Observing the Role of Inflammation in Peripheral Artery Disease and Its Impact on Heart and Mobility Health: PANACEA-O.

Protocol Title Peripheral Arterial Disease and InflammatioN Study Assessing the Cardiovascular and Functional Effects - Observational Study: PANACEA-O

This registry aims to collect detailed information about people in Canada who have Peripheral Artery Disease (PAD) and are receiving care in heart clinics while still able to walk and live in the community. Researchers want to better understand what these patients are like at the start of their care and looking at their general health, levels of inflammation in their bodies, and how well they can move and function in daily life.

The results of this study will help healthcare providers better understand what PAD looks like in today's Canadian heart clinics. It will also help guide future research studies that focus on inflammation and PAD. The researchers believe that PAD patients can be routinely recruited from these clinics, and that most of these patients will have high levels of inflammation (shown by high blood CRP levels) and poor physical ability when they first join. The findings will show that there is a strong need to regularly check for PAD in heart clinics so that patients can be identified early and offered new treatments in the future and especially treatments that may help reduce inflammation.

Peripheral arterial disease is a common manifestation of atherosclerosis that can lead to significant morbidity and mortality. Inflammation plays a key role in the pathogenesis of PAD. Although the pathophysiology of intermittent claudication is attributed primarily to a flow-limiting stenosis or occlusion of a conduit artery that limits oxygen delivery during exercise, a large body of evidence indicates that, with exercise, limb ischemia evokes an acute systemic response characterized by increased oxidative stress, inflammation, and endothelial dysfunction and guidelines recommend smoking cessation and supervised exercise therapy to improve IC, but there are few pharmacologic options.

Cilastozol, a selective and potent phosphodiesterase (PDE) 3A inhibitor and naftidrofuryl, a selective inhibitor of the 5-hydroxytryptamine (serotonin) receptor type 2 (5-HT2), both provide modest benefits on maximum walk distance.(3) However, methodologic inconsistencies, lack of hard objective endpoints, and multiple sources of potential bias in the cited studies supporting their approval have resulted in limited availability and uptake of these agents. While the upcoming STRIDE trial will evaluate the role of semaglutide in improving functional capacity in patients with T2D and PAD, additional strategies need to be evaluated.

The prevalence of PAD in an ambulatory population of patients at risk for this condition is unknown. There currently exists no registry (local or regional) that routinely documents this condition. There are some contemporary registries that exist, but this is mainly among patients with PAD who have already received a revascularization procedure. Furthermore, the prevalence of PAD, inflammation, and functional status is unknown.

The specific aims of this registry are to (1) capture the detailed patient demographic and prevalence of inflammation (i.e., CRP) among PAD patients in an ambulatory population of patients followed in Canadian cardiovascular clinics and (2) determine baseline functional capacity in these PAD patients at baseline with a 6- minute walk distance. The results of this prospective registry can help inform both the landscape of PAD in contemporary Canadian cardiovascular clinics as well as to inform enrollment of future clinical trials in this space targeting inflammation and PAD (i.e., PANACEA). It is hypothesized that PAD patients can be routinely recruited in cardiovascular clinics in Canada, with the vast majority having elevated CRP and relatively poor functional capacity at baseline. The results of this registry will demonstrate the unmet need to routinely screen and identify PAD patients within cardiovascular for future therapies that may be particularly helpful in this population, including those potentially targeting inflammation

The results of this registry have the potential to significantly impact clinical practice guidelines for the management of PAD. By providing robust data on the prevalence of inflammation and its correlation with functional impairment in PAD patients, this registry will underscore the importance of routine screening for PAD in cardiovascular clinics. The identification of patients with elevated CRP and poor functional capacity at baseline will highlight the need for early and targeted interventions, potentially leading to the development of new therapeutic strategies aimed at reducing inflammation and improving outcomes in this high-risk population. Additionally, the registry data may inform the design and enrollment of future clinical trials, contributing to the advancement of evidence-based practices in the management of PAD.

Inclusion Criteria:

• Age >/= 19 years of age

• Ability to provide informed consent before any trial-related activities

• Symptomatic PAD with intermittent claudication corresponding to Fontaine stage IIa meeting all of the following:

  1. Stable symptoms of PAD with intermittent claudication in Fontaine stage IIa (able to walk without stopping more than 200 m/656 feet/2 blocks) for at least 90 days prior to the day of screening based on patient interview.
  2. Ankle-brachial-index (ABI) equal to or below 0.90 (the leg with lowest index is chosen in case of bilateral disease) or ≥ 50% stenosis in peripheral artery (excluding carotid) documented by X-ray angiography, MR angiography, CT angiography or Doppler ultrasound, or a history of lower extremity revascularization

Exclusion Criteria:

• Current or previous treatment with any immunomodulating agent within 90 days prior to the day of screening.
• Walking ability limited by conditions other than PAD
• Planned orthopaedic surgery in the legs, or other major surgery known on the day of screening (surgery affecting walking ability).
• Vascular revascularisation procedure for PAD of any kind 180 days prior to the day of screening.
• Planned arterial revascularisation known on the day of screening.
• Myocardial infarction, stroke, hospitalisation for unstable angina pectoris or transient ischemic attack within 180 days prior to the day of screening.
• Heart failure presently classified as being in New York Heart Association (NYHA) class III-IV.
• Signs/symptoms of critical limb ischemia (leg gangrene, rest pain, ischemic wounds, etc)