University of Groningen Chronic limb-threatening ischemia Ipema, Jetty

University of Groningen

Chronic limb-threatening ischemia

Ipema, Jetty

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10.33612/diss.170945328

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2021

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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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2

Drug-coated balloon angioplasty vs.

standard percutaneous transluminal

angioplasty in below-the-knee

peripheral arterial disease:

a systematic review and

meta-analysis

Eur J Vasc Endovasc Surg. 2020;59:265-275

Jetty Ipema

Eline Huizing

Michiel A Schreve

Jean-Paul PM de Vries

Çagdas Ünlü

Objective: The aim was to review and analyse the literature on clinical

outcomes of drug- coated balloon (DCB) vs. standard percutaneous transluminal

angioplasty (PTA) for the treatment of infrapopliteal arterial disease.

Methods: This is a systematic review and meta-analysis. The MEDLINE,

EMBASE and Cochrane Database of Systematic Reviews were searched for

studies published between January 2008 and November 2018. Two authors

independently performed the search, study selection, assessment of

methodological quality and data extraction. Studies were eligible when

reporting outcomes of PTA and DCBs in infrapopliteal arteries, published in

English, human studies and full text was available. Methodological quality

was determined by MINORS and Cochrane risk of bias tool. GRADE

methodology was used to rate the evidence for observed outcomes. The primary

outcome was 12-month limb salvage rate. Secondary outcomes were 12-month

survival, amputation-free survival (AFS), restenosis, and target lesion

revascularization (TLR) rates. Inclusion criteria for pooling data were

randomized controlled trials and comparative studies with 12-month outcomes.

Results: Ten studies representing 1593 patients met the inclusion criteria.

The quality was assessed as moderate or low. Data from five studies were

pooled, and 12-month outcomes for DCB vs. PTA were limb salvage rate,

94.0% vs. 95.7% (odds ratio [OR]: 0.92; 95% confidence interval [CI]:

0.39-2.21); and survival rate, 89.8% vs. 92.9% (OR: 0.69; 95% CI: 0.39-1.21).

Data from four studies were pooled, and 12-month outcomes for PTA vs.

DCB were restenosis rate, 62.0% vs. 32.9% (OR: 2.87; 95% CI: 0.83-9.92);

and TLR rate, 27.8% vs. 14.0% (OR: 2.76; 95% CI: 0.90-8.48). Pooled data

from two studies showed 12-month AFS rate for DCB vs. PTA, 82.5% vs.

88.7% (OR: 0.79; 95% CI: 0.23-2.75). No statistically significant differences

were found.

Conclusion: Based on this systematic review and meta-analysis no significant

differences in limb salvage, survival, restenosis, TLR, and AFS rates were found

when DCB angioplasty was compared with standard PTA. 

Introduction

Peripheral arterial disease affects millions of people worldwide.

_{The end stage}

of peripheral arterial disease is characterised by critical limb ischaemia (CLI),

which is associated with rest pain and tissue necrosis, resulting in impaired

quality of life and high morbidity and mortality. CLI is often caused by

infrapopliteal atherosclerosis. Percutaneous transluminal angioplasty (PTA) is

the preferred treatment option for infrapopliteal arterial disease, but success

rates are moderate.

_{In recent years, drug-coated balloons (DCBs) have been used}

to probably improve outcomes. This was based on the use of DCBs in cardiac

small vessel disease.

A meta-analysis of randomised trials published in 2016 showed no

differences between standard PTA and DCB angioplasty in clinical outcomes at

12 months.

_{In the last two years, new case series and comparative studies and}

one large randomised controlled trial have been performed with the use of new

types of DCBs with promising results. Whether DCB or standard PTA is the best

treatment option for infrapopliteal arterial disease in preventing amputation

remains unclear. Therefore, this meta-analysis was conducted to determine

current rates of limb salvage, survival, amputation-free survival (AFS),

restenosis, and target lesion revascularisation (TLR) from randomised trials

and comparative studies of DCB and PTA and case series of DCB use in patients

with infrapopliteal arterial disease.

Methods

This report was written in accordance with the Preferred Reporting Items for

Systematic Reviews and Meta-Analyses (PRISMA) guidelines for reporting

systematic reviews and meta-analyses.

Literature search

The MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews

were searched for eligible articles published between 1 January 2008 and 16

November 2018. The following keywords were used: below the knee,

infrapopliteal, tibial arteries, tibial artery, crural, peripheral arterial disease,

peripheral artery disease, critical limb ischaemia, arterial occlusive disease,

drug coated balloon, drug coated PTA, drug coated balloon angioplasty, drug

eluting balloon, drug eluting PTA, and drug eluting PTA angioplasty. A full

search strategy can be found in Appendix A. No individual authors of the

included articles were contacted.

Inclusion and exclusion criteria

Articles were eligible if they included DCB angioplasty or compared DCB

angioplasty with standard PTA of infrapopliteal arteries in patients with

peripheral arterial disease, were published in English, included human subjects,

and had a full text available. Exclusion criteria were case reports, articles with

fewer than 50 infrapopliteal angioplasties, the use of other types of balloons or

stents, cutting balloon, cryoplasty, or laser technique, reviews, commentaries,

letters to the editor, or conference abstracts.

Data collection and quality assessment

After duplicates were removed, two authors (J.I., E.H.) screened the titles and

abstracts of the identified studies for relevance. Of the remaining relevant

studies, full texts were read by two authors (J.I., E.H.), and a final selection of

relevant studies was made. The Methodological Index for Non-randomised

Studies (MINORS) score

_{was used to assess the quality of non-comparative}

quality, 9-14 moderate quality, and 15-16 good quality. The Cochrane tool for

assessing risk of bias in randomised clinical trials was used to assess the

quality of randomised trials.

_{Every study was assessed on seven domains and}

risk of bias was rated as low, high, or unclear. The quality of the evidence for the

outcomes of randomised controlled trials and comparative studies was assessed

by the Grading of Recommendations, Assessment, Development and Evaluation

(GRADE) approach.

_{In case of discrepancy between the authors during the}

search, selection, and quality assessment, a third author (C.U.) was consulted

until agreement was reached.

Outcome measures and data analysis

The primary outcome was the 12-month limb salvage rate. 12-month

secondary outcomes were rates for survival, AFS, restenosis, and TLR. Two

authors (J.I., E.H.) independently performed data extraction. Data extracted

included year of publication, study design, sample size, study period,

inclusion criteria, exclusion criteria, baseline demographics, type of balloon,

and 12-month survival, limb salvage, AFS, restenosis, and TLR rates. Limb

salvage was defined as avoidance of major amputation (above the ankle). AFS

was defined as avoidance of major amputation and/or death. The definition of

restenosis was >50% recurrent stenosis on duplex ultrasound or angiography,

or a peak systolic velocity rate ≥2.5 on duplex ultrasound. TLR included any

clinically driven repeat percutaneous intervention of the target lesion or bypass

surgery of the target vessel. Meta-analysis was performed with Meta-Analyst

3.1 software (Tufts University, Medford, MA, USA). Data were pooled when

meeting the following criteria: randomised trial or comparative study and

outcome at 12 months. A random effects model was used for pooled data

analysis. Results were presented as Odds Ratios (OR) with 95% confidence

interval (CI). The presence of heterogeneity between studies was determined

Results

Included studies

The search identified 1042 articles. After removal of duplicates and screening

of titles and abstracts, 51 were eligible for the full text review. The full text

reading resulted in 10 articles

_{that met the inclusion criteria (Figure 2.1),}

consisting of three prospective case series,

_{one retrospective case series,}

four randomised trials,

_{and two retrospective comparative studies.}

Reasons for exclusion were not in English,

_{no DCB,}

_{article type,}

_{full text}

not available,

_{other outcomes (one each describing number of DCB procedures}

performed,

_{haemodynamic parameters to diagnose CLI,}

_{and number of PTAs}

performed

_{), comparing DCB with drug-eluting stent,}

_duplicates,

overlapping data,

_{and fewer than 50 below-the-knee angioplasties.}

The included case series were of moderate quality as assessed by the

MINORS score (Table 2.1). Unbiased assessment of the endpoint was not

described in any of the studies. According to the Cochrane tool for assessing risk

of bias in randomised clinical trials all studies had unclear or high risk of bias

for blinding (Table 2.2). The quality of the evidence for the outcomes of the

randomised and comparative studies were moderate or low according to the

GRADE score due to risk of inconsistency of results and indirectness of evidence

(Table 2.3).

The 10 included studies represented 1593 patients, of which 1236 underwent

DCB angioplasty and 357 underwent standard PTA. Included patients were

classified as Rutherford category 3 or higher, except for one study that included

four patients with Rutherford category 2.

_{Different types of DCB were used:}

including Lutonix 014 DCB Catheter (Lutonix, Minneapolis, MN, USA),

_Lutonix

DCB (Bard Lutonix, New Hope, MN, USA),

_{Passeo-18 Lux DEB (Biotronik AG,}

Buelach, Switzerland),

_{Luminor 14/35 paclitaxel eluting peripheral dilatation}

balloon catheters (iVascular SLU, Barcelona, Spain),

_{Luminor 14 DEB (iVascular,}

Barcelona, Spain),

_{IN.PACT Amphirion DEB (Medtronic, Minneapolis, MN,}

USA),

_{leg flow paclitaxel coated balloons (Cardionovum Sp.z.o.o, Warsaw,}

Poland),

_{and Elutax Aachen resonance (Aachen Resonance Holding AG, Aachen,}

Figure 2.1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram for literature search to identify studies reporting on percutaneous transluminal and drug-coated balloon angioplasty.

a _{Some articles had more than one reason to be excluded.}

All studies included the anterior tibial, posterior tibial, and peroneal

arteries. Two studies also included (distal) popliteal artery occlusions,

_and

four also included lesions in the tibioperoneal trunk.

_Simultaneous

treatment of inflow lesions was performed in eight studies, one excluded patients

with inflow lesions,

_{and one did not mention the presence or treatment of}

inflow lesions.

_{Characteristics and baseline data of the included studies are}

Table 2.3. Grading of Recommendations, Assessment, Development and Evaluation approach for quality assessment of randomized controlled trials and comparative studies reporting on percutaneous transluminal angioplasty and drug-coated balloon angioplasty for infrapopliteal arterial disease

Certainty assessment № of studies Study

design Risk of bias Inconsis-tency of results Indirect-ness of evidence Imprecision Other conside-rations Limb salvage (follow-up: 12 months)

511-13,19,20 _Randomized

trials Not serious Not serious Serious

b _{Not serious None}

Survival (follow-up: 12 months)

511-13,19,20 _Randomized

trials Not serious Not serious Serious

b _{Not serious None}

Restenosis (follow-up: 12 months)

411-13,19 _Randomized

trials Not serious Serious

a _Seriousb _{Not serious None}

TLR (follow-up: 12 months)

411,13,19,20 _Randomized

trials Not serious Serious

a _Seriousb _{Not serious None}

№ of patients Effect Certainty

DCB PTA Relative

(95% CI) Absolute(95% CI)

375/399

(94.0%) 269/281 (95.7%) OR 0.922(0.385-2.210) 3 fewer per 1.000(from 61 fewer to 23 more) ⨁⨁⨁◯MODERATE

364/405

(89.9%) 261/281 (92.9%) OR 0.687(0.392- 1.205) 29 fewer per 1.000 (from 92 fewer to 11 more) ⨁⨁⨁◯MODERATE 72/219

(32.9%) 111/179 (62.0%) OR 0.349(0.101-1.207) 257 fewer per 1.000 (from 479 fewer to 43 more) ⨁⨁◯◯LOW

49/350

(14.0%) 65/234 (27.8%) OR 0.383(0.124-1.185) 149 fewer per 1.000 (from 232 fewer to 35 more) ⨁⨁◯◯LOW CI = Confidence interval; DCB = drug-coated balloon; OR = Odds ratio; PTA = percutaneous

transluminal angioplasty.

a_{Test of heterogeneity I}2 _{with high percentage and low p-value.}

b_{Differences in populations (age, morbidity). Differences in duration of antiplatelet therapy and use}

of different types of DCBs.

Article

Criterion Thieme ₂₀₁₈15 ₂₀₁₈Ozpak 14 Schmidt ₂₀₁₁18 Steiner ₂₀₁₆17

1. A clearly stated aim 2 2 2 2

2. Inclusion of consecutive patients 0 2 2 2

3. Prospective collection of data 2 2 2 2

4. Endpoint appropriate to the aim of the study 2 2 2 2

5. Unbiased assessment of the study endpoint 0 0 0 0

6. Follow-up period appropriate to the aim of the study 2 2 2 2

7. Loss to follow-up less than 5% 0 2 2 0

8. Prospective calculation of the study size 1 0 0 0

Total MINORS score 9 12 12 10

Maximum possible score 16 16 16 16

0 = not reported, 1 = reported but inadequate, 2 = reported and adequate

Table 2.1. Methodological index for non-randomized studies to assess the quality of non-comparative studies reporting on percutaneous transluminal angioplasty and drug- coated balloon angioplasty for infrapopliteal arterial disease

Certainty assessment № of studies Study

design Risk of bias Inconsis-tency of results Indirect-ness of evidence Imprecision Other conside-rations Limb salvage (follow-up: 12 months)

511-13,19,20 _Randomized

trials Not serious Not serious Serious

b _{Not serious None}

Survival (follow-up: 12 months)

511-13,19,20 _Randomized

trials Not serious Not serious Serious

b _{Not serious None}

Restenosis (follow-up: 12 months)

411-13,19 _Randomized

trials Not serious Serious

a _Seriousb _{Not serious None}

TLR (follow-up: 12 months)

411,13,19,20 _Randomized

trials Not serious Serious

a _Seriousb _{Not serious None}

№ of patients Effect Certainty

DCB PTA Relative

(95% CI) Absolute(95% CI)

375/399

(94.0%) 269/281 (95.7%) OR 0.922(0.385-2.210) 3 fewer per 1.000(from 61 fewer to 23 more) ⨁⨁⨁◯MODERATE

364/405

(89.9%) 261/281 (92.9%) OR 0.687(0.392- 1.205) 29 fewer per 1.000 (from 92 fewer to 11 more) ⨁⨁⨁◯MODERATE 72/219

(32.9%) 111/179 (62.0%) OR 0.349(0.101-1.207) 257 fewer per 1.000 (from 479 fewer to 43 more) ⨁⨁◯◯LOW

49/350

(14.0%) 65/234 (27.8%) OR 0.383(0.124-1.185) 149 fewer per 1.000 (from 232 fewer to 35 more) ⨁⨁◯◯LOW

Article

Domain Liistro ₂₀₁₃12 ₂₀₁₄Zeller 19 ₂₀₁₅Zeller 20 Haddad ₂₀₁₇11

1. Selection bias; random sequence generation 1 0 1 0

2. Selection bias; allocation concealment 1 0 1 0

3. Reporting bias; selective reporting 1 2 1 1

4. Other bias; other sources of bias 1 1 1 1

5. Performance bias; blinding participants and personnel 2 2 0 0

6. Detection bias; blinding outcome assessment 0 0 0 0

7. Attrition bias; incomplete outcome data 1 1 1 1

0 = unclear risk of bias, 1 = low risk of bias, 2 = high risk of bias

Table 2.2 Cochrane tool for assessing risk of bias in randomized clinical trials reporting on percutaneous transluminal angioplasty and drug-coated balloon angioplasty for infrapopliteal arterial disease

Meta-analysis

Data from four randomised trials and one comparative study were pooled, and

12-month outcomes for DCB vs. PTA were limb salvage rate, 375/399 (94.0%)

vs. 269/281 (95.7%) (odds ratio (OR): 0.92; 95% confidence interval (CI):

0.39-2.21), and survival rate, 364/405 (89.8%) vs. 261/281 (92.9%) (OR: 0.69; 95%

CI: 0.39-1.21). Data from three randomised trials and one comparative study

were pooled, and 12-month outcomes for PTA vs. DCB were restenosis rate,

111/179 (62.0%) vs. 72/219 (32.9%) (OR: 2.87; 95% CI: 0.83-9.92), and TLR rate,

65/234 (27.8%) vs. 49/350 (14.0%) (OR: 2.76; 95% CI: 0.90-8.48). Pooling data

of two studies resulted in 12-month AFS rates for DCB vs. PTA of 221/261

(82.5%) vs. 125/141 (88.7%) (OR: 0.79; 95% CI: 0.23-2.75). No statistically

significant differences were found when DCB and PTA were compared for all

outcomes. Results can be seen in Figure 2.2.

Outcomes of case series

Analysis of two case series,

_{together including 522 patients, showed the}

6-month limb salvage rate was 97%, and the survival rate was 91.2%-93.3%. The

12-month limb salvage rate was 96%, survival rates were 83.7%-88.7%, and AFS

rates were 79.8%-86.6% in two studies consisting of respectively 104 and 208

patients mainly categorised as Rutherford 5.

_{More details about these studies}

Figure 2.2. Forest plots of the pooled 12-month rates for limb salvage (A), survival (B), restenosis (C), target lesion revascularisation (D), and amputation-free survival (E) in patients treated endovascularily (Ev) with drug-coated balloon (DCB) or percutaneous transluminal angioplasty (PTA). CI = confidence interval.

Study Study design Study period

Schmidt 201118 _{Prospective case series 01-2009 till 02-2010}

Liistro 201312 _{Randomized trial 11-2010 till 10-2011}

Zeller 201419 _{Randomized trial 09-2009 till 07-2012}

Zeller 201520 _{Randomized trial 07-2012 till 06-2013}

Oz 201613 _{Retrospective comparative 10-2012 till 09-2014}

Tolva 201616 _{Retrospective comparative 01-2011 till 03-2013}

Steiner 201617 _{Retrospective case series 05-2013 till 10-2014}

Haddad 201711 _{Randomized trial 06-2013 till 12-2014}

Ozpak 201814 _{Prospective case series 08-2010 till 12-2013}

Thieme 201815 _{Prospective case series NA}

Inclusion criteria Exclusion criteria

CLI or severe claudication, BTK lesions (stenosis ≥70% or occlusions), lesion length ≥80 mm Diabetes, CLI (Rutherford 4-6), PTA of at least one BTK vessel, stenosis/occlusion >40 mm of at least one tibial vessel with distal runoff to the foot, agreement 12-month angiographic follow-up

Life expectancy <1 year, allergy to paclitaxel, contraindication to combined antiplatelet therapy, planned major amputation before PTA

NA Failure to obtain <30% residual stenosis

post-treatment of iliac or femoropopliteal inflow lesions

Single/sequential de novo or restenotic lesions, in-stent restenosis (≥70% diameter reduction/ occlusion) in the infrapopliteal arteries ≥30 mm, maximum two vessels treated, reference vessel diameter of 2-4 mm, inflow free from flow- limiting lesion, minimum one nonoccluded crural vessel with distal runoff, successful wire crossing of the lesion

Beyond the ankle, acute thrombus, planned major amputation, previous bypass surgery, previous stent implantation

Diabetes, Rutherford 3-6, PTA of at least one infrapopliteal lesion (stenosis ≥70 or occlusion), TASC ≥ A)

De novo tibial arteries stenosis, Rutherford >4 Recurrent stenosis, inability to undergo aortography before the procedure, inability to give informed consent

Rutherford 3-6, treated with Lutonix DCB BTK CLI (Rutherford 4-6), planned for PTA, alone or in addition to more proximal endovascular recanalisation procedure, stenosis/occlusion >30 mm, agreement 12-month FU

Life expectancy <1 year, allergy to paclitaxel, contraindication to combined antiplatelet therapy

PAD by claudication/resting pain with Rutherford 3-5 and ankle-brachial index score 0.4-0.7, angiographically atherosclerotic disease of IP arteries and at least two vessels

Angiographically evident thrombus, history of thrombolysis <72 hours, prior ballooning/ stenting of other lower limb arteries, history of thrombophlebitis or DVT, life expectancy <1 year, intolerance to medication

Rutherford 3-5, stenosis >70% or occlusion of minimum one BTK and above the ankle arteries, inline flow to at least one patent inframalleolar outflow vessel

Neurotropic ulcer, heel pressure ulcer or ulcer involving calcaneus, pregnancy, life expectancy <1 year, allergy to medication BTK = below-the-knee; CLI = critical limb ischaemia; IC = intermittent claudication; PTA =

percutaneous transluminal angioplasty; NA = not available; FU = follow-up; DVT = deep vein thrombosis; DCB = drug-coated balloon; PAD = peripheral arterial disease; IP = infrapopliteal.

Table 2.4. Study characteristics of the included studies reporting on percutaneous transluminal angioplasty and drug-coated balloon angioplasty for infrapopliteal arterial disease

Study Study design Study period

Schmidt 201118 _{Prospective case series 01-2009 till 02-2010}

Liistro 201312 _{Randomized trial 11-2010 till 10-2011}

Zeller 201419 _{Randomized trial 09-2009 till 07-2012}

Zeller 201520 _{Randomized trial 07-2012 till 06-2013}

Oz 201613 _{Retrospective comparative 10-2012 till 09-2014}

Tolva 201616 _{Retrospective comparative 01-2011 till 03-2013}

Steiner 201617 _{Retrospective case series 05-2013 till 10-2014}

Haddad 201711 _{Randomized trial 06-2013 till 12-2014}

Ozpak 201814 _{Prospective case series 08-2010 till 12-2013}

Thieme 201815 _{Prospective case series NA}

Inclusion criteria Exclusion criteria

CLI or severe claudication, BTK lesions (stenosis ≥70% or occlusions), lesion length ≥80 mm Diabetes, CLI (Rutherford 4-6), PTA of at least one BTK vessel, stenosis/occlusion >40 mm of at least one tibial vessel with distal runoff to the foot, agreement 12-month angiographic follow-up

Life expectancy <1 year, allergy to paclitaxel, contraindication to combined antiplatelet therapy, planned major amputation before PTA

NA Failure to obtain <30% residual stenosis

post-treatment of iliac or femoropopliteal inflow lesions

Single/sequential de novo or restenotic lesions, in-stent restenosis (≥70% diameter reduction/ occlusion) in the infrapopliteal arteries ≥30 mm, maximum two vessels treated, reference vessel diameter of 2-4 mm, inflow free from flow- limiting lesion, minimum one nonoccluded crural vessel with distal runoff, successful wire crossing of the lesion

Beyond the ankle, acute thrombus, planned major amputation, previous bypass surgery, previous stent implantation

Diabetes, Rutherford 3-6, PTA of at least one infrapopliteal lesion (stenosis ≥70 or occlusion), TASC ≥ A)

De novo tibial arteries stenosis, Rutherford >4 Recurrent stenosis, inability to undergo aortography before the procedure, inability to give informed consent

Rutherford 3-6, treated with Lutonix DCB BTK CLI (Rutherford 4-6), planned for PTA, alone or in addition to more proximal endovascular recanalisation procedure, stenosis/occlusion >30 mm, agreement 12-month FU

Life expectancy <1 year, allergy to paclitaxel, contraindication to combined antiplatelet therapy

PAD by claudication/resting pain with Rutherford 3-5 and ankle-brachial index score 0.4-0.7, angiographically atherosclerotic disease of IP arteries and at least two vessels

Angiographically evident thrombus, history of thrombolysis <72 hours, prior ballooning/ stenting of other lower limb arteries, history of thrombophlebitis or DVT, life expectancy <1 year, intolerance to medication

Rutherford 3-5, stenosis >70% or occlusion of minimum one BTK and above the ankle arteries, inline flow to at least one patent inframalleolar outflow vessel

Neurotropic ulcer, heel pressure ulcer or ulcer involving calcaneus, pregnancy, life expectancy <1 year, allergy to medication

Study Schmidt 201118 _{Liistro 2013}12 _{Zeller 2014}19 _{Zeller 2015}20

Patients - number 104 132 358 72

DCB 65 239 36

PTA 67 119 36

Mean age - years 73.6

DCB 74 73.3 72.9 PTA 75 71.7 69.9 Male 69 (66.3) 106 (80.3) 266 (74.3) 57 (79.1) DCB 54 (83.1) 182 (76.2) 27 (75.0) PTA 52 (77.6) 84 (70.6) 30 (83.3) Diabetes mellitus 74 (71.1) 132 (100) 263 (73.5) 48 (66.7) DCB 65 (100) 181 (75.7) 22 (61.1) PTA 67 (100) 82 (68.9) 26 (72.2) Hyperlipidemia 68 (65.4) 39 (29.5) 255 (71.2) 49 (68.1) DCB 23 (35.4) 175 (73.2) 26 (72.2) PTA 16 (23.9) 80 (67.2) 23 (63.9) Hypertension 95 (91.3) 98 (74.2) 322 (89.9) 62 (86.1) DCB 46 (70.8) 214 (89.5) 31 (86.1) PTA 52 (77.6) 106 (89.1) 31 (86.1) Smoking 32 (30.8) 20 (15.2) 52 (14.5) 40 (55.6) DCB 13 (20.0) 36 (15.1) 20 (55.6) PTA 7 (10.4) 16 (13.4) 20 (55.6)

Rutherford category, range 3-6 4-6 3-6 2-5

Rutherford category, n (%) 3 Total 19 (17.5) DCB 0 (0) 7 (19.4) PTA 1 (0.8) 5 (13.9) 4 Total 19 (17.5) DCB 2 (2.8) 34 (14.2) 2 (5.6) PTA 3 (4.2) 21 (17.6) 2 (5.6) 5 Total 70 (64.2) DCB 56 (78.9) 201 (84.1) 26 (72.2) PTA 59 (81.9) 92 (77.3) 26 (72.2) 6 Total 1 (0.9) DCB 13 (18.3) 4 (1.7) PTA 10 (13.9) 5 (4.2)

Oz 201613 _{Tolva 2016}16 _{Steiner 2016}17 _{Haddad 2017}11 _{Ozpak 2018}14 _{Thieme 2018}15

51 138 208 93 123 314 29 70 48 22 68 45 74.1 66.0 73.5 63.4 65.4 52-74 (range) 63.5 66.1 53-77 (range) 37 (72.5) 72 (52.2) 138 (66.4) 69 (56.0) 224 (71.3) 22 (75.9) 37 (52.9) 15 (68.2) 35 (51.5) 51 (100) 23 (16.7) 144 (69.2) 89 (95.7) 44 (35.7) 197 (62.7) 29 (100) 12 (17.1) 47 (97.9) 22 (100) 11 (16.2) 42 (93.3) 34 (24.6) 160 (76.9) 85 (91.4) 50 (40.6) 194 (61.8) 18 (25.7) 45 (93.8) 16 (23.5) 40 (88.9) 198 (95.2) 79 (84.9) 78 (63.4) 273 (86.9) 40 (83.3) 39 (86.7) 74 (53.6) 54 (26.0) 68 (73.1) 84 (68.2) 40 (12.7) 21 (72.4) 36 (51.4) 32 (66.7) 12 (54.5) 38 (55.9) 36 (80.0) 3-6 4-6 3-6 4-6 3-5 3-5 85 (38.6) 76 (24.3) 13 (41.9) 9 (34.6) 27 (12.3) 32 (10.2) 8 (25.8) 45 (64) 10 (38.5) 43 (63) 102 (46.4) 205 (65.5) 9 (29.0) 17 (24) 6 (23.1) 14 (21) 6 (2.7) 1 (3.5) 8 (11) 1 (3.8) 11 (16)

Table 2.5. Baseline data of the included studies reporting on percutaneous transluminal angioplasty and drug-coated balloon angioplasty for infrapopliteal arterial disease

Study Schmidt 201118 _{Liistro 2013}12 _{Zeller 2014}19 _{Zeller 2015}20

Patients - number 104 132 358 72

DCB 65 239 36

PTA 67 119 36

Mean age - years 73.6

DCB 74 73.3 72.9 PTA 75 71.7 69.9 Male 69 (66.3) 106 (80.3) 266 (74.3) 57 (79.1) DCB 54 (83.1) 182 (76.2) 27 (75.0) PTA 52 (77.6) 84 (70.6) 30 (83.3) Diabetes mellitus 74 (71.1) 132 (100) 263 (73.5) 48 (66.7) DCB 65 (100) 181 (75.7) 22 (61.1) PTA 67 (100) 82 (68.9) 26 (72.2) Hyperlipidemia 68 (65.4) 39 (29.5) 255 (71.2) 49 (68.1) DCB 23 (35.4) 175 (73.2) 26 (72.2) PTA 16 (23.9) 80 (67.2) 23 (63.9) Hypertension 95 (91.3) 98 (74.2) 322 (89.9) 62 (86.1) DCB 46 (70.8) 214 (89.5) 31 (86.1) PTA 52 (77.6) 106 (89.1) 31 (86.1) Smoking 32 (30.8) 20 (15.2) 52 (14.5) 40 (55.6) DCB 13 (20.0) 36 (15.1) 20 (55.6) PTA 7 (10.4) 16 (13.4) 20 (55.6)

Rutherford category, range 3-6 4-6 3-6 2-5

Rutherford category, n (%) 3 Total 19 (17.5) DCB 0 (0) 7 (19.4) PTA 1 (0.8) 5 (13.9) 4 Total 19 (17.5) DCB 2 (2.8) 34 (14.2) 2 (5.6) PTA 3 (4.2) 21 (17.6) 2 (5.6) 5 Total 70 (64.2) DCB 56 (78.9) 201 (84.1) 26 (72.2) PTA 59 (81.9) 92 (77.3) 26 (72.2) 6 Total 1 (0.9) DCB 13 (18.3) 4 (1.7) PTA 10 (13.9) 5 (4.2)

Oz 201613 _{Tolva 2016}16 _{Steiner 2016}17 _{Haddad 2017}11 _{Ozpak 2018}14 _{Thieme 2018}15

51 138 208 93 123 314 29 70 48 22 68 45 74.1 66.0 73.5 63.4 65.4 52-74 (range) 63.5 66.1 53-77 (range) 37 (72.5) 72 (52.2) 138 (66.4) 69 (56.0) 224 (71.3) 22 (75.9) 37 (52.9) 15 (68.2) 35 (51.5) 51 (100) 23 (16.7) 144 (69.2) 89 (95.7) 44 (35.7) 197 (62.7) 29 (100) 12 (17.1) 47 (97.9) 22 (100) 11 (16.2) 42 (93.3) 34 (24.6) 160 (76.9) 85 (91.4) 50 (40.6) 194 (61.8) 18 (25.7) 45 (93.8) 16 (23.5) 40 (88.9) 198 (95.2) 79 (84.9) 78 (63.4) 273 (86.9) 40 (83.3) 39 (86.7) 74 (53.6) 54 (26.0) 68 (73.1) 84 (68.2) 40 (12.7) 21 (72.4) 36 (51.4) 32 (66.7) 12 (54.5) 38 (55.9) 36 (80.0) 3-6 4-6 3-6 4-6 3-5 3-5 85 (38.6) 76 (24.3) 13 (41.9) 9 (34.6) 27 (12.3) 32 (10.2) 8 (25.8) 45 (64) 10 (38.5) 43 (63) 102 (46.4) 205 (65.5) 9 (29.0) 17 (24) 6 (23.1) 14 (21) 6 (2.7) 1 (3.5) 8 (11) 1 (3.8) 11 (16)

This systematic review and meta-analysis was conducted to combine the most

recent data on DCB use in infrapopliteal arterial disease. The main finding is that

no significant differences in limb salvage, survival, restenosis, TLR, and AFS rates

were found when DCB angioplasty was compared with standard PTA.

When taking a closer look at the results of limb salvage, it can be concluded

that patency improvement in some studies did not result in better limb salvage

for DCB compared with PTA. A study of Zeller et al.

_{that used the IN.PACT DCB}

showed an even higher amputation rate in the DCB treatment group. The authors

attributed this to the absence of standard wound care and a standard protocol

for amputation decision making. The importance of a dedicated multidisciplinary

wound care team is supported by the results of the studies in this systematic

review. The best limb salvage rates were seen in the studies of Liistro et al.

_and

Haddad et al.,

_{both of which describe the use of a dedicated multidisciplinary}

wound care team.

The second explanation for the higher amputation rate was described by

Katsanos et al.:

_{paclitaxel leads to microparticle formation that may cause}

distal embolization leading to more amputations. Kolodgie et al.

_{showed this}

phenomenon for the IN.PACT DCB compared with Lutonix 035 DCB in a healthy

swine model. However, besides Zeller et al.,

_{two other studies also used}

IN.PACT DCB, of which Liistro et al.

_{reported no major amputations in the DCB}

group, and the prospective case series of Schmidt et al.

_{including 104 patients}

with 109 treated legs showed a limb salvage rate of 96%.

Katsanos et al.

_{recently showed a significantly increased risk of death after}

one year when using paclitaxel coated balloons and stents in the femoropopliteal

arteries. They mentioned, as a possible explanation, paclitaxel toxicity due to

prolonged exposure of up to two months after application and a high release in

the systemic circulation. This current meta-analysis also shows that one-year

survival tends to be lower after infrapopliteal angioplasty with DCB compared

with standard PTA, although not significantly. From the pooled studies, only Oz et

al.

_{favoured DCB over PTA in mortality as an outcome. The difference might be in}

the received paclitaxel dose, because the patients in the Oz et al. study evidently

had shorter lesions, resulting in the use of shorter balloons and less paclitaxel

administration. Another explanation for the favorable PTA outcome could be that

DCB was used more often in patients with more challenging lesions, whereas

PTA was used more often in patients with less difficult lesions. Unfortunately,

in these studies no information was given about the severity or length or

calcification of the lesions, so this could not be determined.

There might be bias in the current meta-analysis because of differences in

balloon inflation time between the studies. Two studies reported an inflation

time of <2 min,

_{whereas the other studies had an inflation time of >2 min.}

Literature describes favorable outcomes for prolonged inflation time.

Taking a closer look at the results of this study, TLR rates were lower for DCB

compared with PTA in the studies with a longer inflation time.

_{This suggests}

that prolonged inflation time improves patency rates in DCB compared with PTA.

Another point of heterogeneity between the studies was anticoagulation after

the intervention. All patients received aspirin (100 mg daily) and clopidogrel (75

mg daily), but some had dual therapy for four weeks whereas others had it for 12

weeks. One study

_{showed significantly less restenosis and lower TLR rates with}

DCB compared with PTA and these patients received dual antiplatelet therapy

for 12 weeks. However, two other studies

_{had similar outcomes, but these}

patients received dual antiplatelet therapy for only four weeks. This suggests that

when using DCB, shorter dual antiplatelet therapy is justified without a higher

risk of restenosis, corresponding to the findings in cardiology.

_Furthermore,

shorter dual antiplatelet therapy may lead to fewer bleeding complications.

The outcomes of the studies in this meta-analysis were assessed as moderate

and low quality according to the GRADE scoring system, mostly due to

indirectness of evidence. Baseline characteristics differed for the presence of

diabetes mellitus, hypertension, hyperlipidaemia, and smoking status. As

mentioned before, the anticoagulation regimen, type of DCB, and paclitaxel dose

also varied between the studies. This might also explain the heterogeneity

between the studies for restenosis and TLR. For limb salvage, some studies did

not describe a definition for major amputation, causing a bias for this outcome

measure. The aforementioned heterogeneity is a limitation of this meta-analysis,

though it gives a realistic representation of the population and variety of

treatment options. Taking into account the results of the risk of bias assessment,

blinding participants and personnel was not performed or not clearly described

in the included studies. Moreover, blinding of personnel is not feasible as the

treating physician has to know the type of balloon. Detection bias was not

described in any of the studies. The study of Zeller et al.

_{could have reporting}

bias due to post-hoc analysis which was not predefined.

This study showed that the DCB group consisted of a total of 1236 patients

compared with 357 in the standard PTA group. This can be explained by the fact

that the case series included only patients treated with DCB. In the meta-analysis

the case series were not included so the distribution between the groups is more

equal. In addition, one of the randomised trials had unequal group numbers due

to a 2:1 ratio of DCB to PTA based on their power calculation.

As CLI involves such a large number of patients, the cost effectiveness of the

treatment is of great importance as DCBs are more expensive than standard PTA

balloons. Though, a prospective economic study of DCB vs. PTA showed that

patients treated with DCB had less repeat target limb revascularisations during

a follow-up period of two years, leading to non-significantly different overall

costs.

_{In two other studies DCB was cost effective compared with PTA, but these}

studies examined patency and no clinical outcomes.

_{However, these studies}

were all focused on infrainguinal disease. No research has yet been performed to

study DCB cost effectiveness in below-the-knee interventions.

Conclusion

In patients with peripheral arterial disease who underwent infrapopliteal

angioplasty, no significant differences in limb salvage, survival, restenosis, TLR,

and AFS rates were found when DCB angioplasty was compared with standard

PTA.

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Appendix A - Full search strategy

Component of search Search terms

1. Below the knee ((((((below the knee) OR infrapopliteal) OR tibial arteries[MeSH Terms]) OR tibial artery[MeSH Terms]) OR tibial arter*) OR crural) AND

2. Peripheral arterial

disease (((((((((((peripheral artery disease[MeSH Terms]) OR peripheral arterial disease[MeSH Terms]) OR arterial disease, peripheral[MeSH Terms]) OR PAD) OR peripheral artery disease) OR peripheral arterial disease) OR critical limb isch*) OR arterial occlusive disease[MeSH Terms]) OR disease, arterial occlusive[MeSH Terms]) OR arterial occlu-sive disease) OR CLI)

AND

3. Drug coated balloon (((((((((((((drug coated balloon) OR DCB) OR drug coated PTA balloon) OR drug coated PTA) OR angioplasty, balloon[MeSH Terms]) OR drug coated balloon angioplasty) OR drug-coated*) OR drug eluting balloon) OR DEB) OR drug eluting PTA balloon) OR drug eluting PTA) OR drug eluting balloon angioplasty) OR drug-eluting*)

Component of search Search terms

1. Below the knee ‘below the knee’ OR ‘infrapopliteal angioplasty’/exp OR ‘infrapopliteal artery’/exp OR ‘infrapopliteal artery disease’/exp OR ‘infrapopliteal’ OR ‘tibial artery’/exp OR ‘tibial arter*’ OR ‘crural’

AND

2. Drug coated balloon ‘drug coated balloon’ OR ‘dcb’ OR ‘drug coated pta balloon’ OR ‘drug coated pta’ OR ‘percutaneous transluminal angioplasty balloon’/ exp OR ‘drug coated balloon angioplasty’ OR ‘drug-coated*’ OR ‘drug eluting balloon’ OR ‘deb’ OR ‘drug eluting pta balloon’ OR ‘drug eluting pta’ OR ‘drug eluting balloon angioplasty’ OR ‘drug-eluting*’

AND

3. Peripheral arterial

disease ‘peripheral vascular diseases’/exp OR ‘peripheral occlusive artery disease’/exp OR ‘critical limb ischemia’/exp OR ‘pad’ OR ‘peripheral artery disease’ OR ‘peripheral arterial disease’ OR ‘critical limb isch*’ OR ‘arterial occlusive disease’ OR ‘cli’

Search strategy MEDLINE

Component of search Search terms

#1 MeSH descriptor: [Tibial Arteries] explode all trees

#2 “below the knee” OR “infrapopliteal” OR “tibial arter*” OR “crural” OR

#1

#3 MeSH descriptor: [Peripheral Arterial Disease] explode all trees

#4 MeSH descriptor: [Arterial Occlusive Diseases] explode all trees

#5 MeSH descriptor: [Peripheral Vascular Diseases] explode all trees

#6 “PAD” OR “peripheral artery disease” OR “peripheral arterial disease”

OR “critical limb isch*” OR “arterial occlusive disease” OR “CLI” OR #3 OR #4 OR #5

#7 MeSH descriptor: [Angioplasty, Balloon] explode all trees

#8 “drug coated balloon” OR “DCB” OR “drug coated PTA balloon” OR

“drug coated PTA” OR “drug coated balloon angioplasty” OR “drug-coated*” OR “drug eluting balloon” OR “DEB” OR “drug eluting PTA balloon” OR “drug eluting PTA” OR “drug eluting balloon angioplasty” OR “drug-eluting*” OR #7

#9 #2 AND #6 AND #8