Recent advances and controversial issues in the optimal management of asymptomatic carotid stenosis.

OBJECTIVE: The optimal management of patients with asymptomatic carotid stenosis (AsxCS) is enduringly controversial. We updated our 2021 Expert Review and Position Statement, focusing on recent advances in the diagnosis and management of patients with AsxCS. METHODS: A systematic review of the literature was performed up to August 1, 2023, using PubMed/PubMed Central, EMBASE and Scopus. The following keywords were used in various combinations: "asymptomatic carotid stenosis," "carotid endarterectomy" (CEA), "carotid artery stenting" (CAS), and "transcarotid artery revascularization" (TCAR). Areas covered included (i) improvements in best medical treatment (BMT) for patients with AsxCS and declining stroke risk, (ii) technological advances in surgical/endovascular skills/techniques and outcomes, (iii) risk factors, clinical/imaging characteristics and risk prediction models for the identification of high-risk AsxCS patient subgroups, and (iv) the association between cognitive dysfunction and AsxCS. RESULTS: BMT is essential for all patients with AsxCS, regardless of whether they will eventually be offered CEA, CAS, or TCAR. Specific patient subgroups at high risk for stroke despite BMT should be considered for a carotid revascularization procedure. These patients include those with severe (≥80%) AsxCS, transcranial Doppler-detected microemboli, plaque echolucency on Duplex ultrasound examination, silent infarcts on brain computed tomography or magnetic resonance angiography scans, decreased cerebrovascular reserve, increased size of juxtaluminal hypoechoic area, AsxCS progression, carotid plaque ulceration, and intraplaque hemorrhage. Treatment of patients with AsxCS should be individualized, taking into consideration individual patient preferences and needs, clinical and imaging characteristics, and cultural, ethnic, and social factors. Solid evidence supporting or refuting an association between AsxCS and cognitive dysfunction is lacking. CONCLUSIONS: The optimal management of patients with AsxCS should include BMT for all individuals and a prophylactic carotid revascularization procedure (CEA, CAS, or TCAR) for some asymptomatic patient subgroups, additionally taking into consideration individual patient needs and preference, clinical and imaging characteristics, social and cultural factors, and the available stroke risk prediction models. Future studies should investigate the association between AsxCS with cognitive function and the role of carotid revascularization procedures in the progression or reversal of cognitive dysfunction.

An international, multispecialty, expert-based Delphi Consensus document on controversial issues in the management of patients with asymptomatic and symptomatic carotid stenosis.

OBJECTIVE: Despite the publication of various national/international guidelines, several questions concerning the management of patients with asymptomatic (AsxCS) and symptomatic (SxCS) carotid stenosis remain unanswered. The aim of this international, multi-specialty, expert-based Delphi Consensus document was to address these issues to help clinicians make decisions when guidelines are unclear. METHODS: Fourteen controversial topics were identified. A three-round Delphi Consensus process was performed including 61 experts. The aim of Round 1 was to investigate the differing views and opinions regarding these unresolved topics. In Round 2, clarifications were asked from each participant. In Round 3, the questionnaire was resent to all participants for their final vote. Consensus was reached when ≥75% of experts agreed on a specific response. RESULTS: Most experts agreed that: (1) the current periprocedural/in-hospital stroke/death thresholds for performing a carotid intervention should be lowered from 6% to 4% in patients with SxCS and from 3% to 2% in patients with AsxCS; (2) the time threshold for a patient being considered "recently symptomatic" should be reduced from the current definition of "6 months" to 3 months or less; (3) 80% to 99% AsxCS carries a higher risk of stroke compared with 60% to 79% AsxCS; (4) factors beyond the grade of stenosis and symptoms should be added to the indications for revascularization in AsxCS patients (eg, plaque features of vulnerability and silent infarctions on brain computed tomography scans); and (5) shunting should be used selectively, rather than always or never. Consensus could not be reached on the remaining topics due to conflicting, inadequate, or controversial evidence. CONCLUSIONS: The present international, multi-specialty expert-based Delphi Consensus document attempted to provide responses to several unanswered/unresolved issues. However, consensus could not be achieved on some topics, highlighting areas requiring future research.

Involvement of Inflammation in Venous Thromboembolic Disease: An Update in the Age of COVID-19.

The inflammatory process is strongly involved in the pathophysiology of venous thromboembolism (VTE) and has a significant role in disease prediction. Inflammation most probably represents a common denominator through which classical and nonclassical risk factors stimulate thrombotic process. Inflammation of the venous wall promotes the release of tissue factor, inhibits the release of anticoagulant factors, and hampers endogenous fibrinolysis. Systemic inflammatory response also inhibits restoration of blood flow in the occluded vessel. Recent studies indicate that increased inflammatory response ("cytokine storm") is related to prothrombotic state and thromboembolic events in patients with coronavirus disease 2019 (COVID-19). The growing evidence of involvement of inflammation in the pathogenesis of VTE indicates the importance of anti-inflammatory treatment and prevention of VTE. While aspirin was shown to be effective in prevention of recurrent venous thrombosis after treatment with anticoagulant drugs, some other anti-inflammatory drugs like nonsteroidal anti-inflammatory agents may have prothrombotic effect, thus potentially increasing the risk of VTE. Recently, new specific anti-inflammatory drug inhibitors of inflammatory markers that have been shown to be involved in the pathogenesis of VTE are being searched. As thrombogenesis is based on activation of coagulation provoked by inflammation, then prevention and treatment of VTE should include both anticoagulant and anti-inflammatory agents. Combined treatment is related to increased risk of bleeding complications, therefore subtherapeutic doses of both drugs should be used to improve the efficacy of management of VTE without increasing the risk of bleeding.

An International Delphi Consensus on Diagnostic Criteria for Buerger's Disease.

BACKGROUND: Buerger's disease (BD) remains a debilitating condition. Despite multiple published diagnostic criteria for BD, none is universally accepted as a gold standard. METHODS: We conducted a 2-round modified Delphi consensus study to establish a consensus on the diagnostic. The questionnaire included statements from several commonly used diagnostic criteria for BD. Qualitative and quantitative analysis methods were performed. An agreement level of 70% was applied. RESULTS: Twenty nine experts from 18 countries participated in this study. Overall, 75 statements were circulated in Round 1. Of these, 28% of statements were accepted. Following comments, 21 statements were recirculated in Round 2 and 90% were accepted. Although more than 90% of the experts did not agree that the diagnosis of BD can be based only on clinical manifestation, none of the nonclinical manifestations of BD were agreed as a part of the diagnostic criteria. There was an agreement that a history of tobacco consumption in any form, not necessarily confined to the current use, should be a part of the diagnostic criteria of BD. The history of thrombophlebitis migrans, even if not present at presentation, was accepted as a clue for BD diagnosis. It was also agreed that discoloration of the toes or fingers could be included in the diagnostic criteria of BD. Experts agreed that histology results could differentiate BD from atherosclerosis obliterans and other types of vasculitis. The presence of corkscrew collaterals on imaging and burning pain reached the agreement at the first round but not at the second. There was no consensus regarding age cut-off, the requirement of normal lipid profile, and normal blood glucose for BD diagnosis. CONCLUSIONS: The present study demonstrated discrepancies in the various published diagnostic criteria for BD and their selective utilization in routine clinical practice worldwide. We propose that all published diagnostic criteria for BD be re-evaluated for harmonization and universal use.

Inflammatory and Prothrombotic Biomarkers, DNA Polymorphisms, MicroRNAs and Personalized Medicine for Patients with Peripheral Arterial Disease.

Classical risk factors play a major role in the initiation and development of atherosclerosis. However, the estimation of risk for cardiovascular events based only on risk factors is often insufficient. Efforts have been made to identify biomarkers that indicate ongoing atherosclerosis. Among important circulating biomarkers associated with peripheral arterial disease (PAD) are inflammatory markers which are determined by the expression of different genes and epigenetic processes. Among these proinflammatory molecules, interleukin-6, C-reactive protein, several adhesion molecules, CD40 ligand, osteoprotegerin and others are associated with the presence and progression of PAD. Additionally, several circulating prothrombotic markers have a predictive value in PAD. Genetic polymorphisms significantly, albeit moderately, affect risk factors for PAD via altered lipoprotein metabolism, diabetes, arterial hypertension, smoking, inflammation and thrombosis. However, most of the risk variants for PAD are located in noncoding regions of the genome and their influence on gene expression remains to be explored. MicroRNAs (miRNAs) are single-stranded, noncoding RNAs that modulate gene expression at the post-transcriptional level. Patterns of miRNA expression, to some extent, vary in different atherosclerotic cardiovascular diseases. miRNAs appear to be useful in the detection of PAD and the prediction of progression and revascularization outcomes. In conclusion, taking into account one's predisposition to PAD, i.e., DNA polymorphisms and miRNAs, together with circulating inflammatory and coagulation markers, holds promise for more accurate prediction models and personalized therapeutic options.

Optimal Management of Asymptomatic Carotid Stenosis in 2021: The Jury is Still Out. An International, Multispecialty, Expert Review and Position Statement.

OBJECTIVES: The recommendations of international guidelines for the management of asymptomatic carotid stenosis (ACS) often vary considerably and extend from a conservative approach with risk factor modification and best medical treatment (BMT) alone, to a more aggressive approach with a carotid intervention plus BMT. The aim of the current multispecialty position statement is to reconcile the conflicting views on the topic. MATERIALS AND METHODS: A literature review was performed with a focus on data from recent studies. RESULTS: Several clinical and imaging high-risk features have been identified that are associated with an increased long-term ipsilateral ischemic stroke risk in patients with ACS. Such high-risk clinical/imaging features include intraplaque hemorrhage, impaired cerebrovascular reserve, carotid plaque echolucency/ulceration/ neovascularization, a lipid-rich necrotic core, a thin or ruptured fibrous cap, silent brain infarction, a contralateral transient ischemic attack/stroke episode, male patients < 75 years and microembolic signals on transcranial Doppler. There is growing evidence that 80-99% ACS indicate a higher stroke risk than 50-79% stenoses. CONCLUSIONS: Although aggressive risk factor control and BMT should be implemented in all ACS patients, several high-risk features that may increase the risk of a future cerebrovascular event are now documented. Consequently, some guidelines recommend a prophylactic carotid intervention in high-risk patients to prevent future cerebrovascular events. Until the results of the much-anticipated randomized controlled trials emerge, the jury is still out regarding the optimal management of ACS patients.

Use of the walking impairment questionnaire as a measure of functional assessment.

Background: A significant consequence of peripheral arterial disease (PAD) is an impaired functional capacity and deteriorated quality of life. Therefore, our study aimed to investigate the usefulness of a symptom questionnaire and walk tests for the determination of the functional capacity of patients with intermittent claudication. Patients and methods: The study included 53 patients (38 males) with stable claudication distance (50-300m). A detailed history and physical examination, ankle-brachial index (ABI), treadmill exercise test, and 6-minute walk test were performed and compared to walking impairment questionnaire (WIQ). Results: Claudication distance reported from patients' history and 6-minute walk test were significantly correlated with ABI (p=0.033, p=0.044). There were no significant correlations between ABI and treadmill walk test or WIQ. Results of WIQ were significantly correlated with the history and the most of performed walk tests: treadmill initial and maximal claudication distance (p=0.004 and 0.012, respectively) and 6-minute walk test (p=0.026). 6-minute walk test was correlated with maximal claudication distance of treadmill (p=0.018), but not with an initial claudication distance. Conclusions: The validity of WIQ is comparable to walk tests and represents the useful technique for the investigation of the functional capacity of patients with PAD. A self-report based on WIQ enables a longer period of observation. It should be routinely used as a basic diagnostic tool for the estimation of the functional capacity of PAD patients with stable intermittent claudication.

Lipid-lowering and anti-thrombotic therapy in patients with peripheral arterial disease.

Patients with peripheral arterial disease (PAD) are at very high risk of cardiovascular events, but risk factor management is usually suboptimal. This Joint Task Force from the European Atherosclerosis Society and the European Society of Vascular Medicine has updated evidence on the management on dyslipidaemia and thrombotic factors in patients with PAD. Guidelines recommend a low-density lipoprotein cholesterol (LDLC) goal of more than 50% reduction from baseline and <1.4 mmol/L (<55 mg/dL) in PAD patients. As demonstrated by randomized controlled trials, lowering LDL-C not only reduces cardiovascular events but also major adverse limb events (MALE), including amputations, of the order of 25%. Addition of ezetimibe or a PCSK9 inhibitor further decreases the risk of cardiovascular events, and PCSK9 inhibition has also been associated with reduction in the risk of MALE by up to 40%. Furthermore, statin- based treatment improved walking performance, including maximum walking distance, and pain-free walking distance and duration. This Task Force recommends strategies for managing statin-associated muscle symptoms to ensure that PAD patients benefit from lipid-lowering therapy. Antiplatelet therapy, either daily clopidogrel 75 mg or the combination of aspirin 100 mg and rivaroxaban (2×2.5 mg) is also indicated to prevent cardiovascular events. Dual pathway inhibition (aspirin and rivaroxaban) may be considered following revascularization, taking into account bleeding risk. This Joint Task Force believes that adherence with these recommendations for lipid-lowering and antithrombotic therapy will improve the morbidity and mortality in patients with PAD.

Why to evaluate the functional capacity in PAD patients?

In patients with peripheral arterial disease (PAD), the ability to perform physical exercise is an essential and most important indicator of a patient's health and quality of life. In many cases, there exists a discrepancy between lower extremity blood flow, the extent of arterial occlusion shown by morphological investigation and functional impairment. Reversal of lower extremity arterial obstruction with revascularization does not always reverse functional impairment of diseased leg. Further, training exercise and drug treatment can improve functional performance although they are not associated with an improvement in arterial obstruction. Therefore, the determination of functional impairment and its recovery after different therapeutic procedures should be determined using objective tests. The most frequently used functional tests are treadmill exercise testing and a 6-minute walk test. The constant load test, in which results are expressed as a walked distance, does not always permit an accurate assessment of the full range of functional impairment of PAD patients. Recently, as a substitute for a constant-load test, the graded treadmill test is used. With this test, it is possible to identify those individuals with exercise limitations who are not caused only by deterioration of the blood flow of lower limbs. The 6-minute walk test is simple to perform and requires minimal equipment. However, the correlation between the 6-minute walk test and the graded treadmill test is relatively weak, indicating that peak performance on a graded treadmill may reflect different pathophysiological mechanisms of limitations. In conclusion: for the determination of limitations of mobility and quality of life in patients with PAD, objective measures of functional impairment are needed. The determination of functional capacity is related to the quality of life and is a useful tool for investigation of the success of revascularization of peripheral arteries and conservative treatment.

Factors influencing recanalization of thrombotic venous occlusions.

The outcome of a thrombotic vessel occlusion is related to the resolution of thrombus and restitution of blood flow. Thrombus formation simultaneously activates an enzymatic process that mediates endogenous fibrinolysis to maintain vessel patency. The balance between coagulation and fibrinolysis determines the extent of thrombus formation, its resolution, and clinical outcome. Endogenic fibrinolysis is frequently unable to overcome coagulation and to resolve the thrombus. Therefore, for a complete resolution of thrombus in an acute phase, exogenic fibrinolytic agents are needed. Currently, tissue plasminogen activator (tPA) is most frequently used for therapeutic thrombolysis. Also, heparins, particularly low-molecular-weight heparins and direct oral anticoagulants which are known as anticoagulant drugs, have some pro-fibrinolytic properties. Besides the extent and age of a clot, different other factors influence the lysis of thrombus. Thrombus structure is one of the most important determinants of thrombus lysis. The concentration of thrombolytic agent (tPA) around and inside of thrombus importantly determines clot lysis velocity. Further, flow-induced mechanical forces which stimulate the transport of thrombolytic agent into the clot influence thrombolysis. Inflammation most probably represents a basic pathogenetic mechanism of activation of coagulation and influences the activity of the fibrinolytic system. Inflammation increases tissue factor release, platelet activity, fibrinogen concentration and inhibits fibrinolysis by increasing plasminogen activator inhibitor 1. Therefore, recanalization of a thrombotic vessel occlusion is inversely related to levels of some circulating inflammatory agents. Consequently, inhibition of inflammation with anti-inflammatory drugs may improve the efficacy of prevention of thromboembolic events and stimulate recanalization of thrombotic occlusions of veins.

Deep vein thrombosis and properties of the arterial wall.

BACKGROUND: Deep vein thrombosis (DVT) affects more than one out of 1,000 people every year, of which 50 % develop post-thrombotic syndrome (PTS). Studies indicated that patients with DVT have deteriorated arterial wall function, while less is known about the association with PTS. We therefore investigated this relationship further. PATIENTS AND METHODS: A total of 120 patients treated for DVT of the lower extremity and a control group of 40 subjects without DVT were included. We assessed the presence of PTS using the Villalta scale. Flow-mediated dilation (FMD) and nitroglycerin-mediated dilation (NMD) were calculated and reactive hyperaemia index (RHI) and augmentation index (AI) were obtained. RESULTS: Patients with a history of DVT had lower FMD (4.0 % vs. 8.0 %, p < 0.001), lower NMD (12 % vs. 19 %, p = 0.001), and increased diameter of brachial artery (4.8 mm vs. 4.4 mm, p = 0.017). Peripheral arterial tonometry showed higher AI in patients with DVT (22.0 vs. 6.0, p = 0.004), while there was no difference in RHI. No differences in values between PTS-positive and PTS-negative patients were found. CONCLUSIONS: We confirmed the association between DVT and deteriorated functional properties of the arterial wall. Endothelial dysfunction of the large arteries, increased arterial stiffness, and increased diameter of the brachial artery were found in patients with DVT. However, there was no association between functional capability of the arterial wall and the incidence of PTS in DVT patients.

Insufficient Recanalization of Thrombotic Venous Occlusion-Risk for Postthrombotic Syndrome.

PURPOSE: To investigate the relationship between recanalization rate of occluded veins after deep venous thrombosis (DVT) and development of postthrombotic syndrome (PTS). MATERIALS AND METHODS: Patients treated for DVT of the lower limbs were evaluated 12-36 months after acute DVT. Of 100 patients, 34 developed PTS, defined as Villalta score of ≥ 5. Symptoms and signs of PTS were assessed, and ultrasound examination of the veins was performed, checking for residual thrombus and presence of reflux. RESULTS: Patients with PTS were older (64.0 y vs 55.5 y; P = .007) and more frequently experienced recurrent DVT (15% vs 3%; P = .030). Patients with PTS had a lower rate of recanalization. Patients with residual thrombus appeared to be at increased risk for PTS development compared with patients with total recanalization (odds ratio 6.0; 95% confidence interval, 1.7-21.9; P = .006). No difference in the presence of reflux was observed. CONCLUSIONS: Incomplete or absent recanalization is associated with a higher incidence of PTS, probably as a consequence of deteriorated blood flow and increased venous pressure. This suggests early recanalization could improve the outcome of DVT treatment in selected patients.

Relationship between endothelial function of micro- and macrocirculation in patients with peripheral arterial disease.

BACKGROUND: In the pathogenesis of peripheral arterial occlusive disease (PAD), different risk factors of atherosclerosis are involved which stimulate the development of the functional and morphological deterioration of vessel walls in macro- and microcirculation. The endothelial dysfunction (ED) of macrovessels has been proven, however, data on ED in microcirculation are sparse. Therefore, we have studied the relationship between micro- and macrocirculation in PAD patients. PATIENTS AND METHODS: The study included 85 participants: 30 patients had PAD without diabetes mellitus, 30 patients had PAD and diabetes mellitus type 2, and 25 were healthy controls. Flow-mediated dilation (FMD) and endothelium-independent dilation (NMD) were studied as markers of macrocirculation, while ED of microcirculation was determined by peripheral arterial tonometry, which enabled calculation of the reactive hyperemia index (RHI). Simultaneously, the augmentation index (AI) as a measure of arterial stiffness was calculated. RESULTS: In comparison to healthy subjects, PAD patients had reduced FMD (5.7 ± 1.3 % vs. 10.0 ± 2.4 %, p < 0.001) and significantly decreased NMD (11.0 ± 2.9 % vs 23.0 ± 9.0 %, p < 0.001). Low-flow-mediated constriction was not significantly different between the groups. In both groups of patients, RHI was significantly lower than in the controls (1.75 ± 0.45 vs. 2.05 ± 0.54, p = 0.033). Furthermore, AI as an indicator of arterial stiffness was significantly higher in patient groups than in controls. However, there were no significant differences between the groups of PAD patients with and without diabetes mellitus in indicators of the functional capability of micro- and macrocirculation. An interrelationship was shown between risk factors and both FMD and NMD. Significant correlation was also found between FMD and RHI, as was a borderline correlation between FMD and AI. CONCLUSIONS: In PAD patients with and without diabetes, the functional capability of the entire arterial system is deteriorated. These patients have ED in micro- and macrocirculation, as well as increased arterial stiffness.
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ESVM guidelines - the diagnosis and management of Raynaud's phenomenon.

Regarding the clinical diagnosis of Raynaud's phenomenon and its associated conditions, investigations and treatment are substantial, and yet no international consensus has been published regarding the medical management of patients presenting with this condition. Most knowledge on this topic derives from epidemiological surveys and observational studies; few randomized studies are available, almost all relating to drug treatment, and thus these guidelines were developed as an expert consensus document to aid in the diagnosis and management of Raynaud's phenomenon. This consensus document starts with a clarification about the definition and terminology of Raynaud's phenomenon and covers the differential and aetiological diagnoses as well as the symptomatic treatment.

Non-coronary atherosclerosis.

During the last decades, the clinical and research interest in atherosclerosis has been mostly focused on coronary arteries. After the publications of the European Society Guidelines and AHA/ACC Guidelines on Peripheral artery diseases, and of the Registry REduction in Atherothrombosis for Continued Health Registry, there has been an increased interest in atherosclerosis of the lower extremity arteries and its presence in multifocal disease. However, awareness in the general population and the medical community of non-coronary artery diseases, and of its major prognostic implications remain relatively low. The aim of this general review stemming out of an ESC Working Group on Peripheral Circulation meeting in 2011 is to enhance awareness of this complex disease highlighting the importance of the involvement of atherosclerosis at different levels with respect to clinical presentation, diagnosis, and co-existence of the disease in the distinct arterial territories. We also emphasize the need of an interdisciplinary approach to face the broad and complex spectrum of multifocal disease, and try to propose a series of tentative recommendations and measures to be implemented in non-coronary atherosclerosis.

Markers of preclinical atherosclerosis and their clinical relevance.

The estimation of risk for atherosclerotic and cardiovascular events based only on the presence of classical risk factors is often insufficient. Therefore, efforts have been made to find markers that indicate the presence of preclinical disease in individual subjects: blood markers of atherosclerosis and preclinical deterioration of the arterial wall. Elevated levels of several inflammatory mediators have been found in subjects with atherosclerosis. Increased basal levels of cytokines, the cell adhesion molecules, selectins and acute-phase reactants such as high sensitive C-reactive protein (hsCRP), fibrinogen, and serum amyloid A are related to an increased risk of cardiovascular events. For clinical purposes, the most promising inflammatory biomarker appears to be hsCRP. In the last decade, markers of plaque stability and unstable coronary artery disease have been sought. Further, markers of endothelial dysfunction, like circulating molecules as well as indicators of functional deterioration of the arterial wall were identified. It was shown that endothelial dysfunction is closely related to different risk factors of atherosclerosis, and to their intensity and duration. Intima-media thickness measurement has emerged as one of the methods of choice for determining the anatomic extent of preclinical atherosclerosis and for assessing cardiovascular risk.Determination of markers of preclinical atherosclerosis improve individual risk determination and could influence the decision of a clinician to intervene with medication and to use more aggressive treatment of risk factors in high risk subjects and in patients with atherosclerotic disease.

Do the Effects of Secondary Prevention of Cardiovascular Events in PAD Patients Differ from Other Atherosclerotic Disease?

Atherosclerosis is considered a generalized disease. Similar or identical etiopathogenetic mechanisms and risk factors are involved in various atherosclerotic diseases, and the positive effects of preventive measures on atherogenesis in different parts of the arterial system were shown. However, until know, great emphasis has been placed on the aggressive pharmacological management of coronary artery disease (CHD), while less attention has been devoted to the management of peripheral arterial disease (PAD), despite its significant morbidity and mortality. Data on the efficacy of preventive measures in PAD patients have mostly been gained from subgroup analyses from studies devoted primarily to the management of coronary patients. These data have shown that treatment of risk factors for atherosclerosis with drugs can reduce cardiovascular events also in patients with PAD. The effects of some preventive procedures in PAD patients differ from coronary patients. Aspirin as a basic antiplatelet drug has been shown to be less effective in PAD patients than in coronary patients. The latest Antithrombotic Trialists' Collaboration (ATC) meta-analysis demonstrates no benefit of aspirin in reducing cardiovascular events in PAD. Statins reduce cardiovascular events in all three of the most frequently presented cardiovascular diseases, including PAD to a comparable extent. Recent studies indicate that in PAD patients, in addition to a reduction in cardiovascular events, statins may have some hemodynamic effects. They prolong walking distance and improve quality of life. Similarly, angiotensin enzyme inhibitors are also effective in the prevention of cardiovascular events in coronary, cerebrovascular, as well as PAD patients and show positive effects on the walking capacity of patients with intermittent claudication. In PAD patients, the treatment of hypertension and diabetes also effectively prevents cardiovascular morbidity and mortality. As PAD patients are at a highest risk of cardiovascular complications, the risk factors of atherosclerosis should be treated intensively in this group of patients. Most of the preventive measures, including the drugs used for prevention of CHD, are also effective in PAD patients.

Statins and Venous Thromboembolic Disease - Where are we Now?

Classical risk factors for atherosclerosis also play a role in the pathogenesis of venous thromboembolism (VTE). Low-density lipoprotein cholesterol has prothrombotic and endothelium- deteriorating effects which are not limited to the arterial system. The association between hypercholesterolemia and VTE has been established, but the benefits of statins in the prevention of VTE assessed by observation studies seemed equivocal. The large, randomized trial Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) recorded the occurrence of VTE as a protocol-specified endpoint and reported a reduced incidence of VTE among subjects taking 20 mg of rosuvastatin daily vs placebo (hazard ratio 0.57; 95% confidence interval 0.37-0.86; p=0.007). Similar results were confirmed by meta-analyses of observation studies and randomized trials. Recently, a Mendelian randomization study that took the presence of gene variants coding for less efficient hydroxymethyl-glutaryl coenzyme A reductase activity as a proxy for statin treatment, confirmed a small, but significant negative association between the score of selected genetic polymorphisms and the incidence of VTE. However, since the protective effects of statins are limited, they should not be substituted for guideline-recommended VTE prophylaxis or anticoagulation treatment.