Counseling Intervention and Cardiovascular Events in People With Peripheral Artery Disease: A Post Hoc Analysis of the BIP Randomized Clinical Trial.

Importance: It is unclear whether counseling to promote walking reduces the risk of major adverse cardiovascular events (MACE) in people with peripheral artery disease (PAD). Objective: To test whether a counseling intervention designed to increase walking reduced the risk of MACE in patients with PAD. Design, Setting, and Participants: The BIP trial was a randomized clinical trial, with recruitment performed between January 2015 and July 2018 and follow-up concluded in August 2023. Participants with walking impairment due to PAD from vascular departments in the Australian cities of Brisbane, Sydney, and Townsville were randomly allocated 1:1 to the intervention or control group. Data were originally analyzed in March 2024. Intervention: Four brief counseling sessions aimed to help patients with the challenges of increasing physical activity. Main Outcomes and Measures: The primary outcome was the between-group difference in risk of MACE, which included myocardial infarction (MI), stroke, and cardiovascular death. The relationship between Intermittent Claudication Questionnaire (ICQ) scores, PAD Quality of Life (PADQOL) scores, and MACE was examined with Cox proportional hazard regression analyses. Results: A total of 200 participants were included, with 102 allocated to the counseling intervention (51.0%) and 98 to the control group (49.0%).Participants were followed up for a mean (SD) duration of 3.5 (2.6) years. Median (IQR) participant age was 70 (63-76) years, and 56 of 200 participants (28.0%) were female. A total of 31 individuals had a MACE (composed of 19 MIs, 4 strokes, and 8 cardiovascular deaths). Participants allocated to the intervention were significantly less likely to have a MACE than participants in the control group (10 of 102 participants [9.8%] vs 21 of 98 [21.4%]; hazard ratio [HR], 0.43; 95% CI, 0.20-0.91; P = .03). Greater disease-specific quality of life (QOL) scores at 4 months (ICQ: HR per 1-percentage point increase, 0.97; 95% CI, 0.95-0.99; P < .001; PADQOL factor 3 [symptoms and limitations in physical functioning]: HR per 1-unit increase, 0.91; 95% CI, 0.84-0.98; P = .01) and at 12 months (ICQ: HR per 1-percentage point increase, 0.97; 95% CI, 0.95-0.99; P = .003; PADQOL factor 3: HR per 1-unit increase, 0.91; 95% CI, 0.84-0.98; P = .02) were associated with a lower risk of MACE. In analyses adjusted for ICQ or PADQOL factor 3 scores at either 4 or 12 months, allocation to the counseling intervention was no longer significantly associated with a lower risk of MACE. Conclusions and Relevance: This post hoc exploratory analysis of the BIP randomized clinical trial suggested that the brief counseling intervention designed to increase walking may reduce the risk of MACE, possibly due to improvement in QOL. Trial Registration: anzctr.org.au Identifier: ACTRN12614000592640.

Effect of Brief Counseling by Allied Health Professionals on Step Count of People With Peripheral Artery Disease: A Randomized Clinical Trial.

Importance: It is unclear how to effectively promote walking in people with peripheral artery disease (PAD). Objective: To test whether brief counseling delivered by allied health professionals increases step count in participants with PAD. Design, Setting, and Participants: In this randomized clinical trial, participants with symptomatic PAD were recruited from sites in Australia and randomly allocated 1:1 to the counseling intervention or an attention control. Data were collected from January 2015 to July 2021, and data were analyzed from March to November 2022. Interventions: Two 1-hour face-to-face and two 15-minute telephone counseling sessions designed to increase walking. Main Outcomes and Measures: The primary outcome was the between-group difference in change in daily step count estimated by accelerometer recordings over 7 days at baseline and 4 months, using imputation for missing values. Other outcomes at 4, 12, and 24 months included step count, 6-minute walk distance, and disease-specific and generic measures of health-related quality of life. Risk of major adverse limb events was assessed over 24 months. Results: Of 200 included participants, 144 (72.0%) were male, and the mean (SD) age was 69.2 (9.3) years. The planned sample of 200 participants was allocated to the counseling intervention group (n = 102) or attention control group (n = 98). Overall, 198 (99.0%), 175 (87.5%), 160 (80.0%) and 143 (71.5%) had step count assessed at entry and 4, 12, and 24 months, respectively. There was no significant between-group difference in the primary outcome of change in daily step count over 4 months (mean steps, 415; 95% CI, -62 to 893; P = .07). Participants in the counseling group had significantly greater improvement in the secondary outcome of disease-specific Intermittent Claudication Questionnaire score at 4 months (3.2 points; 95% CI, 0.1-6.4; P = .04) and 12 months (4.3 points; 95% CI, 0.5-8.1; P = .03) but not at 24 months (1.2 points; 95% CI, -3.1 to 5.6; P = .57). Findings were similar for mean PAD Quality of Life Questionnaire component assessing symptoms and limitations in physical functioning (4 months: 1.5 points; 95% CI, 0.3-2.8; P = .02; 12 months: 1.8 points; 95% CI, 0.3-3.3; P = .02; 24 months: 1.3 points; 95% CI. -0.5 to 3.1; P = .16). There was no significant effect of the intervention on change in mean 6-minute walking distance (4 months: 9.3 m; 95% CI, -3.7 to 22.3; P = .16; 12 months: 13.8 m; 95% CI, -4.2 to 31.7; P = .13; 24 months: 1.2 m; 95% CI, -20.0 to 22.5; P = .91). The counseling intervention did not affect the rate of major adverse limb events over 24 months (12 [6.0%] in the intervention group vs 11 [5.5%] in the control group; P > .99). Conclusions and Relevance: This randomized clinical trial found no significant effect of brief counseling on step count in people with PAD. Alternate interventions are needed to enable walking. Trial Registration: Australian New Zealand Clinical Trials Registry Identifier: ACTRN12614000592640.

Health-related quality of life amongst people diagnosed with abdominal aortic aneurysm and peripheral artery disease and the effect of fenofibrate.

The aims of this study were, firstly, to assess the effect of concurrent peripheral artery disease (PAD) on the health-related quality of life (QOL) of people diagnosed with a small abdominal aortic aneurysm (AAA); and secondly, to test whether the peroxisome proliferator-activated receptor α agonist fenofibrate improved QOL of people diagnosed with a small AAA, including those diagnosed with concurrent PAD. The study included both a cross-sectional observational study and a randomized placebo-controlled clinical trial. 140 people diagnosed with a 35-49 mm diameter AAA, 56 (40%) of whom had concurrent PAD, and 25 healthy controls were prospectively recruited. QOL was assessed with the short form (SF) 36. Findings in participants that were diagnosed with both AAA and PAD were compared separately with those of participants that had a diagnosis of AAA alone or who had neither AAA nor PAD diagnosed (healthy controls). All participants diagnosed with an AAA were then randomly allocated to 145 mg of fenofibrate per day or identical placebo. Outcomes were assessed by changes in the domains of the SF-36 and ankle brachial pressure Index (ABPI) from randomization to 24 weeks. Data were analyzed using Mann-Whitney U tests. Participants diagnosed with both AAA and PAD had significantly worse QOL than participants diagnosed with AAA alone or healthy controls. Fenofibrate did not significantly alter SF-36 scores or ABPI over 24 weeks. Fenofibrate does not improve QOL of people diagnosed with small AAA, irrespective of whether they have concurrent PAD.Trial registration: ACTN12613001039774 Australian New Zealand Clinical Trials Registry.

Efficacy of Telmisartan to Slow Growth of Small Abdominal Aortic Aneurysms: A Randomized Clinical Trial.

Importance: Currently there is no drug therapy for abdominal aortic aneurysm (AAA). Objective: To test the efficacy of the angiotensin receptor blocker telmisartan in slowing AAA growth in the Telmisartan in the Management of Abdominal Aortic Aneurysm (TEDY) trial. Design, Setting, and Participants: A randomized, double-blind, placebo-controlled trial recruited participants between September 6, 2011, and October 5, 2016, to evaluate the efficacy of telmisartan treatment in patients with AAA. Participants with 35- to 49-mm AAAs recruited from Australia, the Netherlands, and the US were randomized 1:1 to receive telmisartan, 40 mg, or identical placebo. Analyses were conducted according to intention-to-treat principles. Final follow-up was conducted on October 11, 2018, and data analysis was performed between June and November 2019. Intervention: Telmisartan, 40 mg, or identical placebo. Main Outcomes and Measures: The primary outcome of the difference in AAA growth, assessed on core imaging laboratory-read ultrasonographic scanning, was tested with linear mixed-effects models. Other outcomes included effects on blood pressure, computed tomographic (CT)-measured AAA diameter and volume, time to AAA-related events (AAA repair or mortality due to AAA rupture), and health-related quality of life. Results: Of 300 intended participants, 210 were enrolled and randomized to receive telmisartan (n = 107) or placebo (n = 103). Of patients included in the intention-to-treat analysis (telmisartan: n = 106, placebo: n = 101), 183 were men (88%); mean (SD) age was 73.5 (7.9) years. At 1 year, participants receiving telmisartan had mean lower systolic (8.9; 95% CI, 4.1-13.8 mm Hg; P < .001) and diastolic (7.0; 4.3-9.8 mm Hg; P < .001) blood pressure levels compared with participants receiving placebo. A total of 188 participants (91%) received at least 2 ultrasonographic scans and 133 participants (64%) had at least 2 CT scans. There was no significant difference in ultrasonographic-assessed AAA growth rates among those assigned telmisartan (1.68 mm/y) or placebo (1.78 mm/y): mean difference, -0.11 mm/y (95% CI, -0.60 to 0.38 mm/y; P = .66). Telmisartan had no significant effects on AAA growth assessed by CT-measured AAA diameter (mean difference, -0.01 mm/y; 95% CI, -0.02 to 0.01 mm/y; P = .23) or volume (mean difference, -0.02 cm3/y; 95% CI, -0.04 to 0.00 cm3/y; P = .11), AAA-related events (relative risk, 1.35; 95% CI, 0.54-3.35; P = .52), or health-related quality of life (mean difference in physical component score at 24 months, 0.4; 95% CI, 0.4-0.4; P = .80). Hypotensive symptoms (eg, syncope) were twice as common among participants receiving telmisartan compared with placebo (28 [26%] vs 13 [13%]; P = .02), but overall adverse event rates were otherwise similar for both groups. Conclusions and Relevance: This underpowered study did not show a treatment effect for telmisartan on small AAA growth. Future trials will need to ensure adequate sample size and duration of follow-up. Trial Registrations: anzctr.org.au Identifier: ACTRN12611000931976; ClinicalTrials.gov Identifier: NCT01683084.

A Randomised Controlled Trial Assessing the Effects of Peri-operative Fenofibrate Administration on Abdominal Aortic Aneurysm Pathology: Outcomes From the FAME Trial.

OBJECTIVE: Experimental studies suggest that fenofibrate prevents abdominal aortic aneurysm (AAA) development by lowering aortic osteopontin (OPN) concentration and reducing the number of macrophages infiltrating the aortic wall. The current study examined the effects of a short course of fenofibrate on AAA pathology in people with large AAAs awaiting aortic repair. METHODS: This randomised double blind parallel trial included male and female participants aged ≥ 60 years who had an asymptomatic AAA measuring ≥ 50 mm and were scheduled to undergo open AAA repair. Participants were allocated to fenofibrate (145 mg/day) or matching placebo for at least two weeks before elective AAA repair. Blood samples were collected at recruitment and immediately prior to surgery. AAA biopsies were obtained during aortic surgery. The primary outcomes were (1) AAA OPN concentration; (2) serum OPN concentration; and (3) number of AAA macrophages. Exploratory outcomes included circulating and aortic concentrations of other proteins previously associated with AAA. Outcomes assessed at a single time point were compared using logistic regression. Longitudinal outcomes were compared using linear mixed effects models. RESULTS: Forty-three participants were randomised. After three withdrawals, 40 were followed until the time of surgery (21 allocated fenofibrate and 19 allocated placebo). As expected, serum triglycerides reduced significantly from recruitment to the time of surgery in participants allocated fenofibrate. No differences in any of the primary and exploratory outcomes were observed between groups. CONCLUSION: A short course of 145 mg of fenofibrate/day did not lower concentrations of OPN or aortic macrophage density in people with large AAAs.

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

OBJECTIVE: The aims of this study were firstly to assess the correlation between disease specific measures of quality of life (QOL) and physical performance and activity, and secondly to identify demographic, clinical, functional, and physical activity measures independently associated with QOL in people with intermittent claudication. METHODS: This was a cross sectional observational study of 198 people with intermittent claudication caused by peripheral artery disease who were recruited prospectively. QOL was assessed with the intermittent claudication questionnaire (ICQ) and the eight-theme peripheral artery disease quality of life questionnaire. Physical performance was assessed with the six minute walk test (6MWT) and short physical performance battery (SPPB), and an accelerometer was used to measure seven day step count. The associations between QOL scores and 6MWT distance, SPPB scores and seven day step count were examined using Spearman Rho's (ρ) correlation and multivariable linear regression. RESULTS: ICQ scores were significantly correlated with 6MWT distance (ρ = 0.472, p < .001), all four SPPB scores (balance ρ = 0.207, p = .003; gait speed ρ = 0.303, p < .001; chair stand ρ = 0.167, p = .018; total ρ = 0.265, p < .001), and seven day step count (ρ = 0.254, p < .001). PADQOL social relationships and interactions (ρ = 0.343, p < .001) and symptoms and limitations in physical functioning (ρ = 0.355, p < .001) themes were correlated with 6MWT distance. The 6MWT distance was independently positively associated with ICQ and both PADQOL theme scores (ICQ: B 0.069, p < .001; PADQOL social relationships and interactions: B 0.077, p < .001; PADQOL symptoms and limitations in physical functioning: B 0.069, p < .001). CONCLUSION: Longer 6MWT distance independently predicted better physical and social aspects of QOL in people with intermittent claudication supporting its value as an outcome measure.

Randomized Placebo-Controlled Trial Assessing the Effect of 24-Week Fenofibrate Therapy on Circulating Markers of Abdominal Aortic Aneurysm: Outcomes From the FAME -2 Trial.

Background There is no drug therapy for abdominal aortic aneurysm ( AAA ). FAME-2 (Fenofibrate in the Management of Abdominal Aortic Aneurysm 2) was a placebo-controlled randomized trial designed to assess whether administration of 145 mg of fenofibrate/d for 24 weeks favorably modified circulating markers of AAA. Methods and Results Patients with AAA s measuring 35 to 49 mm and no contraindication were randomized to fenofibrate or identical placebo. The primary outcome measures were the differences in serum osteopontin and kallistatin concentrations between groups. Secondary analyses compared changes in the circulating concentration of AAA -associated proteins, and AAA growth, between groups using multivariable linear mixed-effects modeling. A total of 140 patients were randomized to receive fenofibrate (n=70) or placebo (n=70). By the end of the study 3 (2.1%) patients were lost to follow-up and 18 (12.9%) patients had ceased trial medication. A total of 85% of randomized patients took ≥80% of allocated tablets and were deemed to have complied with the medication regimen. Patients' allocated fenofibrate had expected reductions in serum triglycerides and estimated glomerular filtration rate, and increases in serum homocysteine. No differences in serum osteopontin, kallistatin, or AAA growth were observed between groups. Conclusions Administering 145 mg/d of fenofibrate for 24 weeks did not significantly reduce serum concentrations of osteopontin and kallistatin concentrations, or rates of AAA growth in this trial. The findings do not support the likely benefit of fenofibrate as a treatment for patients with small AAA s. Clinical Trial Registration URL : www.anzctr.org.au . Unique identifier: ACTRN 12613001039774.

Inositol in the MAnaGemENt of abdominal aortic aneurysm (IMAGEN): study protocol for a randomised controlled trial.

BACKGROUND: An abdominal aortic aneurysm (AAA) is a focal dilation of the abdominal aorta and is associated with a risk of fatal rupture. Experimental studies suggest that myo-inositol may exert beneficial effects on AAAs through favourable changes to biological pathways implicated in AAA pathology. The aim of the Inositol in the MAnaGemENt of abdominal aortic aneurysm (IMAGEN) trial is to assess if myo-inositol will reduce AAA growth. METHODS/DESIGN: IMAGEN is a multi-centre, prospective, parallel-group, randomised, double-blind, placebo-controlled trial. A total of 164 participants with an AAA measuring ≥ 30 mm will be randomised to either 2 g of myo-inositol or identical placebo twice daily for 12 months. The primary outcome measure will be AAA growth estimated by increase in total infrarenal aortic volume measured on computed tomographic scans. Secondary outcome measures will include AAA diameter assessed by computed tomography and ultrasound, AAA peak wall stress and peak wall rupture index, serum lipids, circulating AAA biomarkers, circulating RNAs and health-related quality of life. All analysis will be based on the intention-to-treat principle at the time of randomisation. All patients who meet the eligibility criteria, provide written informed consent and are enrolled in the study will be included in the primary analysis, regardless of adherence to dietary allocation. DISCUSSION: Currently, there is no known medical therapy to limit AAA progression. The IMAGEN trial will be the first randomised trial, to our knowledge, to assess the value of myo-inositol in limiting AAA growth. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12615001209583 . Registered on 6 November 2015.

Fenofibrate in the management of AbdoMinal aortic anEurysm (FAME): study protocol for a randomised controlled trial.

BACKGROUND: Abdominal aortic aneurysm (AAA) is a slowly progressive destructive process of the main abdominal artery. Experimental studies indicate that fibrates exert beneficial effects on AAAs by mechanisms involving both serum lipid modification and favourable changes to the AAA wall. METHODS/DESIGN: Fenofibrate in the management of AbdoMinal aortic anEurysm (FAME) is a multicentre, randomised, double-blind, placebo-controlled clinical trial to assess the effect of orally administered therapy with fenofibrate on key pathological markers of AAA in patients undergoing open AAA repair. A total of 42 participants scheduled for an elective open AAA repair will be randomly assigned to either 145 mg of fenofibrate per day or identical placebo for a minimum period of 2 weeks prior to surgery. Primary outcome measures will be macrophage number and osteopontin (OPN) concentration within the AAA wall as well as serum concentrations of OPN. Secondary outcome measures will include levels of matrix metalloproteinases and proinflammatory cytokines within the AAA wall, periaortic fat and intramural thrombus and circulating concentrations of AAA biomarkers. DISCUSSION: At present, there is no recognised medical therapy to limit AAA progression. The FAME trial aims to assess the ability of fenofibrate to alter tissue markers of AAA pathology. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12612001226897 . Registered on 20 November 2012.

Efficacy of brief behavioral counselling by allied health professionals to promote physical activity in people with peripheral arterial disease (BIPP): study protocol for a multi-center randomized controlled trial.

BACKGROUND: Physical activity is recommended for people with peripheral arterial disease (PAD), and can improve walking capacity and quality of life; and reduce pain, requirement for surgery and cardiovascular events. This trial will assess the efficacy of a brief behavioral counselling intervention delivered by allied health professionals to improve physical activity in people with PAD. METHODS: This is a multi-center randomised controlled trial in four cities across Australia. Participants (N = 200) will be recruited from specialist vascular clinics, general practitioners and research databases and randomised to either the control or intervention group. Both groups will receive usual medical care, a written PAD management information sheet including advice to walk, and four individualised contacts from a protocol-trained allied health professional over 3 months (weeks 1, 2, 6, 12). The control group will receive four 15-min telephone calls with general discussion about PAD symptoms and health and wellbeing. The intervention group will receive behavioral counselling via two 1-h face-to-face sessions and two 15-min telephone calls. The counselling is based on the 5A framework and will promote interval walking for 3 × 40 min/week. Assessments will be conducted at baseline, and 4, 12 and 24 months by staff blinded to participant allocation. Objectively assessed outcomes include physical activity (primary), sedentary behavior, lower limb body function, walking capacity, cardiorespiratory fitness, event-based claudication index, vascular interventions, clinical events, cardiovascular function, circulating markers, and anthropometric measures. Self-reported outcomes include physical activity and sedentary behavior, walking ability, pain severity, and health-related quality of life. Data will be analysed using an intention-to-treat approach. An economic evaluation will assess whether embedding the intervention into routine care would likely be value for money. A cost-effectiveness analysis will estimate change in cost per change in activity indicators due to the intervention, and a cost-utility analysis will assess change in cost per quality-adjusted life year. A full uncertainty analysis will be undertaken, including a value of information analysis, to evaluate the economic case for further research. DISCUSSION: This trial will evaluate the efficacy and cost-effectiveness of a brief behavioral counselling intervention for a common cardiovascular disease with significant burden. TRIAL REGISTRATION: ACTRN 12614000592640 Australian New Zealand Clinical Trials Registry. Registration Date 4 June 2014.

Important observations made managing carotid body tumors during a 25-year experience.

OBJECTIVES: Our objective was to assess the short- and long-term outcome for patients after carotid body tumor (CBT) resection and discuss the potential pitfalls of the treatment. METHODS: An analysis was undertaken of all patients who underwent CBT resection at Royal Brisbane and Women's Hospital and Greenslopes Private Hospital between 1982 and 2007. Primary tumor characteristics, surgical technique, and outcomes were recorded and analyzed. RESULTS: A total of 49 consecutive CBT resections (2 recurrent tumors) were carried out in 39 patients (26 women [56%]) who were a mean age of 49 years (range, 17-75 years). A nontender neck mass was the presenting complaint in 85%, followed by screening in familial or contralateral tumors in 26%. Familial cases occurred in 11 patients (28%). There were no operative deaths. Complications occurred in 13 of the 49 operations (27%), predominantly temporary nerve palsies and were more likely to occur in tumors of large volume or in cases of removal of coexisting vagal tumors. Malignant disease was present in seven cases (15%). All patients have been followed-up postoperatively for a mean of 11 years (range, 2-26 years). Metachronous paragangliomas have been discovered in six patients, all with familial disease. CONCLUSIONS: Early resection of carotid body tumors should be undertaken while still small to minimize the risk of neural injury, which increases with tumor size. In cases of bilateral CBT, we recommend that the smaller tumor be resected first, before the staged resection of the larger contralateral tumor. In familial or bilateral tumor cases, other synchronous and metachronous paragangliomas should be excluded. Mandatory lifelong follow-up is essential.

Open surgery for atherosclerotic chronic mesenteric ischemia.

BACKGROUND: This study was undertaken to document the results of our current practice of open mesenteric revascularization to enable comparison with the recent trend of percutaneous endovascular therapy for the treatment of chronic mesenteric ischemia. METHODS: Patients were identified via operation code data as well ongoing audit data from 1992 until 2006. Only patients with a history of chronic mesenteric ischemia secondary to atherosclerosis for 3 months or longer were included in the study. Follow-up data have been collected prospectively and include clinical examination and history, as well as graft surveillance consisting of mesenteric duplex ultrasonography, computed tomography, and/or angiography every 6 months for 3 years and then yearly thereafter. RESULTS: Thirty-nine consecutive patients underwent 41 open revascularization procedures for chronic mesenteric ischemia, comprising 67 bypass grafts. The mean patient age was 65 years (range, 45-85 years), and 44% (n = 17) were male. Symptoms were present on average for 11 months (range, 4-48 months) before treatment. The average weight loss was 11.4 kg, and three patients (7.6%) also had evidence of ischemic enteritis. There was one perioperative death, thus giving a perioperative mortality rate of 2.5%. Perioperative morbidity occurred in five patients (12.2%). Primary graft patency was 92% at 5 years. Seven patients died during follow-up, which ranged from 4 to 161 months (mean, 39 months)-one (2.5%) from mesenteric ischemia. Two (5%) other patients have had recurrent mesenteric ischemic symptoms. CONCLUSIONS: Open surgical mesenteric revascularization by bypass grafting for atherosclerotic-induced chronic mesenteric ischemia can be performed with low mortality and morbidity and provides excellent long-term primary patency rates and symptom-free outcomes. Pending more data on the acute and long-term results of endovascular techniques, open mesenteric revascularization remains the gold standard for most patients with chronic mesenteric ischemia.