Peripheral arterial disease (PAD) is defined as an atherosclerotic process that leads to stenosis and occlusion in non-cerebral and non-coronary arteries [1]. More than 200 million patients worldwide have PAD and the incidence of PAD has increased to nearly 20% in people over 70 [2, 3]. Following coronary heart disease and stroke, PAD has become the third cause of atherosclerotic vascular morbidity [2]. Further prevalence data demonstrates that the number of asymptomatic PAD patients is several times larger than that of the PAD patients with intermittent claudication [1, 4]. Though no obvious clinical symptoms, asymptomatic PAD patients still have a similar risk of premature mortality to that of symptomatic PAD patients, and it is much higher than that of those without PAD [5]. Early detection and treatment of asymptomatic PAD not only prevent its progression, but also lower the risk of developing cardiovascular events, such as myocardial infarction and stroke.

However, sufficient attention has not been paid to asymptomatic PAD, though several studies have been conducted to assess the value of screening for PAD patients [6, 7]. But there was no randomized controlled trials (RCTs) that evaluate the benefits of screening for asymptomatic PAD only, which might lead to different judgement and conflicting recommendations on screening for asymptomatic PAD. The lack of convincing evidence also affects clinical decisions on the treatment for asymptomatic PAD. Thus, the recommendations on screening and treatment for asymptomatic PAD might be impacted by conflicts of interest since transparency among guideline writers was rather low [8, 9]. According to a research in opioid for chronic pain, the organizations funded by opioid manufacturers appeared to oppose to draft guidelines on prescribing opioids, which is worthy of note [10].

In this study, we aimed to systematically appraise the guidelines on the screening and treatment for asymptomatic PAD and find out the agreements and the differences in the recommendations.

The systematic review was performed according to the Cochrane methodology [11]. Clinical practice guidelines were defined as statements that contained recommendations with an objective to optimize patient care [12]. There were four steps in the process of the systematic review, including searching for guidelines, selecting guidelines according to specific criteria, appraising the quality of guidelines, and synthesizing recommendations.

As far as we know, this is the first guideline appraisal on asymptomatic PAD. In summary, 14 guidelines were identified which covered the management of asymptomatic PAD. Seven guidelines lacked a systematic literature review and nine reported too little information about COI, resulting in low AGREE scores for rigor of development and editorial independence. Ten guidelines contained recommendations about screening with five guidelines at strong strength, three at moderate to strong strength, while others being against it or finding insufficient evidence. ABI test was generally recommended, sometimes with other non-invasive examinations. Its target group is the middle-aged population with increasing cardiovascular risk and elderly. Smoking cessation, hypertension treatment and diabetes therapy were also generally recommended while arterial reconstruction was not indicated. Lipid lowering and antiplatelet therapy were recommended by some guidelines but with controversy in target value.

PAD is a condition with significant morbidity `and mortality, affecting nearly 200 million people worldwide [1]. Notably, nearly 90% of these individuals are asymptomatic [30]. However, insufficient attention has been paid to these populations. Among the 14 included guidelines, only SVS guideline [26] specially focused on the asymptomatic individuals. Conflicting recommendations were observed both on screening and treatment. For screening for asymptomatic patients, several guidelines supported it at different strength while two were against the screening or considered evidence being insufficient to recommend. AHA/ACC guideline [18] used invasive and non-invasive angiography as screening methods and is the only included guideline which put screening in the “harm” category. It is worth noting that AHA/ACC guidelines met the threshold for an AGREE II score of “recommended for use in clinical practice”, making its recommendations appear to be reliable. The recommendation of screening was mainly on the basis of two studies [31, 32]. Catalano M et al. [31] conducted a randomized, placebo-controlled, double-blind clinical trial to assess the medical efficacy of aspirin and a high dose antioxidant vitamin combination in PAD patients to reduce the risk of vascular event. However, not all the patients were asymptomatic PAD and 76% of them were with type 2 diabetes. Minar et al. [32] performed a randomized trial to investigate the effect of different dosage of aspirin in PAD population, rather than the asymptomatic patients. Till now, there was no randomized controlled trial (RCT) directly analyze the effect of screening for PAD in terms of some important outcomes, such as mortality, which is most important for guideline developers to provide recommendations. Since no RCT was avaiable, meta-analyses have been the main source of evidences, but it is not able to reclassify the asymptomatic participants from intermediate to high cardiovascular risk. Fares et al. [30] conducted a meta-analysis in 19 studies and observed large inconsistency in results, which demonstrated the heterogeneity in the risk of the populations and a range of cardiovascular risk among asymptomatic patients. The absence of evidence of high quality and the lager heterogeneity in the selected population might account for the conflicting recommendations in screening.

In terms of treatment, the conflicting recommendations were mainly observed in the target value of lipid lowering and antiplatelet therapy. As it is shown in Table 3, the recommendations from BWG, CEVF and ESC appeared a more aggressive treatment policy, which might be explained by the financial relationship between developers and pharmaceutical industry. In 2011, Institute of Medicine published the standard on conflict of interest, requiring that there should be no COI on committee chairs and less than 50% of committee members having commercial relationship [33]. According to the standard, only two guidelines (ACCF/AHA, AHA/ACC) met the requirement, indicating that the transparency among guideline writers and industry became a problem. When there is no clear-cut evidence at high quality, the decision may be easily affected by the commercial relationship. The aggressive policy to lower the target value increased the dosage of stain or antiplatelet drug, which might be related to the interest of the industry. Concerning the incomplete information in the included guidelines about potential COI, a transparent development process should be highlighted to ensure that the clinical guidelines establishing appropriate care for asymptomatic PAD patients. Apart from the pharmaceutical treatment and arterial reconstruction, smoking cessation was recommended by five guidelines [16, 19‐21, 26]. Smoking has been demonstrated as an important risk factor of PAD [1]. The recommendation of smoking cessation was at level of evidence B in three guidelines [16, 20, 21] and at level of evidence A [26] in one guideline. Healthy diet and physical activity were only recommended by ESC guideline [21] while they were not mentioned by others. The recommendation was at the level of evidence C but supporting evidence was not provided. In a word, RCTs in asymptomatic PAD patients should be performed to directly investigate the effect of lifestyle modification.

To make up for the lack of clear-cut evidence as described above and decrease the impact of financial relationship with pharmaceutical industry, RCTs of PAD screening versus no screening should be performed in asymptomatic PAD patients. After detection of PAD, interventions are advocated by some included guidelines, which mainly recommend lifestyle intervention, lipid lowing and antiplatelet therapy. However, whether these interventions would be effective in the asymptomatic PAD population is still difficult to answer. The dosage of antiplatelet therapy and target value are also controversy in different guidelines. Without the clear-cut evidence for treatment, the recommendation for medication is more sensitive to conflicts of interest with pharmaceutical industry and biased toward a more aggressive treatment policy. Thus, RCTs for treatment should also be performed to investigate intervention versus no intervention in asymptomatic population. Once the beneficial effect is confirmed, further prospective studies should be carried out to investigate the suitable dosage or target value.

There were several limitations in our study. Firstly, all the selected guidelines were only in English, resulting in the potential selecting bias. Fortunately, even though their official language was not English, some organizations appeared to publish the guidelines in English version. Secondly, we selected AGREE II as the assessment tool, rather than other appraisal tools, such as the four-item Global Rating Scale (GRS) [34]. Although AGREE II instrument has been recognized and widely used in the guideline appraisal [14, 35, 36], whether results using other appraisal tools are consistent remains unkown. Thirdly, the appraisal using the AGREE instrument was only based on the whole guidelines, rather than specific or individual recommendations. This might weaken the aim of the guideline appraisal which is to provide a whole picture for assessing the quality of reporting recommendations and suggestion on how to improve in the future. Finally, we did not restricted the regions of the included guidelines. Hence, the results may be not that generalizable to readers from the specific region, such as countries with greater or lesser burden of diseases.

Current guidelines about asymptomatic PAD varied in the methodological quality and fell short of the standard in the rigor of development and editorial independence. The conflicting recommendations were both on the screening and treatment. Increasing effort is needed to provide the clear-cut evidence with high quality and transparency among guideline developers and industry.