Accuracy of Peripheral Arterial Disease Registers in UK General Practice: Case-Control Study

Background: Approximately 20% of the UK population aged 55 to 75 years have evidence of peripheral arterial disease (PAD). PAD affects quality of life and life expectancy if not appropriately diagnosed and managed. At risk patients require accurate diagnosis to ensure optimal treatment to slow disease progression and minimize adverse outcomes. Aim: To assess the accuracy of general practice (GP) registration of the diagnosis of peripheral arterial disease (PAD). Design and Setting: An observational analytic case-control study. As part of a National Institute for Health Research–funded (ISRCTN13301188) project assessing novel diagnostic methods set in GP practice. Methods: A total of 125 patients registered as having PAD and 125 age- and sex-matched controls were recruited from 15 general practices across North East England. The register was then assessed for accuracy of diagnosis. Duplex vascular ultrasound scanning (DUS) undertaken by vascular scientists was used as the gold standard reference for PAD. Results: The PAD register had a sensitivity of 86% (95% CI 77%-92%) and specificity of 74% (95% CI 67%-81%) when compared with DUS. The positive predictive value, however, was 69.6% (95% CI 63%-75%) and negative predictive value 88.8% (95% CI 82%-92%). The overall diagnostic effectiveness of the PAD register was 79.2% (95% CI 73%-84%). Conclusion: This analysis indicates that while PAD is detected with reasonable sensitivity in primary care, many patients registered with a diagnosis of PAD lacked DUS-proven disease. Improved approaches to the objective diagnosis of PAD may improve diagnosis and management of PAD in primary care.

(CLI). CLI has a 50% to 60% 5-year survival and is associated with minor and major amputations. 5 The prevalence of PAD in the population depends on whether the diagnosis is made on clinical grounds only instead of using objective methods such as ankle brachial pressure index (ABPI). It also depends on the definition of PAD used and the population studied. 6 The standard test recommended by NICE (National Institute for Health and Care Excellence) for confirmation of a diagnosis of PAD in GP is the ABPI. ABPI is noninvasive, inexpensive, and has reasonable inter-and intraobserver reliability, 7 though it is not without a number of limitations in assessing PAD in primary care. 8 It is a clinical imperative that "at-risk" patients are accurately diagnosed to ensure optimal, early treatment to reduce risk of disease progression, while minimizing unnecessary treatment of patients without proven disease.
Assessment of PAD in primary care classically relies on a combination of clinical assessment, ABPI measurements, and clinical risk stratifying tools. 6 Previous work has assessed these components individually in their clinical utility at assessing peripheral vascular disease in primary care. 6 This study examines the GP's assessment of peripheral arterial disease as a whole and uses duplex ultrasound scanning as a gold standard investigation for comparison given its very high correlation with digital subtraction angiography in identifying lower limb PAD. 9 In doing so, this work investigates the accuracy of PAD registers and highlights a need for improved assessment of PAD in primary care.

Design
As part of a diagnostic evaluation for a new diagnostic test in PAD (NOTEPAD Study), patients registered with PAD and control group patients with no registered diagnosis of PAD were recruited over a 16-month period between May 2015 and September 2016 from 15 different GPs across the North East of England. The control group patients were matched for age and sex.
Duplex ultrasound scanning (DUS) undertaken by appropriately trained vascular scientists formed the comparative standard for PAD diagnosis for the wider study. The vascular scientists were blinded to the registry status of the patient being assessed. All patients included had documented ABPI values reassessed as part of this trial with additional multisite photoplethysmography (MPPG) measurements recorded as part of a wider National Institute for Health Research (NIHR)-funded (ISRCTN13301188) NOTEPAD project investigating novel diagnostic methods of assessing PAD. The MPPG evaluation will be analyzed and published separately.

Setting
All measurements and patient information were recorded within the participating GP, including DUS assessment. This was to reduce biasing participants who were unable to attend a tertiary centre for assessment and to investigate new methods of PAD assessment in primary care.

Participants
Those eligible were identified by the GP and invited to attend for initial screening. Patients included were all older than 45 years. Baseline demographics and comorbidities were recorded by a vascular research nurse specialist who was blinded to the registry status of the patient. At this point, patients were informed of the purpose of their participation as part of an informed consent process. Control group patients matched for age and sex were then identified and invited for participation across the different sites. Patients were recruited over a 1-year period. Participants were coded using the GP site, followed by the number that patient corresponded to in chronological order of recruitment from that practice. For example, the second patient at GP site 2 was encoded 2-002. No information regarding the vascular status of that patient was included in the coding structure so as to maintain the blinded status of the individual being assessed by the vascular scientist.

Statistical Analysis
The R programming language was used for data cleaning and analysis. 10 Pearson's chi-square test with Yates' continuity correction was applied to categorical data to assess independence and the Welch 2-sample t test was used to assess significant difference between the means of the 2 groups.

Duplex Vascular Ultrasound Scan
All patients underwent bilateral DUS in the primary care setting. Each scan was performed by a trained vascular scientist. The vascular scientist was blinded to the registry status of the patient and received only the coded participant number presenting for assessment. They did not have access to the patient's GP records and produced and submitted their reports as soon as the vascular assessment had been performed. Patients were assessed while lying supine and the limb was scanned from the groin to the ankle. Waveforms and velocities were measured to gauge the presence of PAD and how severe it was. A summary judgment of the patient's flow status was then made. Degree of vessel disease was scored and assessed using a DUS grading scheme. The scan protocol is given in the appendix.

Results
A total of 258 patients were recruited from 15 different GPs across the North East of England from May 2015 to September 2016. Of these, 8 did not attend as invited for DUS imaging, leaving 250 patients (125 registered and 125 non-PAD registered) for analysis. Table 1 summarizes the baseline demographics for both PAD and non-PAD registered patients.

Discussion
The results of this case-control study suggest that GPs are good at detecting and registering PAD in their patients, with the PAD register demonstrating a sensitivity of 86%. There is however some room for improvement given the high rate of false positives (30.4%). While the false negative rate was much lower at 11.2%, this still represents a relatively large proportion of the population lacking complete risk factor control strategies. Transversely, the suggestion is many patients are potentially being exposed to the side effects of PAD-protective medication despite lacking true PAD. The reasons for misdiagnosing PAD are likely to be multifaceted but include the limitations of ABPI and clinical risk stratifying tools. Although previous work formally assessing these tools highlights their strengths as diagnostic adjuncts for the GP, this study depicts a potentially more applicable representation of how well they are used in the clinical environment.
Accurate and timely identification of PAD is important in prognostication and treatment planning. 11 Detecting and screening for PAD in primary care has traditionally depended on ABPI and cardiovascular risk factor scoring systems. 6 When used in isolation, these typically have low yields in identifying PAD in patients in primary care. 6 Furthermore, a recent Cochrane review identified a lack of evidence in the accuracy of ABPI readings in diagnosing PAD in people with intermittent claudication. 12 ABPI is widely lauded as an effective investigation comparable to angiographic imaging with a sensitivity of 95% and specificity of 99%. 13 While there is some evidence to suggest that ABPI is effective at identifying the presence of PAD in asymptomatic at risk individuals in the hospital setting, 14 ABPI has been demonstrated to be less effective at detecting lower grade stenosis, as may be present in asymptomatic patients in the community at risk of developing ischemic leg disease. 15 Lewis et al 16 improved the accuracy of ABPI by combining measurements with wave volume analysis, producing a 100% sensitive and 76% specific instruments when compared with DUS. 16 There are a number of reasons that potentially explain the limitations of ABPI as a diagnostic tool in primary care. 8 Despite efforts to standardize methodology, there still exists a lack of clear consensus in practice about which of the 2 brachial systolic values are used to calculate ABPI, 17 the environmental factors such as practitioner room temperature and referral value thresholds. 8,18 Previous investigators have explored exercise stress tests pre-ABPI as a means of improving diagnostic accuracy. 19 However, this is often limited by the presence of bilateral disease and the most symptomatic limb limiting participation. 18 Apart from the fact stress testing means more equipment and more time taken for an already lengthy investigation in time-pressured GP consultations.
ABPI is just one facet in assessing suspected PAD. Many practitioners use the presence of intermittent claudication symptoms. The shared clinical features and typical patient demographics of PAD and lumbar spinal stenosis mean there is potential for misdiagnosis. 20 Studies by Han et al 20 and Uesugi et al 21 demonstrated that PAD is present in 4.1% and 6.7% of lumbar spinal stenosis patients, respectively, meaning a percentage of patients experience diagnostic overshadowing. Although this study would suggest more people are being diagnosed with PAD than have disease, it is worth noting that the absence of intermittent claudication may still falsely reassure the GP that PAD is absent. McDermott et al 22 found IC was present in only 28.5% of patients with established PAD and absence of symptoms was more common in male, older, and diabetic patients.
PAD and its association to IHD and ischemic stroke is well described 23,24 owing to a number of common risk factors. 25 This may lead to presumptive diagnoses of PAD despite absent clinical or radiographic evidence. Clinical scoring systems that help guide diagnosis of related cardiovascular disease risk in primary care do not always correlate with presence of PAD, despite sharing many risk factors. 26 Of all 258 patients invited to follow up, only 8 did not attend for DUS imaging. All control group patients were age-and sex-matched from the GP registers and were therefore likely to be representative of the general population. Equal numbers of cases and controls were assessed, appropriately matched for age and gender. All measurements, including duplex ultrasound scanning were performed within the practice to represent better the population under the care of the community physician. Although previous work has assessed different tools available to the practitioner in terms of sensitivity and specificity, this study evaluates how well current practice in primary care is establishing the burden of PAD in their practices.

Limitations
GP registers were taken from practices listed under a research registry collaborative and selected based on willingness to cooperate with the study in order to allow for sufficient recruitment of patient numbers. All practices were within one region of the United Kingdom and may not be representative of national and international populations. Practices may have varied in their means of forming a diagnosis, for example, all practices studied had the capacity to measure ABPI, though how many PAD registered patients diagnosis was based on an ABPI value is not known.

Implications for Research and Practice
In light of these limitations, new objective assessment tools for PAD in primary care have been evaluated. The use of photoplethysmography in determining pulsatile changes in the microcirculation of the skin at the toes is long standing. 27 More sophisticated applications of this vascular optics technology can be used to identify changes in waveforms between healthy and arterially diseased legs. 28 Further work performed as part of this study aims to assess its potential for the GP in providing a more sensitive and specific tool in assessing PAD, and without adding to an already time pressured consultation. Definition: A diagnosis of PAD will be made if there is any of (a) At least one stenosis of >50% (b) An occlusion (c) General narrowing of such a degree that the flow is impeded and the waveform is damped in popliteal or distal segment.

Declaration of Conflicting Interests
The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Between 2014 and 2018 Dr John Allen was the Chief Investigator on an NIHR i4i funded grant (II-C1-0412-20003) to develop a miniaturized fast and accessible version of the MPPG vascular assessment technology-specifically for peripheral arterial disease (PAD) detection in a primary care setting. He is a coauthor on published patents in relation to the GP device. There are no other potential conflicts of interest to report.

Funding
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This report is independent research funded by the National Institute for Health Research (Invention for Innovation, "Innovative photoplethysmography technology for rapid non-invasive assessment of peripheral arterial disease in primary care," II-C1-0412-20003) (ISRCTN13301188). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research, or the Department of Health and Social Care.

Ethical Approval and NIHR
Ethical approval was sought and granted from the Health Research Authority (HRA) (January 14, 2015, reference number 14/ NE/1238) via the Integrated Research Application System (IRAS reference number 164338). All patients who had ABPI measurements as part of this trial had additional photoplethysmography measurements recorded as part of a broader NIHR-funded trial reference number: ISRCTN13301188.