Long-Term Efficacy and Safety of Direct Oral Anticoagulants at Reduced Doses in the Secondary Prevention of Venous Thromboembolism and Post-Thrombotic Syndrome.

Background: Anticoagulation for venous thromboembolism (VTE) is required for at least three to six months; however, it is advisable to extend the duration in certain cases, in which case a reduced dose of Direct Oral Anticoagulants (DOACs) may be an option. Our objective was to investigate the efficacy and safety of reduced-dose DOACs in extended anticoagulation treatment compared to full doses. Methods and Results: This retrospective single-centre study included 185 patients treated with DOACs for at least 6 months who were divided into two groups: (1) the Full Dose (FD) group (n = 113) and (2) the Reduced Dose (RD) group (n = 72), which included patients treated with Apixaban at 2.5 mg bis in die (BID) and Rivaroxaban at 10 mg once daily (OD). Post-thrombotic syndrome (PTS) and its progression were evaluated. During an overall follow-up of 48.32 ± 29.49 months, no VTE occurred, and no patients experienced major bleeding; clinically relevant non-major bleeding occurred in three patients in each group (2.7% vs. 4.2% in FD vs. RD, respectively, p = 0.57). From baseline to follow-up, the prevalence of PTS was not significantly decreased in either group (FD: 54.9% vs. 51.3%, p = 0.29; RD 51.4% vs. 44.4%, p = 0.12); conversely, the Villalta score values were significantly decreased at the last follow-up (FD: 5.51 ± 4.18 vs. 5.51 ± 4.18, p < 0.001; RD 5.49 ± 4.06 vs. 5.11 ± 3.73, p = 0.006). Conclusion: In this real-world retrospective registry, very long-term extended anticoagulant therapy with DOACs at full or reduced doses showed comparable efficacy, safety, and impact on PTS progression. Larger studies are needed.

Superficial Venous Thrombosis: A Comprehensive Review.

Superficial venous thrombosis (SVT), an inflammatory-thrombotic process of a superficial vein, is a relatively common event that may have several different underlying causes. This phenomenon has been generally considered benign, and its prevalence has been historically underestimated; the estimated incidence ranges from about 0.3 to 1.5 event per 1000 person-years, while the prevalence is approximately 3 to 11%, with different reports depending on the population studied. However, such pathology is not free of complications; indeed, it could extend to the deep circulation and embolize to pulmonary circulation. For this reason, an ultrasound examination is recommended to evaluate the extension of SVT and to exclude the involvement of deep circulation. Also, SVT may be costly, especially in the case of recurrence. Therefore, accurate management is necessary to prevent sequelae and costs related to the disease. This review aims to analyse the epidemiology of SVT, its complications, optimal medical treatment, and open questions with future perspectives.

The Role of Heparin in COVID-19: An Update after Two Years of Pandemics.

Coronavirus disease 2019 (COVID-19) is associated with an increased risk of venous thromboembolism (VTE) and coagulopathy, especially in critically ill patients. Endothelial damage induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is emerging as a crucial pathogenetic mechanism for the development of complications in an acute phase of the illness and for several postdischarge sequalae. Heparin has been shown to have a positive impact on COVID-19 due to its anticoagulant function. Moreover, several other biological actions of heparin were postulated: a potential anti-inflammatory and antiviral effect through the main protease (Mpro) and heparansulfate (HS) binding and a protection from the damage of vascular endothelial cells. In this paper, we reviewed available evidence on heparin treatment in COVID-19 acute illness and chronic sequalae, focusing on the difference between prophylactic and therapeutic dosage.

Insights from Experiences on Antiplatelet Drugs in Stroke Prevention: A Review.

Reduction of hazard risk of cerebral ischemic event (stroke, transient ischemic attack (TIA)) represents the hard point to be achieved from primary or secondary preventive strategy in the best clinical practice. However, results from clinical trials, recommendations, guidelines, systematic review, expert opinions, and meta-analysis debated on the optimal pharmacotherapy to achieve the objective. Aspirin and a number of antiplatelet agents, alone or in combination, have been considered from large trials focused on stroke prevention. The present review summarizes, discusses results from trials, and focuses on the benefits or disadvantages originating from antiplatelet drugs. Sections of the review were organized to show both benefits or consequences from antiplatelet pharmacotherapy. Conclusively, this review provides a potential synopsis on the most appropriate therapeutic approach for stroke prevention in clinical practice.

Plasma heme oxygenase-1 is decreased in peripheral artery disease patients.

Peripheral artery disease (PAD) is a common manifestation of atherosclerosis. A number of emerging risk factors, including oxidative stress biomarkers, free radicals and heat shock proteins, may add to the established risk factors for cardiovascular disease (CVD). The present study assessed surrogate markers of oxidative stress, including total reduced glutathione (GSH), lipid hydroperoxides (LOOH), isoprostanes, heme oxygenase­1 (HO­1) and metabolic biomarkers, such as adiponectin and lactate, in PAD patients (n=27). Healthy age­matched volunteers (n=27) served as controls. GSH and LOOH were evaluated by measuring total thiol groups and iron oxidation, respectively, by spectrophotometric analysis. Adiponectin, isoprostanes and HO­1 levels were determined using commercially available ELISA kits and lactate level was determined colorimetrically. Results from patients with PAD demonstrated no significant difference in GSH content and LOOH formation when compared with healthy controls (5.1±7.6 vs. 6.9±9.1 nmol/ml and 6.8±14.2 vs. 8.3±14.9 nmol/ml, respectively), however, isoprostanes were demonstrated to be significantly reduced (3.8±4.8 pg/ml vs. 120±91 pg/mll; P<0.001). Furthermore, HO­1, a protective heat shock protein, was significantly reduced in PAD patients (0.8±0.7 vs. 3.4±1.3 ng/ml; P<0.001). Adiponectin, an antiatherogenic adipokine, was not significantly different between the two groups (1.4±0.2 vs. 1.5±0.5 µg/ml), whereas serum lactate was significantly higher in PAD patients compared with controls (0.11±0.01 vs. 0.1±0.01 mM; P<0.05). Using multivariate analysis, HO­1, hypertension, smoking and dyslipidemia were indicated to be independently associated with the presence of PAD, while only ankle­brachial index was an independent predictor of severity of PAD. The oxidative pathway may be partially involved in the onset and progression of PAD and may represent a target to reduce the risk of ischemic events.

Circulating miR-130a, miR-27b, and miR-210 in Patients With Peripheral Artery Disease and Their Potential Relationship With Oxidative Stress.

Some emerging risk factors such as oxidative stress biomarkers and microRNAs (miRs) may add additional value to the established risk factors for peripheral artery disease (PAD). We enrolled 27 patients with PAD and 27 age-matched controls. We examined the levels of a series of miRs (miR-130a, miR-27b, and miR-210) in serum samples. The level of well-established oxidative stress biomarkers, such as lipid hydroperoxides, isoprostanes, hemeoxygenase-1 (HO-1) and reduced glutathione, was also measured in plasma and their relationship with the miRs was determined. Levels of miR-130a, miR-27b, and miR-210 were significantly increased in patients with PAD when compared to the controls. The level of miR-130 was positively correlated with body mass index, whereas miR-210 was inversely associated with pain-free walking distance (PfWD). None of the evaluated miRs was associated with lowered PfWD of patients with PAD (stage IIa > 250 m, IIb < 250 m) or oxidative stress parameters. In conclusion, our findings suggest the need for more research to assess if miRs can serve as useful markers for the early diagnosis and monitoring of PAD.

Low levels of inflammation and the absence of subclinical atherosclerosis in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease. Patients with RA have an increased risk for the development of cardiovascular diseases, however, the pathophysiological mechanisms of arterial complications in RA remain to be fully elucidated. Understanding the early markers of vascular damage may aid in preventing cardiovascular complications in patients with RA. The current study investigated this by recruiting 30 patients with RA and 30 healthy subjects. Intima­media thickness (IMT) was used to detect the presence of atherosclerotic disease and was measured in the carotid and femoral arteries. Tumor necrosis factor α, interleukin­6 (IL­6), IL­8, IL­10 and matrix metalloproteinase­2 were measured as markers of inflammation. An IMT ≥0.9 mm was observed in 7/30 patients with RA, however, no significant differences between patients with RA and the controls were observed in the inflammatory markers analyzed. Of note, these results indicated that the appropriate management of RA may have affected the inflammatory status of these patients and consequently may have impacted upon subclinical atherosclerosis.

Arterial Plaques in Peripheral Arteries Diagnosed by Ultrasound in a Cohort of Patients With Type 2 Diabetes Mellitus: A Single-Center Surveillance.

Macroangiopathy (eg, peripheral arterial disease) diagnosis in type 2 diabetes mellitus (T2DM) can be carried out by ultrasound. A surveillance study was performed in 366 consecutive patients (166 patients with T2DM and 200 non-T2DM) aiming to evaluate the frequency of single or multiple arterial plaques (Aplqs) in lower limbs and the relationship with different factors (age, duration of T2DM, glycemic balance, DM treatment, smoking habit, and microalbuminuria). Single and multiple Aplqs, respectively, were found in 10.2% and 38.6% among the patients with T2DM. Age, male gender (P < .0002), duration of T2DM (P < .009), insulin therapy (P < .03), and mediocalcinosis (P < .001) were risk factors in patients with T2DM. In conclusion, Aplqs of lower limbs are frequent in T2DM and several factors can play a determining role. Ultrasound is a helpful diagnostic tool.

Medical treatment of critical limb ischemia: current state and future directions.

Atherosclerotic critical limb ischemia (CLI) is manifested by ischemic rest pain, non-healing ulcers or gangrene. The incidence of CLI is estimated to be approximately 500-1000 new cases per year per million people and is expected to grow in developed countries as the population ages with an increasing prevalence of diabetes. Patients diagnosed with CLI are at very high risk of major amputation and cardiovascular morbidity and mortality and experience poor physical function and quality of life. The goals of treatment for CLI are relieving ischemic pain, healing ulcers, preventing limb loss, improving patient function and quality of life, and prolonging survival. Prompt surgical or endovascular revascularization is currently recommended for limb salvage in CLI. All patients with CLI should receive cardiovascular risk reduction therapies, focused on optimizing antiplatelet therapy and risk factor management, to reduce cardiovascular event rates. Adjunctive pharmacotherapy with antithrombotic drugs, statins, and beta-blockers is critical to decrease perioperative cardiovascular complications in patients undergoing surgical vascular reconstruction and enhance postrevascularization arterial and graft patency. In non-reconstructable patients with stable pain and tissue loss, evidence suggests that prostanoids, dedicated wound care programs, and several mechanical devices, such as spinal cord stimulation, intermittent pneumatic compression, and hyperbaric oxygen therapy, can alleviate ischemic symptoms and improve limb salvage. Current medical armamentarium used in treating ischemic wounds also includes ultrasound and negative pressure wound therapy. Therapeutic neovascularization, including gene- and cell-based approaches, is a novel promising tool in the management of CLI under ongoing investigation.

Increased prevalence of peripheral arterial disease in osteoporotic postmenopausal women.

The aim of this study was to investigate the prevalence and correlates of peripheral arterial disease (PAD) in a population of osteoporotic postmenopausal women. The presence of PAD was assessed by ankle brachial index (ABI) in 345 ambulatory osteoporotic postmenopausal women, and in 360 community-based, age- and race-matched postmenopausal women with normal bone mineral density (BMD) (control group). PAD was detected in 63/345 (18.2%) osteoporotic women and in 14/360 (3.8%) control subjects (P < 0.0001). The mean ABI values were significantly lower in the osteoporosis group than in the control group (0.98 +/- 0.09 vs. 1.04 +/- 0.06, P < 0.0001). No difference in cardiovascular risk factors was observed between osteoporotic patients and controls, or between osteoporotic patients with and without PAD. Osteoporotic patients with PAD had lower femoral neck BMD T scores than those without PAD (-4.2 +/- 0.7 vs. -2.3 +/- 0.7, P < 0.0001). Only 4 PAD patients (5.1%) had intermittent claudication. In multivariate logistic regression analysis, factors independently associated with PAD within osteoporotic patients were lower femoral neck BMD T score (odds ratio (OR) = 0.20, 95% confidence interval (CI), 0.05-0.70, P = 0.01) and systolic blood pressure (OR = 1.02, 95% CI, 1.00-1.03, P = 0.01). This study shows for the first time an increased prevalence of PAD among osteoporotic postmenopausal women, with a lower femoral neck BMD T score being a significant independent predictor. The findings suggest that vascular status evaluation should be done in osteoporotic postmenopausal women in order to identify candidate patients for preventive and therapeutic cardiovascular interventions.

Impaired cognitive performance in asymptomatic peripheral arterial disease: relation to C-reactive protein and D-dimer levels.

BACKGROUND AND PURPOSE: asymptomatic peripheral arterial disease (APAD), a highly prevalent condition in the general older population, is associated with an increased risk of cerebrovascular events because of co-existing clinical or subclinical cerebral atherosclerosis. The purpose of this study was to investigate whether cognitive function is impaired in stroke- and transient ischaemic attack-free patients with APAD, and whether inflammatory and haemostatic markers are associated independently with neuropsychological performance. METHODS: cognitive performances of 164 well-functioning, community-dwelling patients with APAD were compared with those of 164 age-, gender- and education-matched healthy control subjects on six neuropsychological tests. Levels of C-reactive protein (CRP), D-dimer and fibrinogen were also analysed in all participants. RESULTS: patients with APAD scored significantly worse (P < 0.0001) than control subjects on five cognitive tests assessing domains of verbal working memory, attention, perceptuomotor speed, mental flexibility, visuoconstructive skills and visual memory. Multiple linear regression analyses showed that CRP and D-dimer were significant, independent predictors of poorer performances on four and three cognitive tests, respectively, within patients with APAD. CONCLUSIONS: patients with APAD show cognitive impairment in a range of psychometric tests, and CRP and D-dimer appear to be independent negative predictors of some cognitive performances. These findings suggest the need for screening for APAD among at-risk subjects in order to identify patients to be treated for prevention of functional decline and dementia. They also support the hypothesis that inflammation and hypercoagulability are implicated in the pathophysiology of cognitive dysfunction associated with APAD.