Awareness of smoking cessation amongst German vascular surgeons.

Background: Smoking represents the well-known enemy of vascular well-being. Numerous previous studies emphasised the important role of smoking on the development and progression of atherosclerotic cardiovascular disease. The current study aimed to identify hurdles and barriers for an insufficient implementation of secondary prevention in the treatment of lower extremity peripheral arterial disease (PAD). Methods: All members of the German Society for Vascular Surgery and Vascular Medicine (DGG) with valid email addresses were invited to participate in an electronic survey on smoking. Results are descriptively presented. Results: Amongst 2716 invited participants, 327 (12%) submitted complete responses, thereof 33% women and 80% between 30 and 59 years old (87% board certified specialists). 83% were employed by hospitals (56% teaching hospital, 14% university, 13% non-academic) and 16% by outpatient facilities. 6% are active smokers (63% never) while a mean of five medical education activities on smoking cessation were completed during the past five years of practice. Only 27% of the institutions offered smoking cessation programs and 28% of the respondents were aware of local programs while a mean of 46% of their patients were deemed eligible for participation. 63% of the respondents deemed outpatient physicians primarily responsible for smoking cessation, followed by medical insurance (26%). Conclusions: The current nationwide survey of one scientific medical society involved in the care of patients with vascular disease revealed that smoking cessation, although being commonly accepted as important pillar of comprehensive holistic care, is not sufficiently implemented in everyday clinical practice.

Association Between Mental Health Burden, Clinical Presentation, and Outcomes in Individuals With Symptomatic Peripheral Artery Disease: A Scientific Statement From the American Heart Association.

Along with the rising burden of peripheral artery disease (PAD), mental health concerns are increasingly being recognized as a comorbidity to address in the chronic disease management of symptomatic PAD. Apart from a high prevalence of comorbid mental health conditions, the role of pain and changing health behaviors and the broader impacts of illness and adaptation to living with PAD require specialized behavioral health expertise. This scientific statement builds a case that this expertise should be integrated within the multidisciplinary PAD team. Furthermore, areas such as cognitive dysfunction and palliative care are highlighted as needing psychological interventions. Although much of the evidence of the efficacy of psychological and psychotropic interventions has been extrapolated from other cardiovascular populations, evidence for the role of psychological interventions for behavior change, for example, uptake of exercise regimens, is increasingly being accrued within PAD. Areas for behavioral health needs and interactions with PAD treatment are discussed, including the use of opioids, depression management, anxiety and stress reduction interventions, the use of benzodiazepines and antidepressants, smoking cessation, rehabilitation trajectories after amputation, and the role of cognitive decline for PAD treatment and outcomes. A case summary highlights the stigma around mental health and vascular disease and the fragmentation of care. This scientific statement provides remarks for building a road map for integrated behavioral PAD care and potential solutions to overcome these barriers. Instrumental to reaching these changes are interprofessional advocacy efforts and initiatives that help break down the stigma around mental health and promote evidence-based collaborative, nonhierarchical, and multidisciplinary PAD care.

Impact of geriatric nutritional risk index on prognosis in peripheral artery disease patients undergoing endovascular therapy.

The prevalence of peripheral artery disease continues to rise, with major amputations and mortality remaining prominent. Frailty is a significant risk factor for adverse outcomes in the management of the vascular disease. The geriatric nutritional risk index has been used to predict adverse outcomes in lower extremity peripheral artery disease and is a nutrition-based surrogate for frailty. The authors recruited 126 patients with peripheral artery disease who underwent endovascular stent implantation. As in previous reports, malnutrition was diagnosed by the geriatric nutritional risk index. The authors used Kaplan-Meier and multivariate Cox proportional hazards regression analyses to analyze the risk of major adverse limb events, which included mortality, major amputation, and target limb revascularization. There were 67 major adverse limb events during a median follow-up of 480 days. Malnutrition on the basis of the geriatric nutritional risk index was present in 31% of patients. Cox regression analysis showed that malnutrition based on the geriatric nutritional risk index was an independent predictor of major adverse limb events. Kaplan-Meier analysis showed that major adverse limb events increased with worsening malnutrition. Our single-center, retrospective evaluation of geriatric nutritional risk index (as a synonym for body health) correlates with an increased risk of major adverse limb events. Future directions should focus not only on identifying these patients but also on modifying risk factors to optimize long-term outcomes.

Causal Association of Cardiovascular Risk Factors and Lifestyle Behaviors With Peripheral Artery Disease: A Mendelian Randomization Approach.

Background We investigated the causal associations between the genetic liability to cardiovascular and lifestyle risk factors and peripheral artery disease (PAD), using a Mendelian randomization approach. Methods and Results We performed a 2-sample inverse-variance weighted Mendelian randomization analysis, multiple sensitivity analyses to assess pleiotropy and multivariate Mendelian randomization analyses to assess mediating/confounding factors. European-ancestry genomic summary data (P<5×10-8) for type 2 diabetes, lipid-fractions, smoking, alcohol and coffee consumption, physical activity, sleep, and education level were selected. Genetic associations with PAD were extracted from the Million-Veteran-Program genome-wide association studies (cases=31 307, controls=211 753, 72% European-ancestry) and the GoLEAD-SUMMIT genome-wide association studies (11 independent genome-wide association studies, European-ancestry, cases=12 086, controls=449 548). Associations were categorized as robust (Bonferroni-significant (P<0.00294), consistent over PAD-cohorts/sensitivity analyses), suggestive (P value: 0.00294-0.05, associations in 1 PAD-cohort/inconsistent sensitivity analyses) or not present. Robust evidence for genetic liability to type 2 diabetes, smoking, insomnia, and inverse associations for higher education level with PAD were found. Suggestive evidence for the genetic liability to higher low-density lipoprotein cholesterol, triglyceride-levels, alcohol consumption, and inverse associations for high-density lipoprotein cholesterol, and increased sleep duration were found. No associations were found for physical activity and coffee consumption. However, effects fully attenuated for low-density lipoprotein cholesterol and triglycerides after correcting for apoB, and for insomnia after correcting for body mass index and lipid-fractions. Nonsignificant attenuation by potential mediators was observed for education level and type 2 diabetes. Conclusions Detrimental effects of smoking and type 2 diabetes, but not of low-density lipoprotein cholesterol and triglycerides, on PAD were confirmed. Lower education level and insomnia were identified as novel risk factors for PAD; however, complete mediation for insomnia and incomplete mediation for education level by downstream risk factors was observed.

Long-Term Treatment with the Combination of Rivaroxaban and Aspirin in Patients with Chronic Coronary or Peripheral Artery Disease: Outcomes During the Open Label Extension of the COMPASS trial.

AIMS: To describe outcomes of patients with chronic coronary artery disease (CAD) and/or peripheral artery disease (PAD) enrolled in the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) randomized trial who were treated with the combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily during long-term open-label extension (LTOLE). METHODS AND RESULTS: Of the 27 395 patients enrolled in COMPASS, 12 964 (mean age at baseline 67.2 years) from 455 sites in 32 countries were enrolled in LTOLE and treated with the combination of rivaroxaban and aspirin for a median of 374 additional days (range 1-1191 days). During LTOLE, the incident events per 100 patient years were as follows: for the primary outcome [cardiovascular death, stroke, or myocardial infarction (MI)] 2.35 [95% confidence interval (CI) 2.11-2.61], mortality 1.87 (1.65-2.10), stroke 0.62 (0.50-0.76), and MI 1.02 (0.86-1.19), with CIs that overlapped those seen during the randomized treatment phase with the combination of rivaroxaban and aspirin. The incidence rates for major and minor bleeding were 1.01 (0.86-1.19) and 2.49 (2.24-2.75), compared with 1.67 (1.48-1.87) and 5.11 (95% CI 4.77-5.47), respectively, during the randomized treatment phase with the combination. CONCLUSION: In patients with chronic CAD and/or PAD, extended combination treatment for a median of 1 year and a maximum of 3 years was associated with incidence rates for efficacy and bleeding that were similar to or lower than those seen during the randomized treatment phase, without any new safety signals.

Association between secondhand smoke and peripheral arterial disease: a meta-analysis of cross-sectional studies.

PURPOSE: The association between secondhand smoke (SHS) and peripheral arterial disease (PAD) was inconsistent and the studies were relatively scarce, hence, we conducted a meta-analysis of the association between SHS and PAD. MATERIALS AND METHODS: We systematically searched three electronic databases (PubMed, EMBASE, and Web of Science), and calculated the pooled prevalence risk ratio (RR) and estimated standard error by random effect model from the meta-analysis. Furthermore, we performed a subgroup meta-analysis according to the location of SHS exposure. RESULTS: We initially identified 502 articles from the electronic database, and 6 articles, cross-sectional data from 4 cross-sectional studies and 2 prospective cohort studies, were included in the meta-analysis. Among these six articles, two studies showed a significant correlation between SHS exposure and PAD, whereas no study showed a negative correlation between SHS exposure and PAD. In the meta-analysis, pooled prevalence showed a significant association between SHS exposure and PAD (RR = 1.23; 95% confidence interval [CI] 1.08-1.41; z = 3.02, p = 0.003). In the subgroup analysis based on location of SHS exposure, the prevalence RR of PAD at home was 1.30 (95% CI 1.14-1.49, Z-3.99, p < 0.0001). The prevalence RR in the subgroup of SHS exposure at work was not significant (RR = 0.89; 95% CI 0.55-1.44; z = 0.48, p = 0.63). CONCLUSION: Exposure to SHS was significantly and positively associated with PAD. Moreover, we found a significant association between exposure to SHS and PAD at home, but the association was not significant at work.

The Impact of Atrial Fibrillation on Outcomes of Peripheral Arterial Disease: Analysis of Routinely Collected Primary Care Data.

BACKGROUND: The combination of peripheral arterial disease and atrial fibrillation is linked with high risk of mortality and stroke. This study aims to investigate the impact of atrial fibrillation on patients with diagnosed peripheral arterial disease. METHODS: This is a retrospective study using The Health Improvement Network database, which contains prospectively collected data from participating primary care practices. Patients with a new diagnosis of peripheral arterial disease between January 8, 1995 and January 5, 2017 were identified in the database alongside relevant demographic information, clinical history, and medications. Every patient in the dataset with peripheral arterial disease and baseline atrial fibrillation (case) was matched to a patient without atrial fibrillation (control) with similar characteristics using propensity score matching. Cox-regression analysis was performed and hazard ratios (HR) calculated for the outcomes of death, stroke, ischemic heart disease, heart failure, and major amputation. RESULTS: Prevalence of atrial fibrillation in this cohort was 10.2%. All patients with peripheral arterial disease and atrial fibrillation (n = 5685) were matched with 5685 patients without atrial fibrillation but otherwise similar characteristics. After multivariate analysis, atrial fibrillation was independently associated with mortality (HR 1.18; 95% confidence interval [CI], 1.12-1.26; P < .01), cerebrovascular events (HR 1.35; 95% CI, 1.17-1.57; P < .01), and heart failure (HR 1.87; 95% CI, 1.62-2.15; P < .01), but not with ischemic heart disease or limb loss. CONCLUSION: In peripheral arterial disease patients, atrial fibrillation is a risk factor for mortality, stroke, and heart failure. This emphasizes the need for proactive surveillance and holistic management of these patients.

Microvascular Complications, Peripheral Artery Disease and Mortality in Patients with Type 2 Diabetes Mellitus, in Two Counties of Southern Lithuania over 13 Years: Analysis Using a Cohort Database of the National Health Insurance.

Background and Objectives: People living with diabetes mellitus are at risk of developing many serious and life-threatening complications. The present study aimed to determine the occurrence of microvascular complications, peripheral artery disease, and mortality in patients with type 2 diabetes mellitus (T2DM), in 2 Lithuanian counties. Materials and Methods: The data on residents aged ≥ 18 years, who were diagnosed for the first time in 2004 with uncomplicated T2DM, were obtained from the National Health Insurance Fund database. The occurrence of T2DM microvascular complications, peripheral artery disease, and mortality during the period from 2004 to 2016 were assessed by gender and age groups (<65 and ≥65 years). Results: During the 13 years, 46.9% of the patients developed T2DM complications. More men than women developed at least 1 T2DM complication (50.8% vs. 44.8%, p = 0.035). The mean time for developing any T2DM complication was 9.2 years. The probability of occurrence of any complication was 0.07 in the second year and increased to 0.59 in the thirteenth year of living with diabetes. Within the 13 years, 38.2% of the patients died. More men (43.1%) than women (35.5%) died during the analysis period (p = 0.036). Mortality was higher among older patients (60.7%) than among younger patients (22.2%) (p < 0.001). Conclusions: The results of this study provide a comprehensive picture of microvascular complications, peripheral artery disease, and mortality among patients with T2DM of two Lithuanian counties. Information about the occurrence of T2DM complications and mortality will assist further studies in estimating the burden of T2DM and in performing economic evaluations of T2DM prevention and treatment in Lithuania.

Factors affecting vitamin D status in outpatients with abdominal aortic aneurysm and peripheral artery disease- a single centre study.

BACKGROUND AND AIMS: Vitamin D (VD) deficiency is considered an important risk factor for the development of atherosclerosis and aortic aneurysms. The deficiency is claimed to enhance degeneration and remodeling of collagen and elastin fibers in the artery wall, leading to its weakening and progressive dilatation. This study aimed to assess vitamin D status, in outpatients with abdominal aneurysms (AAA) and peripheral artery disease (PAD) not treated with VD, and factors affecting serum 25-OH-D levels. METHODS AND RESULTS: This cross-sectional study involved 59 outpatients with AAA and 150 with PAD. AAA was defined as local dilation of the aorta diameter >30 mm in imaging. None of the patients was prescribed VD containing medicines. Serum 25-OH, iPTH, phosphorus and calcium levels were assessed in all study participants. VD status was categorized according to commonly used cut-offs for serum 25-OH-D (<20 ng/mL - deficiency, <30 ng/mL -insufficiency). Serum 25-OH-D levels were similar in patient with AAA and PAD [1-3Q: 26.2 (18.8-37.6) vs 21.8 (15.9-31.4) ng/mL; p = 0.30], with deficiency noted in 25.4% with AAA and 41.8% with PAD (p < 0.05). Multiple regression analysis revealed that VD deficiency was explained by past stroke episodes [OR = 2.80 (95%CI: 1.22-6.41)]. Secondary hyperparathyroidism was diagnosed in 1.7% of patients with AAA and 1.9% with PAD. CONCLUSIONS: The frequency of VD deficiency in outpatient with AAA is not greater than in those with PAD. Past stroke episode is associated with an increased occurrence of VD deficiency in both outpatients with AAA and PAD other than sun exposure and diet.

Patients with Diabetes Complicated by Peripheral Artery Disease: the Current State of Knowledge on Physiotherapy Interventions.

Diabetes mellitus (DM) is one of the major public health problems that account for morbidity, mortality, and disability worldwide. The presence of DM increases the risk of peripheral artery disease (PAD), as well as accelerates its course, making these patients more susceptible to ischemic events and impaired functional status. Unfortunately, alternative treatments for vascular complications in diabetes are poorly researched. Physiotherapy (kinesitherapy combined with different physical therapy agents) in individuals with DM and coexisting PAD may offer an important complementary therapy alternative. Early therapeutic measures can significantly improve patient outcomes, reduce cardiovascular risk, and improve daily life quality. The article provides an update on the current state of knowledge on physiotherapy interventions in the course of DM in patients with coexisting PAD.

Evidence-Based Recommendations for Medical Management of Peripheral Artery Disease.

Patients with lower limb artery stenosis or occlusion (peripheral artery disease; PAD) have been determined to be at very high risk of both major adverse cardiovascular events, such as myocardial infarction and stroke, and major adverse limb events, such as amputation and requirement for artery surgery.Effective medical management has been identified as key in reducing this risk; however, this is often poorly implemented in clinical practice. Thus, the aim of this narrative review was to summarize the current evidence on the medical management of PAD in order to inform clinicians and highlight recommendations for clinical practice. International guidelines, randomized controlled trials, and relevant systematic reviews and meta-analyses have been included in this study. The focus was the management of the key modifiable risk factors to mitigate possible adverse events through prescription of anti-platelet and anticoagulation drugs and medications to control low-density lipoprotein cholesterol, blood pressure, and diabetes and aid smoking cessation. The available evidence from randomized clinical trials provide a strong rationale for the need for holistic medical management programs that are effective in achieving uptake of these medical therapies in patients with PAD. In conclusion, people with PAD have some of the highest adverse event rates among those with cardiovascular diseases. Secondary preventive measures have been proven effective in reducing these adverse events; however, they remain to be adequately implemented. Thus, the need for an effective implementation program has emerged to reduce adverse events in this patient group.

Epidemiology of peripheral artery disease.

Peripheral artery disease (PAD) is the clinical manifestation of atherosclerosis that primarily affects peripheral arteries within the lower extremities. In this brief review, we describe the epidemiology and burden of disease of PAD within the United States, particularly among high-risk populations. Although the prevalence of PAD continues to increase and is typically higher among the elderly as well as men, women in lower socioeconomic strata are affected at rates two times that of men. Among racial/ethnic groups, Black and African-American patients both experience higher rates of disease as well as lower rates of access to preventative care. Moreover, despite an overall decrease in amputation rates among all patients with PAD, high-risk populations remain disproportionally affected. Specifically, patients in rural areas, African-American and Native-American patients, and those of low socioeconomic status carry the highest risk of amputation. Efforts to improve care among PAD patients should target these high-risk populations and offer comprehensive, evidence-based preventative care. Wide adoption and integration of these practices into comprehensive care models may help to mitigate amputation in the highest-risk populations. As our treatment pathways continue to evolve, we must place further emphasis on patient input and quality of life as we work toward continual improvement in the care of patients with PAD.

Intake of marine n-3 polyunsaturated fatty acids and the risk of incident peripheral artery disease.

BACKGROUND: A high intake of marine n-3 polyunsaturated fatty acids (PUFAs) may lower the risk of coronary heart disease and ischemic stroke. The association between intake of marine n-3 PUFAs and development of peripheral artery disease (PAD), however, remains unexplored. We hypothesised that intake of marine n-3 PUFAs, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and the sum of EPA + DHA was associated with a lower risk of incident PAD. METHODS: We used data from the Danish Diet, Cancer and Health cohort and investigated the associations between intake of EPA, DHA and EPA + DHA and development of PAD. Information on intake of n-3 PUFAs was obtained through a validated food frequency questionnaire. Potential PAD cases were identified through linkage to the Danish National Patient Register and subsequently, all cases were validated. RESULTS: Data were available from 55,248 participants and during a median of 13.6 years of follow-up, 950 cases of PAD were identified. Multivariate Cox regression analyses with adjustments for established risk factors showed no statistically significant associations between intake of EPA (p = 0.255), DHA (p = 0.071) or EPA + DHA (p = 0.168) and the rate of incident PAD. CONCLUSIONS: We did not confirm our hypothesis that intake of EPA, DHA or EPA + DHA was associated with a lower risk of incident PAD.

Eligibility for Low-Dose Rivaroxaban Based on the COMPASS Trial: Insights from the Veterans Affairs Healthcare System.

INTRODUCTION: Low-dose rivaroxaban reduced major adverse cardiac and limb events among patients with stable atherosclerotic vascular disease (ASCVD) in the COMPASS trial. The objective of our study was to evaluate the eligibility and budgetary impact of the COMPASS trial in a real-world population. METHODS: The VA administrative and clinical databases were utilized to conduct a cross-sectional study to identify patients eligible for low-dose rivaroxaban receiving care at all 141 facilities between October 1, 2014 and September 30, 2015. Proportion of patients with stable ASCVD eligible for low-dose rivaroxaban and prevalence of multiple risk enrichment criteria among eligible patients. Pharmaceutical budgetary impact using VA pharmacy pricing. Chi-squared and Student's t tests were used to compare patients eligible versus ineligible patients. RESULTS: From an initial cohort of 1,248,214 patients with ASCVD, 488,495 patients (39.1%) met trial eligibility criteria. Eligible patients were older (74.2 vs 64.5 years) with higher proportion of hypertension (84.1% vs 82.1%) and diabetes (46.2% vs 32.9) compared with ineligible patients (p < 0.001 for all comparisons). A median of 38.7% (IQR 4.6%) of total ASCVD patients per facility were rivaroxaban eligible. Estimated annual VA pharmacy budgetary impact would range from $0.47 billion to $1.88 billion for 25% to 100% treatment penetration. Annual facility level pharmaceutical budgetary impact would be a median of $12.3 million (IQR $8.0-$16.3 million) for treatment of all eligible patients. Among eligible patients, age greater than 65 years was the most common risk enrichment factor (86.9%). Prevalence of eligible patients with multiple enrichment factors varied from 34.2% (one factor) to 6.2% (four or more). CONCLUSION: Over one third of patients with stable ASCVD may qualify for low-dose rivaroxaban within the VA. Additional studies are needed to understand eligibility in other populations and a formal cost-effectiveness analysis is warranted.

Rivaroxaban and Aspirin in Patients With Symptomatic Lower Extremity Peripheral Artery Disease: A Subanalysis of the COMPASS Randomized Clinical Trial.

Importance: Patients with symptomatic lower extremity peripheral artery disease (LE-PAD) experience an increased risk of major vascular events. There is limited information on what clinical features of symptomatic LE-PAD prognosticate major vascular events and whether patients at high risk have a greater absolute benefit from low-dose rivaroxaban and aspirin. Objective: To quantify the risk of major vascular events and investigate the response to treatment with low-dose rivaroxaban and aspirin among patients with symptomatic LE-PAD based on clinical presentation and comorbidities. Design, Setting, and Participants: This is a subanalysis of a previously reported subgroup of patients with symptomatic LE-PAD who were enrolled in a large, double-blind, placebo-controlled randomized clinical trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies [COMPASS]) in 602 centers in 33 countries from March 2013 to January 2020. Data analysis was completed from May 2016 to June 2020. Interventions: A combination of low-dose rivaroxaban and aspirin compared with aspirin alone. Main Outcomes and Measures: Thirty-month incidence risk of myocardial infarction, stroke and cardiovascular death (MACE), major adverse limb events (MALE) including major vascular amputation, and bleeding. Results: The COMPASS trial enrolled 4129 patients with symptomatic LE-PAD (mean [SD] age, 66.8 [8.8] years; 2932 men [71.0%]). The 30-month Kaplan-Meier incidence risk of MACE or MALE, including major amputation, was 22.6% in those with prior amputation (this outcome was observed in 54 patients), 17.6% (n = 15) in those with Fontaine III or IV symptoms, and 11.8% (n = 142) in those with previous peripheral artery revascularization, classifying these features as high-risk limb presentations. The 30-month incidence risk of MACE or MALE, including major amputation, was 14.1% (n = 118) in those with kidney dysfunction, 13.5% (n = 67) in those with heart failure, 13.4% (n = 199) in those with diabetes, and 12.8% (n = 222) in those with polyvascular disease, classifying these features as high-risk comorbidities. Among patients with either high-risk limb presentations or high-risk comorbidities, treatment with rivaroxaban and aspirin compared with aspirin alone was associated with an estimated 4.2% (95% CI, 1.9%-6.2%) absolute risk reduction for MACE or MALE, including major amputation, at 30 months. Although the estimated absolute risk increase of major bleeding was higher with rivaroxaban and aspirin in combination than aspirin alone (2.0% [95% CI, 0.5%-3.9%]) for patients with either high-risk limb presentation or high-risk comorbidity, the estimated absolute risk increase of fatal or critical organ bleeding was low in this high-risk group (0.4% [95% CI, 0.2%-1.8%]), such that the net clinical benefit was estimated to be 3.2% (95% CI, 0.6%-5.3%). Conclusions and Relevance: Patients with LE-PAD with high-risk limb presentations or high-risk comorbidities had a high incidence of major vascular events. For these patients, treatment with rivaroxaban and aspirin in combination compared with aspirin alone led to a large absolute reduction in vascular risk.

Intracranial and systemic atherosclerosis in the NAVIGATE ESUS trial: Recurrent stroke risk and response to antithrombotic therapy.

BACKGROUND: Non-stenotic intracranial and systemic atherosclerosis are associated with ischemic stroke. We report frequency and response to anticoagulant vs. antiplatelet prophylaxis of patients with embolic stroke of undetermined source (ESUS) who have non-stenotic intracranial atherosclerosis and/or systemic atherosclerosis. METHODS: Exploratory analysis of the international NAVIGATE ESUS randomized trial comparing rivaroxaban 15mg daily with aspirin 100mg daily in 7213 patients with recent ESUS. Among participants with results of intracranial arterial imaging with either computed tomographic angiography (CTA) or magnetic resonance angiography (MRA), the frequency and predictors of non-stenotic intracranial and systemic atherosclerosis and responses to antithrombotic therapy were assessed. RESULTS: Among 4723 participants with available intracranial CTA or MRA results (65% of the trial cohort), the prevalence of intracranial atherosclerosis was 16% (n=739). Patient features independently associated with intracranial atherosclerosis included East Asian region (odds ratio 2.7, 95%CI 2.2,3.3) and cervical carotid plaque (odds ratio 2.3, 95%CI 1.9,2.7), among others. The rate of recurrent ischemic stroke averaged 4.8%/year among those with intracranial atherosclerosis vs. 5.0.%/year for those without (HR 0.95, 95%CI 0.65, 1.4). Among those with intracranial atherosclerosis, the recurrent ischemic stroke rate was higher if assigned to rivaroxaban (5.8%/year) vs. aspirin (3.7%/year), but the difference was not statistically significant (HR 1.6, 95%CI 0.78, 3.3). There was trend for the effect of antithrombotic treatments to be different according to the presence or absence of intracranial atherosclerosis (pinteraction=0.09). Among participants with evidence of systemic atherosclerosis by either history or imaging (n=3820), recurrent ischemic stroke rates were similar among those assigned to rivaroxaban (5.5%/year) vs. aspirin (4.9%/year)(HR 1.1, 95%CI 0.84, 1.5). CONCLUSIONS: East Asia region was the strongest factor associated with intracranial atherosclerosis. There were no statistically significant differences between rivaroxaban and aspirin prophylaxis for recurrent ischemic stroke in patients with non-stenotic intracranial atherosclerosis and/or systemic atherosclerosis.

Association of Perceived Stress Levels With Long-term Mortality in Patients With Peripheral Artery Disease.

Importance: Identifying modifiable risk factors, such as stress, that could inform the design of peripheral artery disease (PAD) management strategies is critical for reducing the risk of mortality. Few studies have examined the association of self-perceived stress with outcomes in patients with PAD. Objective: To examine the association of high levels of self-perceived stress with mortality in patients with PAD. Design, Setting, and Participants: This cohort study analyzed data from the registry of the Patient-Centered Outcomes Related to Treatment Practices in Peripheral Arterial Disease: Investigating Trajectories (PORTRAIT) study, a multicenter study that enrolled patients with new or worsening symptoms of PAD who presented to 16 subspecialty clinics across the US, the Netherlands, and Australia from June 2, 2011, to December 3, 2015. However, the present study included only patients in the US sites because assessments of mortality for patients in the Netherlands and Australia were not available. Data analysis was conducted from July 2019 to March 2020. Exposure: Self-perceived stress was quantified using the 4-item Perceived Stress Scale (PSS-4), with a score range of 0 to 16. A score of 6 or higher indicated high stress in this cohort. Missing scores were imputed using multiple imputation by chained equations with predictive mean matching. Stress was assessed at baseline and at 3-, 6-, and 12-month follow-up. Patients who reported high levels of stress at 2 or more follow-up assessments were categorized as having chronic stress. Main Outcomes and Measures: All-cause mortality was the primary study outcome. Such data for the subsequent 4 years after the 12-month follow-up were obtained from the National Death Index. Results: The final cohort included 765 patients, with a mean (SD) age of 68.4 (9.7) years. Of these patients, 57.8% were men and 71.6% were white individuals. High stress levels were reported in 65% of patients at baseline and in 20% at the 12-month follow-up. In an adjusted Cox proportional hazards regression model accounting for demographics, comorbidities, disease severity, treatment type, and socioeconomic status, exposure to chronic stress during the 12 months of follow-up was independently associated with increased risk of all-cause mortality in the subsequent 4 years (hazard ratio, 2.12; 95% CI, 1.14-3.94; P = .02). Conclusions and Relevance: In thie cohort study of patients with PAD, higher stress levels in the year after diagnosis appeared to be associated with greater long-term mortality risk, even after adjustment for confounding factors. These findings suggest that, given that stress is a modifiable risk factor for which evidence-based management strategies exist, a holistic approach that includes assessment of chronic stress has the potential to improve survival in patients with PAD.

Cost-Effectiveness of Coronary and Peripheral Artery Disease Antithrombotic Treatments in Finland.

INTRODUCTION: Currently, 15-20% of individuals with coronary artery disease (chronic coronary syndrome [CCS]) or peripheral artery disease (PAD) receiving routine treatment experience cardiovascular events (CVEs) within 3-4 years. Using PICOSTEPS (Patients-Intervention-Comparators-Outcomes-Setting-Time-Effects-Perspective-Sensitivity analysis) reporting, we evaluated the cost-effectiveness of recently approved rivaroxaban 2.5 mg twice daily in combination with acetylsalicylic acid 100 mg daily (RIV + ASA) for the prevention of CVEs among Finns with CCS or symptomatic PAD. METHODS: Myocardial infarction, ischemic stroke, intracranial hemorrhage, acute limb ischemia, amputations, major extracranial bleeding, venous thromboembolism, and cardiovascular deaths were modeled in a Markov model examining a cohort of patients with CCS or symptomatic PAD. Relative effects of the intervention (RIV + ASA) and comparator (ASA) were based on the COMPASS trial. The primary outcome was 3%/year discounted incremental cost-effectiveness ratio (ICER), defined as cost (2019 euros) per quality-adjusted life year (QALY) gained in the Finnish setting over a lifetime horizon. In addition to nonfatal and fatal CVEs, the effects factored Finnish non-CVE mortality, quality of life, and direct costs from a public payer perspective. Disaggregated costs and QALYs, costs per life year gained (LYG), and ischemic strokes avoided, net monetary benefit (NMB), expected value of perfect information (EVPI), economic value-added (EVA), cost-effectiveness table, and acceptability frontier were examined. Probabilistic and deterministic sensitivity analyses were conducted. RESULTS: In the deterministic comparison with ASA over a lifetime horizon, RIV + ASA resulted in a benefit of 0.404 QALYs and 0.474 LYGs for an additional cost of €3241, resulting in an ICER of €8031/QALY. The probabilistic ICER was €4313/QALY (EVPI €1829/patient). RIV + ASA had positive NMB (€8791/patient), low EVPI (€88/patient), high EVA (€8703/patient), and 91% probability of cost-effectiveness using the willingness-to-pay of €25,254/QALY. The primary result was conservative and robust for RIV + ASA. CONCLUSION: RIV + ASA was a cost-effective treatment alternative compared with ASA in patients with CCS or symptomatic PAD in Finland.

Finland lacks published evidence on the cost-effectiveness of approved interventions for the prevention of cardiovascular events among individuals with chronic coronary syndrome (stable coronary artery disease) or symptomatic peripheral artery disease at risk of cardiovascular complications. Rivaroxaban 2.5 mg twice daily plus acetylsalicylic acid 100 mg once daily is indicated and reimbursed in Finland for the prevention of cardiovascular events for patients with stable coronary artery disease or symptomatic peripheral artery disease. We assessed the effectiveness and costs of treatment with rivaroxaban plus acetylsalicylic acid in comparison with treatment with acetylsalicylic acid. That is, we examined whether rivaroxaban is cost-effective when prescribed in combination with acetylsalicylic acid.Cardiovascular events with their associated costs and impact on quality of life were modeled over the lifetime of patients. The main effectiveness outcome was quality-adjusted life years (modeled survival multiplied by the expected quality of life), and costs included those relevant to the Finnish public payer in 2019. Extensive sensitivity analyses were carried out to evaluate the impacts of different model inputs and rationale.Rivaroxaban plus acetylsalicylic acid had high probability of being cost-effective, compared with acetylsalicylic acid. By valuing quality-of-life benefit with a plausible willingness-to-pay, net cost savings of €8791 per patient could be gained or economic value added by €8703 per patient if rivaroxaban was used.

Association of aortic valve calcification with carotid artery lesions and peripheral artery disease in patients with chronic kidney disease: a cross-sectional study.

BACKGROUND: Patients with chronic kidney disease (CKD) reportedly have a high prevalence of aortic valve calcification (AVC). In population-based studies, AVC is considered a manifestation of systemic atherosclerosis. The association of AVC with atherosclerotic lesions has not been fully investigated in predialysis patients. The present study was performed to determine whether carotid artery lesions and peripheral artery disease (PAD) are associated with AVC in patients with CKD not on dialysis. METHODS: In total, 749 patients were included in this cross-sectional study. AVC was evaluated using echocardiography. Carotid artery lesions including carotid artery plaque (CAP) and PAD were simultaneously examined in each patient. A logistic regression analysis was applied to determine the factors associated with AVC. RESULTS: AVC, CAP, and PAD were found in 201, 583, and 123 patients, respectively. In the multivariable analyses adjusted for covariates including the estimated glomerular filtration rate and makers of mineral metabolism (serum calcium, serum phosphorus, parathyroid hormone, 1,25-dihydroxyvitamin D, and fibroblast growth factor 23), AVC was significantly associated with the presence of CAP [odds ratio (OR), 3.37; 95% confidence interval (CI), 1.43-7.95], the presence of PAD (OR, 1.76; 95% CI, 1.10-2.81), the CAP score (per 1.0-point increase) (OR, 1.06; 95% CI, 1.02-1.11), and the ankle-brachial blood pressure index (per 0.1-point increase) (OR, 0.83; 95% CI, 0.72-0.95). CONCLUSIONS: AVC was associated with atherosclerotic lesions independent of kidney function and mineral metabolism. We consider that this association between AVC and atherosclerosis might reflect the burden of shared atherosclerotic risk factors.

Rationale and design of the granulocyte-macrophage colony stimulating factor in peripheral arterial disease (GPAD-3) study.

BACKGROUND: Lower extremity peripheral arterial disease (PAD) is a public health problem and many patients with PAD experience claudication despite adequate medical and/or surgical management. Mobilization of endogenous progenitor cells using Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) is a novel therapeutic option that has shown promising results in experimental models and phase I/IIA clinical trials. The GPAD-3 trial will study the effect of two successive administrations of GM-CSF at 3-month interval for improving claudication among patients with lower extremity PAD. METHODS: We plan to recruit 176 patients in this ongoing randomized, double-blind, placebo-controlled Phase IIB trial. After screening for inclusion and exclusion criteria, eligible subjects undergo a 4-week screening phase where they perform subcutaneous placebo injections thrice weekly and walk at least three times a day until they develop claudication. After the screening phase, eligible subjects undergo baseline testing and are randomized 2:1 to receive 500 µg/day of GM-CSF subcutaneously thrice weekly for three weeks or placebo injections. After 3 months, follow-up endpoint testing is performed and subjects in the GM-CSF group receive the second administration of the drug for three weeks while subjects in placebo group receive matching placebo injections. All participants undergo endpoint testing at six-month and nine-month follow-up. The primary endpoint is change in 6-min walk distance between baseline and 6-month follow-up. CONCLUSION: GPAD-3 explores a novel approach to address the need for alternative therapies that can alleviate symptoms among patients with lower extremity PAD. If successful, this study will pave the way for a pivotal Phase III trial.