Systematic review & network meta-analysis of randomised controlled trials comparing antithrombotic drugs for cardiovascular risk reduction in patients with lower limb peripheral arterial disease.

Research Question 

Which antithrombotic medication regimen is most effective at reducing the risk of subsequent adverse cardiovascular and limb events in patients with peripheral arterial disease? 

Background 

Peripheral arterial disease (PAD) is commonly caused by atherosclerosis of the limbs and effects in excess of 200 million people worldwide. The systemic nature of atherosclerotic disease means PAD patients are at increased risk of myocardial infarction, ischemic stroke, and cardiovascular death as well as limb ischemia or amputation. Placing PAD patients on antithrombotic medication regimens mitigates or prevents these adverse occurrences. Multiple RCTs have compared differing antithrombotic medication regimens leading to a complex evidence base. Currently two different antithrombotic medication regimens are recommended in the UK by the National Institute of Clinical Excellence(NICE) but uncertainty remains which is optimal. 

Aims & Objectives 

This research aims to define the relative efficacy and risks of previously investigated antithrombotic medications in preventing major cardiovascular events, limb loss and mortality in patients with PAD. The secondary aim is to investigate whether different patient groups have differing outcomes from alternative antithrombotic regimens. 

Methods 

The research will be registered on the PROSPERO registry. 

Searches

A systematic search to identify randomized control trials (RCTs) evaluating the effects of antithrombotic medication regimens in patients with PAD will be undertaken in English on, Medline, Embase, Cochrane (CENTRAL), Web of Science and Google Scholar 

Screening / Data Extraction / Quality Assessment 

Screening of title and abstract will be used to identify RCTs of anti-thrombotic medication regimens which will undergo subsequent full text review to identify those that are conducted on or have an identified subgroup of PAD patients. Once a study has been identified for inclusion, all publications and the protocol will be sought and reviewed together. Data will be extracted independently by 2 individuals. Risk of bias assessments will be undertaken using the Cochrane “RoB 2” tool by individuals with domain expertise 

Data synthesis

Included studies will be summarised. A network meta-analysis (NMA) will be undertaken to allow direct and indirect comparisons to be included. Anti-thrombotic medication regimens will be grouped and the completeness of potential networks for the primary objectives explored followed by subgroup patient analyses. Analysis will be undertaken using a random-effects model and level inconsistency in the model reported using the Q statistic. Each possible pairwise comparison of relative effects and a league table of the relative effects of medication regimens with associated uncertainty will be reported. Patient Involvement 

Individuals with lived experience of PAD will provide their views at 2 focus groups. Firstly regarding the completeness and quality of the evidence prior to analysis results being available and subsequently on completion to aid presentation of results in a meaningful way to patients. 

Timelines for delivery 

This research will take 12 months from commencement. 

Anticipated impact and dissemination 

Clarifying optimal antithrombotic regimen is anticipated to improve PAD patient outcomes and cost effectiveness of treatments. It is anticipated this will influence future guidelines and NICE recommendations. Result will be disseminated via publications, conference presentations and stake holders presentations.