; 15 to

19, fair; and ≤14, poor.

Table 8.1. List of the categories of medical therapy and different types of medication within each category, corresponding to the included studies.

Category Medication

Antiplatelet therapy Aspirin, clopidogrel, ticagrelor Antihypertensives Renin-angiotensin system inhibitors:

angiotensin-converting enzyme inhibitors, angiotensin receptor blockers

β-Blockers Calcium antagonists

Lipid-lowering therapy Low-, moderate-, high-intensity statins

Stem cell therapy Autologous bone marrow stem cell therapy, autologous venous endothelial cells, bone marrow mononuclear cells, peripheral blood stem cells, peripheral blood progenitor cells, bone marrow mesenchymal stem cells, autologous venous smooth muscle cells Growth factors Hepatocyte growth factor, non-viral 1 riferminogene

pecaplasmid (non-viral 1 fibroblast growth factor), vascular endothelial growth factor

Prostanoids Alprostadil, iloprost Type 3 phosphodiesterase inhibitor Cilostazol

Glucose-lowering therapy Insulin

Neuromodulation Spinal cord stimulation Glycosaminoglycans Sulodexide

Evidence synthesis

The search resulted in 3631 articles after removal of duplicates, and 428 remained

for full text reading after titles and abstracts were screened. After full text

reading, 77 articles reported clinical endpoints in CLTI patients. Based on the

primary endpoint, major amputation after at least 6 months of follow-up, final

inclusion resulted in 42 articles. These included studies focusing on antiplatelet

therapy,

_{antihypertensive medication,}

_statins,

_{stem cell therapy,}

growth factors,

_prostanoids,

_cilostazol,

_{glucose control,}

_{spinal cord}

stimulation,

_sulodexide,

_{and hemodilution.}

_{Multiple types of medication}

were studied in some of the articles. Data extracted from the studies can be found

in Appendix B.

The quality of the included studies by category were fair for spinal cord

stimulation, sulodexide, and hemodilution, fair to good for antiplatelet therapy,

prostanoids, and stem cell therapy (one study was assessed excellent), and good

for growth factors, cilostazol, glucose control, antihypertensives, and statins. A

detailed explanation is provided in Appendix D.

Antiplatelet therapy

The main goal of antiplatelet therapy in PAD patients is secondary prevention

of cardiovascular events, but few studies reported major amputation outcomes.

A large retrospective study of 7778 patients showed lower rate of major

amputation for patients receiving aspirin compared with patients not receiving

aspirin (hazard ratio [HR] 0.77; p < 0.001).

_{In addition, AFS was better for}

patients prescribed aspirin (HR 0.82; p < 0.001). Another study focused on the

combination of aspirin and clopidogrel as dual antiplatelet therapy (DAPT) vs.

aspirin monotherapy in CLTI patients undergoing EVT.

_{The DAPT group had}

lower rates for 2-year major amputation (HR 0.56) and mortality (HR 0.83),

although this was not significant. These results are in line with another study on

DAPT effect showing no significant differences in major amputation (p = 0.248)

and AFS (p = 0.751) rates after a median follow-up of 2.7 years.

_{In addition, DAPT}

did not result in higher rates of bleeding complications.

_{Different combinations}

and aspirin, clopidogrel, and warfarin) showed no significant differences in

1-year survival, major amputation, primary patency, and bleeding complications

between patients undergoing venous graft or prosthetic bypass surgery.

Ticagrelor is currently widely prescribed for cardiac patients. The search

identified only one study investigating ticagrelor in patients with CLTI.

_{A total of}

37 patients with high on-treatment platelet reactivity to clopidogrel undergoing

complex peripheral endovascular procedures received ticagrelor and aspirin

up to 6 months after the intervention, followed by ticagrelor only thereafter. No

major and minor bleeding events or other severe complications were detected.

Moreover, platelet inhibition below the cutoff value of 234 platelet reaction units

measured by the VerifyNow P2Y12 Assay (Accumetrics, San Diego, CA, USA) was

achieved in all patients.

Antihypertensives

Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor

blockers (ARBs) are types of renin-angiotensin system (RAS) inhibitors that

have beneficial effects in patients with cardiovascular disease and are also

ecommended as secondary prevention for PAD patients.

This systematic review identified four retrospective comparative studies of

RAS inhibitors in CLTI patients undergoing revascularization, comparing ACEIs

or ARBs with no ACEIs or ARB.

_{No significant differences were found in 3-}

and 5-year MALEs and major amputation rates or in 5-year reinterventions rates.

However, one study showed higher 1-year major amputation and AFS rates in

patients with rest pain using ACEIs before lower extremity revascularization

compared with no ACEIs, but this effect was not seen in patients with ulceration

or gangrene.

_{Another study showed significantly better 3-year survival and}

lower MACEs for patients receiving ACEI or ARB compared with patients who did

not use these medications.

Two studies comparing β-blockers vs. no β-blockers were identified.

_The

rates for 3-year limb salvage and freedom from MALEs were not significantly

different. On one hand, one study found no differences in 3-year survival, freedom

from cardiovascular death, and combined death and major amputation.

_{On the}

found after a median follow-up of 2.7 years with β-blocker use compared with no

β-blocker use, and the same was found for the use of calcium channel blockers. In

addition, the use of calcium channel blockers showed a significantly lower major

amputation rate.

Lipid-lowering therapy

Statin use plays a central role in cardiovascular risk management. Five studies

compared statin use vs. no statin use in patients undergoing revascularization.

Two of these studies showed better limb salvage rates with statin use after 2 and

2.7 years of follow-up.

_{The other studies showed no significant differences,}

although a trend toward higher limb salvage rates was seen with statin use.

Regarding survival, four of five studies showed significant better survival up to

5 years with statin use.

_{Primary patency after 2 years of follow-up seems}

better in patients using statins, but 1-year results were not different.

One study compared the extent to which different statin intensities reduced

cholesterol.

_{In terms of the primary endpoint, no differences were found in}

3-year limb salvage and MALEs rates. Regarding other endpoints, patients on

higher-intensity statins had lower 3-year mortality and MACEs rates compared

with patients using low- or moderate-intensity statins.

Stem cell therapy

Multiple studies in recent years have focused on stem cell therapy. Regarding

limb salvage treatment, no significant differences were shown between stem cell

therapy and control or standard therapy, except for one prospective comparative

trial and one small randomized controlled trial.

_{Long-term limb}

salvage rates have not been studied in comparative trials. Survival rates were not

found to be favorable with stem cell therapy. Two studies, however, compared

stem cell therapy with conservative management and reported significantly

better wound healing results after 3, 6, and 12 months with stem cell therapy

compared with controls.

Most stem cell research has been focused on bone marrow mononuclear

cells (BMMNC). A difference in intramuscular and intra-arterial administration

study compared BMMNC with bone marrow mesenchymal stem cells (BMMSC).

No difference in major amputation was observed, but BMMSC resulted in longer

painless walking time and better 6-week wound healing.

Growth factors

Because mortality and morbidity rates remain high in CLTI patients, therapies

are still being developed to improve perfusion in ischemic tissues. Among these

are strategies for upregulating angiogenesis with growth factors or transferring

genes that encode for these growth factors. These are most commonly

administered via intramuscular injections.

Hepatocyte growth factor (HGF) is a specific type of growth factor. The

current review identified one trial involving HGF and CLTI patients. No significant

differences were found in wound healing, major amputation, and mortality rates

between HGF and placebo. A significant decrease in pain in the HGF group was

observed (p = 0.04).

Vascular endothelial growth factor (VEGF) is another type of growth factor.

One study reported no differences between VEGF and placebo in major

amputation, nonfatal stroke and nonfatal myocardial infarction, and mortality.

Riferminogene pecaplasmid, also called nonviral fibroblast growth factor 1,

is a recombinant DNA plasmid allowing expression of fibroblast growth factor.

The study identified by the search showed no favorable effects compared with

placebo in 1-year limb salvage and survival.

Prostanoids

Prostaglandins and prostacyclins are types of prostanoids. Of the prostaglandin

group, alprostadil has been studied for CLTI. Compared with placebo, major

amputation and wound healing outcomes did not improve after intravenous

administration of alprostadil in a randomized trial.

_{In hemodialysis patients}

with Fontaine stage 4 receiving alprostadil, the 1-year major amputation rate

was 8.2%, mortality rate was 35%, and AFS rate 41% and comparable with

hemodialysis patients undergoing revascularization.

_{Alprostadil is not currently}

part of the standard treatment in CLTI patients.

No significant differences were found between the use of iloprost and EVT in

major amputation and AFS after 18 months of follow-up.

_{However, compared}

with antibiotic treatment, patients receiving iloprost had a lower 18-month

major amputation rate of 6.3% vs. 26.7% (p = 0.0323).

_{For patients not}

suitable for revascularization, 5-year major amputation rates were 6% vs. 21%

(p < 0.0001), and survival rates were 69% vs. 47% (p < 0.0001) in patients

receiving iloprost vs. patients receiving no iloprost.

_{A significant reduction of}

pain measured in visual analog scale score was observed after 1 year in a case

series of 44 patients with Fontaine 3 and 4 where revascularization was not

an option and who received iloprost for 1 week (p < 0.0001).

_{The 1-year major}

amputation rate in this study group was 11%, 1-year reintervention was 11%,

and 1-year mortality was 7%.

Cilostazol

Only one retrospective comparative study in CLTI patients after EVT was found

comparing cilostazol vs. no cilostazol.

_{The 5-year limb salvage and AFS were}

significantly better with cilostazol use than with no cilostazol (p < 0.01). Overall

5-year survival and 5-year reintervention showed no significant differences.

Glucose-lowering therapy

Because many CLTI patients suffer from diabetes mellitus (DM), strict glucose

regulation is of great importance to reduce complications. One study was found

in which nondiabetic patients were compared with noninsulin-dependent

diabetic (NIDDM) and insulin-dependent diabetic (IDDM) patients undergoing

EVT. The 4-year Kaplan-Meier analysis of survival showed no differences

between NIDDM and IDDM patients vs. nondiabetic patients. Major amputation

outcomes were significantly lower for nondiabetic patients compared with IDDM

patients (p = 0.001).

Spinal cord stimulation

The rationale behind spinal cord stimulation is that it improves microvascular

perfusion by suppressing sympathetic vasoconstriction and activating

vasodilatory molecules. One retrospective case series of 101 patients with

Fontaine stage 4 showed major amputation and mortality rates of 8.9% and

5.8%, respectively, after a median follow-up of 69 months.

_{These patients did}

not undergo revascularization simultaneously.

Sulodexide

Although this drug seems promising because of its antithrombotic and

fibrinolytic characteristics, only one study was identified.

_{No better outcomes}

for patients with sulodexide compared with controls were shown in 6-month

major amputation, wound healing, and reintervention rates. Sulodexide is not

currently being used in the treatment of CLTI.

Hemodilution

Isovolumic hemodilution was identified in one study.

_{In the study group,}

250 mL blood was withdrawn from all patients four times over four consecutive

weeks and replaced with an equal volume of hydroxyl-ethyl starch solution. It

causes a decrease in hematocrit and erythrocyte aggregation and in fibrinogen and

plasma viscosity. Results showed lower major amputation rates and better wound

healing compared with medication only. No difference was shown for 5-year

survival (p = 0.815); however, this study was nonrandomized and the study

population was small.

In addition to revascularization and in no-option CLTI patients, different medical

adjunctive therapies are available to improve limb salvage, of which the following

were reviewed in this systematic review: antiplatelets, antihypertensives,

lipid-lowering therapy, stem cell therapy, growth factors, prostanoids, cilostazol,

glucose-lowering therapy, spinal cord stimulation, sulodexide, and hemodilution.

Regarding major amputation, calcium channel blockers, iloprost, cilostazol,

and hemodilution showed significantly better outcomes, but data are limited.

Stem cell therapy showed no better limb salvage compared with controls.

Antiplatelets, antihypertensives, and statins are important in secondary

prevention of cardiovascular events, but a clear improvement of limb salvage

was not shown in the studies that the search identified.

Guidelines agree that all PAD patients should have the best medical therapy

consisting of antiplatelet drugs, statins, and if necessary, antihypertensives,

because they reduce the risk of adverse events and cardiovascular death.

These medical therapies provide secondary prevention but do not serve as the

primary treatment of the impaired limb perfusion. The current review showed

few comparative studies focusing on antiplatelet therapy adjunctive to

revascularization, including major amputation, as an endpoint. The only

comparative study of antiplatelet monotherapy in this review was a retrospective

study comparing aspirin use vs. no aspirin use, showing improved limb salvage

with aspirin use. In addition, some studies compared monotherapy with DAPT of

aspirin and clopidogrel. DAPT showed no evident improvement of limb salvage

and survival compared with monotherapy. Patency outcomes in CLTI patients

using DAPT after revascularization have not yet been studied.

A problem of both aspirin and clopidogrel is high on-treatment platelet

reactivity to either one or both of these drugs. Ticagrelor, a direct P2Y12 inhibitor,

is a drug that has no high on-treatment platelet reactivity and could therefore

be more effective. Ticagrelor has shown favorable results over clopidogrel in

cardiac patients and is now part of the standard treatment in this patient

category.

_{The current review found only one study of ticagrelor in CLTI patients,}

which was a retrospective case series. Although it was shown to be safe and

effective, with 12-month limb salvage of 100% and AFS of 92%, prospective

research is needed to further clarify the role of ticagrelor in CLTI.

Based on the Dutch Bypass Oral Anticoagulants or Aspirin Study, some

guidelines advise a vitamin K antagonist, such as warfarin, in patients

undergoing a venous bypass to improve patency and lower the risk for ischemic

events.

_{However, this was not supported by the current review based on one}

study that showed no differences in 1-year major amputation, primary patency

rates, and mortality between patients with a venous and a prosthetic bypass.

The results of the studies of antihypertensives in this review showed no

favorable effect of their use on limb outcomes, although survival seems better.

Moreover, one study showed even higher major amputation rates in patients with

rest pain using ACEIs compared with patients not on ACEI therapy. The authors

suggest that the inferior result is caused by inhibition of VEGF by ACEI, resulting

in inhibition of neovascularization and angiogenesis. However, the effect was not

seen in patients with ulceration or gangrene.

Calcium channel blockers, however, showed significantly better limb salvage.

Calcium channel blockers reduce the inflow of calcium in the cardiac muscle tissue

and smooth muscles of the vessel wall, resulting in relaxation of the muscle tissue,

which results in dilation of the coronary and peripheral vessels. The increased

blood flow to the limbs could be an explanation for the favorable effect of calcium

channel blockers, although this was only based on one retrospective study.

The choice of which antihypertensive drug is prescribed to PAD patients is

often determined by the comorbidity, but all groups of antihypertensive drugs

have been shown to reduce cardiovascular events.

_{In this review focusing on}

CLTI patients, lower mortality and MACEs were seen with ACEIs or ARBs but not

with β-blockers. The role of calcium channel blockers related to mortality was

not studied in this patient population.

The effect of statins on limb salvage remains unclear. Although a trend

toward lower major amputation rate was seen with patients on statin treatment

compared with patients not using statins, most of the studies showed no

significant difference. However, mortality and major adverse cardiac and

cerebrovascular events were obviously lower with statin use. Moreover, high-

intensity statin use was even better compared with low- to moderate-intensity

statin use. This highlights the importance of statin prescription in CLTI patients

as secondary prevention.

Stem cells can induce angiogenesis by producing growth factors and by

differentiating into endothelial cells. They can be derived from autologous bone

marrow, peripheral blood, or other tissues such as adipose and muscle tissues.

A meta-analysis of ten studies comparing bone marrow stem cell therapy

with placebo in patients with CLTI showed no significant differences in major

amputation, mortality and AFS rates.

_{This is in line with the results of the}

current review. Most studies included in the current review were pilot studies,

studies with small numbers of patients, or case series. The quality of the studies

ranged from fair to good. Therefore, more research with higher-quality evidence

is necessary.

The current review does not support the use of growth factor or gene therapy,

but data are limited. A meta-analysis of five randomized trials comparing growth

factor therapy with placebo was published in 2014.

_{No significant differences}

were found in 1-year major amputation, 1-year mortality, and 6-month wound

healing rates, which confirm the current review. So far, benefits for growth factor

and gene therapy have not been proven in CLTI patients, and therefore, larger

randomized trials are needed. The same applies to some other treatment

options, including iloprost and hemodilution. Compared with endovascular

therapy, iloprost was not favorable but could be valuable in patients with no

revascularization options. Hemodilution also seems promising in no-option CLTI

patients, but this was based on only one study with quality assessed as fair.

The phosphodiesterase III inhibitor, cilostazol, a platelet aggregation inhibitor,

is administered to reduce symptoms and improve walking distance in patients

with claudication. The current review identified one study and showed better

limb salvage and AFS outcomes in CLTI patients using cilostazol, although the

reintervention rate did not differ. The American Heart Association guideline

recommends cilostazol in patients with claudication, but it is not mentioned in the

context of CLTI.

_{Other guidelines, such as the National Institute for Health and}

Care Excellence and European Society for Vascular Surgery guidelines

do not mention cilostazol

_{possibly because cilostazol has been associated}

cilostazol could be valuable in CLTI patients.

Limitations

As a result of the primary endpoint, many studies with clinical endpoints, except

for major amputation after at least 6 months of follow-up, were excluded in the

end. This endpoint was chosen because of its clinical relevance. However, some

studies did not report major amputation rate but reported AFS, which is also

a relevant outcome in the treatment of CLTI. For instance, one excluded study

showed better AFS with aspirin or clopidogrel use compared with no antiplatelet

therapy.

_{In addition, another excluded study showed better AFS in patients}

using sarpogrelate compared with patients not on this medication.

_These

results confirm the importance of antiplatelet therapy in CLTI patients.

Regarding glucose-lowering medications, the included study compared

patients with and without diabetes. One of the excluded studies compared

different intensities of insulin therapy and showed no significant difference in

the 6-month freedom from combined restenosis, amputation, ulceration, sudden

cardiac arrest, and death.

_{However, because impaired glucose control damages}

the microcirculation, optimal regulation of glucose levels should be further

explored to improve limb salvage and wound healing.

Another interesting study reported mortality in patients receiving the

combination of ACEI and statin therapy vs. patients receiving none or one of

these two medications.

_{The 3-year survival was better in patients on ACEI and}

statin therapy, which corresponds to the results of the included studies.

Other reasons for final exclusion were the lack of mentioning the follow-up

duration and major amputation as an endpoint, but less than 6 months of

follow-up. Some therapies did not focus on major amputation as an endpoint

but were focused on wound healing and pain improvement. These included,

for example, spinal cord stimulation, L-propionyl-carnitine, and growth factor

therapy. Although these therapies are currently not useful to improve limb

salvage, they could be valuable to improve quality of life by reducing pain.

The current review maintained strict inclusion criteria regarding the study

population. Only patients with CLTI were included, whereas studies focusing

on patients with other stages of PAD were excluded, resulting in the exclusion

of recently published, important randomized trials, such as the Examining Use

of Ticagrelor in Peripheral Artery Disease (EUCLID) trial, the Cardiovascular

Outcomes for People Using Anticoagulation Strategies (COMPASS) trial, and the

Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects

with Elevated Risk (FOURIER trial).

_{Because of the new insights of these}

studies, the effects in CLTI patients, as a complicated subgroup of PAD, should be

further explored.

Conclusion

Even though various medical treatment options are available, the treatment of

CLTI patients remains complicated. Options for medical therapies adjunctive

to revascularization to improve limb salvage could involve calcium channel

blockers, iloprost, cilostazol, or hemodilution, but not enough evidence is

available to incorporate these as standard of care in CLTI patients. Moreover,

medical therapies are limited in no-option CLTI patients, comprising patients

not suitable for revascularization. In these patients, a favorable role of

iloprost was observed regarding pain reduction, and stem cell therapy shows

potential to improve wound healing. Other medications, such as antiplatelets,

antihypertensives, and statins, play a role in secondary prevention of

cardiovascular adverse events, but improvement of limb salvage remains

doubtful and is currently not the primary treatment goal. Besides invasive

and medical treatment, the importance of lifestyle change, especially smoking

cessation, should not be underestimated. Overall, large randomized trials are

needed to further clarify the role of potential beneficial medical therapies in

CLTI patients.

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10. Spiliopoulos S, Katsanos K, Pastromas G, Diamantopoulos A, Kitrou P, Siablis D, et al. Initial experience with ticagrelor in patients with critical limb ischemia and high on-clopidogrel platelet reactivity undergoing complex peripheral endovascular procedures. Cardiovasc Intervent Radiol. 2014;37:1450–7.

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34. Lu D, Chen B, Liang Z, Deng W, Jiang Y, Li S, et al. Comparison of bone marrow mesenchymal stem cells with bone marrow-derived mononuclear cells for treatment of diabetic critical limb ischemia and foot ulcer: A double-blind, randomized, controlled trial. Diabetes Res Clin Pract. 2011;92:26–36.

35. Lu D, Jiang Y, Deng W, Zhang Y, Liang Z, Wu Q, et al. Long-Term Outcomes of BMMSC Compared with BMMNC for Treatment of Critical Limb Ischemia and Foot Ulcer in Patients with Diabetes. Cell Transplant. 2019;28:645-652.

36. Dubský M, Jirkovská A, Bem R, Fejfarová V, Pagacová L, Nemcová A, et al. Comparison of the effect of stem cell therapy and percutaneous transluminal angioplasty on diabetic foot disease in patients with critical limb ischemia. Cytotherapy. 2014;16:1733–8.

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38. Belch J, Hiatt WR, Baumgartner I, Driver IV, Nikol S, Norgren L, et al. Effect of fibroblast growth factor NV1FGF on amputation and death: a randomised placebo-controlled trial of gene therapy in critical limb ischaemia. Lancet. 2011;377:1929–37.

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Appendix A - Full search strategy

Component of search Search terms

1. (medical therapy OR medicine therapy) AND

2. (critical limb isc* OR CLI OR CLTI OR chronic limb threatening isch*)

Filters activated: published in the last 10 years, humans.

Component of search Search terms

1. ‘medical therapy’ OR ‘medicine therapy’ (MeSH) AND

2. ‘CLI’ OR ‘critical limb isch*’ OR ‘CLTI’ OR ‘chronic limb threatening isch*’isch*)

Component of search Search terms

#1 medical AND (‘therapy’/exp OR therapy)

#2 (‘medicine’/exp OR medicine) AND (‘therapy’/exp OR therapy) #3 ‘critical limb ischemia’/exp OR ‘critical limb ischemia’

#4 cli

#5 clti

#6 chronic AND limb AND threatening AND ischemia

#7 #1 OR #2

#8 #3 OR #4 OR #5 OR #6

#9 #7 AND #8

#10 #9 AND (2009:py OR 2010:py OR 2011:py OR 2012:py OR 2013:py OR 2014:py OR 2015:py OR 2016:py OR 2017:py OR 2018:py OR 2019:py)

MEDLINE

EMBASE

Appendix B - Baseline data and results of the

included studies

Antiplatelet therapy: aspirin, clopidogrel, ticagrelor Study Study design Study

population Medication Pt, n Endpoints Major amputation Thott 201712 _{Retrospective}

comparative CLTI patients undergoing EVT DAPT (aspirin + clopidogrel) vs aspirin 599 vs 1342 Median FU 2-years 13% vs 17%, HR 0.79, p=ns Spiliopoulos

201410 Retrospective _{case series} CLTI patients _{with high} on-treatment platelet reactivity to clopidogrel undergoing EVT Ticagrelor + aspirin for 6 months, thereafter ticagrelor 37 1-year 0% Suckow 201311 Retrospective _comparative, matched cohort CLTI patients undergoing OR: venous vs prosthetic Aspirin Aspirin + clopidogrel Aspirin + warfarin Aspirin + clopidogrel + warfarin Total 204 vs 204 1-year 16% vs 24%, p=0.24 5% vs 0%, p =0.47 14% vs 9%, p =0.44 14% vs 20%, p=0.14 Baubeta

Fridh 20189 Retropective _comparative CLTI patients DAPT vs no _DAPT

Aspirin vs no aspirin 566 7778 Median FU 2.7 years HR 1.13, p=0.248 HR 0.77, p<0.001 AFS = amputation-free survival. CLTI = chronic limb-threatening ischemia. DAPT = dual antiplatelet therapy. EVT = endovascular treatment. FU = follow-up. HR = hazard ratio. n = number. ns = non-significant. Pt = patient. TLR = target lesion revascularization. vs = versus.

Mortality AFS Reintervention Primaty patency Bleeding Median FU 2-years 29% vs 43%, HR 0.83, p=ns 6-months 4.7% vs 3.3%, HR 1.4, p=ns Freedom from cardiovascular death/ amputation 1-year 92.1% 15.8% TLR free survival 12-months 67.3% 0% Survival -year 89% vs 85%, p=0.88 95% vs 64%, p=0.19 83% vs 80%, p=0.77 95% vs 85%, p=0.37 1-year 70% vs 74%, p=0.6 65% vs 55%, p=0.66 78% vs 80%, p=0.52 75% vs 59%, p=0.65 1-year 14% vs 11%, p=0.56 7% vs 13%, p=0.41 12% vs 16%, p=0.38 19% vs 17%, p=0.8 Median FU 2.7 years Death/major amputation HR 1.02, p=0.751 HR 0.82, p<0.001

Antiplatelet therapy: aspirin, clopidogrel, ticagrelor Study Study design Study

population Medication Pt, n Endpoints Major amputation Thott 201712 _{Retrospective}

comparative CLTI patients undergoing EVT DAPT (aspirin + clopidogrel) vs aspirin 599 vs 1342 Median FU 2-years 13% vs 17%, HR 0.79, p=ns Spiliopoulos

201410 Retrospective _{case series} CLTI patients _{with high} on-treatment platelet reactivity to clopidogrel undergoing EVT Ticagrelor + aspirin for 6 months, thereafter ticagrelor 37 1-year 0% Suckow 201311 Retrospective _comparative, matched cohort CLTI patients undergoing OR: venous vs prosthetic Aspirin Aspirin + clopidogrel Aspirin + warfarin Aspirin + clopidogrel + warfarin Total 204 vs 204 1-year 16% vs 24%, p=0.24 5% vs 0%, p =0.47 14% vs 9%, p =0.44 14% vs 20%, p=0.14 Baubeta

Fridh 20189 Retropective _comparative CLTI patients DAPT vs no _DAPT

Aspirin vs no aspirin 566 7778 Median FU 2.7 years HR 1.13, p=0.248 HR 0.77, p<0.001 AFS = amputation-free survival. CLTI = chronic limb-threatening ischemia. DAPT = dual antiplatelet therapy. EVT = endovascular treatment. FU = follow-up. HR = hazard ratio. n = number. ns = non-significant. Pt = patient. TLR = target lesion revascularization. vs = versus.

Mortality AFS Reintervention Primaty patency Bleeding Median FU 2-years 29% vs 43%, HR 0.83, p=ns 6-months 4.7% vs 3.3%, HR 1.4, p=ns Freedom from cardiovascular death/ amputation 1-year 92.1% 15.8% TLR free survival 12-months 67.3% 0% Survival -year 89% vs 85%, p=0.88 95% vs 64%, p=0.19 83% vs 80%, p=0.77 95% vs 85%, p=0.37 1-year 70% vs 74%, p=0.6 65% vs 55%, p=0.66 78% vs 80%, p=0.52 75% vs 59%, p=0.65 1-year 14% vs 11%, p=0.56 7% vs 13%, p=0.41 12% vs 16%, p=0.38 19% vs 17%, p=0.8 Median FU 2.7 years Death/major amputation HR 1.02, p=0.751 HR 0.82, p<0.001

Antihypertensives: RAS-inhibitors Study Study design Study

population Medication Pt, n Endpoints Major amputation Armstrong

201513 Retrospective _comparative CLTI patients _{undergoing DSA} or EVT

ACEI/ARB vs no

ACEI/ARB 269 vs 195 3-yearHR 0.74, p=0.1 Bodewes

201814 Retrospective _comparative CLTI patients _{undergoing EVT} or open repair

ACEI/ARB vs no

ACEI/ARB 604 vs 557 5-yearHR 0.82, p=0.29 Kray

201715 Retrospective _comparative CLTI patients _{with rest pain} undergoing EVT or open repair CLTI patients with ulceration/ gangrene un-dergoing EVT or open repair ACEI before procedure vs no ACEI before procedure 1189 vs 1867 4485 vs 7285 No ACEI vs ACEI 1-year: OR 0.71, p=0.01 ACEI vs no ACEI 1-year 42.2% vs. 40.9%, p=0.17 Baubeta Fridh 20189 Retrospective

comparative CLTI patients ACEI/ARB vs no 6085 Median FU 2.7 years HR 1.07, p=0.149 Antihypertensives: Beta blockade

Soga

201516 Retrospective _comparative CLTI patients _{undergoing EVT} β-blocker vs no _β-blocker 305 vs ₃₀₅ Limb salvage _3-year 88.3% vs 88.8%, p=0.41 Baubeta Fridh 20189 Retrospective

comparative CLTI patients β-blocker vs no β-blocker 5391 Median FU 2.7 years HR 1.03, p=0.553 Antihypertensives: Calcium channel blockers

Baubeta Fridh 20189

Retrospective

compara-tive CLTI patients Calcium channel blockers vs no calcium channel blockers

3339 Median FU 2.7 years

HR 0.90, p=0.042 ACEI = angiotensin-converting enzyme inhibitor. ARB = angiotensin receptor blocker. CLTI = chronic limb-threatening ischemia. CV = cardiovascular. DSA = digital subtraction angiography. EVT = endovascular treatment. FU = follow-up. HR = hazard ratio. MACE = major adverse cardiac events. MALE = major adverse limb events. n = number. ns = non-significant. OR = odds ratio. Pt = patient. RAS = renin-angiotensin system. vs = versus.

*MACE was defined as myocardial infarction, stroke or death.

Mortality MALE AFS Reintervention MACE* 3-year

HR 0.71, p=0.02 3-yearHR 0.97, p=0.2 3-yearHR 0.79, p=ns 3-yearHR 0.76, p=0.04 5-year, HR 0.78, p=? 5-yearHR 0.95, p=0.68 5-year HR 1.05, p=0.63 1-year ACEI vs no ACEI, rest pain HR 1.37, p=0.01 Death/major amputation Median FU 2.7 years HR 1.01, p=0.640 30-day 1.0% vs 3.7%, p=0.03 Survival 3-year 63.0% vs 62.4%, p=0.70 Freedom from MALE 3-year 43.6% vs 44.9%, p=0.58 Death/major amputation 3-year 58.8% vs 58.5%, p=0.76 Freedom from CV death 3-year 76.0% vs 78.2%, p=0.66 Death/major amputation Median FU 2.7 years HR 1.09, p=0.003 Death/major amputation Median FU 2.7 years HR 0.94, p=0.040

Antihypertensives: RAS-inhibitors Study Study design Study

population Medication Pt, n Endpoints Major amputation Armstrong

201513 Retrospective _comparative CLTI patients _{undergoing DSA} or EVT

ACEI/ARB vs no

ACEI/ARB 269 vs 195 3-yearHR 0.74, p=0.1 Bodewes

201814 Retrospective _comparative CLTI patients _{undergoing EVT} or open repair

ACEI/ARB vs no

ACEI/ARB 604 vs 557 5-yearHR 0.82, p=0.29 Kray

201715 Retrospective _comparative CLTI patients _{with rest pain} undergoing EVT or open repair CLTI patients with ulceration/ gangrene un-dergoing EVT or open repair ACEI before procedure vs no ACEI before procedure 1189 vs 1867 4485 vs 7285 No ACEI vs ACEI 1-year: OR 0.71, p=0.01 ACEI vs no ACEI 1-year 42.2% vs. 40.9%, p=0.17 Baubeta Fridh 20189 Retrospective

comparative CLTI patients ACEI/ARB vs no 6085 Median FU 2.7 years HR 1.07, p=0.149 Antihypertensives: Beta blockade

Soga

201516 Retrospective _comparative CLTI patients _{undergoing EVT} β-blocker vs no _β-blocker 305 vs ₃₀₅ Limb salvage _3-year 88.3% vs 88.8%, p=0.41 Baubeta Fridh 20189 Retrospective

comparative CLTI patients β-blocker vs no β-blocker 5391 Median FU 2.7 years HR 1.03, p=0.553 Antihypertensives: Calcium channel blockers

Baubeta Fridh 20189

Retrospective

compara-tive CLTI patients Calcium channel blockers vs no calcium channel blockers

3339 Median FU 2.7 years

HR 0.90, p=0.042 ACEI = angiotensin-converting enzyme inhibitor. ARB = angiotensin receptor blocker. CLTI = chronic limb-threatening ischemia. CV = cardiovascular. DSA = digital subtraction angiography. EVT = endovascular treatment. FU = follow-up. HR = hazard ratio. MACE = major adverse cardiac events. MALE = major adverse limb events. n = number. ns = non-significant. OR = odds ratio. Pt = patient. RAS = renin-angiotensin system. vs = versus.

*MACE was defined as myocardial infarction, stroke or death.

Mortality MALE AFS Reintervention MACE* 3-year

HR 0.71, p=0.02 3-yearHR 0.97, p=0.2 3-yearHR 0.79, p=ns 3-yearHR 0.76, p=0.04 5-year, HR 0.78, p=? 5-yearHR 0.95, p=0.68 5-year HR 1.05, p=0.63 1-year ACEI vs no ACEI, rest pain HR 1.37, p=0.01 Death/major amputation Median FU 2.7 years HR 1.01, p=0.640 30-day 1.0% vs 3.7%, p=0.03 Survival 3-year 63.0% vs 62.4%, p=0.70 Freedom from MALE 3-year 43.6% vs 44.9%, p=0.58 Death/major amputation 3-year 58.8% vs 58.5%, p=0.76 Freedom from CV death 3-year 76.0% vs 78.2%, p=0.66 Death/major amputation Median FU 2.7 years HR 1.09, p=0.003 Death/major amputation Median FU 2.7 years HR 0.94, p=0.040

Lipid-lowering therapy

Study Study design Study

population Medication Pt, n Endpoints Major amputation Aiello

201217 Retrospective _comparative CLTI patients _{undergoing EVT} Statin vs no _statin 319 _vs 327 Limb salvage 2-year 83 vs 62, p=0.001 Westin

201418 Retrospective _comparative CLTI patients _{undergoing DSA} and/or EVT Statin vs no statin 246 vs 134 1-year HR 0.68, p=0.3 Tomoi

201319 Retrospective _comparative CLTI patients _{undergoing EVT} for BTK disease Statin vs no statin 169 vs 643 Limb salvage 4-year HR 1.46, p=0.24 Foley 201721 _{Retrospective}

case series CLTI patients undergoing DSA or EVT High-intensity statin vs low-/ moderate-intensity statin 237 vs 74 3-year HR 1.1, p=0.8 Suckow

201520 Prospective _comparative CLTI patients _undergoing infrainguinal bypass surgery, using statins Statin vs no statin 1537 vs 530 1-year 12% vs 11%, p=0.84 Baubeta

Fridh 20189 Retrospective _comparative CLTI patients _after revascularization

Statin vs no

statin 6883 Median FU 2.7 years HR 0.70, p<0.001 AFS = amputation-free survival. CLTI = chronic limb-threatening ischemia. DSA = digital subtraction angiography. EVT = endovascular treatment. FU = follow-up. HR = hazard ratio. MACE = major adverse cardiovascular events. MALE = major adverse limb events. n = number. ns = non-significant. Pt = patient. vs = versus.

*MACCE = major adverse cardiac and cerebrovascular events.

Mortality MALE AFS Primaty

patency Secondary patency MACE Overall survival 2-year 77% vs 62%, p=0.038 2-year 43% vs 33%, p=0.007 2-year 65 vs 51, p=0.001 1-year survival 87% vs 79%, p<0.05 1-year 76% vs 62%, p<0.05 1-year 62% vs 52%, p=0.5 1-year 82% vs 58%, p=0.02 MACCE* 1-year HR 0.53, p=0.048 Survival 4-year HR 0.92, p=0.65 CV death 4-year HR 1.07, p=0.82 4-year HR 1.34, p=0.29 4-year HR 0.88, p=0.47 3-year HR 0.53, p=0.021 3-year HR 1.21, p=0.493 3-year HR 0.54, p=0.039 5-year survival 60% vs 51%, p=0.003 Median FU 2.7 years Death/major amputation HR 0.58, p<0.001

Lipid-lowering therapy

Study Study design Study

population Medication Pt, n Endpoints Major amputation Aiello

201217 Retrospective _comparative CLTI patients _{undergoing EVT} Statin vs no _statin 319 _vs 327 Limb salvage 2-year 83 vs 62, p=0.001 Westin

201418 Retrospective _comparative CLTI patients _{undergoing DSA} and/or EVT Statin vs no statin 246 vs 134 1-year HR 0.68, p=0.3 Tomoi

201319 Retrospective _comparative CLTI patients _{undergoing EVT} for BTK disease Statin vs no statin 169 vs 643 Limb salvage 4-year HR 1.46, p=0.24 Foley 201721 _{Retrospective}

case series CLTI patients undergoing DSA or EVT High-intensity statin vs low-/ moderate-intensity statin 237 vs 74 3-year HR 1.1, p=0.8 Suckow

201520 Prospective _comparative CLTI patients _undergoing infrainguinal bypass surgery, using statins Statin vs no statin 1537 vs 530 1-year 12% vs 11%, p=0.84 Baubeta

Fridh 20189 Retrospective _comparative CLTI patients _after revascularization

Statin vs no

statin 6883 Median FU 2.7 years HR 0.70, p<0.001 AFS = amputation-free survival. CLTI = chronic limb-threatening ischemia. DSA = digital subtraction angiography. EVT = endovascular treatment. FU = follow-up. HR = hazard ratio. MACE = major adverse cardiovascular events. MALE = major adverse limb events. n = number. ns = non-significant. Pt = patient. vs = versus.

*MACCE = major adverse cardiac and cerebrovascular events.

Mortality MALE AFS Primaty

patency Secondary patency MACE Overall survival 2-year 77% vs 62%, p=0.038 2-year 43% vs 33%, p=0.007 2-year 65 vs 51, p=0.001 1-year survival 87% vs 79%, p<0.05 1-year 76% vs 62%, p<0.05 1-year 62% vs 52%, p=0.5 1-year 82% vs 58%, p=0.02 MACCE* 1-year HR 0.53, p=0.048 Survival 4-year HR 0.92, p=0.65 CV death 4-year HR 1.07, p=0.82 4-year HR 1.34, p=0.29 4-year HR 0.88, p=0.47 3-year HR 0.53, p=0.021 3-year HR 1.21, p=0.493 3-year HR 0.54, p=0.039 5-year survival 60% vs 51%, p=0.003 Median FU 2.7 years Death/major amputation HR 0.58, p<0.001

Stem cell therapy Study Study

design Study population Medication Pt, n Endpoints Major

amputation AFS Giles

201332 Prospective _comparative CLTI _{patients not} suitable for EVT or OR Autologous BMCT vs poor prognosis bypass surgery 20 vs 35 Mean FU 2.5 years 20% vs 20% 1-year 78% vs 69%, p=0.60 Benoit 201131 Randomized _controlled trial CLTI patients not suitable for EVT or OR Autologous BMCT vs placebo 34 vs 14 6-months 29.4% vs 35.7%, p=0.412 Wang

201823 Randomized _{clinical trial,} retropecttive analysis CLTI patients not suitable for EVT or OR BMCT in ethnic minorities vs white people Ethnic minorities BMCT versus control White people BMCT versus control 28 vs 91 1-year 7.1% vs 22.2%, p=0.24 18.7% vs 22.2%, p=0.78 1-year 89% vs 77%, p=ns Dubský

201436 Retrospective _comparative CLTI _patients, di-abetic foot disease

PTA vs stem cell therapy (BMM-NC 20 patients and PBSC 11 patients) vs control 30 vs 31 vs 23 1-year 17% vs 16% vs 43% 6-months p=0.02 12 months p=0.0029 Powell 201222 Randomized _controlled trial CLTI patients not suitable for EVT or OR BMCT (Ixmyelocel-T) vs control 48 vs 24 1-year 20.8% vs 25.0% 1-year HR 0.676, p=0.3880 Lu 201134 Randomized _controlled trial Bilateral CLTI, DM BMMSC vs BMMNC 20 vs 21 6-months 0% vs 0%

Mortality Reintervention Wound healing Pain

improvement Improvement Fonainte/ Rutherford

MACE 1.5 years

75% for BMCT Resolution of rest pain 1.5 years 58% for BMCT 6-months 1 vs 1 6-months38.2% vs 28.6% 1-year 3.6% vs 11.1%, p=0.43 4.4% vs 7.4%, p=0.62 1-year 4.78 vs 3.26, p=0.04 6-min walking distance 188 vs 250, p=0.14 1-year 13% vs 10% vs 9% 3-months 23.3% vs 46.7% vs 17.4%, p=0.032 6-months 34.4% vs 63.3% vs 9.5%, p=0.005 1-year 57.7% vs 84% vs 19.1%, p=0.013 and p=0.046 1-year 8% vs 8% p=1.000 6 weeks

Stem cell therapy Study Study

design Study population Medication Pt, n Endpoints Major

amputation AFS Giles

201332 Prospective _comparative CLTI _{patients not} suitable for EVT or OR Autologous BMCT vs poor prognosis bypass surgery 20 vs 35 Mean FU 2.5 years 20% vs 20% 1-year 78% vs 69%, p=0.60 Benoit 201131 Randomized _controlled trial CLTI patients not suitable for EVT or OR Autologous BMCT vs placebo 34 vs 14 6-months 29.4% vs 35.7%, p=0.412 Wang

201823 Randomized _{clinical trial,} retropecttive analysis CLTI patients not suitable for EVT or OR BMCT in ethnic minorities vs white people Ethnic minorities BMCT versus control White people BMCT versus control 28 vs 91 1-year 7.1% vs 22.2%, p=0.24 18.7% vs 22.2%, p=0.78 1-year 89% vs 77%, p=ns Dubský

201436 Retrospective _comparative CLTI _patients, di-abetic foot disease

PTA vs stem cell therapy (BMM-NC 20 patients and PBSC 11 patients) vs control 30 vs 31 vs 23 1-year 17% vs 16% vs 43% 6-months p=0.02 12 months p=0.0029 Powell 201222 Randomized _controlled trial CLTI patients not suitable for EVT or OR BMCT (Ixmyelocel-T) vs control 48 vs 24 1-year 20.8% vs 25.0% 1-year HR 0.676, p=0.3880 Lu 201134 Randomized _controlled trial Bilateral CLTI, DM BMMSC vs BMMNC 20 vs 21 6-months 0% vs 0%

Mortality Reintervention Wound healing Pain

improvement Improvement Fonainte/ Rutherford

MACE 1.5 years

75% for BMCT Resolution of rest pain 1.5 years 58% for BMCT 6-months 1 vs 1 6-months38.2% vs 28.6% 1-year 3.6% vs 11.1%, p=0.43 4.4% vs 7.4%, p=0.62 1-year 4.78 vs 3.26, p=0.04 6-min walking distance 188 vs 250, p=0.14 1-year 13% vs 10% vs 9% 3-months 23.3% vs 46.7% vs 17.4%, p=0.032 6-months 34.4% vs 63.3% vs 9.5%, p=0.005 1-year 57.7% vs 84% vs 19.1%, p=0.013 and p=0.046 1-year 8% vs 8% p=1.000 6 weeks