Antithrombotics after infra‐inguinal peripheral endovascular treatment

Objectives

This is a protocol for a Cochrane Review (intervention). The objectives are as follows:

To determine the effects of antithrombotic agents compared with each other, with placebo, or with no treatment, in people with infra‐inguinal (below the anatomical level of the inguinal ligament) peripheral arterial disease who are undergoing peripheral endovascular treatment.

Background

Description of the condition

Lower limb peripheral artery disease (PAD) refers to the obstruction or narrowing of the large arteries of the lower limbs, most commonly caused by atheromatous plaque or thrombus. The resulting stenosis or occlusion, if severe enough, can result in impairment of oxygen supply to the muscle and other tissues during exercise that results in limiting symptoms. In more severe cases, blood flow becomes inadequate to meet the resting metabolic demands of the tissue, resulting in ischaemic rest pain, ischaemic ulceration, or gangrene. The major risk factors for PAD are the same as those for coronary artery disease, namely smoking, diabetes, dyslipidaemia, and hypertension. People with PAD are at increased risk of morbidity and mortality from cardiovascular events, including myocardial infarction and stroke (Dormandy 1999; Fowkes 2008; Hooi 2004; Pande 2011).

Although in many cases of less severe disease people can be asymptomatic, the major clinical manifestations of PAD are intermittent claudication (IC) and critical limb‐threatening ischaemia (CLTI). IC typically presents as exercise‐induced ischaemic pain in the leg muscles, from which relief is generally gained by rest. A person with CLTI will experience (often extreme) pain in the foot at rest, while the skin and other tissues of the affected limb may become more susceptible to ulceration and poor wound healing, including the development of gangrene. While people with symptoms of IC can go on to develop CLTI, CLTI can often present without a history of previous IC. The progression from asymptomatic disease is often categorised by the Fontaine classification criteria (Fontaine 1954; Table 1). In addition, there are other classification systems for PAD, such as the Rutherford classification and the Wound, Ischaemia, and Foot Infection (WIfI) classification for CLTI (Mills Sr 2014).

1. Fontaine classification of peripheral arterial disease ^a.

Stage	Description
I	Asymptomatic
II	Mild claudication pain
IIa	Claudication distance > 200 metres
IIb	Claudication distance < 200 metres
III	Rest pain (especially at night)
IV	Ulceration and/or gangrene of the limb

^aFontaine 1954

Non‐modifiable risk factors for developing PAD include race, gender, and age (Vitalis 2017). The prevalence of lower limb PAD increases with age, and is more common in men than women (Dormandy 2000). In Scotland, in 2010, the prevalence of IC ranged from 0.7% to 1.7% in people aged 16 to 54 years, and was 7.4% in those over 74 years old (Bromley 2011). In 2010, a global estimate of 202 million people were living with PAD, an increase of 28.7% in low‐ and middle‐income countries, and 13.1% in higher‐income countries, compared with the preceding 10 years (Fowkes 2013). The five‐year cumulative incidence rate for asymptomatic people with PAD who deteriorate to IC is 7%; 21% of whom progress to CLTI (Sigvant 2016). The annual incidence of CLTI is estimated at 220 to 3500 per one million people, with a prevalence of approximately 1% of the population (Nehler 2014).

Diagnosis and treatment

Several bodies have developed guidelines addressing the diagnosis and management of PAD, including the National Institute for Health and Care Excellence (NICE 2018), the American Heart Association (Gerhard‐Herman 2017), the European Society of Cardiology and European Society for Vascular Surgery (Aboyans 2018), the Inter‐Society Consensus for the Management of Peripheral Arterial Disease (TASC II (Dormandy 2000b; Norgen 2007; TASC 2015)), the Asia‐Pacific Consensus Statement on the Management of PAD (Abola 2020), and the Global Vascular Guidelines (Conte 2019). These organisations broadly agree on the overall diagnosis and management of PAD.

Following a thorough clinical history and physical examination of the lower limbs, including the peripheral pulses, a diagnosis of PAD may be confirmed using the ankle‐brachial index ((ABI) an ABI of less than 0.90 is suggestive of PAD), and invasive or non‐invasive imaging, or both. Non‐invasive imaging includes duplex ultrasound of the lower limbs, which can establish the extent of atherosclerosis, and magnetic resonance (MR) or computerised tomography (CT) angiography, which may be undertaken to provide additional information on the anatomy of the stenosis or occlusion, if required prior to revascularisation (Aboyans 2018; Gerhard‐Herman 2017; NICE 2018).

For those with IC, initial treatment of PAD involves reduction of cardiovascular risk factors, including the use of statins and antiplatelet medication, with the main aim of reducing the risk of other cardiovascular diseases, including myocardial infarction and stroke (Aboyans 2018; Gerhard‐Herman 2017; NICE 2018). Disease‐specific treatment includes the use of exercise programmes (Lane 2017; NICE 2018). In people in whom symptoms do not improve with exercise and risk factor management, medical management, using pharmacological interventions, such as cilostazol (Aboyans 2018; Gerhard‐Herman 2017; Hirsch 2006), naftidrofuryl (Aboyans 2018; NICE 2018), and pentoxifylline (Aboyans 2018; Gerhard‐Herman 2017; Hirsch 2006), are suggested by some national guidelines. However, there is a degree of uncertainty as to which, if any of these medications provides most clinical benefit (Broderick 2020; Brown 2021; de Backer 2012).

Revascularisation procedures (including percutaneous balloon angioplasty, percutaneous transluminal angioplasty (Fakhry 2018), stenting (Bachoo 2010), or bypass grafting (Antoniou 2017)), may be required in those in whom disease is severe enough to cause symptoms that the person is unable to tolerate, or that threaten the loss of a limb (as in people with CLTI). People with CLTI are more urgently referred for possible revascularisation after thorough assessment by a vascular multidisciplinary team and adequate pain management (NICE 2018). Finally, in those with disease that is not amenable to revascularisation procedures, or those with established gangrene, amputation may be needed (Conte 2019).

Description of the intervention

Peripheral arterial disease is increasingly treated with endovascular techniques, including percutaneous transluminal angioplasty (PTA), during which the diseased artery is dilated, using a balloon. In certain circumstances, a bare metal or covered stent is deployed inside the diseased artery. Drug‐coated balloons and drug‐eluting stents are now increasingly used to try and prolong the beneficial effects of the treatment. Other, more recent endovascular techniques, include the use of atherectomy devices, which remove the atheromatous material from the inside of the artery by shaving, drilling, or cutting (Bhat 2017).

Following endovascular treatment with PTA, local thrombolysis, percutaneous transluminal thromboembolectomy, angioplasty, and stent implantation or atherectomy, antithrombotic drugs are routinely given to prevent the treated section of the artery from becoming narrow, or blocked again, due to thrombosis or the development of neointimal hyperplasia. Neointimal hyperplasia is an abnormal growth of smooth muscle cells that causes the inside of the artery to gradually thicken; it occurs as a response to injury to the artery, caused by the endovascular treatment itself. However, the optimum regimen (ideal antithrombotic drug, dose, and length of treatment) is not clear. This is further complicated because of the availability of a wide range of both endovascular treatments and antithrombotic drugs.

How the intervention might work

Endovascular treatments damage the atherosclerotic plaque causing arterial narrowing, which activates the coagulation system, including platelet aggregation. This can lead to a prothrombotic environment around the treated lesion, a phenomenon initially described by Virchow (Blann 2002; Virchow 1856). If natural thrombosis is allowed to occur, it can lead to early thrombotic occlusion of the treated vessel. Restenosis can occur in the treated arterial segment, due to neointimal hyperplasia, and the original atherosclerotic processes that characterise PAD can also continue to progress. Early occlusion or later restenosis can lead to recurrence of, and even worsening of PAD symptoms, including potential limb loss (Davies 2011; Tosaka 2012). Drug interventions with antithrombotic agents could prevent early thrombotic occlusion, prevent the development of intimal hyperplasia, or both, and therefore, lead to the sustained success of endovascular treatment (Blann 2002; Gawaz 1996; Hess 2017).

Antithrombotic drugs fundamentally prevent thrombosis formation through different mechanisms. Antithrombotic drugs can be broadly divided into antiplatelet drugs and anticoagulants. Antiplatelets, such as aspirin, clopidogrel, and ticagrelor interfere with platelet aggregation during primary haemostasis, and limit thrombus formation. Anticoagulants, such as warfarin, heparin (and its derivatives), and the more recent direct oral anticoagulants (such as apixaban, rivaroxaban, dabigatran, and edoxaban), prolong clotting time by inhibiting varying aspects of the coagulation cascade, which occurs following primary platelet aggregation (Blann 2002; Nutescu 2016).

Why it is important to do this review

Current peri‐interventional treatment strategies following endovascular treatments mostly include administration of an antiplatelet, such as aspirin or clopidogrel, both before and immediately after treatment. Other strategies include initial administration of either unfractionated or low molecular weight heparin (Ellis 1989), followed by an antiplatelet or anticoagulant drug on a more long‐term basis (Do 1994; Hess 1985; Shammas 2003; Watson 2000). The advent of direct oral anticoagulant drugs, such as apixaban, rivaroxaban, and dabigatran has added to the arsenal of drugs that can circumvent the natural disease process before or following peripheral arterial disease interventions (Harky 2019). We will investigate and present the current evidence for antithrombotic drug interventions after peripheral endovascular treatment for peripheral arterial disease. Given the increased number of available antithrombotic drugs, this review will provide a timely update to help guide best practice. We hope this will inform decision‐making for both healthcare professionals and people with PAD, and make an important contribution to the sustained success of treatment for PAD. This review will replace the previous review on this topic (Robertson 2012).

Objectives

To determine the effects of antithrombotic agents compared with each other, with placebo, or with no treatment, in people with infra‐inguinal (below the anatomical level of the inguinal ligament) peripheral arterial disease who are undergoing peripheral endovascular treatment.

Methods

Criteria for considering studies for this review

Types of studies

We will include all prospective randomised controlled trials (RCTs) that compare any antithrombotic agent with either placebo, no treatment, or with any other antithrombotic agent, following endovascular treatment of infra‐inguinal peripheral arterial disease (PAD; disease below the anatomical level of the inguinal ligament in the lower limb). We will include studies in which the randomised participants are either exclusively people with PAD, or in which PAD is a clearly defined, prespecified subgroup of the study population.

We will exclude retrospective trials and any trials without a comparison group.

Types of participants

We will include all studies in which participants received an antithrombotic agent after undergoing peripheral endovascular surgery for the treatment of symptomatic PAD below the level of the inguinal ligament. This includes symptoms of intermittent claudication (IC), symptoms of critical limb threatening ischaemia (CLTI), or both, defined as stages II to IV on the Fontaine classification or stages II to VI on the Rutherford classification (Rutherford 1997).

When data are available from our included studies, we will report the analysis of our primary and secondary outcomes separately, based on the severity of symptoms from PAD, whether participants had endovascular intervention for symptoms of IC, or symptoms of CLTI.

Endovascular treatment may include percutaneous transluminal angioplasty (PTA) alone, or combined with thrombolysis, thromboembolectomy, angioplasty and stent implantation, or other techniques. We will only include studies in which participants had both limbs treated if both limbs received exactly the same treatment (e.g. both received plain balloon angioplasty, or bare metal stent insertion, etc). If it is not possible to tell from the individual study data whether both limbs received the same treatment, we will include the study if it is clear that > 50% of the interventions were performed on a single limb. We will exclude participants undergoing endovascular treatment for arterial trauma, and endovascular treatment for acute limb ischaemia.

Types of interventions

We will include studies in which participants were randomised to receive antithrombotic therapy (antiplatelet, anticoagulant, or combined therapy) versus placebo or no treatment; one antithrombotic regimen (antiplatelet, anticoagulant, or combined) versus another; or antithrombotic therapy (antiplatelet, anticoagulant, or combined) versus an alternative treatment. We will include studies that compare different doses, intensities, and duration of the same agent.

These are the comparisons of interest.

• Antiplatelets versus placebo or no treatment

• Antiplatelets versus antiplatelet

• Antiplatelet versus anticoagulant

• Antiplatelets versus alternative or combined treatment

• Anticoagulant versus placebo or no treatment

• Anticoagulant versus anticoagulant

• Anticoagulant versus alternative or combined treatment

• Combined treatment versus placebo or no treatment

• Combined treatment versus alternative or combined treatment

Antithrombotic agents are likely to include:

• Aspirin

• Clopidogrel

• Dipyridamole

• Ticagrelor

• Fondaparinux

• Unfractionated heparin

• Low molecular weight heparin

• Warfarin

• Rivaroxaban

• Apixaban

• Edoxaban

• Dabigatran

Types of outcome measures

We plan to report all outcomes at 30 days, 12 months, and longer than 12 months, when possible. However, this will depend on the time points reported by the included studies.

Primary outcomes

• Primary patency (defined as a patent artery without the need for any further intervention, assessed on magnetic resonance (MR), computerised tomography (CT), or digital subtraction angiography, or on arterial duplex (ultrasound) scanning)

• Amputation (defined as major limb amputation above the level of the ankle)

Secondary outcomes

• Death (from all causes)

• Major bleeding (defined as bleeding that is fatal, symptomatic, causes a drop in haemoglobin levels, or requires a blood transfusion of two units or more (Schulman 2005))

• Cardiovascular adverse events (myocardial infarction (MI), stroke)

• Adverse events related to medication (minor bleeding, gastrointestinal side effects)

• Secondary patency (defined as patency rates where further intervention was required to restore blood flow through a completely blocked section of the initially treated artery, assessed on CT, MR, or digital subtraction angiography, or on arterial duplex scanning)

• Quality of life ((QoL) reported on validated scales, such as the Short Form 36‐Item Questionnaire (SF‐36), the European Quality of Life Questionnaire (EuroQol), or the Vascular Quality of Life Questionnaire (VascuQoL (Alabi 2017)))

• Major adverse limb events (MALE, defined as the need for major vascular amputation or any vascular reintervention, including surgical or endovascular reintervention, such as thrombectomy, thrombolysis, or repeat revascularisation)

• Amputation‐free survival (defined as survival without the need for a major limb amputation above the level of the ankle)

Search methods for identification of studies

Electronic searches

The Cochrane Vascular Information Specialist aims to identify all relevant RCTs, regardless of language or publication status (published, unpublished, in press, or in progress).

The Information Specialist will search the following databases for relevant trials:

• the Cochrane Vascular Specialised Register via the Cochrane Register of Studies (CRS‐Web);

• the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO);

• MEDLINE Ovid (MEDLINE Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Ovid MEDLINE Daily and Ovid MEDLINE; from 1946 onwards);

• Embase Ovid (from 1974 onwards);

• CINAHL EBSCO (from 1982 onwards).

The Information Specialist has devised a draft search strategy for RCTs for MEDLINE, which is displayed in Appendix 1. We will use this as the basis for search strategies for the other databases listed.

The Information Specialist will search the following trials registries:

• the World Health Organization International Clinical Trials Registry Platform (who.int/trialsearch);

• the US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (clinicaltrials.gov).

Searching other resources

We will review the reference lists of included trials for any additional relevant studies.

Data collection and analysis

Selection of studies

We plan to use Covidence to assess studies for selection (Covidence). Two review authors (RG, ES) will independently evaluate full‐text articles, identified as potentially relevant after abstract and title screening, against the specified inclusion criteria. We will resolve any disagreements by discussion with a third review author (KP).

We will illustrate the study selection process in a PRISMA diagram (Liberati 2009). We will list all articles excluded after full‐text assessment in a Characteristics of excluded studies table, and will provide the reasons for their exclusion.

Data extraction and management

Two review authors will independently extract data from the included studies (ES, KP). We will resolve any disagreements by discussion with a third review author (RG).

We will collect data using a data collection form, and for each included study, we will include:

• study methods: study design, number of participants, exclusions post‐randomisation, any losses to follow‐up, intention‐to‐treat (ITT) analysis, duration of study;

• participant characteristics: country, setting, age, sex, inclusion and exclusion criteria;

• interventions and comparisons;

• outcomes: planned, reported, time points;

• funding source and declaration of interest from the study authors.

Assessment of risk of bias in included studies

Two review authors (MG, FK) will independently assess the risk of bias for each included trial, using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreements by discussion with a third author (MT).

Measures of treatment effect

We plan to base our analysis on the ITT data from the individual included trials. We will use odds ratios (OR) with their 95% confidence intervals (CIs) to report dichotomous outcome data; and mean differences (MD) with their 95% CI for continuous outcome data. When the same outcome is reported using different scales in included studies, we will use the standardised MD (SMD).

Unit of analysis issues

The unit of analysis will be the individual participating in the included randomised trial, as the majority of studies will involve participants who have had only one limb treated. If we identify studies in which participants had treatment for both limbs, we will only include studies in which participants received identical treatment for both limbs. In these studies, the unit of analysis will be the limb rather than the participant. If data are available for the individual limbs, we will pool their data for the outcomes of primary and secondary graft patency, amputation, and MALE.

When it is not possible to tell from the individual study data whether both limbs received the same treatment, we will include the study if it is clear that the majority of the interventions were performed on a single limb. We will explore this decision with sensitivity analysis.

Dealing with missing data

We will include all available data from studies; we will describe missing data for each study in the Characteristics of included studies table, and we will consider it in the risk of bias assessment. We will discuss the extent to which the missing data could alter the results of the review. We will perform data analysis on an ITT basis. When data are found to be missing from the included trial reports, we will attempt to contact the study authors to ask for the missing data. We will consider if data are missing at random, and investigate the possible impact of including studies with missing data in a sensitivity analysis (Higgins 2021).

Assessment of heterogeneity

We will inspect forest plots visually to consider the direction and magnitude of effects and the degree of overlap between CIs. We will use the I² statistic to measure heterogeneity among the trials in each analysis; we acknowledge that there is substantial uncertainty in the value of I² when there are only a small number of studies. If we identify substantial heterogeneity, we will report it and explore possible causes by prespecified subgroup analysis. As strict thresholds for the interpretation of the I² are not recommended, we will use the rough guide to the interpretation provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021), as follows.

• 0% to 40%: might not be important

• 30% to 60%: may represent moderate heterogeneity

• 50% to 90%: may represent substantial heterogeneity

• 75% to 100%: may represent considerable heterogeneity

When I² lies in an area of overlap between two categories (e.g. between 50% and 60%), we will consider differences in participants and interventions among the trials contributing data to the analysis (Deeks 2021).

Assessment of reporting biases

We plan to assess the presence of publication and reporting bias with the use of funnel plots, if we include sufficient studies (i.e. more than 10) in the meta‐analysis (Higgins 2021).

Data synthesis

We will undertake meta‐analysis only when this is meaningful, that is if the treatments, participants, and the underlying clinical questions are similar enough for pooling to be appropriate. We will use Cochrane's statistical software, Review Manager Web, to analyse our data (RevMan Web 2021). We plan to conduct a fixed‐effect meta‐analysis of included studies when we do not find substantial heterogeneity (I² statistic less than 50%). If we find substantial heterogeneity (I² statistic greater than 50%), we will use a random‐effects model. If there is substantial clinical, methodological, or statistical heterogeneity across trials that prevents the pooling of data, we will use a narrative approach to data synthesis (Deeks 2021).

Subgroup analysis and investigation of heterogeneity

We plan to conduct the following subgroup analysis if sufficient data are available for our primary outcomes.

• Severity of symptoms from PAD (IC versus CLTI)

• Anatomical level of treatment (above the knee versus below the knee versus distal treatment (treatment of the tibial or foot vessels, or both))

• Occlusions > 10 cm versus occlusions < 10 cm

• Stenosis > 50%

• Separate endovascular intervention techniques (e.g. plain balloon angioplasty, drug‐coated balloon, bare‐metal stent, covered stent, drug‐eluting stent, etc.)

• Duration of antithrombotic therapy

• Transition from dual antiplatelet agents in the peri‐procedural period to a single agent after a fixed period versus no transition

Sensitivity analysis

We plan to conduct sensitivity analyses for our primary outcomes, in which we exclude studies at high risk of bias (low methodological quality). We will consider studies at high risk of overall bias, if we assessed them at high risk of bias in two or more domains.

We will also perform sensitivity analysis when we include studies with missing data (> 20%), or with mixed populations (as described above), in the analysis. In these sensitivity analyses, we will exclude studies with > 20% missing data or mixed populations from the meta‐analyses.

Summary of findings and assessment of the certainty of the evidence

We will construct a summary of findings (SoF) table to present the main findings from the review (see Table 2 for an example SOF table). The population of interest will be participants receiving peripheral endovascular treatment for symptomatic PAD. We will create one SOF table for each comparison (antithrombotic agents versus placebo, or other antithrombotic drugs, the same agent with different dosages, intensities and duration, or versus no drug treatment). We will assess the certainty of the evidence using the GRADE approach (Atkins 2004). We will assign one of four levels of certainty: high, moderate, low, or very low, based on overall risk of bias, directness of the evidence, inconsistency of results, precision of the estimates, and risk of publication bias (Atkins 2004; Schünemann 2021). Our SoF table will include the most clinically relevant outcomes listed in Types of outcome measures.

2. Example summary of findings table.

Antithrombotic therapy versus placebo or no treatment following peripheral endovascular treatment
Patient or population: people who have undergone peripheral endovascular treatment to treat symptomatic peripheral arterial diseasea Settings: hospital Intervention: antithrombotic drug treatment Comparison: placebo or no treatment
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with placebo or no treatment	Risk with antithrombotic drug
Primary patency (follow‐up)	Study population		OR [value] ([value] to [value])	[value] ([value])	[Delete as appropriate] ⊕⊝⊝⊝ very low ⊕⊕⊝⊝ low ⊕⊕⊕⊝ moderate ⊕⊕⊕⊕ high
	[value] per 1000	[value] per 1000 ([value] to [value])
Amputation (follow‐up)	Study population		OR [value] ([value] to [value])	[value] ([value])	[Delete as appropriate] ⊕⊝⊝⊝ very low ⊕⊕⊝⊝ low ⊕⊕⊕⊝ moderate ⊕⊕⊕⊕ high
	[value] per 1000	[value] per 1000 ([value] to [value])
Death (all causes) (follow‐up)	Study population		OR [value] ([value] to [value])	[value] ([value])	[Delete as appropriate] ⊕⊝⊝⊝ very low ⊕⊕⊝⊝ low ⊕⊕⊕⊝ moderate ⊕⊕⊕⊕ high
	[value] per 1000	[value] per 1000 ([value] to [value])
Major bleeding (follow‐up)	Study population		OR [value] ([value] to [value])	[value] ([value])	[Delete as appropriate] ⊕⊝⊝⊝ very low ⊕⊕⊝⊝ low ⊕⊕⊕⊝ moderate ⊕⊕⊕⊕ high
	[value] per 1000	[value] per 1000 ([value] to [value])
Cardiovascular events (follow‐up)	Study population		OR [value] ([value] to [value])	[value] ([value])	[Delete as appropriate] ⊕⊝⊝⊝ very low ⊕⊕⊝⊝ low ⊕⊕⊕⊝ moderate ⊕⊕⊕⊕ high
	[value] per 1000	[value] per 1000 ([value] to [value])
Adverse events related to medication (follow‐up)	Study population		OR [value] ([value] to [value])	[value] ([value])	[Delete as appropriate] ⊕⊝⊝⊝ very low ⊕⊕⊝⊝ low ⊕⊕⊕⊝ moderate ⊕⊕⊕⊕ high
	[value] per 1000	[value] per 1000 ([value] to [value])
Secondary patency (follow‐up)	Study population		OR [value] ([value] to [value])	[value] ([value])	[Delete as appropriate] ⊕⊝⊝⊝ very low ⊕⊕⊝⊝ low ⊕⊕⊕⊝ moderate ⊕⊕⊕⊕ high
	[value] per 1000	[value] per 1000 ([value] to [value])
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; CLTI: critical limb threatening ischaemia; IC: intermittent claudication; OR: odds ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect

^aThis includes symptoms of IC, symptoms of CLTI, or both, defined as stages II to IV on the Fontaine classification or stages II to VI on the Rutherford classification

These will be:

• Primary patency

• Amputation

• Death (all causes)

• Major bleeding

• Cardiovascular events

• Adverse events related to medication

• Secondary patency

We will base our conclusions only on findings from the quantitative or narrative synthesis of included studies. We will avoid making any recommendations for practice, and will suggest priorities for future research, and outline what the remaining uncertainties are in the area.

Notes

Parts of the methods section of this protocol are based on a standard template established by Cochrane Vascular.

Appendices

Appendix 1. MEDLINE search strategy

1	Arterial Occlusive Diseases/
2	Arteriolosclerosis/
3	Arteriosclerosis/
4	Arteriosclerosis Obliterans/
5	Femoral Artery/
6	Iliac Artery/
7	Intermittent Claudication/
8	Ischemia/dt, et, mo, su, th [Drug Therapy, Etiology, Mortality, Surgery, Therapy]
9	Leg/bs [Blood Supply]
10	exp Peripheral Vascular Diseases/
11	Popliteal Artery/
12	Tibial Arteries/
13	arteriosclero*.ti,ab.
14	arteriopathic.ti,ab.
15	claudic*.ti,ab.
16	CLI.ti,ab.
17	dysvascular*.ti,ab.
18	PVD.ti,ab.
19	PAOD.ti,ab.
20	(peripheral adj3 dis*).ti,ab.
21	(("lower extrem*" or arter* or crural or femdist* or femoral or fempop* or iliac or infrainquinal or infrapopliteal or inguinal or limb or peripher* or popliteal or tibial or vascular or vein* or veno*) adj2 (block* or harden* or lesio* or obliter* or obstruct* or occlus* or reocclus* or re‐occlus* or restenos* or steno* or stiffen*)).ti,ab.
22	or/1‐21
23	exp Anticoagulants/
24	exp Platelet Aggregation Inhibitors/
25	exp Coumarins/
26	exp Heparin/
27	exp Aspirin/
28	anticoagulant*.ti,ab.
29	antiplatelet*.ti,ab.
30	Antithrombotic*.ti,ab.
31	apixaban.ti,ab.
32	aspirin.ti,ab.
33	clopidogrel.ti,ab.
34	dabigatran.ti,ab.
35	direct oral anticoagulant*.ti,ab.
36	DOAC*.ti,ab.
37	edoxaban.ti,ab.
38	heparin.ti,ab.
39	rivaroxaban.ti,ab.
40	ticagrelor.ti,ab.
41	warfarin.ti,ab.
42	or/23‐41
43	22 and 42
44	exp Endovascular Procedures/
45	exp Blood Vessel Prosthesis/
46	Blood Vessel Prosthesis Implantation/
47	exp Stents/
48	endovasc*.ti,ab.
49	endostent*.ti,ab.
50	EVAR.ti,ab.
51	EVRAR.ti,ab.
52	TEVAR.ti,ab.
53	stent*.ti,ab.
54	endoprosthe*.ti,ab.
55	endograft*.ti,ab.
56	or/44‐55
57	43 and 56
58	randomized controlled trial.pt.
59	controlled clinical trial.pt.
60	randomized.ab.
61	placebo.ab.
62	drug therapy.fs.
63	randomly.ab.
64	trial.ab.
65	groups.ab.
66	or/58‐65
67	exp animals/ not humans.sh.
68	66 not 67
69	57 and 68

Contributions of authors

MT drafted the protocol. For the full review, he will assess the risk of bias, enter data into RevMan Web, conduct data analysis, interpret data, draft the final review, update the review, and be the guarantor of the review.
RG drafted the protocol. For the full review, she will select studies, obtain studies, enter data into RevMan Web, conduct data analysis, interpret data, draft the final review, and update the review.
ES drafted the protocol. For the full review, he will select studies, obtain studies, extract data, enter data into RevMan Web, conduct data analysis, interpret data, draft the final review, and update the review.
KP drafted the protocol. For the full review, she will extract data, enter data into RevMan Web, conduct data analysis, interpret data, draft the final review, and update the review.
MG checked the protocol. For the full review, he will assess the risk of bias, interpret data, draft the final review, and update the review.
FK checked the protocol. For the full review, she will assess the risk of bias, interpret data, draft the final review, and update the review.
VP checked the protocol. For the full review, he will interpret data, draft the final review, and update the review.

Sources of support

Internal sources

• No sources of support provided

External sources

• Chief Scientist Office, Scottish Government Health Directorates, The Scottish Government, UK

  The Cochrane Vascular editorial base is supported by the Chief Scientist Office.

Declarations of interest

MT: none known
RG: none known
ES: none known
KP: none known
MG: none known
FK: none known
VP: none known

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