First update of the International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes – Chapter 1: update on national regulatory frameworks pertinent to clinical islet xenotransplantation

Islet xenotransplantation represents an attractive solution to overcome the shortage of human islets for use in type 1 diabetes. The wide‐scale application of clinical islet xenotransplantation, however, requires that such a procedure takes place in a specifically and tightly regulated environment. With a view to promoting the safe application of clinical islet xenotransplantation, a few years ago the International Xenotransplantation Association (IXA) published a Consensus Statement that outlined the key ethical and regulatory requirements to be satisfied before the initiation of xenotransplantation studies in diabetic patients. This earlier IXA Statement also documented a disparate regulatory landscape among different geographical areas. This situation clearly fell short of the 2004 World Health Assembly Resolution WHA57.18 that urged Member States “to cooperate in the formulation of recommendations and guidelines to harmonize global practices” to ensure the highest ethical and regulatory standards on a global scale. In this new IXA report, IXA members who are active in xenotransplantation research in their respective geographic areas herewith briefly describe changes in the regulatory frameworks that have taken place in the intervening period in the various geographic areas or countries. The key reassuring take‐home message of the present report is that many countries have embraced the encouragement of the WHO to harmonize the procedures in a more global scale. Indeed, important regulatory changes have taken place or are in progress in several geographic areas that include Europe, Korea, Japan, and China. Such significant regulatory changes encompass the most diverse facets of the clinical application of xenotransplantation and comprise ethical aspects, source animals and product specifications, study supervision, sample archiving, patient follow‐up and even insurance coverage in some legislations. All these measures are expected to provide a better care and protection of recipients of xenotransplants but also a higher safety profile to xenotransplantation procedures with an ultimate net gain in terms of international public health.     

First update of the International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes – Chapter 3: Porcine islet product manufacturing and release testing criteria

In the 2009 IXA consensus, the requirements for the quality and control of manufacturing of porcine islet products were based on the U.S. regulatory framework where the porcine islet products fall within the definition of somatic cell therapy under the statutory authority of the U.S. Food and Drug Administration (FDA). In addition, porcine islet products require pre‐market approval as a biologic product under the Public Health Services Act and they meet the definition of a drug under the Federal Food, Drug, and Cosmetic Act (FD&C Act). Thus, they are subject to applicable provisions of the law and as such, control of manufacturing as well as reproducibility and consistency of porcine islet products, safety of porcine islet products, and characterization of porcine islet products must be met before proceeding to clinical trials. In terms of control of manufacturing as well as reproducibility and consistency of porcine islet products, the manufacturing facility must be in compliance with current Good Manufacturing Practices (cGMP) guidelines appropriate for the initiation of Phase 1/2 clinical trials. Sponsors intending to conduct a Phase 1/2 trial of islet xenotransplantation products must be able to demonstrate the safety of the product through the establishment of particular quality assurance and quality control procedures. All materials (including animal source and pancreas) used in the manufacturing process of the porcine islet products must be free of adventitious agents. The final porcine islet product must undergo tests for the presence of these adventitious agents including sterility, mycoplasma (if they are cultured), and endotoxin. Assessments of the final product must include the safety specifications mentioned above even if the results are not available until after release as these data would be useful for patient diagnosis and treatment if necessary. In addition, a plan of action must be in place for patient notification and treatment in case the sterility culture results are positive. In terms of the characterization of porcine islet products and product release criteria, the information on the porcine islet products should be acquired from a sample of the final product to be used for transplantation and must include the morphology of the islets, specific identity, purity, viability, and potency of the product. In addition, information on the quantity of the islet products should also be provided in a standardized fashion and this should be in terms of islet equivalents and/or cell numbers. The current consensus was created to provide guidelines that manufacturing facilities may find helpful in the manufacture of and the release criteria for porcine islet products including encapsulated islets and combined islet products. Our intent with the above recommendations is to provide a framework for individual porcine islet manufacturing facilities to ensure a high level of safety for the initiation of Phase 1/2 clinical trials on porcine islet xenotransplantation.     

First update of the International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes—Executive summary

The International Xenotransplantation Association has updated its original “Consensus Statement on Conditions for Undertaking Clinical Trials of Porcine Islet Products in Type 1 Diabetes,” which was published in Xenotransplantation in 2009. This update is timely and important in light of scientific progress and changes in the regulatory framework pertinent to islet xenotransplantation. Except for the chapter on “informed consent,” which has remained relevant in its 2009 version, all other chapters included in the initial consensus statement have been revised for inclusion in this update. These chapters will not provide complete revisions of the original chapters; rather, they restate the key points made in 2009, emphasize new and under‐appreciated topics not fully addressed in 2009, suggest relevant revisions, and communicate opinions that complement the consensus opinion. Chapter 1 provides an update on national regulatory frameworks addressing xenotransplantation. Chapter 2 a, previously Chapter 2, suggests several important revisions regarding the generation of suitable source pigs from the perspective of the prevention of xenozoonoses. The newly added Chapter 2b discusses conditions for the use of genetically modified source pigs in clinical islet xenotransplantation. Chapter 3 reviews porcine islet product manufacturing and release testing. Chapter 4 revisits the critically important topic of preclinical efficacy and safety data required to justify a clinical trial. The main achievements in the field of transmission of all porcine microorganisms, the rationale for more proportionate recipient monitoring, and response plans are reviewed in Chapter 5. Patient selection criteria and circumstances where trials of islet xenotransplantation would be both medically and ethically justified are examined in Chapter 6 in the context of recent advances in available and emerging alternative therapies for serious and potentially life‐threatening complications of diabetes. It is hoped that this first update of the International Xenotransplantation Association porcine islet transplant consensus statement will assist the islet xenotransplant scientific community, sponsors, regulators, and other stakeholders actively involved in the clinical translation of islet xenotransplantation.     

First update of the International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes—Chapter 2a: source pigs—preventing xenozoonoses

Chapter 2 of the original consensus statement published in 2009 by IXA represents an excellent basis for the production of safe donor pigs and pig‐derived materials for porcine islet xenotransplantation. It was intended that the consensus statement was to be reviewed at interval to remain relevant. Indeed, many of the original salient points remain relevant today, especially when porcine islet xenotransplantation is performed in conjunction with immunosuppressants. However, progress in the field including demonstrated safe clinical porcine xenograft studies, increased understanding of risks including those posed by PERV, and advancement of diagnostic capabilities now allow for further consideration. Agents of known and unknown pathogenic significance continue to be identified and should be considered on a geographic, risk‐based, dynamic, and product‐specific basis, where appropriate using validated, advanced diagnostic techniques. PERV risk can be sufficiently reduced via multicomponent profiling including subtype expression levels in combination with infectivity assays. Barrier facilities built and operated against the AAALAC Ag Guide or suitable alternative criteria should be considered for source animal production as long as cGMPs and SOPs are followed. Bovine material‐free feed for source animals should be considered appropriate instead of mammalian free materials to sufficiently reduce TSE risks. Finally, the sponsor retention period for archival samples of donor materials was deemed sufficient until the death of the recipient if conclusively determined to be of unrelated and non‐infectious cause or for a reasonable period, that is, five to 10 yrs. In summary, the safe and economical production of suitable pigs and porcine islet xenograft materials, under appropriate guidance and regulatory control, is believed to be a viable means of addressing the unmet need for clinical islet replacement materials.     

Japanese Orthopaedic Association (JOA) clinical practice guidelines on the management of lateral epicondylitis of the humerus - Secondary publication

BackgroundThe guidelines presented herein provide recommendations for the management of patients with lateral epicondylitis of the humerus. These recommendations are endorsed by the Japanese Orthopaedic Association (JOA) and Japan Elbow Society.MethodsThe JOA lateral epicondylitis guideline committee revised the previous guidelines on the basis of the “Medical Information Network Distribution Service Handbook for Clinical Practice Guideline Development 2014”, which emphasized the importance of the balance between benefit and harm, and proposed a desirable method for preparing clinical guidelines in Japan. These guidelines consist of 11 clinical questions (CQs), 9 background questions (BQs), and 3 future research questions (FRQs). For each CQ, outcomes from the literature were collected and evaluated systematically according to the adopted study design.ResultsThe committee proposed recommendations for each CQ by determining the level of evidence and assessing the consensus rate. Physical therapy was the best recommendation with the best evidence. The BQs and FRQs were answered by collecting evidence based on the literature.ConclusionsThe guidelines presented herein were reviewed systematically, and recommendations were proposed for each CQ. These guidelines are expected to be widely used not only by surgeons or physicians but also by other healthcare providers, such as nurses, therapists, and athletic trainers.     

Department of Veterans Affairs Consensus: Preradiation dental treatment guidelines for patients with head and neck cancer

Few protocols have been published for the dental management of patients with head and neck cancer to prevent complications from head and neck radiation therapy. Radiation therapy not only affects the tumor cells targeted, but also the dentition, bone, salivary gland, and oral soft tissue structures. A comprehensive dental evaluation prior to head and neck radiation therapy can help prevent many complications. The following clinical guidelines were established by a workgroup of oral health providers within the Department of Veterans Affairs. This workgroup focused on developing a set of recommendations regarding dental care prior to the initiation of head and neck radiation therapy based on the best clinical evidence and expert consensus. A systematic algorithm was developed for the evaluation including pre‐exam data gathering, examination, education, and treatment, followed by maintenance and postradiation dental follow‐up. This document is evidence‐based, patient‐centered, consistent with accepted practices of care and safety, and in accordance with applicable statutes and regulations.     

Pivot‐shift test: Analysis and quantification of knee laxity parameters using a navigation system

Lachman, drawer, and pivot‐shift (PS) tests are important in the assessment of ACL reconstruction. The goal of this work was to analyze the reliability of the PS test using a navigation system, identifying a set of new quantitative parameters and evaluating their clinical relevance. Eighteen patients that underwent anatomic double‐bundle ACL reconstruction were included. The new dynamic parameters were: anteroposterior translation of the medial and lateral compartments and the joint center and internal/external and varus/valgus rotations of the joint. For each parameter we measured the peaks and the areas obtained during the test. Intratester repeatability, comparisons of pre‐ and postoperative laxities, and correlations between the PS peaks and the corresponding peaks obtained with standard static tests were evaluated. Areas, peaks, and static laxity outcomes were compared, grouping patients according to the preoperative International Knee Documentation Committee (IKDC) score. The PS test was reliable in identifying the surgical reconstruction. Correlation analysis showed good coefficients both for pre‐ and postoperative values. Patients with IKDC grade “D” had larger areas during the PS compared to patients with grade “C”. Our analysis is helpful for characterizing patient‐specific laxity and surgical performance, thus highlighting the clinical relevance of the PS test. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:164–169, 2010     

Induction therapy in adult intestinal transplantation: reduced incidence of rejection with “2‐dose” alemtuzumab protocol

The incidence of early rejection after intestinal transplantation correlates with heightened risk of graft loss and mortality. Many different induction or pre‐conditioning protocols have been reported in the last 10 yr to improve outcomes; however, sepsis remains prevalent and diminishes long‐term results. We recently began a “2‐dose” alemtuzumab trial protocol – 15 mg at day 0 and 15 mg repeated on day 7 – with the hope of reducing our infection rate. We compared three different protocols used at our institution (daclizumab, conventional “4‐dose” alemtuzumab, and “2‐dose” alemtuzumab). There was a significantly lower rate of early rejection with the “2‐dose” alemtuzumab protocol in our study group of mainly (88%) intestinal grafts without accompanying liver engraftment with its protective immunologic effect. Sepsis remained low. Longer follow‐up will be required to evaluate the effects of this new protocol on longer‐term outcomes.     

Pre‐operative fasting: a nationwide survey of German anaesthesia departments

Background: Shorter pre‐operative fasting improves clinical outcome without an increased risk. Since October 2004, German Anaesthesiology Societies have officially recommended a fast of 2 h for clear fluids and 6 h for solid food before elective surgery. We conducted a nationwide survey to evaluate the current clinical practice in Germany. Methods: Between July 2006 and January 2007, standardized questionnaires were mailed to 3751 Anaesthesiology Society members in leading positions requesting anonymous response. Results: The overall response rate was 66% (n=2418). Of those, 2148 (92%) claimed familiarity with the new guidelines. About a third (n=806, 34%) reported full adherence to the new recommendations, whereas 1043 (45%) reported an eased fasting practice. Traditional Nil per os after midnight was still recommended by 157 (7%). Commonest reasons reported for adopting the new guidelines were: ‘improved pre‐operative comfort’ (84%), and ‘increased patient satisfaction’ (83%); reasons against were: ‘low flexibility in operation room management’ (19%), and ‘increased risk of aspiration’ (13%). Conclusion: Despite the apparent understanding of the benefits from reduced pre‐operative fasting, full implementation of the guidelines remains poor in German anaesthesiology departments.     

First update of the International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes—Chapter 5: recipient monitoring and response plan for preventing disease transmission

Xenotransplantation of porcine cells, tissues, and organs may be associated with the transmission of porcine microorganisms to the human recipient. A previous, 2009, version of this consensus statement focused on strategies to prevent transmission of porcine endogenous retroviruses (PERVs). This version addresses potential transmission of all porcine microorganisms including monitoring of the recipient and provides suggested approaches to the monitoring and prevention of disease transmission. Prior analyses assumed that most microorganisms other than the endogenous retroviruses could be eliminated from donor animals under appropriate conditions which have been called “designated pathogen‐free” (DPF) source animal production. PERVs integrated as proviruses in the genome of all pigs cannot be eliminated in that manner and represent a unique risk. Certain microorganisms are by nature difficult to eliminate even under DPF conditions; any such clinically relevant microorganisms should be included in pig screening programs. With the use of porcine islets in clinical trials, special consideration has to be given to the presence of microorganisms in the isolated islet tissue to be used and also to the potential use of encapsulation. It is proposed that microorganisms absent in the donor animals by sensitive microbiological examination do not need to be monitored in the transplant recipient; this will reduce costs and screening requirements. Valid detection assays for donor and manufacturing‐derived microorganisms must be established. Special consideration is needed to preempt potential unknown pathogens which may pose a risk to the recipient. This statement summarizes the main achievements in the field since 2009 and focus on issues and solutions with microorganisms other than PERV.     

Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: clinical trial design

The International Campaign for Cures of Spinal Cord Injury Paralysis established a panel tasked with reviewing the methodology for clinical trials for spinal cord injury (SCI), and making recommendations on the conduct of future trials. This is the fourth of four papers. Here, we examine the phases of a clinical trial program, the elements, types, and protocols for valid clinical trial design. The most rigorous and valid SCI clinical trial would be a prospective double-blind randomized control trial utilizing appropriate placebo control subjects. However, in specific situations, it is recognized that other trial procedures may have to be considered. We review the strengths and limitations of the various types of clinical trials with specific reference to SCI. It is imperative that the design and conduct of SCI clinical trials should meet appropriate standards of scientific inquiry to insure that meaningful conclusions about efficacy and safety can be achieved and that the interests of trial subjects are protected. We propose these clinical trials guidelines for use by the SCI clinical research community.     

A canine hybrid double‐bundle model for study of arthroscopic ACL reconstruction

Development and validation of a large animal model for pre‐clinical studies of intra‐articular anterior cruciate ligament (ACL) reconstruction that addresses current limitations is highly desirable. The objective of the present study was to investigate a translational canine model for ACL reconstruction. With institutional approval, adult research hounds underwent arthroscopic debridement of the anteromedial bundle (AMB) of the ACL, and then either received a tendon autograft for “hybrid double‐bundle” ACL reconstruction (n = 12) or no graft to remain ACL/AMB‐deficient (n = 6). Contralateral knees were used as non‐operated controls (n = 18) and matched canine cadaveric knees were used as biomechanical controls (n = 6). Dogs were assessed using functional, diagnostic imaging, gross, biomechanical, and histologic outcome measures required for pre‐clinical animal models. The data suggest that this canine model was able to overcome the major limitations of large animal models used for translational research in ACL reconstruction and closely follow clinical aspects of human ACL reconstruction. The “hybrid double‐bundle” ACL reconstruction allowed for sustained knee function without the development of osteoarthritis and for significantly improved functional, diagnostic imaging, gross, biomechanical, and histologic outcomes in grafted knees compared to ACL/AMB‐deficient knees. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1171–1179, 2015.     

The International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of xenocorneal transplantation

To develop an international consensus regarding the appropriate conditions for undertaking clinical trials in xenocorneal transplantation, here we review specific ethical, logistical, scientific, and regulatory issues regarding xenocorneal transplantation, and propose guidelines for conduct of clinical xenocorneal transplantation trials. These proposed guidelines are modeled on the published consensus statement of the International Xenotransplantation Association regarding recommended guidelines for conduct of clinical islet xenotransplantation. It is expected that this initial consensus statement will be revised over time in response to scientific advances in the field, and changes in the regulatory framework based on accumulating clinical experience.     

Regulatory considerations of delayed autologous islet infusion in a 4‐year‐old child undergoing total pancreatectomy for chronic pancreatitis

In patients undergoing total pancreatectomy for chronic pancreatitis, isolation, and infusion of autologous islets must comply with Good Manufacturing Practices standards established by the Food and Drug Administration (FDA) but does not standardly require an Investigational New Drug (IND) status. We report a case of a 4‐year‐old child with severe hereditary pancreatitis who developed clinical sepsis during total pancreatectomy (TP) surgery; subsequent pancreas, islet, and blood cultures were positive for Enterococcus. Because of clinical deterioration, planned islet infusion was aborted and islets were kept viable in a culture period while the patient was stabilized. Two days later, 38 000 islet equivalents (IEQ, 2808 IEQ/kg) were infused in a second procedure. Because maintaining the islets in culture met the FDA standard for “more than minimal” tissue manipulation, an emergency IND was obtained from the FDA to permit delayed infusion. The patient tolerated islet infusion well, and subsequently has partial islet graft function with normal glucoses and minimal insulin needs. This case highlights the possibility to delay islet infusion in an emergency, the potential for success with few islets in a young child, and the need to consider regulatory complexities of islet transplant in this situation.     

Executive summary

Abstract:  The International Xenotransplantation Association islet xenotransplantation consensus statement describes the conditions for undertaking clinical trials of porcine islet products in type 1 diabetes. Chapter 1 reviews the key ethical requirements and progress toward the definition of an international regulatory framework for clinical trials of xenotransplantation. Chapters 2 to 7 provide in depth and agreed-upon recommendations on source pigs, pig islet product manufacturing and release testing, preclinical efficacy and complication data required to justify a clinical trial, strategies to prevent transmission of porcine endogenous retrovirus, patient selection for clinical trials, and informed consent. It is planned to update this initial consensus statement in a year's time in light of progress in research, changes in the regulatory framework, and comments submitted after publication.     

Guidelines for Perioperative Care for Pancreaticoduodenectomy: Enhanced Recovery After Surgery (ERAS®) Society Recommendations

Background

Protocols for enhanced recovery provide comprehensive and evidence-based guidelines for best perioperative care. Protocol implementation may reduce complication rates and enhance functional recovery and, as a result of this, also reduce length-of-stay in hospital. There is no comprehensive framework available for pancreaticoduodenectomy.

Methods

An international working group constructed within the Enhanced Recovery After Surgery (ERAS^®) Society constructed a comprehensive and evidence-based framework for best perioperative care for pancreaticoduodenectomy patients. Data were retrieved from standard databases and personal archives. Evidence and recommendations were classified according to the GRADE system and reached through consensus in the group. The quality of evidence was rated “high”, “moderate”, “low” or “very low”. Recommendations were graded as “strong” or “weak”.

Results

Comprehensive guidelines are presented. Available evidence is summarised and recommendations given for 27 care items. The quality of evidence varies substantially and further research is needed for many issues to improve the strength of evidence and grade of recommendations.

Conclusions

The present evidence-based guidelines provide the necessary platform upon which to base a unified protocol for perioperative care for pancreaticoduodenectomy. A unified protocol allows for comparison between centres and across national borders. It facilitates multi-institutional prospective cohort registries and adequately powered randomised trials.     

Staying at the cutting edge: a review and analysis of evidence reporting and grading; the recommendations of the American Urological Association

The American Urological Association (AUA), as the premier urological organization in the USA, has been a pioneering force in the development of practice guidelines. Recently the AUA evaluated their guidelines development procedures and implemented several changes that resulted in more scientifically rigorous, transparent and efficient processes. These changes include narrowing the scope of the guideline, strengthening the systematic literature review, updating data‐analysis capabilities, altering panel members’ roles to exclude laborious data extraction, and identifying and specifying levels of evidence for guideline recommendations. In addition to a more scientifically sound guideline, the outcome of these modifications is a timely, less costly document involving fewer burdens on panel members.     

First update of the International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes—Chapter 2b: genetically modified source pigs

Genetic modification of the source pig offers the opportunity to improve the engraftment and survival of islet xenografts. The type of modification can be tailored to the transplant setting; for example, intraportal islet xenografts have been shown to benefit from the expression of anticoagulant and anti‐inflammatory transgenes, whereas cytoprotective transgenes are probably more relevant for encapsulated islets. The rapid development of pig genetic engineering, particularly with the introduction of genome editing techniques such as CRISPR‐Cas, has accelerated the generation of new pig lines with multiple modifications. With pre‐clinical testing in progress, it is an opportune time to consider any implications of genetic modification for the conditions for undertaking clinical trials. Obviously, the stringent requirements to fulfill designated pathogen‐free status that are applied to wild‐type pigs will apply equally to genetically modified (GM) source pigs. In addition, it is important from a safety perspective that the genetic modifications are characterized at the molecular level (e.g., integration site, absence of off‐target mutations), the phenotypic level (e.g., durability and stability of transgene expression), and the functional level (e.g., protection of islets in vitro or in vivo, absence of detrimental effects on insulin secretion). The assessment of clinical trial protocols using GM pig islets will need to be performed on a case‐by‐case basis, taking into account a range of factors including the particular genetic modification(s) and the site and method of delivery.     

Japanese Orthopaedic Association (JOA) clinical practice guidelines on the management of soft tissue tumors 2020 - Secondary publication

BackgroundThese clinical practice guidelines are intended to provide recommendations based on the best evidence obtained to date on key issues in clinical practice to improve the prognosis, diagnostic and therapeutic processes for patients with soft tissue tumors.MethodsThe Guidelines Development Committee and Systematic Review Committee were composed of a multidisciplinary team of specialists who play an important role in soft tissue tumor care. Clinical questions (CQs) were determined by choosing key decision-making points based on Algorithms for the diagnosis and treatment of soft tissue tumors. The guidelines were developed according to the “Medical Information Network Distribution Service (Minds) Handbook for Clinical Practice Guideline Development 2014” and “Minds Manual for Clinical Practice Guideline Development 2017.” Recommendation strength was rated on two levels and the strength of evidence was rated on four levels. The recommendations were decided based on agreement by 70% or more voters.ResultsTwenty-two CQs were chosen by the Guidelines Development Committee. The Systematic Review Committee reviewed the evidence concerning each CQ, a clinical value judgment was added by experts, and the text of each recommendation was determined.ConclusionWe established 22 CQs and recommendations for key decision-making points in the diagnosis and treatment of soft tissue tumors according to the Minds Clinical Practice Guideline development methods. We hope that these guidelines will assist the decision-making of all medical staff engaged in the treatment and diagnosis of soft tissue tumors, and eventually lead to improved soft tissue tumor care in the country.     

ABPI reporting and compression recommendations in global clinical practice guidelines on venous leg ulcer management: A scoping review

Clinical practice guidelines (CPGs) for venous leg ulcer (VLU) management recommend below‐knee compression to improve healing outcomes after calculating the ankle‐brachial pressure index (ABPI) to rule out significant arterial disease. This systematic scoping review aimed to complete a qualitative and quantitative content analysis of international CPGs for VLU management to determine if consensus existed in relation to recommendations for compression application based on an ABPI reading and clinical assessment. Our review shows that there is a lack of consensus across 13 VLU CPGs and a lack of clear guidance in relation to the specific ABPI range of compression therapy that can be safely applied. An area of uncertainty and disagreement exists in relation to an ABPI between 0.6 and 0.8, with some guidelines advocating that compression is contraindicated and others that there should be reduced compression. This has implications in clinical practice, including when it is safe to apply compression. In addition, the inconsistency in the levels of evidence and the grades of recommendation makes it difficult to compare across various guidelines.