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Antiplatelet and Anticoagulant Use in Randomised Trials of Patients Undergoing Endovascular Intervention for Peripheral Arterial Disease: Systematic Review and Narrative Synthesis

Open ArchivePublished:April 04, 2020DOI:https://doi.org/10.1016/j.ejvs.2020.03.010

      Objective

      Randomised trials of new devices for peripheral arterial endovascular intervention are published regularly. The evidence for which antiplatelet and/or anticoagulant (antithrombotic) therapy to use after an intervention is lacking. The aim of this systematic review was to examine the antithrombotic regimens in randomised trials for peripheral arterial endovascular intervention to understand choices made and trends with time or type of device.

      Methods

      Data sources were the Medline, Embase, and Cochrane Library databases. Randomised trials including participants with peripheral arterial disease undergoing any endovascular arterial intervention were included. Trial methods were assessed to determine whether an antithrombotic protocol had been specified, its completeness, and the agent(s) prescribed. Antithrombotic therapy protocols were classed as peri-procedural (preceding and during intervention), immediate post-procedural (up to 30 days following intervention), and maintenance post-procedural (therapy continuing beyond 30 days).

      Results

      Ninety-four trials were included in narrative synthesis. Study quality was low. None of the trials justified their antithrombotic therapy protocol. Only 29% of trials had complete peri-procedural antithrombotic protocols, and 34% had complete post-procedural protocols. In total, 64 different peri-procedural protocols, and 51 separate post-procedural protocols were specified. Antiplatelet monotherapy and unfractionated heparin were the most common regimen choices in the peri-procedural setting, and dual antiplatelet therapy (55%) was most commonly utilised post procedure. Over time there has been an increasing tendency to use dual therapy (p < .001). This corresponds with the introduction of newer technologies and trials focussed on below knee intervention.

      Conclusion

      Randomised trials comparing different types of peripheral endovascular arterial intervention have a high level of heterogeneity in their antithrombotic regimens. Antiplatelet therapy needs to be standardised in trials comparing endovascular technologies to reduce potential confounding. To do this, an independent randomised trial specifically examining antiplatelet therapy following peripheral arterial endovascular intervention is needed.

      Keywords

      This systematic review demonstrates the lack of standardisation and poor reporting of antithrombotic therapy in randomised controlled trials of endovascular intervention. It shows a high degree of heterogeneity in antiplatelet regimens for trials of peripheral endovascular intervention, and an increasing trend for use of dual antiplatelet therapy post intervention. The results highlight the need for clarity in the reporting of antithrombotic therapy as a co-intervention in trials of endovascular intervention and the need for a randomised trial of antiplatelet therapy after endovascular intervention.

      Introduction

      New devices to perform endovascular treatment for peripheral arterial disease are frequently made available. Within the last 10 years, drug eluting technology, atherectomy devices, and new stents have all become available. Randomised trials to support their use are also published with some regularity and are often sponsored by the manufacturer of the device as part of the regulatory process.
      • Dake M.D.
      • Ansel G.M.
      • Jaff M.R.
      • Ohki T.
      • Saxon R.R.
      • Smouse H.B.
      • et al.
      Durable clinical effectiveness with paclitaxel-eluting stents in the femoropopliteal artery: 5-year results of the Zilver PTX randomized trial.
      Antiplatelet or anticoagulant therapy is usually given as a co-intervention when a peripheral arterial endovascular intervention is performed. The literature to support the choice of antithrombotic therapy after peripheral endovascular intervention is lacking,
      • Ambler G.K.
      • Waldron C.A.
      • Contractor U.B.
      • Hinchliffe R.J.
      • Twine C.P.
      Antiplatelet therapy for peripheral arterial disease: an umbrella review and meta-analysis of preventative and treatment outcomes.
      especially when compared with the literature on percutaneous coronary intervention.
      • Lopes R.D.
      • Hong H.
      • Harskamp R.E.
      • Bhatt D.L.
      • Mehran R.
      • Cannon C.P.
      • et al.
      Safety and efficacy of antithrombotic strategies in patients with atrial fibrillation undergoing percutaneous coronary intervention: a network meta-analysis of randomized controlled trials.
      Guidelines to direct antithrombotic regimens after peripheral arterial endovascular intervention are therefore limited and conflicted.
      • Aboyans V.
      • Ricco J.B.
      • Bartelink M.E.L.
      • Bjorck M.
      • Brodmann M.
      • Cohnert T.
      • et al.
      Editor's Choice – 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral arterial diseases, in collaboration with the European Society for vascular surgery (ESVS).
      • Alonso-Coello P.
      • Bellmunt S.
      • McGorrian C.
      • Anand S.S.
      • Guzman R.
      • Criqui M.H.
      • et al.
      Antithrombotic therapy in peripheral artery disease: antithrombotic Therapy and Prevention of thrombosis, 9th ed: American College of chest physicians evidence-based clinical practice guidelines.
      • Conte M.S.
      • Bradbury A.W.
      • Kolh P.
      • White J.V.
      • Dick F.
      • Fitridge R.
      • et al.
      Global vascular guidelines on the management of chronic limb-threatening ischemia.

      National Institute for Health and Care Excellence (NICE). Peripheral Arterial Disease: Diagnosis and management [Internet]. [London]: NICE; 2012 [updated 2018 Apr; cited 2020 Feb 16]. (Clinical guideline [CG147]). Available from: https://www.nice.org.uk/guidance/cg147/resources/peripheral-arterial-disease-diagnosis-and-management-pdf-35109575873989 [Internet]. [London]: NICE; 2009 [updated 2016 Apr; cited 2016 Dec 16]. (Clinical guideline [CG90]). Available from: https://www.nice.org.uk/guidance/cg90.

      What is clear, however, is that more aggressive antiplatelet regimens have a significantly higher major bleeding risk.
      • Ambler G.K.
      • Waldron C.A.
      • Contractor U.B.
      • Hinchliffe R.J.
      • Twine C.P.
      Antiplatelet therapy for peripheral arterial disease: an umbrella review and meta-analysis of preventative and treatment outcomes.
      The true risks and benefits of an endovascular intervention cannot be understood without concomitant regard for antithrombotic therapy.
      A recent survey of international practice has shown that prescribing after peripheral arterial endovascular intervention is heterogeneous, and that dual antiplatelet therapy is often used.
      • Wong K.H.F.
      • Bosanquet D.
      • Ambler G.K.
      • Qureshi M.I.
      • Hinchliffe R.J.
      The CLEAR (Considering leading Experts' Antithrombotic Regimens around peripheral angioplasty) survey: an international perspective on antiplatelet and anticoagulant practice for peripheral arterial endovascular intervention.
      There is no evidence to guide this practice, but anecdotally some of the recent randomised trials for new devices used dual antiplatelet regimens. With the recent concerns about a higher mortality rate in the intervention arm of some of these trials,
      • Katsanos K.
      • Spiliopoulos S.
      • Kitrou P.
      • Krokidis M.
      • Karnabatidis D.
      Risk of death following application of paclitaxel-coated balloons and stents in the femoropopliteal artery of the leg: a systematic review and meta-analysis of randomized controlled trials.
      it is more important than ever to understand factors which could potentially lead to confounding of outcomes.
      The aim of this systematic review was therefore to examine antiplatelet and anticoagulant (antithrombotic) use as co-interventions in randomised trials of peripheral arterial endovascular intervention in order to compare regimens, try to understand choices made, and examine the trends over time.

      Material and Methods

      A systematic review was carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      MEDLINE and EMBASE were searched via Ovid from inception to 15 January 2019 focusing on randomised trials including patients undergoing any endovascular intervention for peripheral arterial disease. The Cochrane library database and the Cochrane collaboration central register of controlled clinical trials were searched separately. There was no language restriction on any search. The grey literature was not specifically searched. The full search strategy is shown in Appendix A. The study was registered on PROSPERO on 14 May 2019 (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID&equals;135100).

      Screening and selection

      Randomised controlled trials including participants with chronic atherosclerotic peripheral arterial disease of the lower limb undergoing any endovascular intervention as the main therapy or adjunctive therapy with another endovascular intervention were included. Non-randomised trials were excluded. Trials studying patients treated by open surgery or conservative treatments were excluded. Trials including any patients with non-atherosclerotic lower limb disease such as aneurysms were excluded as were trials examining acute disease presentations. Study selection was performed by screening titles and abstracts (K.C. and 50% of excluded studies checked by H.C.). Full texts of potentially eligible studies were screened by two of the authors (K.C. and H.C.) independently. Disagreements were resolved by discussion or consulting a third author (R.H.).

      Data extraction and definitions

      Two authors (H.L. and K.C.) independently extracted data. If any disagreements arose a consensus was reached with reference to a third author (G.K.A.). The following data were extracted from each study using a pre-specified proforma: year of publication; endovascular interventions; number of patients; population; primary outcome; Rutherford classification; target artery (divided into “iliac”, which included common and external iliac, “femoropopliteal”, and “below the knee”); antithrombotic agents(s), dose, and duration (i.e., antithrombotic protocol). The protocols were classified as peri-procedural phase (during or before the procedure), immediate post-procedural phase (up to 30 days post procedure), and maintenance post-procedural phase (more than 30 days post procedure).
      Antithrombotic protocols were analysed based on how well they were specified in each published trial, which was defined as follows:
      • 1.
        Did not mention any protocol
      • 2.
        Failed to completely specify a protocol (incomplete protocol)
      Subgroups:
      • A.
        The protocol was only “recommended”, and the use was left at the discretion of the treating physician.
      • B.
        Unspecified antithrombotic agent(s).
      • C.
        The antithrombotic agent was clearly specified but the dosage was unspecified.
      • D.
        More than one protocol was specified.
      • 3.
        Had a completely specified protocol (complete protocol)
      To meet the requirement
      • Lopes R.D.
      • Hong H.
      • Harskamp R.E.
      • Bhatt D.L.
      • Mehran R.
      • Cannon C.P.
      • et al.
      Safety and efficacy of antithrombotic strategies in patients with atrial fibrillation undergoing percutaneous coronary intervention: a network meta-analysis of randomized controlled trials.
      the following criteria had to be met:
      • A.
        The antiplatelet/anticoagulant agent(s) was/were specified
      • B.
        Antithrombotic dosage was specified
      • C.
        The duration of antiplatelet/anticoagulant prescription/administration was specified
      • D.
        The antiplatelet/anticoagulant protocol was applied to all the subjects in the trial.
      Antiplatelet agents were grouped into aspirin alone; P2Y12 receptor antagonist alone; dual antiplatelet therapy (“dual therapy”: combination of aspirin and P2Y12 receptor antagonist); other antiplatelet combination; no antiplatelet agent. Anticoagulation was grouped into unfractionated heparin (“heparin”) low molecular weight heparin; other anticoagulant (including direct oral anticoagulant); no anticoagulant.

      Quality assessment

      There is no validated assessment tool to measure the quality of study protocols. Even though there is no formal analysis of the results from the included studies, a marker of quality was felt to be important for adding context to the outcomes examined in narrative review. The quality of included trials was therefore assessed using the Cochrane Risk of Bias Assessment tool.

      Narrative synthesis

      Trial protocols were grouped as percentages of total numbers of trials in any given pre-specified group. Subgroup analyses were performed by type of endovascular intervention. Trials with more than one protocol were considered separately. Additionally, dual antiplatelet trends were examined over time and with target artery.
      Meta-analysis was not performed as the objective of this review was to assess medication protocols across randomised trials reporting outcomes for endovascular interventions. These trials do not break down results by medication. To tabulate results by type of endovascular intervention the number of intervention arms from separate trials were combined.

      Statistical analysis

      Statistical analysis was performed in the R statistical programming environment version 3.5.1. Changes in frequency of dual antiplatelet use with time were assessed using logistic regression analysis. Comparisons of antiplatelet use according to the different arterial segments treated were performed using Fisher's exact test. P values < .05 were considered statistically significant.

      Results

      The PRISMA flow diagram is shown in Fig. 1. A total of 5025 publications were identified by the search strategy, of which 456 were assessed as full text. Ninety-four randomised trials were included for narrative synthesis.
      Figure 1
      Figure 1PRISMA flow diagram showing the searching, screening and selection process for included studies to examine the antithrombotic regimens in randomised trials for peripheral arterial endovascular intervention.
      The majority of trials (54, 57%) treated more than 50% of patients for claudication (Rutherford 1–3). Twenty-one (22%) included more than 50% of patients with chronic limb threatening ischaemia (Rutherford 4–6). Nine (10%) gave a mean or median Rutherford score so were impossible to assess accurately, and 10 (11%) gave no information of degree of ischaemia or symptoms (Appendix B).
      The most frequent primary outcome measure from the included trials was primary patency (28 trials, 30%). Included studies most commonly compared plain balloon angioplasty with arterial stenting (bare metal, covered, drug eluting, or absorbable; 23 trials, 24%), followed by plain balloon angioplasty vs. drug coated balloon angioplasty (21 trials, 22%). Appendix B shows details of all included trials, and a summary of all trial comparisons is provided in Appendix C. Thirty-eight trials (40%) were company sponsored. None of the trials justified their antithrombotic therapy protocol.

      Quality of included studies

      The overall quality of studies was judged as being low. Eighty-nine studies (95%) had a high risk of bias in at least one domain; however, much of the high risk was due to a lack of personnel blinding which is impractical in many trials of this type (Fig. 2).
      Figure 2
      Figure 2Risk of bias graph for included studies to examine the antithrombotic regimens in randomised trials for peripheral arterial endovascular intervention. This is the review authors' judgements about each risk of bias item presented as percentages across all included studies. The darker the bar the higher risk of bias in that domain.
      There were more concerning sources of bias from allocation concealment being unclear in 70% of trials and blinding of outcome assessment being unclear in 72% of trials. There was also evidence of selective reporting (32%) and incomplete reporting (29%).

      Peri-procedural protocols

      Completeness of protocol

      Of the 94 included trials, four (4%) specified separate antithrombotic protocols for each intervention arm (see ‘Trials with different antithrombotic regimens in each peri-procedural arm’). Heparin and antiplatelet agents could not be cleanly separated peri-procedurally as many trials used them interchangeably or even used heparin in one arm and antiplatelet agents in another.
      Of the 90 remaining randomised trials there were 64 different peri-procedural protocols. Thirteen studies (14%) did not mention any peri-procedural protocol, 51 (57%) had incomplete protocols, and 26 (29%) had complete protocols (Table 1, Table 2).
      Table 1Peri-procedural antithrombotic protocols in randomised trials of lower limb endovascular intervention, stratified by type of intervention. Comparisons including plain balloon angioplasty in an arm
      ComparisonAll
      All refers to the cumulative use in protocols across all comparisons in Tables 1 and 2.


      n = 90
      PBA vs. BMS

      n = 16
      PBA vs. DES

      n = 3
      PBA vs. ATH

      n = 3
      PBA vs. DCB

      n = 21
      DCB + BMS vs. PBA + BMS

      n = 2
      PBA vs. BT

      n = 5
      CRYO vs. PBA

      n = 6
      PBA vs. PBA + BT

      n = 2
      PBA vs. CBA

      n = 2
      PBA vs. laser

      n = 4
      Laser vs. laser vs. PBA

      n = 2
      Completeness of drug protocol
       Did not mention any protocol13 (14)1 (6)0 (0)0 (0)5 (24)0 (0)0 (0)1 (17)0 (0)0 (0)2 (50)0 (0)
      Incomplete protocol51 (57)8 (50)2 (67)2 (67)14 (67)2 (100)2 (40)3 (50)1 (50)1 (50)0 (0)0 (0)
      Only recommended a protocol10 (11)4 (25)1 (33)1 (33)3 (14)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)2 (100)
      Drug unspecified11 (12)2 (13)0 (0)1 (33)2 (10)0 (0)1 (20)0 (0)0 (0)0 (0)0 (0)0 (0)
      Dose unspecified24 (27)2 (13)0 (0)0 (0)8 (38)2 (100)1 (20)2 (33)1 (50)0 (0)0 (0)0 (0)
      Specified more than one protocol6 (7)0 (0)1 (33)0 (0)1 (5)0 (0)0 (0)1 (17)0 (0)1 (50)0 (0)0 (0)
       Fully specified and complete protocol26 (29)7 (44)1 (33)1 (33)2 (10)0 (0)3 (60)2 (33)1 (50)1 (50)2 (50)2 (100)
      Peri-procedural antithrombotic use
       Unspecified19 (21)3 (19)1 (33)1 (33)6 (29)0 (0)0 (0)1 (17)0 (0)0 (0)2 (50)2 (100)
       Antiplatelet only10 (11)4 (25)0 (0)0 (0)2 (10)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)
       Anticoagulant only17 (19)3 (19)1 (33)0 (0)2 (10)0 (0)3 (60)0 (0)2 (100)0 (0)2 (50)0 (0)
       Antiplatelet and anticoagulant44 (49)6 (38)1 (33)2 (67)11 (52)2 (100)2 (40)5 (83)0 (0)2 (100)0 (0)0 (0)
      Peri-procedural anticoagulation use
       Heparin51 (57)8 (50)2 (67)1 (33)13 (62)2 (100)5 (100)4 (67)2 (100)1 (50)2 (50)2 (100)
       LMWH1 (1)0 (0)0 (0)0 (0)1 (5)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)
       Other anticoagulant combination11 (12)3 (19)0 (0)1 (33)1 (5)0 (0)0 (0)1 (17)0 (0)1 (50)0 (0)0 (0)
       No anticoagulant protocol specified27 (30)5 (31)1 (33)1 (33)6 (29)0 (0)0 (0)1 (17)0 (0)0 (0)2 (50)0 (0)
      Peri-procedural antiplatelet use
       Aspirin13 (14)4 (25)0 (0)1 (33)1 (5)1 (50)2 (40)0 (0)0 (0)1 (50)0 (0)2 (100)
       P2Y12 receptor antagonist13 (14)3 (19)1 (33)1 (33)2 (10)0 (0)0 (0)1 (17)0 (0)1 (50)0 (0)0 (0)
       Dual antiplatelet therapy25 (28)3 (19)1 (33)0 (0)10 (48)1 (50)0 (0)3 (50)0 (0)0 (0)0 (0)0 (0)
       Other antiplatelet combination6 (7)1 (6)0 (0)1 (33)2 (10)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)
       No antiplatelet protocol specified33 (37)5 (31)1 (33)0 (0)6 (29)0 (0)3 (60)2 (33)2 (100)0 (0)4 (100)0 (0)
      Data are given as n (%). ATH = atherectomy; BMS = bare metal stent; BT = brachytherapy; CBA = cutting balloon angioplasty; CRYO = cryoplasty; DCB = drug coated balloon; DES = drug eluting stent; PBA = plain balloon angioplasty; LMWH = low molecular weight heparin.
      All refers to the cumulative use in protocols across all comparisons in Table 1, Table 2.
      Table 2Peri-procedural antithrombotic protocols in randomised trials of lower limb endovascular intervention, stratified by type of intervention. Comparisons not including plain balloon angioplasty in an arm
      ComparisonAll
      All refers to the cumulative use of protocols across all comparisons in Tables 1 and 2.


      n = 90
      BMS vs. DES

      n = 4
      CS vs. BMS

      n = 2
      BMS vs. BMS

      n = 2
      Other

      n = 16
      Completeness of drug protocol
       Did not mention any protocol13 (14)0 (0)0 (0)1 (50)3 (19)
      Incomplete protocol51 (57)3 (75)2 (100)1 (50)10 (63)
      Only recommended a protocol10 (11)0 (0)0 (0)0 (0)1 (6)
      Drug unspecified11 (12)1 (25)1 (50)1 (50)2 (13)
      Dose unspecified24 (27)2 (50)1 (50)0 (0)5 (31)
      Specified more than one protocol6 (7)0 (0)0 (0)0 (0)2 (13)
       Fully specified and complete protocol26 (29)1 (25)0 (0)0 (0)3 (19)
      Peri-procedural antithrombotic use
       Unspecified19 (21)0 (0)0 (0)1 (50)4 (25)
       Antiplatelet only10 (11)2 (50)0 (0)1 (50)1 (6)
       Anticoagulant only17 (19)0 (0)0 (0)0 (0)3 (19)
       Antiplatelet and anticoagulant44 (49)2 (50)2 (100)0 (0)8 (50)
      Peri-procedural anticoagulation use
       Heparin51 (57)1 (25)1 (50)0 (0)7 (44)
       LMWH1 (1)0 (0)0 (0)0 (0)0 (0)
       Other anticoagulant combination11 (12)1 (25)0 (0)0 (0)3 (19)
       No anticoagulant protocol specified27 (30)2 (50)1 (50)2 (100)6 (38)
      Peri-procedural antiplatelet use
       Aspirin13 (14)1 (25)0 (0)0 (0)1 (6)
       P2Y12 receptor antagonist13 (14)0 (0)1 (50)0 (0)3 (19)
       Dual antiplatelet therapy25 (28)2 (50)1 (50)1 (50)3 (19)
       Other antiplatelet combination6 (7)0 (0)0 (0)0 (0)2 (13)
       No antiplatelet protocol specified33 (37)1 (25)0 (0)1 (50)7 (44)
      Data are given as n (%). ATH = atherectomy; BMS = bare metal stent; CS = covered stent; DES = drug eluting stent; LMWH = low molecular weight heparin.
      All refers to the cumulative use of protocols across all comparisons in Table 1, Table 2.
      The most common reason for an incomplete peri-procedural protocol was an unspecified antithrombotic dose (24 of 51 trials). Many of these trials had ambiguous terms or sentences used for describing peri-procedural protocols including:
      • “Clopidogrel saturation was obtained”
        • Bosiers M.
        • Peeters P.
        • D'Archambeau O.
        • Hendriks J.
        • Pilger E.
        • Duber C.
        • et al.
        AMS INSIGHT—absorbable metal stent implantation for treatment of below-the-knee critical limb ischemia: 6-month analysis.
      • “Appropriate anticoagulation was administered per physician discretion”
        • Krishnan P.
        • Faries P.
        • Niazi K.
        • Jain A.
        • Sachar R.
        • Bachinsky W.B.
        • et al.
        Stellarex drug-coated balloon for treatment of femoropopliteal disease: twelve-month outcomes from the randomized ILLUMENATE pivotal and pharmacokinetic studies.
      • “Systemic intra-procedural anticoagulation was mandatory”
        • Geraghty P.J.
        • Mewissen M.W.
        • Jaff M.R.
        • Ansel G.M.
        Three-year results of the VIBRANT trial of VIABAHN endoprosthesis versus bare nitinol stent implantation for complex superficial femoral artery occlusive disease.

      Peri-procedural antithrombotic agents

      Antiplatelet monotherapy in combination with anticoagulant therapy

      The most common peri-procedural protocol was to use both an antiplatelet and an anticoagulant (44, 49%, Table 1, Table 2 and Appendix E). The antiplatelet used most commonly was aspirin (18 trials, 19%) but the dose varied from 80 mg to 325 mg. Clopidogrel was the second most common, used by 10 trials (11%) with no dose specified in four trials and five using 300 mg.
      Heparin was the most commonly used anticoagulant in combination with an antiplatelet agent. However, the dose varied from 2500 IU to 7500 IU and was different in all but 21 of the 44 trials, which used 5000 IU.

      Antiplatelet monotherapy alone

      Antiplatelet monotherapy alone was used in 10 trials (11%), the most common agents were aspirin and clopidogrel in nine of these 10 trials.

      Anticoagulant therapy alone

      Heparin alone was used in 17 trials (19%). Again, the dose varied, but 5000 IU was most commonly used (six of the 17 trials). Heparin was either not used or not specified in 19 trials (20%).

      Dual antiplatelet therapy in combination with anticoagulant therapy

      Dual antiplatelet therapy in combination with heparin was used by 25 trials (28%) in the peri-procedural phase (Table 1, Table 2). Dual therapy was not used without heparin.
      The dose and duration of dual antiplatelet therapy varied widely (Appendix E) and ranged from 75 mg to 300 mg for both agents. Aspirin and clopidogrel together were used most frequently (20 of the 25 studies) but ticlopidine, prasugrel, unspecified thienopyridines, and abciximab were each used in one trial.
      There was a tendency for more recent trials incorporating antiproliferative drug technology to incorporate the use of dual antiplatelet therapy peri-procedurally, with 19% of plain balloon angioplasty vs. bare metal stent trials using dual antiplatelet therapy compared with 33% use in the plain balloon angioplasty vs. drug eluting stent trials (Table 1).

      Trials with different antithrombotic regimens in each peri-procedural arm

      Four trials (4%) specified separate antithrombotic protocols for each intervention arm. Rand et al.
      • Rand T.
      • Basile A.
      • Cejna M.
      • Fleischmann D.
      • Funovics M.
      • Gschwendtner M.
      • et al.
      PTA versus carbofilm-coated stents in infrapopliteal arteries: pilot study.
      ,
      • Rand T.
      • Lammer J.
      • Rabbia C.
      • Maynar M.
      • Zander T.
      • Jahnke T.
      • et al.
      Percutaneous transluminal angioplasty versus turbostatic carbon-coated stents in infrapopliteal arteries: InPeria II trial.
      compared plain balloon angioplasty with plain balloon angioplasty and covered stenting and used enoxaparin 2 × 40 mg/day for three days in the plain balloon angioplasty group, and clopidogrel 300 mg as loading dose in the covered stenting group. Krankenberg et al.
      • Krankenberg H.
      • Schluter M.
      • Steinkamp H.J.
      • Burgelin K.
      • Scheinert D.
      • Schulte K.L.
      • et al.
      Nitinol stent implantation versus percutaneous transluminal angioplasty in superficial femoral artery lesions up to 10 cm in length: the femoral artery stenting trial (FAST).
      compared plain balloon angioplasty with plain balloon angioplasty and bare metal stenting and used heparin 3000–5000 IU for all participants, then aspirin 500 mg or 100 mg/day for at least 10 days in the plain balloon angioplasty group and dual antiplatelet therapy (aspirin as per the control group and clopidogrel 300 mg) in the plain balloon angioplasty and bare metal stenting group. Gallino et al.
      • Gallino A.
      • Do D.D.
      • Alerci M.
      • Baumgartner I.
      • Cozzi L.
      • Segatto J.M.
      • et al.
      Effects of probucol versus aspirin and versus brachytherapy on restenosis after femoropopliteal angioplasty: the PAB randomized multicenter trial.
      compared plain balloon angioplasty with brachytherapy and used aspirin 100 mg in the plain balloon angioplasty group, and dual antiplatelet therapy (aspirin 100 mg and clopidogrel 300 mg) in the brachytherapy group.

      Post-procedural protocols

      Completeness of protocol

      Of the 94 included randomised trials, seven (7%) trials specified separate post-procedural protocols for each intervention arm (see ‘Trials with different antithrombotic regimens in each post-procedural arm’). Of the 87 remaining randomised trials there were 52 different post-procedural protocols (Table 3, Table 4). These are detailed in Appendix F. Only 31 (36%) trials specified one single protocol for all participants. A total of 56 (64%) trials either did not mention or had an incompletely specified protocol. The most common reason was that the protocol was only “recommended” and its use was left to the discretion of the treating physician (13 trials, 15%). Examples of ambiguous terms or sentences used for describing peri-procedural protocols include:
      • “Alternative dual antiplatelet therapy regimens could be followed if justified by individual patient requirements”
        • Bausback Y.
        • Willfort-Ehringer A.
        • Sievert H.
        • Geist V.
        • Lichtenberg M.
        • Del Giudice C.
        • et al.
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      • “Continuation of clopidogrel was left to the discretion of the physician”
        • Schulte K.L.
        • Pilger E.
        • Schellong S.
        • Tan K.T.
        • Baumann F.
        • Langhoff R.
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        Primary Self-EXPANDing nitinol stenting vs balloon angioplasty with optional bailout stenting for the treatment of infrapopliteal artery disease in patients with severe intermittent claudication or critical limb ischemia (EXPAND study).
      • “At discharge, acetylsalicylic acid at a dose of 150 mg daily was recommended for a prolonged period of time”
        • Poncyljusz W.
        • Falkowski A.
        • Safranow K.
        • Rac M.
        • Zawierucha D.
        Cutting-balloon angioplasty versus balloon angioplasty as treatment for short atherosclerotic lesions in the superficial femoral artery: randomized controlled trial.
      Table 3Postprocedural antithrombotic protocols in randomised trials of lower limb endovascular intervention, stratified by type of intervention. Comparisons including plain balloon angioplasty in an arm
      ComparisonAll
      All refers to the cumulative use of protocols across all comparisons in Tables 3 and 4.


      n = 87
      PBA vs. BMS

      n = 16
      PBA vs. DES

      n = 2
      PBA vs. ATH

      n = 3
      PBA vs. DCB

      n = 21
      CRYO vs. PBA

      n = 6
      PBA vs. CBA

      n = 2
      PBA vs. BT

      n = 5
      PBA vs. PBA + RT

      n = 2
      PBA vs. laser

      n = 4
      Laser vs. laser vs. PBA

      n = 2
      Postprocedural protocol
       Did not mention any protocol19 (22)0 (0)0 (0)0 (0)5 (24)2 (33)0 (0)1 (20)0 (0)4 (100)0 (0)
      Incomplete protocol(s)37 (43)7 (44)1 (50)3 (100)12 (57)2 (33)1 (50)1 (20)1 (50)0 (0)1 (50)
      Only recommended a protocol13 (15)2 (13)0 (0)2 (67)4 (19)0 (0)1 (50)1 (20)0 (0)0 (0)1 (50)
      Drug agent was unspecified12 (14)1 (6)0 (0)0 (0)6 (29)2 (33)0 (0)0 (0)0 (0)0 (0)1 (50)
      Drug dose was unspecified12 (14)4 (25)1 (50)1 (33)2 (10)0 (0)0 (0)0 (0)1 (50)0 (0)0 (0)
      Specified more than 1 protocol0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)
       Fully specified and complete protocol31 (36)9 (56)1 (50)0 (0)4 (19)2 (33)1 (50)3 (60)1 (50)0 (0)1 (50)
      Antithrombotic class
       Unspecified30 (34)2 (13)0 (0)2 (67)7 (33)2 (33)1 (50)2 (40)0 (0)4 (100)1 (50)
       Antiplatelet only55 (63)13 (81)2 (100)1 (33)14 (67)4 (67)1 (50)3 (60)2 (100)0 (0)1 (50)
       Anticoagulant only1 (1)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)
       Both antiplatelet and anticoagulant1 (1)1 (6)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)
      Immediate postprocedural phase
       Aspirin13 (15)4 (25)0 (0)0 (0)1 (5)0 (0)1 (50)4 (80)2 (100)0 (0)1 (50)
       P2Y12 receptor antagonist2 (2)0 (0)1 (50)0 (0)1 (5)0 (0)0 (0)0 (0)0 (0)0 (0)1 (50)
       Dual antiplatelet therapy48 (55)10 (63)1 (50)2 (67)13 (62)4 (67)1 (50)0 (0)0 (0)0 (0)0 (0)
       Other antithrombotic combination4 (5)2 (13)0 (0)0 (0)1 (5)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)
       Not specified20 (23)0 (0)0 (0)1 (33)5 (24)2 (33)0 (0)1 (20)0 (0)4 (100)0 (0)
      Maintenance postprocedural phase
       Aspirin41 (47)14 (88)1 (50)1 (33)8 (38)2 (33)1 (50)3 (60)2 (100)0 (0)1 (50)
       P2Y12 receptor antagonist1 (1)0 (0)1 (50)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)1 (50)
       Dual antiplatelet therapy12 (14)1 (6)0 (0)0 (0)2 (10)0 (0)1 (50)0 (0)0 (0)0 (0)0 (0)
       Other antithrombotic combination1 (1)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)
       Not specified32 (37)1 (6)0 (0)2 (67)11 (52)4 (67)0 (0)2 (40)0 (0)4 (100)0 (0)
      Data are given as n (%). ATH = atherectomy; BMS = bare metal stent; BT = brachytherapy; CRYO = cryotherapy; CBA = cutting balloon angioplasty; DCB = drug coated balloon; DES = drug eluting stent; PBA = plain balloon angioplasty.
      All refers to the cumulative use of protocols across all comparisons in Table 3, Table 4.
      Table 4Postprocedural antithrombotic protocols in randomised trials of lower limb endovascular intervention, stratified by type of intervention. Comparisons not including plain balloon angioplasty in an arm
      ComparisonAll
      All refers to the cumulative use in protocols across all comparisons in Tables 3 and 4.


      n = 87
      BMS vs. DES

      n = 4
      CS vs. BMS

      n = 2
      BMS vs. BMS

      n = 2
      Other

      n = 16
      Postprocedural protocol
       Did not mention any protocol19 (22)0 (0)0 (0)2 (100)5 (31)
      Incomplete protocol(s)37 (43)3 (75)0 (0)0 (0)5 (31)
      Only recommended a protocol13 (15)2 (50)0 (0)0 (0)1 (6)
      Drug agent was unspecified12 (14)0 (0)0 (0)0 (0)2 (13)
      Drug dose was unspecified12 (14)1 (25)0 (0)0 (0)2 (13)
      Specified more than 1 protocol0 (0)0 (0)0 (0)0 (0)0 (0)
       Fully specified and complete protocol31 (36)1 (25)2 (100)0 (0)6 (38)
      Antithrombotic class
       Unspecified30 (34)2 (50)0 (0)2 (100)6 (38)
       Antiplatelet55 (63)2 (50)2 (100)0 (0)10 (63)
       Anticoagulant1 (1)0 (0)0 (0)0 (0)0 (0)
       Both antiplatelet and anticoagulant1 (1)0 (0)0 (0)0 (0)0 (0)
      Immediate post procedural phase
       Aspirin13 (15)0 (0)0 (0)0 (0)0 (0)
       P2Y12 receptor antagonist2 (2)0 (0)0 (0)0 (0)0 (0)
       Dual antiplatelet therapy48 (55)4 (100)2 (100)0 (0)11 (69)
       Other antithrombotic combination4 (5)0 (0)0 (0)0 (0)0 (0)
       Not specified20 (23)0 (0)0 (0)2 (100)5 (31)
      Maintenance post procedural phase
       Aspirin41 (47)0 (0)0 (0)0 (0)8 (50)
       P2Y12 receptor antagonist1 (1)0 (0)0 (0)0 (0)0 (0)
       Dual antiplatelet therapy12 (14)3 (75)2 (100)0 (0)3 (19)
       Other antithrombotic combination1 (1)0 (0)0 (0)0 (0)0 (0)
       Not specified32 (37)1 (25)0 (0)2 (100)5 (31)
      Data are given as n (%). BMS = bare metal stent; CS = covered stent; DES = drug eluting stent.
      All refers to the cumulative use in protocols across all comparisons in Table 3, Table 4.

      Post-procedural antithrombotic agents

      Of the remaining 87 trials, 48 (55%) used antiplatelet agents in the immediate post-procedural phase and 12 (14%) in the maintenance post-procedural phase (Table 3, Table 4 and Appendix F). One trial used oral anticoagulation and one used warfarin for the first 12 weeks then aspirin.

      Immediate post-procedural phase

      Sixty-seven trials (71%) specified an immediate phase post-procedural regimen which was antiplatelet therapy in all but the two trials above (Table 3, Table 4 and Appendix F).

      Antiplatelet monotherapy

      Fifteen trials used antiplatelet monotherapy alone as an immediate post-procedural phase treatment. Aspirin alone was used by 13 trials (15%), although the dose ranged from 100 mg to 300 mg. Two trials used clopidogrel 75 mg alone.

      Dual antiplatelet therapy

      Dual antiplatelet therapy was used in 48 trials (55%). Only 19 (22%) of these trials completely specified the protocol. This was most commonly aspirin and clopidogrel (38 of 48 trials) with a wide variation in doses of each.

      Maintenance post-procedural phase

      Fifty-five trials (63%) specified post-procedural maintenance phase therapy (Table 3, Table 4 and Appendix F).

      Antiplatelet monotherapy

      Antiplatelet monotherapy was the most commonly used maintenance therapy in 43 of the 55 trials specifying a maintenance phase drug. Forty-one of these used aspirin which had the same range of doses as the immediate phase protocols. Ten of the trials specifying aspirin did not specify the dose or duration.

      Dual antiplatelet therapy

      Dual antiplatelet therapy was used in 12 trials (14%), three of which did not specify the agent, dose, and/or duration of therapy. Where specified, clopidogrel and aspirin was the commonest combination (eight trials, 9%). Maintenance phase therapy was not specified in 32 trials (37%).
      Over time there has been an increasing tendency to use dual therapy (Fig. 3A, p < .0001). This corresponds with the introduction of newer technologies such as drug coated balloons and drug eluting stents (Table 3) and also more trials focussed on below knee intervention (Fig. 3B). A greater proportion of these trials used dual therapy in the maintenance phase of the protocol than the trials comparing plain balloons or stents in the femoropopliteal segment (37/71 trials in the femoropopliteal segment used dual therapy, compared with 12/17 trials of below the knee intervention, p = .030).
      Figure 3
      Figure 3The use of dual antiplatelet therapy in the post-procedural phase of randomised controlled trials of lower limb endovascular intervention over (A) time and (B) by arterial territory, where p < .001 for increasing use of dual therapy with time (A) and p = .030 for a greater proportion of dual antiplatelet therapy use in trials of below knee intervention compared with femoropopliteal intervention (B). BTK = below the knee.

      Trials with different antithrombotic regimens in each post-procedural arm

      Seven (7%) trials specified separate post-procedural protocols for each intervention arm. The DEBATE-SFA trial compared femoropopliteal plain balloon angioplasty plus bare metal stenting with drug coated balloon angioplasty plus bare metal stenting, the former receiving post-procedural aspirin monotherapy, and the latter dual antiplatelet therapy.
      • Liistro F.
      • Grotti S.
      • Porto I.
      • Angioli P.
      • Ricci L.
      • Ducci K.
      • et al.
      Drug-eluting balloon in peripheral intervention for the superficial femoral artery: the DEBATE-SFA randomized trial (drug eluting balloon in peripheral intervention for the superficial femoral artery).
      InPeria II compared infrapopliteal plain balloon angioplasty with bare metal stenting. The plain balloon angioplasty group received twice daily enoxaparin 40 mg in addition to aspirin, whereas the stenting group received four weeks of clopidogrel, with subsequent reversion to aspirin monotherapy.
      • Rand T.
      • Lammer J.
      • Rabbia C.
      • Maynar M.
      • Zander T.
      • Jahnke T.
      • et al.
      Percutaneous transluminal angioplasty versus turbostatic carbon-coated stents in infrapopliteal arteries: InPeria II trial.
      The ACHILLES trial compared infra-popliteal plain balloon angioplasty with drug eluting stenting; the plain balloon angioplasty group received aspirin monotherapy and the drug eluting stent group was additionally administered clopidogrel for six months.
      • Scheinert D.
      • Katsanos K.
      • Zeller T.
      • Koppensteiner R.
      • Commeau P.
      • Bosiers M.
      • et al.
      A prospective randomized multicenter comparison of balloon angioplasty and infrapopliteal stenting with the sirolimus-eluting stent in patients with ischemic peripheral arterial disease: 1-year results from the ACHILLES trial.
      The FAST trial compared plain balloon angioplasty with bare metal stenting and administered post-procedural aspirin monotherapy to the plain balloon angioplasty group, and dual antiplatelet therapy (aspirin and clopidogrel) to bare metal stenting patients for at least four weeks.
      • Krankenberg H.
      • Schluter M.
      • Steinkamp H.J.
      • Burgelin K.
      • Scheinert D.
      • Schulte K.L.
      • et al.
      Nitinol stent implantation versus percutaneous transluminal angioplasty in superficial femoral artery lesions up to 10 cm in length: the femoral artery stenting trial (FAST).
      An Austrian study compared infrapopliteal plain balloon angioplasty with carbon coated stenting. Post-procedurally all patients received lifelong aspirin and twice daily enoxaparin for three days, whereas the stented patients additionally received clopidogrel for four weeks.
      • Rand T.
      • Basile A.
      • Cejna M.
      • Fleischmann D.
      • Funovics M.
      • Gschwendtner M.
      • et al.
      PTA versus carbofilm-coated stents in infrapopliteal arteries: pilot study.
      DEBATE in SFA was a three arm study (bare metal stenting vs. bare metal stenting plus cilostazol vs. drug eluting stent for femoropopliteal lesions). Bare metal stent patients received clopidogrel for one month and aspirin for 12 months. Bare metal stent plus cilostazol patients received additional aspirin for 12 months but no clopidogrel, and those in the drug eluting stent group received dual antiplatelet therapy for 12 months.
      • Miura T.
      • Miyashita Y.
      • Soga Y.
      • Hozawa K.
      • Doijiri T.
      • Ikeda U.
      • et al.
      Drug-eluting versus bare-metal stent implantation with or without cilostazol in the treatment of the superficial femoral artery.
      The PAB trial evaluated the effect of probucol and/or brachytherapy on restenosis following femoropopliteal plain balloon angioplasty. All patients received aspirin, but those undergoing stenting and brachytherapy additionally received clopidogrel for “an unlimited time” after the procedure.
      • Gallino A.
      • Do D.D.
      • Alerci M.
      • Baumgartner I.
      • Cozzi L.
      • Segatto J.M.
      • et al.
      Effects of probucol versus aspirin and versus brachytherapy on restenosis after femoropopliteal angioplasty: the PAB randomized multicenter trial.

      Discussion

      There is marked heterogeneity in antithrombotic therapy used in randomised trials of endovascular intervention for peripheral arterial disease. There has been an increasing use of dual antiplatelet therapy over time, which corresponds with the introduction of newer technologies and the new focus towards more distal intervention. None of the trials justified their antithrombotic therapy protocol. The overall quality of included studies was low.
      The marked heterogeneity and lack of justification of antithrombotic regimens reflects the low quality design of many trials included in this study. Even though a formal meta-analysis was not performed, a risk of bias assessment was included as a marker of study quality. This showed a concerning amount of “unclear” bias such as detection bias and attrition bias which can be compensated for by good trial design and follow up. Taken together with a dependence on patency outcomes, a lack of clinically meaningful outcomes, and a lack of independence from company sponsorship in 40% of trials, the overall quality of included trials can only be judged as low. The reliance on participants with claudication in these trials also reduces the generalisability of their findings to the chronic limb threatening ischaemia patient, even though they remain the most at risk after endovascular intervention.
      Peri-procedurally, aspirin remains the most widely adopted antiplatelet monotherapy, despite randomised evidence favouring clopidogrel.
      • Ambler G.K.
      • Waldron C.A.
      • Contractor U.B.
      • Hinchliffe R.J.
      • Twine C.P.
      Antiplatelet therapy for peripheral arterial disease: an umbrella review and meta-analysis of preventative and treatment outcomes.
      ,
      • Alonso-Coello P.
      • Bellmunt S.
      • McGorrian C.
      • Anand S.S.
      • Guzman R.
      • Criqui M.H.
      • et al.
      Antithrombotic therapy in peripheral artery disease: antithrombotic Therapy and Prevention of thrombosis, 9th ed: American College of chest physicians evidence-based clinical practice guidelines.
      The reasons for this were unclear, but clopidogrel has only relatively recently come off patent so cost may be a factor. There is the potential to reduce cardiovascular events peri-procedurally by using clopidogrel in future trials.
      Post-procedurally there was an increasing tendency to use dual antiplatelet therapy over time. This coincides with the introduction of newer technologies such as drug coated balloons and drug eluting stents, and more trials of below knee interventions. It is impossible to know which of these factors has contributed to the change in regimens towards dual therapy and there was no justification in trial protocols for the choice. However, the problem with choosing an antithrombic protocol for a trial of endovascular intervention is that there is no good evidence base on which to base the decision,
      • Ambler G.K.
      • Waldron C.A.
      • Contractor U.B.
      • Hinchliffe R.J.
      • Twine C.P.
      Antiplatelet therapy for peripheral arterial disease: an umbrella review and meta-analysis of preventative and treatment outcomes.
      and this is probably why almost every trial that reports a protocol does something different. While there is neither randomised evidence to guide heparin or antiplatelet therapy, the greatest long term impact seems to be from the antiplatelet agent rather than the heparin. There is separate randomised evidence showing dual antiplatelet therapy reduces graft loss events after open prosthetic lower limb bypass
      • Ambler G.K.
      • Waldron C.A.
      • Contractor U.B.
      • Hinchliffe R.J.
      • Twine C.P.
      Antiplatelet therapy for peripheral arterial disease: an umbrella review and meta-analysis of preventative and treatment outcomes.
      as well as reducing stent thrombosis events after percutaneous coronary intervention.
      • Levine G.N.
      • Bates E.R.
      • Bittl J.A.
      • Brindis R.G.
      • Fihn S.D.
      • Fleisher L.A.
      • et al.
      2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of cardiology/American Heart Association Task Force on clinical practice guidelines: an Update of the 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention, 2011 ACCF/AHA guideline for coronary artery bypass graft surgery, 2012 ACC/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the Diagnosis and management of patients with stable ischemic Heart disease, 2013 ACCF/AHA guideline for the management of ST-Elevation Myocardial Infarction, 2014 AHA/ACC guideline for the management of patients with non-ST-Elevation acute coronary Syndromes, and 2014 ACC/AHA guideline on Perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery.
      This may have influenced the choices made during trial design. “Real world” antiplatelet and anticoagulant practice following peripheral arterial endovascular intervention is known to vary by practitioner with some using dual therapy and some monotherapy.
      • Wong K.H.F.
      • Bosanquet D.
      • Ambler G.K.
      • Qureshi M.I.
      • Hinchliffe R.J.
      The CLEAR (Considering leading Experts' Antithrombotic Regimens around peripheral angioplasty) survey: an international perspective on antiplatelet and anticoagulant practice for peripheral arterial endovascular intervention.
      Again, it is impossible to know whether this has influenced trial design or vice versa. It is arguably most likely that clinical practice and trial design evolved together, influenced by cardiology practice.
      There is the potential for confounding in these trials as a result of differences in antithrombotic regimens. Dual antiplatelet therapy increases the major bleeding risk,
      • Ambler G.K.
      • Waldron C.A.
      • Contractor U.B.
      • Hinchliffe R.J.
      • Twine C.P.
      Antiplatelet therapy for peripheral arterial disease: an umbrella review and meta-analysis of preventative and treatment outcomes.
      which may contribute to late mortality if regimens were continued long term. This is especially relevant in the current climate, as the trials included in this systematic review contributed to the late mortality results attributed to paclitaxel.
      • Katsanos K.
      • Spiliopoulos S.
      • Kitrou P.
      • Krokidis M.
      • Karnabatidis D.
      Risk of death following application of paclitaxel-coated balloons and stents in the femoropopliteal artery of the leg: a systematic review and meta-analysis of randomized controlled trials.
      The strengths of this review are the clear, its all encompassing search protocol and robust reporting of results. This review has some limitations. It was impossible to tell whether some trials used antiplatelet agents alone in the peri-procedural phase or whether they simply made no statement on heparin/anticoagulant use. The practitioners involved in these studies may have given a drug such as heparin which would be common practice. Because of this lack of clarity it was impossible to confidently separate antiplatelet and anticoagulant use in these trials, which means some of the peri-procedural regimens may not reflect “real life” practice during procedures. They are, however, accurate from a published protocol perspective which is how the results are presented. Authors were not contacted for this information as the lack of reporting was used as a marker of quality; this information is vital when reporting trials in this area. The results summarised pertain to the number of trials included and are not proportionally representative of the number of participants included, as the trials recruited varying numbers of participants. Lastly, no time limits were set, and drug availability has not been uniform over the period evaluated.
      Randomised trials comparing different types of peripheral endovascular arterial intervention have a high level of heterogeneity in their antithrombotic regimens and were of low quality. Antiplatelet therapy need to be standardised in trials comparing endovascular technologies to reduce potential confounding. To do this, an independent randomised trial specifically examining antiplatelet therapy following peripheral arterial endovascular intervention is needed.

      Conflict of Interest

      None.

      Funding

      This study was supported by Learning and Research at North Bristol NHS Trust , the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol . The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health and Social Care.

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