2025/08/01 by Michael B. Strong, Alik Farber, David G. Armstrong +26 · 1 voice
Medicine · #Cerebrovascular and Carotid Artery Diseases #Peripheral Artery Disease Management #Stroke Rehabilitation and Recovery
paper · pdf · doi:10.1093/bjs/znaf150
openalex publication_date 2025/08/01 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/30
There comes a point where we need to stop just pulling people out of the river. We need to go upstream and find out why they’re falling in. Peripheral artery disease (PAD) and its most severe manifestation, chronic limb-threatening ischaemia (CLTI), are serious yet under-recognized conditions associated with functional limitation and increased risks of major adverse limb events (MALE), major adverse cardiovascular events, and mortality1. The likelihood of these adverse outcomes is heightened by risk factors, including age, diabetes mellitus, chronic kidney disease, and tobacco use2. Additional influences include healthcare delivery systems, socio-economic status, and the stage of disease at diagnosis. Access to specialized vascular care significantly affects outcomes but frequently correlates with disparities in income levels and facility quality3. While CLTI disproportionately affects vulnerable populations, cultural biases regarding treatment efficacy and avoidance of medical care often result in delayed presentation, which negatively affects outcomes3. Patients with CLTI experience severe impairments in quality of life (QoL)4 and patient-related outcomes are on par with those associated with advanced cancer, heart failure, or chronic obstructive pulmonary disease4,5. CLTI patients suffer chronic pain, loss of autonomy, and increased reliance on caregivers for daily support6. While current estimates indicate that approximately 230 million adults worldwide suffer from PAD—resulting in annual healthcare costs ranging between €185 billion and €325 billion—the ongoing issue of under-recognition suggests that the burden on healthcare systems is far greater7. Medication therapy and lifestyle changes to mitigate cardiovascular and limb-related risks, limb-based interventions, and revascularization remain the mainstays of treatment of PAD and CLTI8. Emerging research into genetic markers for PAD offers promising potential for more intensive and preventive medical management, shifting the clinical approach from reactive treatment to early, proactive, and tailored interventions. Notwithstanding the global growth of PAD and CLTI and development of novel therapeutic approaches, the evidence base defining optimal clinical management of these conditions still lags behind fields such as cardiac disease and cancer. Recent publication of the BEST-CLI9 and BASIL-210 trials has reinvigorated global interest in advancing patient care for CLTI. Recognizing the urgent need for further research and innovation, the Novo Nordisk Foundation (NNF) (Copenhagen, Denmark) funded further analyses of the BEST-CLI data set to enhance the CLTI evidence base. Additionally, NNF supported the establishment of the International BEST-CLI Collaborative, bringing together global CLTI experts to assess the current landscape of management and propose impactful solutions to address the substantial challenges faced by patients and healthcare providers alike. The first meeting of the International BEST-CLI Collaborative was convened in May 2023 in Copenhagen, Denmark. The 31 vascular experts in attendance represented a diverse set of specialties, geographies, health systems, patient populations, and relevant areas of expertise. The focus of this initial meeting was to interpret BEST-CLI and BASIL-2 trial results, to identify regional gaps and disparities in CLTI care, and to establish plans for global dissemination of evidence-based medicine, best practices, and practical implementation tailored to fit diverse countries and regions. The Copenhagen conference culminated in the creation of a ‘white paper’ that summarized the current international landscape of CLTI care. This document critically assessed the relevance and limitations of BEST-CLI and BASIL-2 trial findings for varied global communities, highlighted unresolved research questions, and proposed directions for future research aimed at expanding the CLTI evidence base11. As a next step, the Collaborative decided to map the CLTI ‘patient journey’, to determine what action could be taken to reduce mortality and morbidity for this patient population. In May 2024, the Collaborative convened in Skodsborg, Denmark, with the intention of describing the ‘complete journey’ for an individual patient with CLTI, to identify gaps in care and establish treatment algorithms aligned with available resources. The evaluation process encompassed six distinct, roughly sequential domains that influence the CLTI patient journey: awareness, access, detection, diagnosis, prevention, and treatment (surgical, endovascular, medical, and limb-based). Within each domain, experts considered critical factors, including the status of current initiatives, applicable guidelines, relevant metrics, limitations and gaps, demographic variables, and resource availability across differing geographies. The influence of cost and value of current treatments was also considered. In the course of doing this detailed work, a broader realization emerged from this meeting that the Collaborative could, and should, orient itself to systematically reduce the mortality and morbidity of CLTI, as has been done over the course of some 75 years with coronary artery disease (CAD) (Fig. 1)12. The reduction in death from CAD is a remarkable achievement that required billions of Euros and lifetimes of research, implementation, training, awareness building, improved diagnostics, therapies, medicines, technologies, and treatment innovations. Patients dying from PAD and CLTI are near cousins to CAD patients; in fact, there is a great deal of overlap as myocardial infarction remains the leading killer of PAD patients. The Collaborative realized that to bend the curve for PAD, it is necessary to do more than simply ‘import’ relevant insights from the better-funded, more-established, higher-functioning CAD research establishment. Scores of randomized clinical trials have been completed for cardiometabolic disease, but very few for CLTI (primarily the BEST-CLI and BASIL trials). New science and implementation of best practices based on scientific evidence are crucial steps that need to be followed by the medical community to improve the care of patients with CLTI and PAD in general. This article presents the outcomes of the second meeting of the Collaborative, including recommendations for each phase of the patient journey. In the pages that follow, we highlight areas for scientific research, define relevant metrics, and identify achievable, high-impact interventions (or ‘low-hanging fruit’) that can significantly enhance CLTI care globally. Decline in deaths from cardiovascular disease in relation to scientific advances The timeline shows the steady decline in cardiovascular deaths over the late 20th and early 21st centuries, along with major advances in cardiovascular science and medicine. CABG, Coronary Artery Bypass Graft; NHBPEP, National High Blood Pressure Education Programme; HMG CoA, 1-hydroxy-3-methylglutaryl coenzyme A; NCEP, National Cholesterol Education Programme; PCI, percutaneous coronary intervention; MI, myocardial infarction. N Engl J Med 2012;366:54–63. Despite the growing burden of PAD, public awareness remains alarmingly low. A US-based cross-sectional survey found that only 26% of lay participants were familiar with PAD and just half could identify common risk factors; only 14% understood that PAD may lead to limb amputation. Awareness deficits were particularly pronounced among non-white populations and older adults, groups known to be at heightened risk of PAD13. In Europe, a similar survey reported that 57% of respondents were ‘not at all’ familiar with PAD and 55% were not ‘aware of limb consequences of PAD’14. Supporting evidence from studies in Asia, Africa, and Latin America further highlights the widespread global deficits in public awareness, emphasizing the critical need for targeted education and awareness campaigns15–18. The consequences of limited awareness are significant. Data from the American Heart Association (AHA) indicate that delayed diagnosis and management contribute to higher rates of limb amputation and mortality. Individuals diagnosed with PAD have a 20% 5-year mortality rate, a figure comparable to that of certain cancers, including breast cancer19. The prognosis worsens considerably for patients with CLTI; untreated CLTI carries a major amputation rate exceeding 25% within 1 year, and a mortality rate approaching 25% within one year19,20. Delayed disease discovery, even when coupled with medical care, is associated with a marked increase in death and amputation. For example, the 2-year mortality in the BEST-CLI trial was 20%9 while it approached 25% in the BASIL-2 trial10. These stark statistics illustrate the urgent need to enhance awareness, both for the public and amongst healthcare professionals. Public health initiatives targeting diseases such as breast cancer and human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) have shown that strategic rebranding, combined with consistent public engagement, can significantly enhance awareness and improve health outcomes21. A similar rebranding strategy for PAD and CLTI could elevate their among both the public and healthcare This strategy public to include healthcare with such as those in care, vascular vascular medicine, disease, medicine, and medicine. 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There is to be done to and this understood disease As a next step, the Collaborative to and a to and science on CLTI and PAD, and to the awareness, to detection, diagnosis, and of CLTI. There is a growing awareness of the need for in treatments of PAD patients that this an for a global approach to this disease The BEST-CLI trial was supported by the National and Blood of the National of and The also to the BEST-CLI trial the for New for Association of for for of and and for and and and As of 1 ongoing BEST-CLI research is funded by from the Novo Nordisk Data and Data Novo Nordisk and and and studies supported by National of National of and and and studies supported by National Foundation to in and Novo of a research with the of that or has research between and and and and and Novo Education and of for of The and The for of of and and from the and and and and for healthcare for Novo and and and and and National and Blood and and and and and and income as a or of a scientific for the and and or in the Access (or research from the Novo Nordisk and and as a of the of of the National and and and The of The BEST-CLI data set was available by the National of Heart and Blood to of the research public in