The CLEAR (Considering Leading Experts’ Antithrombotic Regimes around peripheral angioplasty) survey: an international perspective on antiplatelet and anticoagulant practice for peripheral arterial endovascular intervention
Antiplatelet and anticoagulant therapy are commonly used before, during and after peripheral arterial endovascular intervention. This survey aimed to establish antiplatelet and anticoagulant choice for peripheral arterial endovascular intervention in contemporary clinical practice.
Pilot-tested questionnaire distributed via collaborative research networks.
One hundred and sixty-two complete responses were collected from responders in 22 countries, predominantly the UK (48%) and the rest of the European Union (44%). Antiplatelet monotherapy was the most common choice pre-procedurally (62%). In the UK, there was no difference between dual and single antiplatelet therapy use post procedure (50% vs. 37% p = 0.107). However, a significant majority of EU respondents used dual therapy (68% vs. 20% p < 0.001). There was variation in choice of antiplatelet therapy by the device used and the anatomical location of the intervention artery. The majority (82%) of respondents believed there was insufficient evidence to guide antithrombotic therapy after peripheral endovascular intervention and most (92%) would support a randomised trial.
There is widespread variation in the use of antiplatelet therapy, especially post peripheral arterial endovascular intervention. Clinicians would support the development of a randomised trial comparing dual antiplatelet therapy with monotherapy.
KeywordsPlatelet Aggregation Inhibitors Peripheral Arterial Disease Endovascular Procedures Surveys and Questionnaires
Vascular and Endovascular Research Network
Antiplatelet therapy is commonly used before, during and after peripheral arterial endovascular intervention. It is reccomended in guidelines; predominantly due to a reduction in cardiovascular events (Conte et al. 2019; National Institute for Health and Care Excellence 2015). However the clinical benefit to support the use of specific antiplatelet regimens, even for ‘established’ indications such as a reduction in cardiovascular events, is actually marginal (Ambler et al. 2019). As a result, guidelines are conflicted as they interpret the evidence differently (Conte et al. 2019; National Institute for Health and Care Excellence 2015). The evidence for maintenance of lower limb bypass patency (Ambler et al. 2019) and when used following coronary intervention (Levine et al. 2016) is more established. This is probably why randomised trials examining new technologies for use in the peripheral arteries have mandated the use of dual antiplatelet therapy in the intervention arms, but not always the comparator arm (Krankenberg et al. 2007). Perhaps as a result the use of dual antiplatelet therapy after peripheral endovascular intervention has become more prevalent in clinical practice. Add in the constantly emerging evidence in cardiology (Levine et al. 2016), and well publicised trials of direct oral anticoagulants for non-intervened peripheral arterial disease (Anand et al. 2018), and it has become even more confusing for peripheral endovascular practitioners. The benefits of any change in drug regimen or new drug have to be balanced against the risks they pose and the cost (Ambler et al. 2019). When compared to cardiology there is a huge gap in our knowledge for antiplatelet therapy choice around peripheral arterial endovascular intervention; a high-volume procedure which is becoming more common (Cull et al. 2010). The aim of this survey was to establish contemporary practice for antiplatelet and or antithrombotic therapy to inform a clinical trial design comparing antiplatelet or antithrombotic agents after peripheral arterial endovascular intervention.
As no validated reporting guidelines for surveys exist, we followed the 38 point checklist generated from a systematic review of published guidance and reporting practice (Bennett et al. 2011). The survey was designed by the authors (KW, DCB, RJH, CPT) and piloted on 7 vascular surgeons and 2 vascular interventional radiologists at North Bristol NHS Trust. A final 9 item survey was defined (Additional file 1).
Survey protocol, inclusion criteria and dissemination
The United Kingdom based trainee collaborative VERN (Vascular and Endovascular Research Network) agreed to disseminate the survey (Bosanquet et al. 2016). A predefined protocol was specified for the survey and made available on the VERN website (available at https://vascular-research.net/projects/considering-leading-experts-antithrombotic-regimes-after-peripheral-angioplasty-clear-survey/ and included as Additional file 1). This defined the surveyors as any grade in training and respondents as consultant (or equivalent level) vascular interventional radiologists and vascular surgeons working in a centre treating vascular patients. To ensure responses were from consultants and to eliminate duplication, the email addresses of the respondents were collected. To qualify for collaborative authorship surveyors had to collect and input 5 responses. The survey was distributed as an online SurveyMonkey form via the VERN emailing list. Social media was used for advertising. Vascupedia, the Rouleaux Club, Association of Surgeons in Training (ASIT), and STARSurg also distributed the survey via their emailing list. The survey was open from 22nd July to 29th August 2019. Data were coded, collected and stored anonymously on encrypted devices.
Incomplete responses were removed during data cleaning. Five percent of the complete responses were randomly selected and independently verified by directly contacting the responder; correlation was 100%. Categorical data are presented as counts and percentages per group. Statistical comparisons were performed via a predetermined protocol. Significant differences between categorical variables were determined via Chi-squared tests in Excel (Microsoft, version 16.16.4). Results were further analysed and compared by dividing the sample into geographical subgroups if sufficient responses (> 50) were collected. Responses to questions about antithrombotic therapy for different arterial levels were modelled using a mixed effects logistic regression model with a random intercept and fixed slope using the ‘lme4’ package in the R statistical programming environment. The model compared a preference for dual antiplatelet therapy over monotherapy, with participants who expressed a preference for other options removed. All statistical tests were 2-sided with a 0.05 level of significance.
Pre-procedural antithrombotic therapy
Post procedural antithrombotic therapy
Overall, more respondents would use dual antiplatelet therapy (58%) than monotherapy (30%) after an intervention (p < 0.001). Anticoagulants were not used in isolation by any responders but were used by 5% in conjunction with dual antiplatelet therapy. In the UK, there was no difference between dual and monotherapy use post procedure (50% vs. 37% p = 0.107). However, a significant majority of EU respondents used dual therapy (68% vs 20% p < 0.001).
Antithrombotic differences by procedure and anatomical location
Rationale for antithrombotic choice
Internationally, dual antiplatelet therapy is now chosen more commonly than monotherapy after peripheral arterial endovascular intervention. UK based respondents used single and dual therapy equally, while the rest of the EU used dual therapy more commonly. Dual antiplatelet therapy is used significantly more commonly after more distal interventions. There was a difference in how responders chose antiplatelet regimens when asked about newer devices (such as drug coated or eluting devices), with dual therapy being chosen more frequently. This may have been influenced by the early company sponsored randomised trials (Krankenberg et al. 2007), which specified dual therapy when the devices were being used but not necessarily in the control arm. The instructions for use for several major devices also recommend post procedural dual antiplatelet therapy. Again, the reason is unclear. These choices may have contributed to the current clinical confusion and increased use of dual therapy after newer devices. Dual therapy was more commonly chosen as interventions became more distal, which is probably a reflection of the concern raised by responders about loss of patency. Patency is not necessarily related to limb loss, but it is the most commonly used surrogate outcome in randomised trials in the peripheral vasculature as it is easy to power a relatively small sample size, and it is easy to measure. As a result, responders tend to think in terms of patency (84% of responders) post intervention and not in terms of patient-centred outcomes. The widespread use of dual antiplatelet therapy is a concern because of the lack of evidence of benefit but clear evidence of harm (Ambler et al. 2019). For example, in all randomised trials comparing dual with mono antiplatelet therapy for peripheral arterial disease, dual antiplatelet therapy caused 37 more major bleeds per 1000 patients than monotherapy (P < 0.001) but did not clearly improve any post endovascular clinical outcome (Ambler et al. 2019). The Vascular community is behind cardiology in this respect, as there are a number of trials examining antiplatelet therapy after peripheral coronary intervention. While it is tempting to draw practice from these trials it is bad science to do so because of the differences between the flow dynamics in the coronary and peripheral arteries, and the differences in clinical sequelae of loss of patency in the heart and in the leg. The limitations of the survey include not stipulating a certain number of entries from a country to be included in the final analysis, non-response bias (which is a potential flaw in any survey or questionnaire), and response bias in that people who are using the antiplatelet regimes chosen may be more likely to be involved in the questionnaire. These biases should have been reduced by the study design, where surveyors chose respondents rather than respondents being self-selected. There will have been a proportionally higher number of responses from the UK because the distribution lists used were predominantly based in the UK. The other EU countries group was comprised of a low number of responses from a large number of countries. This means that while it is not a true ‘EU’ position the grouping is useful to highlight that there are differences in UK practice which would need to be taken into account for any randomised trial. There was a lack of information on doses of drugs in certain areas such as intraprocedural heparin. This was intentional to pragmatically keep the questionnaire relatively quick to complete but would have added interesting additional information.
There is widespread variation in the use of antiplatelet therapy, especially following peripheral arterial endovascular intervention. Preferences differed by device used and anatomical site of procedure. The majority of interventional radiologists and surgeons agreed that there was insufficient evidence to make robust antiplatelet regime choices post endovascular intervention and would support a randomised trial.
Survey collaborators: Aldo Betanco, Andrea Mingoli, Andrej Isaak, Andrew Holden, Andrew Tambyraja, Angeliki Argyriou, Anthony Dean Godfrey, Ashraf Hassouna, Athanasios Diamantopoulos, Athanasios Saratzis, Atif Sharif, Ayoola Awopetu, Brennig Gwilym, Calvin Eng, Carlo Maturi, Charutha Senaratne, Christopher Graham, Colin Oliver, Coscas Raphael, Cristina L. Espada, Eamon Kavanagh, Eckhard Klenk, Efthymios Beropoulis, Esau Martinez, Eustratia Mpaili, Fabio Verzini, Fernando Gallardo, Gabriele Piffaretti, Gianni Celoria, Gladiol, Gonzalo P. Tapia, Greta Saggu, Hannah Travers, James Gordon-Smith, James Kirk, James Olivier, Jason Chuen, Jennifer Buxton, Jiber Hamid, John Quarmby, Jonathan Nicholls, Konstantinos Stavroulakis, Laura Drudi, Marco V. Usai, Mariano Rotger, Michael Gawenda, Mihai Ionac, Muayyad Almuhdhafer, Ng Jun Jie, Nicola Troisi, Nikesh Dattani, Nikolaos Patelis, Paolo Sapienza, Pasqualino Sirignano, Pierfrancesco Lapolla, Raveen Nijjer, Rengarajan Rajagopal, Roberto farraresi, Rodrigo biagioni, Rohan Pancharatnam, Sandeep Bahia, Simona Sica, Staros Spiliopoulos, Stefano Fazzini, Tanya Moledina, Tasleem Akhtar, Thomas Aherne, Thomas Broszey, Tony Moloney.
The authors would like to thank all consultant surgeons and interventional radiologists who took part in this survey. The dissemination of this study in the UK and abroad would not have been possible without the support of the Rouleaux Club (UK vascular trainees’ association), STARSurg (student research collaborative), Vascupaedia, and the Association of Surgeons in Training (ASiT).
The Vascular and Endovascular Research Network (VERN), UK
KW DB and CT were involved in the design, piloting and dissemination of the survey and writing the manuscript. GA was involved in statistical analysis and writing the manuscript. MQ and RH were involved in writing the manuscript. All authors read and approved the final manuscript.
GA, MQ and RH were supported by the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol.
CT was supported by Research and Development at North Bristol NHS trust.
Ethics approval and consent to participate
Not applicable: Ethics approval was not required as this was a survey of clinicians. Collaborative authorship was predetermined as any surveyor who contributed 5 distinct responses from different consultants during the data collection period.
Consent for publication
The authors declare they have no competing interests.
- Ambler GK, Waldron CA, Contractor UB, Hinchliffe RJ, Twine CP (2019) Antiplatelet therapy for peripheral arterial disease: an umbrella review and meta-analysis of preventative and treatment outcomes. Br J Surg (in press)Google Scholar
- Anand S, Bosch J, Eikelboom J et al (2018) Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet 391:219–229. https://doi.org/10.1016/s0140-6736(17)32409-1 CrossRefPubMedGoogle Scholar
- Levine G, Bates E, Bittl J et al. (2016) 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. Circulation. doi: https://doi.org/10.1161/cir.0000000000000404
- National Institute for Health and Care Excellence (2015). Peripheral arterial disease. Available online at: https://cks.nice.org.uk/peripheral-arterial-disease. Accessed 8 Sept 2019Google Scholar
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