Control of modifiable risk factors and major adverse cardiovascular events in people with peripheral artery disease and diabetes.

BACKGROUND: People with diabetes and peripheral artery disease (PAD) have a high risk of major adverse cardiovascular events (MACE). Prior research suggests that medical therapies aimed to control modifiable risk factors are poorly implemented in patients with PAD. AIM: To examine the association between the control of modifiable risk factors, estimated by the novel PAD-medical score, and the incidence of MACE in people with PAD and diabetes. METHODS: Participants were recruited from out-patient clinics if they had a diagnosis of both PAD and diabetes. Control of reversible risk factors was assessed by a new composite measure, the PAD-medical score. This score takes into account the control of low-density lipoprotein cholesterol, blood pressure, blood glucose, smoking and prescription of an anti-platelet. Participants were followed to record incidence of myocardial infarction, stroke and cardiovascular death (MACE). The association of PAD-medical score with MACE was assessed using Cox proportional hazard analyses adjusting for age, sex and prior history of ischemic heart disease and stroke. RESULTS: Between 2002 and 2020, a total of 424 participants with carotid artery disease (n = 63), aortic or peripheral aneurysm (n = 121) or lower limb ischemia (n = 240) were prospectively recruited, and followed for a median duration (inter-quartile range) of 2.0 (0.2-4.4) years. Only 33 (7.8%) participants had the optimal PAD-medical score of five, with 318 (75%) scoring at least three out of five. There were 89 (21.0%) participants that had at least one MACE during the follow-up period. A one-unit higher PAD-medical score was associated with lower risk of MACE (HR = 0.79, 95%CI: 0.63-0.98) after adjusting for other risk factors. CONCLUSION: The PAD-medical score provides a simple way to assess the control of modifiable risk factors targeted by medical management aimed to reduce the incidence of MACE.

Relationship between requirement to stop during a six-minute walk test and health-related quality of life, physical activity and physical performance amongst people with intermittent claudication.

AIM: A simple objective test is required to identify people with impaired physical aspects of health-related quality of life (QOL) due to intermittent claudication. This study assessed the relationship of QOL, function and physical activity to the need to stop during a six-minute walking test (6MWT) amongst people with intermittent claudication. METHOD: This was a prospective case-control study conducted at two centers in Australia. 173 participants with a history of intermittent claudication and peripheral artery disease diagnosed by ankle brachial pressure index <0.9, completed two 6MWTs one week apart. QOL was assessed with the short form (SF)-36. Physical activity was assessed by an accelerometer to record step count, stepping time and energy expenditure over 7 days. Physical performance was assessed by the Short Physical Performance Battery (SPPB) test. The associations of the need to stop at least once during the 6MWT with QOL, function and activity were assessed using Mann Whitney U test and analysis of covariates. RESULTS: Participants that had to stop at least once during the two 6MWTs (46; 26.6%) had significantly lower scores for three of the domains (physical functioning, role-physical and bodily pain) and the physical component summary (PCS) measure of the SF-36 compared to those who did not need to stop (n = 127; 73.4%). After adjusting for the risk factor co-variates (diabetes, hypertension and ankle brachial pressure index) which were significantly unequally distributed, needing to stop during the 6MWTs was significantly associated with a lower PCS score (adjusted mean 36.5, standard error 0.8 vs. 30.5, standard error 1.3; F = 14.0; P < 0.001; partial eta squared 0.077). Participants that had to stop at least once during the two 6MWTs had significantly lower 7-day step count, time stepping and energy expenditure, but not total SPPB score, compared to those who did not need to stop. CONCLUSIONS: Needing to stop during a 6MWT identified participants with intermittent claudication with poorer QOL and less physical activity compared to those that do not need to stop.

The cost-effectiveness of intensive low-density lipoprotein cholesterol lowering in people with peripheral artery disease.

BACKGROUND: People with peripheral artery disease are at a high risk of major adverse cardiovascular events (MACE) and major adverse limb events (MALE). Randomized controlled trials suggest that intensive lowering of low-density lipoprotein cholesterol (LDL-C) with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors is an effective strategy to prevent these events. This study estimated the potential benefit and cost-effectiveness of administrating PCSK9 inhibitors to a cohort of participants with peripheral artery disease. METHODS: A total of 783 participants with intermittent claudication (IC; n = 582) or chronic limb-threatening ischemia (CLTI; n = 201) were prospectively recruited from three hospitals in Australia. Serum LDL-C was measured at recruitment, and the occurrence of MACE and MALE was recorded over a median (interquartile range) follow-up of 2.2 years (0.3-5.7 years). The potential benefit of administering a PCSK9 inhibitor was estimated by calculating the absolute risk reduction and numbers needed to treat (NNT) based on relative risk reductions reported in published randomized trials. The incremental cost-effectiveness ratio per quality-adjusted life year gained was estimated. RESULTS: Intensive LDL-C lowering was estimated to lead to an absolute risk reduction in MACE of 6.1% (95% confidence interval [CI], 2.0-9.3; NNT, 16) and MALE of 13.7% (95% CI, 4.3-21.5; NNT, 7) in people with CLTI compared with 3.2% (95% CI, 1.1-4.8; NNT, 32) and 5.3% (95% CI, 1.7-8.3; NNT, 19) in people with IC. The estimated incremental cost-effectiveness ratios over a 10-year period were $55,270 USD and $32,800 USD for participants with IC and CLTI, respectively. CONCLUSIONS: This analysis suggests that treatment with a PCSK9 inhibitor is likely to be cost-effective in people with CLTI.

High ankle brachial index predicts high risk of cardiovascular events amongst people with peripheral artery disease.

Ankle-brachial pressure index (ABPI) is commonly measured in people referred to vascular specialists. This study aimed to assess the association of high ABPI (≥ 1.4) with cardiovascular events in people with peripheral artery disease (PAD). 1533 participants with PAD diagnosed by a vascular specialist were prospectively recruited from four out-patient clinics in Australia. ABPI was measured at recruitment and the occurrence of myocardial infarction (MI), stroke or cardiovascular death (major cardiovascular events; MACE) and any amputation were recorded over a median (inter-quartile range) follow-up of 3.3 (1.0-7.1) years. The association of high, compared to normal, low (0.5-0.9) or very low (<0.5), ABPI with clinical events was estimated using Cox proportional hazard analyses, adjusting for traditional risk factors and reported as hazard ratio with 95% confidence intervals. 596 (38.9%), 676 (44.1%), 157 (10.2%) and 104 (6.8%) participants had normal, low, very low and high ABPI, respectively. Participants with high ABPI had increased risk of MACE, MI and death by comparison to those with either normal ABPI [1.69 (1.07, 2.65), 1.93 (1.07, 3.46) and 1.67 (1.09, 2.56)] or either low or very low ABPI [1.51 (1.02, 2.23), 1.92 (1.16, 3.19) and 1.47 (1.02, 2.14)] after adjusting for other risk factors. Findings were similar in a sensitivity analysis excluding people with ABPI only measured in one leg (n = 120). Participants with high ABPI also had an increased risk of MACE and MI compared to those with very low ABPI alone. High ABPI is a strong indicator of excess risk of cardiovascular events amongst people with PAD.

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.

Association of Serum Lipoprotein (a) With the Requirement for a Peripheral Artery Operation and the Incidence of Major Adverse Cardiovascular Events in People With Peripheral Artery Disease.

Background The aim of this study was to assess the relationship between serum lipoprotein (a) (Lp[a]) concentration and the requirement for peripheral artery disease (PAD) operations or incidence of major adverse cardiovascular events. Methods and Results A total of 1472 people with PAD presenting with intermittent claudication (n=355), abdominal aortic aneurysm (n=989) or critical limb ischemia (n=128) were prospectively recruited from 4 outpatient clinics in Australia. Lp(a) was measured in serum samples collected at recruitment using an immunoassay. Participants were followed for a median (interquartile range) of 2.4 (0.1-6.1) years to record requirement for any PAD operation, defined to include any open or endovascular PAD intervention (lower limb peripheral revascularization, abdominal aortic aneurysm repair, other aneurysm repair, or carotid artery revascularization). Myocardial infarctions, strokes, and deaths were also recorded. The association of Lp(a) with events was assessed using Cox proportional hazard analysis adjusting for traditional risk factors. Participants with Lp(a) ≥30 mg/dL had a greater requirement for any PAD operation (hazard ratio, 1.20, 95% CI, 1.02-1.41) and lower limb peripheral revascularization alone (hazard ratio 1.33, 95% CI, 1.06-1.66) but no increased risk of major adverse cardiovascular events or all-cause mortality. Lp(a) ≥50 mg/dL and a 40 mg/dL increase in Lp(a) were also associated with an increased risk of lower limb peripheral revascularization alone but not with other outcomes. Conclusions In participants with PAD referred for hospital management those with high Lp(a) had greater requirement for lower limb peripheral revascularization but Lp(a) was not consistently associated with other clinical events.

Cohort Study Examining the Association Between Blood Pressure and Cardiovascular Events in Patients With Peripheral Artery Disease.

Background Hypertension is an important risk factor for cardiovascular events in patients with peripheral artery disease; however, optimal blood pressure targets for these patients are poorly defined. This study investigated the association between systolic blood pressure ( SBP ) and cardiovascular events in a prospectively recruited patient cohort with peripheral artery disease. Methods and Results A total of 2773 patients were included and were grouped according to SBP at recruitment (≤120 mm Hg, n=604; 121-140 mm Hg, n=1065; and >140 mm Hg, n=1104). Adjusted Cox proportional hazards analyses suggested that patients with SBP ≤120 mm Hg were at greater risk of having a major cardiovascular event (myocardial infarction, stroke, or cardiovascular death) than patients with SBP of 121-140 mm Hg (adjusted hazard ratio, 1.36; 95% CI, 1.08-1.72; P=0.009). Patients with SBP >140 mm Hg had an adjusted hazard ratio of 1.23 (95% CI, 1.00-1.51; P=0.051) of major cardiovascular events compared with patients with SBP of 121-140 mm Hg. These findings were similar in sensitivity analyses only including patients receiving antihypertensive medications or focused on patients with a minimum of 3 months of follow-up. Conclusions This cohort study suggests that patients with peripheral artery disease and SBP ≤120 mm Hg are at increased risk of major cardiovascular events. The findings suggest caution in intensive SBP lowering in this patient group.

Editor's Choice - Metformin Prescription is Associated with a Reduction in the Combined Incidence of Surgical Repair and Rupture Related Mortality in Patients with Abdominal Aortic Aneurysm.

OBJECTIVES: Currently there is no drug therapy for abdominal aortic aneurysm (AAA) and most previous investigations have focused on imaging rather than clinical outcomes. The aim of this study was to assess whether AAA related clinical events were lower in patients prescribed metformin. METHODS: This was a prospective cohort observational study performed in three cities in Australia, which was designed to study risk factors for clinical events not simply to focus on metformin. Patients with an asymptomatic unrepaired AAA of any diameter ≥30 mm were recruited from hospital outpatient clinics and surveillance programs run at four centres. The main outcome was the requirement for AAA repair or AAA related mortality (AAA events). The association between metformin prescription and AAA events was assessed using Kaplan-Meier analysis and Cox proportional hazard analysis. RESULTS: Patients (1,080) with a mean (SD) initial AAA diameter of 46.1 (11.3) mm were followed for a mean (SD) of 2.5 (3.1) years until an AAA event (n = 454), death (n = 176), loss to follow up (n = 128), or completion of current follow up (n = 322). Patients with diabetes who were prescribed metformin (adjusted HR 0.63, 95% CI 0.44-0.93), but not patients with diabetes who were not prescribed metformin (adjusted HR 1.15, 95% CI 0.83-1.59), had a lower incidence of AAA events compared with those without diabetes. Findings were similar in sensitivity analyses restricted to patients with an initial AAA diameter ≤50 mm and patients with a minimum follow up of six months before an AAA event. CONCLUSIONS: These findings suggest that clinically important AAA events may be reduced in patients with diabetes who are prescribed metformin, but not those with diabetes receiving other treatments. A randomised controlled trial is needed to definitively test whether metformin reduces AAA related clinical events in patients with small AAAs who do not have diabetes.

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.

Fenofibrate and Telmisartan in the Management of Abdominal Aortic Aneurysm.

OBJECTIVE: This mini-review provides the rationale and updated progress for ongoing randomized controlled trials assessing fenofibrate and telmisartan efficacy to limit abdominal aortic aneurysm (AAA) growth. METHODS/RESULTS: There remains an urgent need to identify a drug therapy that will limit AAA growth. Data from preclinical and human studies indicate that fenofibrate and telmisartan have the potential to slow aortic destruction. Fenofibrate has been shown to reduce serum and tissue levels of the proinflammatory protein osteopontin, as well as reducing macrophage recruitment to the aortic wall, both of which are integral processes in the development and progression of AAAs. Telmisartan acts via blockade of the angiotensin II receptor, type 1, and also as a peroxisome proliferator-activated receptor gamma agonist. In turn, this inhibits the production of a range of biomarkers associated with AAA progression, including transforming growth factor-beta one, osteoprotegerin, osteopontin and matrix metalloproteinase- 9. Based on these findings, there are currently three randomized controlled trials assessing both fenofibrate and telmisartan as potential interventions to limit aneurysm growth in AAA patients. CONCLUSION: Fenofibrate and telmisartan have potential as repurposed medications to limit AAA growth, and randomized trials for further assessment in AAA patients are ongoing.

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.

A systematic review investigating the association of microRNAs with human abdominal aortic aneurysms.

BACKGROUND AND AIMS: There is increasing interest in identifying novel methods for abdominal aortic aneurysm (AAA) diagnosis. Non-coding RNA molecules such as microRNAs (miRNAs) are stable within the circulation and may serve as biomarkers for AAA. This systematic review aimed to identify miRNAs associated with a diagnosis of human AAA based on currently published original research. METHODS: A systematic search of the MEDLINE and EMBASE databases identified studies assessing miRNA expression in abdominal aortic tissue or circulating blood from human AAA cases compared to non-aneurysmal controls. Data from included studies were extracted to assess methods and results after independent quality assessment by two reviewers. RESULTS: 15 studies were included in this review. 11 studies obtained aortic tissue samples from 195 AAA cases and 104 controls with normal aortas. Nine studies obtained circulating blood samples from 526 AAA cases and 441 controls. miR-21 was differentially expressed in AAA tissue in five separate studies, with four studies reporting upregulation and one reporting downregulation. Seven other miRNAs were differentially expressed in AAA tissue in two separate studies. 15 circulating miRNAs were differentially expressed in two or more separate studies. miR-155 and miR-29b were the only miRNAs differentially expressed in two separate tissue- and blood-based studies. 11 studies offered mechanistic explanations of the role of miRNAs in AAA pathology through exploration of gene targets. Three studies assessed the diagnostic potential of circulating miRNAs with receiver operating characteristic curves. Only one study assessed the prognostic potential of circulating miRNAs in predicting AAA growth. CONCLUSIONS: Several miRNAs have been found to be associated with human AAA. Their utility as AAA biomarkers requires further investigation.

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.

Adaptive dosing approaches to the individualization of 13-cis-retinoic acid (isotretinoin) treatment for children with high-risk neuroblastoma.

PURPOSE: To investigate the feasibility of adaptive dosing and the impact of pharmacogenetic variation on 13-cis-retinoic acid (13-cisRA) disposition in high-risk patients with neuroblastoma. EXPERIMENTAL DESIGN: 13-cisRA (160 mg/m(2) or 5.33 mg/kg/d) was administered to 103 patients ages 21 years or less and plasma concentrations of 13-cisRA and 4-oxo-13-cisRA quantitated on day 14 of treatment. Seventy-one patients were recruited to a dose adjustment group, targeting a 13-cisRA C(max) of 2 µmol/L, with dose increases of 25% to 50% implemented for patients with C(max) values less than 2 µmol/L. A population pharmacokinetic model was applied and polymorphisms in relevant cytochrome P450 genes analyzed. RESULTS: 13-cisRA C(max) values ranged from 0.42 to 11.2 µmol/L, with 34 of 103 (33%) patients failing to achieve a C(max) more than 2 µmol/L. Dose increases carried out in 20 patients in the dose adjustment study group led to concentrations more than 2 µmol/L in 18 patients (90%). Eight of 11 (73%) patients less than 12 kg, receiving a dose of 5.33 mg/kg, failed to achieve a C(max) of 2 µmol/L or more. Significantly, lower C(max) values were observed for patients treated with 5.33 mg/kg versus 160 mg/m(2) (1.9 ± 1.2 vs. 3.1 ± 2.0 µmol/L; mean ± SD; P = 0.023). C(max) was higher in patients who swallowed 13-cisRA capsules as compared with receiving the drug extracted from capsules (4.0 ± 2.2 vs. 2.6 ± 1.8 µmol/L; P = 0.0012). The target C(max) was achieved by 93% (25/27) versus 55% (42/76) of patients in these 2 groups, respectively. No clear relationships were found between genetic variants and 13-cisRA pharmacokinetic parameters. CONCLUSIONS: Dosing regimen and method of administration have a marked influence on 13-cisRA plasma concentrations. Body weight-based dosing should not be implemented for children less than 12 kg and pharmacologic data support higher doses for children unable to swallow 13-cisRA capsules.

Relevance of nonsynonymous CYP2C8 polymorphisms to 13-cis retinoic acid and paclitaxel hydroxylation.

CYP2C8 has a major role in the metabolism of the anticancer agents 13-cis retinoic acid (13cisRA) and paclitaxel. There is evidence that polymorphisms in the CYP2C8 gene contribute to observed interindividual differences in paclitaxel metabolism. However, no studies have been performed to determine the relevance of CYP2C8 polymorphisms to 13cisRA metabolism. In the current study, the effect of two common nonsynonymous CYP2C8 polymorphisms, CYP2C8*3 (R139K and K399R) and *4 (I264M), on the metabolism of 13cisRA and paclitaxel was examined using an Escherichia coli expression system with coexpression of human cytochrome P450 reductase. No statistically significant differences in the level of 13cisRA 4-hydroxylase activity were associated with either CYP2C8 allelic variant compared with the wild-type CYP2C8.1 enzyme. Furthermore, no differences were observed for the CYP2C8.3 or CYP2C8.4 enzymes with respect to paclitaxel 6alpha-hydroxylase kinetics compared with wild-type CYP2C8.1. However, when the effects of the individual polymorphisms making up the CYP2C8*3 allele were considered, a significantly lower level of paclitaxel 6alpha-hydroxylase activity was associated with the K399R enzyme. A lower level of activity was also seen for the R139K enzyme, although this difference was not significant. No differences were observed with respect to 13cisRA 4-hydroxylase activity. We conclude that common CYP2C8 polymorphisms are unlikely to explain reported interindividual variation in 13cisRA or paclitaxel pharmacokinetics.

Role of UDP-glucuronosyltransferase isoforms in 13-cis retinoic acid metabolism in humans.

13-cis Retinoic acid (13cisRA, isotretinoin) is an important drug in both dermatology, and the treatment of high-risk neuroblastoma. 13cisRA is known to undergo cytochrome P450-mediated oxidation, mainly by CYP2C8, but phase II metabolic pathways have not been characterized. In the present study, the glucuronidation activities of human liver (HLM) and intestinal microsomes (HIM), as well as a panel of human UDP-glucuronosyltransferases (UGTs) toward both 13cisRA and the 4-oxo metabolite, 4-oxo 13cisRA, were compared using high-performance liquid chromatography. Both HLM and, to a greater extent, HIM catalyzed the glucuronidation of 13cisRA and 4-oxo 13cisRA. Based on the structures of 13cisRA and 4-oxo 13cisRA, the glucuronides formed are conjugated at the terminal carboxylic acid. Further analysis revealed that UGT1A1, UGT1A3, UGT1A7, UGT1A8, and UGT1A9 were the major isoforms responsible for the glucuronidation of both substrates. For 13cisRA, a pronounced substrate inhibition was observed with individual UGTs and with HIM. UGT1A3 exhibited the highest rate of activity toward both substrates, and a high rate of activity toward 13cisRA glucuronidation was also observed with UGT1A7. However, for both substrates, K(m) values were above concentrations reported in clinical studies. Therefore, UGT1A9 is likely to be the most important enzyme in the glucuronidation of both substrates as this enzyme had the lowest K(m) and is expressed in both the intestine and at high levels in the liver.