Protocol for the Stimulating β3-Adrenergic Receptors for Peripheral Artery Disease (STAR-PAD) trial: a double-blinded, randomised, placebo-controlled study evaluating the effects of mirabegron on functional performance in patients with peripheral arterial disease

IntroductionThere is currently only one approved medication effective at improving walking distance in people with intermittent claudication. Preclinical data suggest that the β3-adrenergic receptor agonist (mirabegron) could be repurposed to treat intermittent claudication associated with peripheral artery disease. The aim of the Stimulating β3-Adrenergic Receptors for Peripheral Artery Disease (STAR-PAD) trial is to test whether mirabegron improves walking distance in people with intermittent claudication.Methods and analysisThe STAR-PAD trial is a Phase II, multicentre, double-blind, randomised, placebo-controlled trial of mirabegron versus placebo on walking distance in patients with PAD. A total of 120 patients aged ≥40 years with stable PAD and intermittent claudication will be randomly assigned (1:1 ratio) to receive either mirabegron (50 mg orally once a day) or matched placebo, for 12 weeks. The primary endpoint is change in peak walking distance as assessed by a graded treadmill test. Secondary endpoints will include: (i) initial claudication distance; (ii) average daily step count and total step count and (iii) functional status and quality of life assessment. Mechanistic substudies will examine potential effects of mirabegron on vascular function, including brachial artery flow-mediate dilatation; MRI assessment of lower limb blood flow, tissue perfusion and arterial stiffness and numbers and angiogenesis potential of endothelial progenitor cells. Given that mirabegron is safe and clinically available for alternative purposes, a positive study is positioned to immediately impact patient care.Ethics and disseminationThe STAR-PAD trial is approved by the Northern Sydney Local Health District Human Research Ethics Committee (HREC/18/HAWKE/50). The study results will be published in peer-reviewed medical or scientific journals and presented at scientific meetings, regardless of the study outcomes.Trial registration numberACTRN12619000423112; Results.

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Differences in Physical Activity between Patients with Peripheral Artery Disease and Healthy Subjects

Journal of Aging Research ◽

10.1155/2020/5093528 ◽

2020 ◽

Vol 2020 ◽

pp. 1-6

Author(s):

Sumiko Shiba ◽

Akiko Shiba ◽

Atsutoshi Hatada

Keyword(s):

Physical Activity ◽

Intermittent Claudication ◽

Peripheral Artery Disease ◽

Activity Level ◽

Leg Pain ◽

Walking Distance ◽

Moderate Intensity ◽

Peripheral Artery ◽

The Subject ◽

Artery Disease

Objectives. Peripheral artery disease (PAD) is a significant prognostic marker of poor long-term survival due to limited physical activity associated with various functional problems, such as intermittent claudication. A physically active lifestyle has the potential to modify peripheral artery risk factors and promote general health. While low daily physical activity levels have been recognized in the population of PAD, the exact level has yet to be quantified due to lack of research. The aim of the present study was to compare physical activity level (PAL) and time spent at activities of different intensity levels between patients with PAD and healthy individuals. The study subjects were 10 patients with PAD and 10 age-matched healthy control subjects. We measured the time spent at light, moderate, or vigorous physical activity using triaxial accelerometer and calculated PAL. Intermittent claudication onset distance and maximum walking distance were defined as the distance walked at which the subject first reported leg pain and the distance at which the subject was unable to continue walking because of leg pain, respectively. Results. Our results showed (i) lower PAL in patients with PAD compared with the controls; (ii) while there was no significant difference in the high-intensity activity between the two groups, the light- and moderate-intensity activities of the PAD group were significantly lower than the controls, the time spent at moderate-intensity activity was approximately 50% less; and (iii) among patients with PAD, low PAL did not correlate directly with intermittent claudication. Conclusions. PAD patients limit the amount of their physical activity, especially light and moderate intensities. Our study highlights the importance of spending more time walking in daily life.

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Individual Differences in Response to Supervised Exercise Therapy for Peripheral Artery Disease

Western Journal of Nursing Research ◽

10.1177/0193945920977479 ◽

2020 ◽

pp. 019394592097747

Author(s):

Mary O. Whipple ◽

Erica N. Schorr ◽

Kristine M.C. Talley ◽

Julian Wolfson ◽

Ruth Lindquist ◽

...

Keyword(s):

Older Adults ◽

Peripheral Artery Disease ◽

Exercise Therapy ◽

Poor Response ◽

Walking Distance ◽

Peripheral Artery ◽

Meaningful Improvement ◽

Supervised Exercise ◽

Patient Reported ◽

Artery Disease

Nonresponse to exercise has been extensively examined in young athletes but is seldom reported in studies of aerobic exercise interventions in older adults. This study examined the prevalence of nonresponse and poor response to exercise in functional and quality of life outcomes and response patterns between and among older adults undergoing 12-weeks of supervised exercise therapy for the management of peripheral artery disease ( N = 44, mean age 72.3 years, 47.7% female). The prevalence of nonresponse (no change/decline in performance) in walking distance was 31.8%. The prevalence of poor response (lack of a clinically meaningful improvement) was 43.2%. Similar patterns of response were observed in both objective and patient-reported measures of physical function. All participants improved in at least one outcome; only two participants improved in all measured outcomes. Additional research should examine modifiable predictors of response to inform programming and maximize an individual’s potential benefit from exercise therapy.

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Abstract 11: Effects of Canakinumab in Patients With Peripheral Artery Disease

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.37.suppl_1.11 ◽

2017 ◽

Vol 37 (suppl_1) ◽

Author(s):

Kerry S Russell ◽

Denise Yates ◽

Andrea Feller ◽

Tianke Wang ◽

Ping Chen ◽

...

Keyword(s):

Peripheral Artery Disease ◽

Vascular Function ◽

Cardiovascular Events ◽

Ankle Brachial Index ◽

Unmet Need ◽

Walking Distance ◽

Plaque Progression ◽

Peripheral Artery ◽

Plaque Volume ◽

Artery Disease

Background: Peripheral artery disease (PAD) affects 8.5 million people in the US. PAD patients are at high risk for cardiovascular events, and their quality of life is often significantly impaired by decreased mobility. Interleukin-1β (IL-1β) may play an important role in this disease by promoting inflammatory responses that drive atherosclerotic plaque progression and impair vascular function. We sought to test whether interruption of IL-1β signaling would improve patient mobility and decrease plaque progression in the lower extremities. Methods: 38 patients (mean age 65; 71% male) with symptomatic PAD (confirmed by ankle-brachial index) were randomized 1:1 to receive Canakinumab (150 mg subcutaneously) or placebo monthly for up to 12 months. Plaque volume in the superficial femoral artery (SFA) was assessed serially using 3.0T MRI. Mobility was assessed serially using the 6-minute walk test (maximum and pain-free walking distance). Results: Canakinumab was safe and well-tolerated. 12 patients discontinued (8 placebo, 4 Canakinumab). MRI data (from 31 patients at 3 months; 21 patients at 12 months) showed no evidence of plaque progression in the SFA at either time point in placebo-treated patients; nor was there a change in plaque volume in the Canakinumab-treated group. There was a serial and significant improvement in placebo-adjusted maximum and pain-free walking distance observed as early as 3 months after treatment with Canakinumab (58-meter improvement over placebo in pain-free distance at 3 months, P=0.01). Two placebo-treated patients required peripheral vascular interventions due to progression of disease; however, no Canakinumab-treated patients required revascularization during the study. Canakinumab decreased markers of systemic inflammation (IL-6 and hsCRP). Conclusions: Treatment with Canakinumab may improve maximum and pain-free walk distance in patients with symptomatic PAD. In conjunction with results soon to be reported for the CANTOS trial of Canakinumab for secondary prevention of cardiovascular events, additional studies may provide support that inhibition of IL-1β signaling can improve symptoms and function in this patient population with high unmet need.

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Advances in Revascularization for Peripheral Artery Disease: Revascularization in PAD

Circulation Research ◽

10.1161/circresaha.121.318261 ◽

2021 ◽

Vol 128 (12) ◽

pp. 1885-1912

Author(s):

Joshua A. Beckman ◽

Peter A. Schneider ◽

Michael S. Conte

Keyword(s):

Intermittent Claudication ◽

Peripheral Artery Disease ◽

Clinical Presentation ◽

Rapid Development ◽

Microvascular Disease ◽

Limb Ischemia ◽

Medical Emergency ◽

Acute Limb Ischemia ◽

Peripheral Artery ◽

Artery Disease

Effective revascularization of the patient with peripheral artery disease is about more than the procedure. The approach to the patient with symptom-limiting intermittent claudication or limb-threatening ischemia begins with understanding the population at risk and variation in clinical presentation. The urgency of revascularization varies significantly by presentation; from patients with intermittent claudication who should undergo structured exercise rehabilitation before revascularization (if needed) to those with acute limb ischemia, a medical emergency, who require revascularization within hours. Recent years have seen the rapid development of new tools including wires, catheters, drug-eluting technology, specialized balloons, and biomimetic stents. Open surgical bypass remains an important option for those with advanced disease. The strategy and techniques employed vary by clinical presentation, lesion location, and lesion severity. There is limited level 1 evidence to guide practice, but factors that determine technical success and anatomic durability are largely understood and incorporated into decision-making. Following revascularization, medical therapy to reduce adverse limb outcomes and a surveillance plan should be put in place. There are many hurdles to overcome to improve the efficacy of lower extremity revascularization, such as restenosis, calcification, microvascular disease, silent embolization, and tools for perfusion assessment. This review highlights the current state of revascularization in peripheral artery disease with an eye toward technologies at the cusp, which may significantly impact current practice.

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Leg heat therapy improves perceived physical function but does not enhance walking capacity or vascular function in patients with peripheral artery disease

Journal of Applied Physiology ◽

10.1152/japplphysiol.00277.2020 ◽

2020 ◽

Vol 129 (6) ◽

pp. 1279-1289

Author(s):

Jacob C. Monroe ◽

Chen Lin ◽

Susan M. Perkins ◽

Yan Han ◽

Brett J. Wong ◽

...

Keyword(s):

Physical Function ◽

Peripheral Artery Disease ◽

Vascular Function ◽

Controlled Study ◽

Peripheral Artery ◽

Walking Capacity ◽

Heat Therapy ◽

Walking Performance ◽

Artery Disease ◽

Potent Vasoconstrictor

This is the first sham-controlled study to investigate the effects of leg heat therapy (HT) on walking performance, vascular function, and quality of life in patients with peripheral artery disease (PAD). Adherence to HT was high, and the treatment was well tolerated. Our findings revealed that HT applied with water-circulating trousers evokes a clinically meaningful increase in perceived physical function and reduces the serum concentration of the potent vasoconstrictor endothelin-1 in patients with PAD.

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Relationship Between Disease Specific Quality of Life Measures, Physical Performance, and Activity in People with Intermittent Claudication Caused by Peripheral Artery Disease

European Journal of Vascular and Endovascular Surgery ◽

10.1016/j.ejvs.2020.02.006 ◽

2020 ◽

Vol 59 (6) ◽

pp. 957-964

Author(s):

Jonathan Golledge ◽

Anthony S. Leicht ◽

Lisan Yip ◽

Sophie E. Rowbotham ◽

Jenna Pinchbeck ◽

...

Keyword(s):

Quality Of Life ◽

Intermittent Claudication ◽

Physical Performance ◽

Peripheral Artery Disease ◽

Peripheral Artery ◽

Quality Of Life Measures ◽

Artery Disease ◽

Disease Specific

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P1234SNF472 IMPROVES LIMB BLOOD PERFUSION AND WALKING ABILITY IN A PERIPHERAL ARTERY DISEASE VASCULAR CALCIFICATION RAT MODEL

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa144.p1234 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Firas Bassissi ◽

Miguel David Ferrer Reynes ◽

M Mar Pérez ◽

Joan Perelló ◽

Carolina Salcedo

Keyword(s):

Peripheral Artery Disease ◽

Vascular Calcification ◽

Rat Model ◽

Blood Perfusion ◽

Walking Distance ◽

Arterial Calcification ◽

Walking Ability ◽

Peripheral Artery ◽

Increased Risk ◽

Artery Disease

Abstract Background and Aims Peripheral Artery disease (PAD) is a common vascular disease associated with functional impairment and increased risk of cardiovascular events in End Stage Kidney Disease (ESKD) patients undergoing dialysis. Poor limb salvage outcomes and high post-amputation mortality in hemodialysis (HD) patients highlight the need for earlier medical therapies. Cilostazol and pentoxifylline are approved for PAD. Their use in HD patients stays limited and cilostazol use requires caution in this population. Clinical studies demonstrate associations between arterial calcification and adverse outcomes in PAD patients. SNF472, a selective calcification inhibitor that interferes in the formation and growth of hydroxyapatite, is in Phase 3 for calciphylaxis treatment. This study aims to evaluate the effects of SNF472 on limb functional recovery and blood perfusion in a Vitamin D3 (VitD)-induced arterial calcification rat model. Method Arterial calcification was induced in 32 Sprague Dawley rats by 3 consecutive daily s.c. doses of 120 kIU/kg VitD. Rats were divided into four groups and treated during 12 days by: placebo s.c, placebo p.o, SNF472 (20 mg/kg/day, s.c.) or cilostazol (20 mg/kg/day, p.o.). An additional group of 8 rats without VitD received vehicle only (sham). Efficacy was evaluated at day 12 and 17 (5 days after treatment stop). Posterior limb blood perfusion was measured using Laser Doppler Imaging and limb walking ability was evaluated by measuring Maximum Walking Distance (MWD) and Maximum Walking Time (MWT) using a treadmill. Rats were sacrificed at day 26 (14 days after treatment stop), and aortas were collected for calcium analysis. Results VitD-induced arterial calcification was associated with decreased blood perfusion and impairment of limb walking ability (MWT and MWD) compared to sham. SNF472 reduced aorta calcification by 41% compared to placebo. No effects of cilostazol on vascular calcification were observed. The inhibition of calcification in SNF472-treated animals was associated with significant higher limb blood perfusion compared to placebo or Cilostazol (1.28 and 1.37-fold higher, respectively at day 12: p< 0.001) and it was translated into a significant improvement in walking ability compared to placebo (515±114 meters vs 334±187 meters, respectively: p<0.05). Conclusion SNF472 shows improvements in vascular calcification, blood perfusion and a functional parameter like walking distance in a PAD vascular calcification rat model. These results suggest that SNF472 may represent a new therapeutic approach for the treatment of PAD associated with high vascular calcification such as in renal disease.

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