Recommendations for the management of the vascular involvement in Behçet's disease by the Japanese National Research Committee for Behçet's disease-secondary publication.

OBJECTIVES: This study aimed to develop clinical guidelines for the management of vascular Behçet's disease (BD) by the Behçet's Disease Research Committee of the Ministry of Health, Labour and Welfare of the Japanese Government. METHODS: A task force proposed clinical questions (CQs) concerning vascular BD based on a literature search. After screening, draft recommendations were developed for each CQ and brushed up in three blinded Delphi rounds, leading to the final recommendations. RESULTS: This study provides recommendations for 17 CQs concerning diagnosis and differential diagnoses, assessment of disease activity, and treatment. The guidelines recommend immunosuppressive treatments, for both arterial and venous involvement with active inflammation. Anticoagulation is also recommended for deep vein thrombosis except in high-risk patients. Surgical and endovascular therapies can be optional, particularly in patients with urgent arterial lesions undergoing immunosuppression. In addition, two sets of algorithms for diagnosis and treatment are shown for arterial and venous involvement. CONCLUSIONS: These recommendations are expected to serve as useful tools in the daily clinical practice of BD. This content has already been published in Japanese in the Guideline for the Management of Behçet's Disease 2020 and is submitted with permission from both the primary and secondary publishers.

Increased Incidence of Cancer in Japanese Patients with Critical Limb Ischemia.

Objective: This multicenter observational study was conducted in order to investigate the incidence of cancer in patients with critical limb ischemia. Materials and Methods: We prospectively investigated the incidence of cancer in 68 patients with critical limb ischemia over a two-year period. Patients underwent an intensive examination at enrollment, which included tumor marker levels and chest and abdominal computed tomography, as well as one- and two-year follow-up examinations. We compared the observed incidence of cancer with the expected incidence calculated from national cancer rates by the standardized incidence ratio (SIR). Results: The majority (83.6%) of the patients were men, and 92.5% of the patients had a peripheral arterial disease that was classified as Fontaine stage III or IV. During enrollment, newly diagnosed cancers were detected in seven patients. Four additional cancers were detected during the follow-up period. All of the detected cancers were asymptomatic. We observed an increased risk of cancer (SIR, 4.04; 95% confidence interval, 1.31-9.42) in patients with critical limb ischemia. Conclusion: This study suggests that critical limb ischemia is associated with an increased risk of cancer. Our findings should be taken into serious consideration by future investigators considering the use of therapeutic angiogenesis.

Evaluation of Risk Factors for Major Amputation in Patients With Diabetes and Peripheral Artery Disease Receiving Antiplatelet Therapy　- Post Hoc Analysis of a Prospective Observational Multicenter Cohort Study (SEASON).

BACKGROUND: Guidelines for peripheral arterial disease (PAD) recommend long-term antiplatelet therapy in symptomatic patients to reduce cardiovascular morbidity and mortality risk. Although diabetes is a known risk factor for PAD, PAD has been undertreated in these patients. This study aimed to evaluate risk factors for major amputation in patients with diabetes undergoing antiplatelet therapy for PAD.Methods and Results:This retrospective analysis of a 2-year observational cohort study (1,745 clinics in Japan, September 2009-2013) evaluated predictors of amputation in patients with diabetes undergoing antiplatelet therapy for PAD. Among 4,016 eligible patients, 52 had an amputation during follow-up. Amputation risk (Cox regression analysis) was predicted at baseline by history of lower extremity revascularization/amputation (hazard ratio [HR]: 2.92; 95% confidence interval [CI]: 1.39, 6.14), chronic kidney disease (HR: 4.19; 95% CI: 1.95, 8.97), and comorbid cerebrovascular and heart disease (HR: 3.32; 95% CI: 1.19, 9.30), and was unaffected by choice of oral antiplatelet therapy. In patients with PAD and diabetes, amputation event rate was highest for those with ankle-brachial pressure index (ABI) <0.40 and progressively decreased at higher ABI cut-offs. CONCLUSIONS: These findings inform real-world understanding of PAD in diabetic patients receiving antiplatelet therapy in Japan, and showed that ABI <0.4 was the strongest risk factor for amputation.

Evaluation of Risk Factors for Limb-Specific Peripheral Vascular Events in Patients With Peripheral Artery Disease: A Post Hoc Analysis of the SEASON Prospective Observational Study.

Surveillance of cardiovascular Events in Antiplatelet-treated arterioSclerosis Obliterans patients in JapaN (SEASON) is a 2-year, prospective, real-world, registry study conducted in Japan from 2009 to 2013. This post hoc analysis evaluated risk factors for limb ischemia in patients with peripheral arterial disease (PAD) and ankle-brachial index (ABI) <0.90. Vascular events were adjudicated by an Efficacy Endpoint Review Committee. Cox regression identified predictors of limb-specific peripheral vascular events (amputation, development of critical limb ischemia, and acute limb ischemia). Patients (n = 6565) were stratified according to ABI: normal (≥1.0; n = 1300), borderline (0.90 ≤ ABI ≤ 1.0; n = 776), and abnormal (<0.90; n = 4489). Compared to normal ABI, patients with ABI <0.90 had a significantly higher risk of any vascular event, all-cause death, and any limb-specific peripheral vascular event. Risk factors for limb-specific vascular events included history of lower extremity revascularization/amputation (adjusted hazard ratio: 2.18; 95% confidence interval [CI]: 1.49-3.20), chronic kidney disease (2.00; 1.33-3.00), diabetes (1.71; 1.16-2.52), and ABI <0.4 (4.45; 2.62-7.55) or <0.7 (1.78; 1.15-2.76). These findings from a Japanese real-world population confirm the increased vascular risk of patients with PAD and ABI <0.90 and identified risk factors for limb-specific peripheral vascular events.

Effect of Anagliptin on Glycemic and Lipid Profile in Patients With Type 2 Diabetes Mellitus.

BACKGROUND: Anagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor expected to improve the lipid profile as well as glycemic control. However, findings from large-scale prospective trials have not been obtained. METHODS: We performed a multicenter prospective trial in patients with type 2 diabetes receiving anagliptin to evaluate its effect on glycemic control and the lipid profile. A total of 95 patients received anagliptin at 200 mg twice daily. Markers of glucose and lipid metabolism were measured at baseline and after 12 and 24 weeks of administration, and the absolute changes and percent changes were determined. RESULTS: Both HbA1c and plasma glucose were significantly decreased by anagliptin therapy. Regarding the lipid profile, total cholesterol (TC) showed a significant decrease at 12 weeks, while TC, low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were significantly decreased at 24 weeks. Multivariate analysis revealed that female sex was an independent predictor of greater reduction of TC, LDL-C, and HDL-C, while a baseline TC level ≥ 200 mg/dL predicted greater reduction of TC and a baseline HDL-C level ≥ 40 mg/dL predicted greater reduction of LDL-C and HDL-C. CONCLUSIONS: This study suggested that anagliptin significantly reduced TC, LDL-C, and HDL-C levels, as well as improving glycemic control, particularly in female patients.

Cystic adventitial disease of the popliteal artery with spontaneous regression.

Cystic adventitial disease (CAD) of the popliteal artery with spontaneous regression is rare. We describe a 44-year-old man with rapid onset of severe intermittent claudication who is currently undergoing conservative follow-up. CAD was diagnosed, and resection of the lesion with autologous vein replacement was scheduled. However, the claudication suddenly improved at 5 weeks after onset. Computed tomography and ultrasound revealed that the cystic lesion in the adventitia had nearly disappeared. This case report describes the imaging findings and the possibility of conservative treatment. CAD can occur in the popliteal artery and is usually treated surgically. However, reports of spontaneous regression are rare. We report our experience with a case of CAD that eventually spontaneously regressed.

Two-Year Follow-Up of Vascular Events in Peripheral Arterial Disease Treated With Antiplatelet Agents: A Prospective Observational Multicenter Cohort Study (SEASON).

The present analysis was intended to evaluate the real-world management of peripheral arterial disease (PAD) in Asia, and to explore cardiovascular events in patients with PAD undergoing antiplatelet therapy over 2 years of follow-up. The Surveillance of cardiovascular Events in Antiplatelet-treated arteriosclerosis Obliterans patients in JapaN (SEASON) registry is a prospective observational multicenter study of cardiovascular events in antiplatelet-treated patients with PAD in Japan. The SEASON registry included 11,375 patients who were scheduled to receive treatment for PAD. Two analysis populations were defined: a real-world population (RWP; n = 10,322) and a definite PAD population (DPP; n = 3992) who had ankle-brachial pressure index (ABPI) <0.9 and intermittent claudication, or a history of lower limb revascularization. The primary outcome measure was the rate of the composite of cerebrovascular, cardiovascular, and peripheral vascular events. The composite event rates (95% confidence interval) were 3.28 (3.00-3.57) and 5.71 (5.13-6.34) events per 100 patient-years in the RWP and DPP groups, respectively. Fontaine IV classification and ABPI <0.4 at baseline were both identified as strong risk factors for vascular events. These findings contribute to understanding the situation for real-world patients with PAD receiving antiplatelet therapy.

Baseline Characterization of Japanese Peripheral Arterial Disease Patients　- Analysis of Surveillance of Cardiovascular Events in Antiplatelet-Treated Arteriosclerosis Obliterans Patients in Japan (SEASON).

BACKGROUND: Despite mounting evidence of increased cardiovascular events in patients with peripheral arterial disease (PAD), the overall incidence of cardiovascular events in PAD patients has not been fully clarified in Japan. The prospective Surveillance of cardiovascular Events in Antiplatelet-treated arterioSclerosis Obliterans patients in JapaN (SEASON) is a prospective observational multicenter study and here we report the baseline clinical characteristics, including atherosclerosis risk factor prevalence, in PAD patients treated with antiplatelet agents. METHODS AND RESULTS: The SEASON registry enrolled 11,375 patients in 1,745 institutions and the data for 10,322 patients were analyzed. At baseline, the average age was 73.8±9.9 years, 60.0% were male and 83.9% were in Fontaine stage I or II. They had arteriosclerosis risk factors, such as current smoking (16.2%), hypertension (61.5%), diabetes mellitus (38.3%) and dyslipidemia (38.8%). There were complications including heart disease (29.7%), cerebrovascular disease (17.1%) and chronic kidney disease (14.3%). A subpopulation analysis revealed that the proportions of patients with risk factors were high in patients with lower ankle-brachial pressure index value. CONCLUSIONS: The baseline characteristics of the SEASON population demonstrate that real-world PAD patients have cardiovascular risk factors and comorbidities next to definite PAD patients. Further analysis of this database will contribute to understanding the real-world situation of PAD patients receiving antiplatelet therapy in Japan. (Circ J 2016; 80: 712-721).

Genome-Wide Association Study of Peripheral Arterial Disease in a Japanese Population.

Characteristics of peripheral arterial disease (PAD) are the occlusion or stenosis of multiple vessel sites caused mainly by atherosclerosis and chronic lower limb ischemia. To identify PAD susceptible loci, we conducted a genome-wide association study (GWAS) with 785 cases and 3,383 controls in a Japanese population using 431,666 single nucleotide polymorphisms (SNP). After staged analyses including a total of 3,164 cases and 20,134 controls, we identified 3 novel PAD susceptibility loci at IPO5/RAP2A, EDNRA and HDAC9 with genome wide significance (combined P = 6.8 x 10-14, 5.3 x 10-9 and 8.8 x 10-8, respectively). Fine-mapping at the IPO5/RAP2A locus revealed that rs9584669 conferred risk of PAD. Luciferase assay showed that the risk allele at this locus reduced expression levels of IPO5. To our knowledge, these are the first genetic risk factors for PAD.

Stent-graft implantation for clinically diagnosed syphilitic aortic aneurysm in an HIV-infected patient.

We describe our experience with stent-graft placement in a patient with a clinically diagnosed syphilitic aortic aneurysm.The patient was a 43-year-old man with syphilitic and human immunodeficiency virus (HIV) co-infection. Computed tomography (CT) revealed an aortic aneurysm with 89 mm in maximum size which was located at distal aortic arch and was considered syphilis derived saccular aneurysm. The aneurysm was judged at high risk of rupture from its shape. We decided to perform stent-graft implantation. Before surgery, the patient was given antibacterial and anti-HIV agents. Hand-made fenestrated stent graft by Tokyo Medical University was implanted. The graft was placed from the ascending aorta to Th 9 level in the descending aorta. The aneurysm completely disappeared during follow-up, with no flare-up of syphilitic infection up to 2 years after surgery.The number of patients with syphilis and human immunodeficiency virus co-infection is now increasing. Stent-graft implantation may be an effective treatment in such immunocompromised patients.

Endovascular stent graft repair for thoracic aortic aneurysms: the history and the present in Japan.

Stent-grafts for endovascular repair of thoracic aortic aneurysms have been commercially available for more than ten years in the West, whereas, in Japan, a manufactured stent-graft was not approved for the use until March 2008. Nevertheless, endovascular thoracic intervention began to be performed in Japan in the early 1990s, with homemade devices used in most cases. Many researchers have continued to develop their homemade devices. We have participated in joint design and assessment efforts with a stent-graft manufacturer, focusing primarily on fenestrated stent-grafts used in repairs at the distal arch, a site especially prone to aneurysm. In March 2008, TAG (W.L. Gore & Associates, Inc., Flagstaff, Arizona, USA) was approved as a stent graft for the thoracic area first in Japan, which was major turning point in treatment for thoracic aortic aneurysms. Subsequently, TALENT (Medtronic, Inc., Minneapolis, Minnesota, USA) was approved in May 2009, and TX2 (COOK MEDICAL Inc., Bloomington, Indiana, USA) in March 2011. Valiant as an improved version of TALENT was approved in November 2011, and TX2 Proform as an improved version of TX2 began to be supplied in October 2012. These stent grafts are excellent devices that showed good results in Western countries, and marked effectiveness can be expected by making the most of the characteristics of each device. A clinical trial in Japan on Najuta (tentative name) (Kawasumi Labo., Inc., Tokyo, Japan) as a line-up of fenestrated stent grafts that can be applied to distal arch aneurysms showing a high incidence, and allow maintenance of blood flow to the arch vessel was initiated. This trial was completed, and Najuta has just been approved in January of 2013 in Japan, and further development is expected. In the U.S., great efforts have recently been made to develop and manufacture excellent stent grafts for thoracic aneurysms, and rapid progress has been achieved. In particular, in the area of the aortic arch, in which we often experience aneurysmal change, but there are no commercially available devices which are urgently needed. Companies are competing keenly to develop devices. To our knowledge, more than 4 manufacturers are involved in the development of functionally new stent grafts in this area. The introduction of branched stent grafts may not be faraway.

A modified Essen stroke risk score for predicting recurrent cardiovascular events: development and validation.

BACKGROUND: The Essen stroke risk score is widely applied to predict the risk of recurrent ischemic stroke. We developed a modified Essen stroke risk score and validated it using a large prospective Effective Vascular Event REduction after STroke (EVEREST) registry including 3588 patients with ischemic stroke in Japan. Patients with cardioembolic stroke were excluded, and follow-up was one-year. METHODS: The modified Essen stroke risk score was calculated from scores for waist circumference, stroke subtype by etiology, and gender in addition to age, hypertension, diabetes mellitus, previous myocardial infarction, other cardiovascular diseases except myocardial infarction and atrial fibrillation, peripheral artery disease, smoking, and previous stroke or transient ischemic attack. A multiple logistic regression model identified the predictors (each assigned one or two points) and provided c-statistics for the modified Essen stroke risk score. We considered two outcomes, recurrent ischemic stroke and cardiovascular events (defined as the combined outcomes of fatal or nonfatal stroke, myocardial infarction, nonfatal unstable angina, and cardiac death). RESULTS: Recurrent ischemic stroke occurred in 121 patients (3·7%) and cardiovascular events occurred in 133 (4·0%) within a year. The c-statistic (used for discrimination) was 0·632 for recurrent stroke and 0·640 for cardiovascular events. Patients scoring 6 or greater were classified as high risk, otherwise were classified as low risk. Kaplan-Meier analysis revealed that the modified risk score was more predictive than the Essen stroke risk score in both men and women. CONCLUSIONS: The modified Essen stroke risk score increased the ability of the Essen stroke risk score to predict recurrent cardiovascular events. Patients with a high modified Essen stroke risk score should be candidates for intensified secondary prevention strategies.

Spontaneous rupture of autogenous saphenous vein graft in bypass surgery for peripheral arterial disease possibly associated with collagen disease.

We encountered two cases of spontaneous rupture of a saphenous vein bypass graft for lower-leg peripheral arterial disease possibly associated with collagen disease. Rupture occurred 5 and 14 days postoperatively. Neither case had any signs of infection, graft degeneration, or evident injury, but both were associated with collagen disease diagnosed at another hospital. We believe that an association with collagen disease might have contributed to vein wall fragility in the present cases.

Efficacy of ezetimibe is associated with gender and baseline lipid levels in patients with type 2 diabetes.

AIM: The combination of ezetimibe and a statin provides greater LDL-C reduction by inhibiting both intestinal cholesterol absorption and endogenous production of cholesterol. The present study was designed to examine the influence of ageing, gender, BMI, levels of LDL-C, and HbA1c on the response to ezetimibe add-on therapy. METHODS: Patients who had been taking a statin for >3 months at the usual dose and whose LDL-C was >120 mg/dL were eligible for this study. Patients were assigned to receive add-on ezetimibe at 10 mg once daily for 12 weeks. RESULTS: Adding ezetimibe to basal statin therapy resulted in a further 15.0% reduction of TC, 20.5% reduction of LDL-C, and 19.7% reduction of non-HDL-C. The change in TC was significantly greater in males than in females. The change in TG was significantly greater in patients with a baseline TG level ≥150 mg/dL. Multivariate regression analysis showed that male sex and LDL-C ≥140 mg/dL were independent predictors of TC reduction after adjustment for age, BMI, and HbA1c. A baseline TG ≥150 mg/dL was also an independent predictor of TG reduction. CONCLUSION: Addition of ezetimibe to ongoing statin therapy was effective in patients with type 2 diabetes. Male sex and baseline LDL-C levels are independent predictors of marked TC reduction by ezetimibe treatment.

Use of side branch of total arch replacement graft as bypass inflow to prevent visceral ischemia with type B aortic dissection.

When operating on patients with type B aortic dissection, the preoperative hemodynamics and malperfusion of visceral organs should be considered. We report a 70-year-old man with dissecting distal arch aneurysm following type B aortic dissection, whose celiac artery arose from a false lumen and who was successfully treated with total arch replacement and ascending graft-celiac artery bypass.

One-year atherothrombotic vascular events rates in outpatients with recent non-cardioembolic ischemic stroke: the EVEREST (Effective Vascular Event REduction after STroke) registry.

BACKGROUND: Patients with recent ischemic stroke may have higher risk of atherothrombosis than stable patients with established vascular events. Our aims were to investigate 1-year atherothrombotic vascular event rates and to assess the risk factors for recurrent ischemic stroke in this population. METHODS: This prospective cohort study was conducted between January 2007 and July 2009 at 313 hospitals in Japan. Outpatients who were at least 45 years of age and who had received oral antiplatelet therapy were enrolled within 2 weeks to 6 months from the last onset of noncardioembolic ischemic stroke. At 12 ± 3 months after enrollment, data on presence/absence of atherothrombotic vascular events were collected. The primary endpoint was the occurrence of fatal or nonfatal ischemic stroke. RESULTS: A total of 3452 patients were enrolled, and 3411 patients who had baseline data were included in the analysis. The 1-year event rate was 3.81% (95% confidence interval 3.15-4.48%) for fatal or nonfatal ischemic stroke and 0.84% (95% confidence interval 0.52-1.15%) for all-cause mortality. The annual rate of recurrent ischemic stroke was significantly higher in patients who had ischemic stroke at least twice than in patients who had first-ever ischemic stroke (5.02% vs 3.59%; P = .0313). In the multivariable Cox regression analysis, recurrent ischemic stroke was significantly associated with age (P = .0033), the presence of diabetes (P = .0129), and waist circumference ≥80 cm (P = .0056). CONCLUSIONS: Patients with recent ischemic stroke have a higher risk of stroke recurrence than stable patients enrolled in the REduction of Atherothrombosis for Continued Health (REACH) registry even though they received antiplatelet therapy. The rigorous management of risk factors is needed.

Obstructive sleep apnea as a potential risk factor for aortic disease.

Obstructive sleep apnea (OSA) is not only a cause of hypertension; it also possibly affects the pathogenesis and progression of aortic disease because an inspiratory effort-induced increase in negative intrathoracic pressure generates mechanical stress on the aortic wall. The objective of the present study was to examine the incidence by location of OSA as a complication in patients with aortic aneurysm and patients with aortic dissection (AD). An overnight sleep study was conducted in the following study groups: the aortic disease group (n = 95) consisting of patients with thoracic aortic aneurysm (TAA, n = 32), patients with abdominal aortic aneurysm (AAA, n = 36), and patients with AD (n = 27); and a control group (n = 32), consisting of patients with coronary risk factors who were matched with the aortic disease group for age, gender, and body mass index (BMI). The 3% oxygen desaturation index (ODI) was significantly higher in all the TAA, AAA, and AD groups (P = 0.045, P = 0.003, and P = 0.005, respectively) than in the control group. The incidence of moderate to severe OSA [apnea hypopnea index (AHI) ≥15 events/h] was significantly higher in the first three groups (P = 0.026, P = 0.001, P = 0.003, respectively) than in the control group, while no significant difference was found between the TAA group and the AAA group with respect to these variables. Furthermore, no significant differences were found between the thoracic AD subgroup and the abdominal AD subgroup with respect to AHI and 3% ODI, as well as with respect to the incidences of moderate to severe OSA. Patients with TAA, patients with AAA, and patients with AD showed high incidences of moderate to severe OSA. Although this result suggests that OSA may be one of risks for aortic disease, unelucidated mechanism(s) other than negative intrathoracic pressure may be involved in the pathogenesis of aortic disease.

Clopidogrel for Atherothrombotic Event Management in Patients with Peripheral Arterial Disease (COOPER) Study: Safety and Efficacy of Clopidogrel versus Ticlopidine in Japanese Patients.

BACKGROUND: Peripheral arterial disease (PAD) has been recognized as an independent risk factor for vascular events and contributes to an adverse prognosis. Long-term administration of clopidogrel is recommended to prevent atherothrombotic events for patients with established PAD. We investigated the benefits of clopidogrel treatment in Japanese patients with PAD. MATERIALS AND METHODS: COOPER (Clopidogrel for atherOthrombOtic event management in patients with PERipheral arterial disease) was a multicenter, randomized, double-blind study to evaluate the safety and efficacy of clopidogrel (75 mg/day) compared to ticlopidine (200 mg/day) in Japanese patients with PAD. The primary endpoint was the cumulative incidence of "safety events of interest" comprising clinically significant bleeding, blood disorders, hepatic dysfunction and other serious adverse events up to 12 weeks. The other safety events and vascular events were also assessed. Patients were followed up to 52 weeks. RESULTS: A total of 431 patients with PAD were randomly assigned to receive either clopidogrel or ticlopidine. The cumulative incidences of "safety events of interest" at 12 weeks were 2.4% and 13.6% of patients who received clopidogrel and ticlopidine, respectively (adjusted hazard ratio, 0.161; 95% confidence interval, 0.062 to 0.416; p <0.0001). Bleeding and vascular events were similar in both groups. CONCLUSION: Clopidogrel demonstrated a favorable benefit/risk profile than ticlopidine in Japanese patients with PAD. ( TRIAL REGISTRATION: ClinicalTrials.gov, Identifier: NCT00862420).