Current Vascular Pharmacology - Volume 9, Issue 1, 2011

Venous thromboembolism (VTE) including lower limb deep vein thrombosis (DVT) and pulmonary embolism (PE) remain important causes of peri-operative morbidity and mortality. This is particularly true following major lower limb and pelvic procedures. Pathogenesis is multi-fold and relates to intra-operative physical venous occlusion, direct and indirect damage to vessel walls and generalized activation of the coagulation cascade secondary to surgical trauma [1]. Historical studies suggest that without thromboprophylactic protection, such events are extremely common post-operatively, with reported rates of DVT as high as 70% [1, 2]. These figures vary greatly however, and appear to be significantly influenced by a variety of factors. For example, the very low rates reported in Asian studies suggest that ethnicity and genetic predisposition may play a major role [3- 5]. Whilst it has been demonstrated that a large number of orthopaedic patients develop calf vein thrombi intra-operatively, the vast majority of these appear to resolve spontaneously without clinical consequence, removed by the body's inherent fibrinolytic system [6]. It would appear that in only a small number of patients do these blood clots propagate causing obstruction of local vasculature or pulmonary embolism. Reported rates of fatal PE are very low, probably less than 0.5% even in those not receiving thromboprophylaxis, suggesting that small venous thromboses may not be as important as has previously been suggested [7, 8]. In patients receiving perioperative low molecular weight heparin (LMWH), radiologically determined rates of DVT remain as high as 13% following hip and 38% following knee replacement. Similar to the pattern seen in unprotected patients, the incidence of clinically significant thrombosis appears to be far lower than this, probably less than 1%. Though rates of fatal pulmonary embolism remain low they are little reduce from those seen in unprotected patients [8, 9]. The use of radiographically determined thrombosis as a surrogate end-point for clinically relevant VTE (pulmonary embolism or post-phlebitic limb) in many studies makes the literature difficult to interpret and has more recently been criticized. Furthermore, the majority of clinically significant thrombotic events appear to occur following discharge from hospital, calling into question our understanding of the natural history of the condition and current thromboprophylaxis protocols which are for the most part in-patient only [10]. This has lead to increasing interest in the concept of prolonged post-discharge therapy. The parenteral route of administration for LMWHs and regular testing required for Warfarin make this approach potentially troublesome. More recently however, several new oral agents have been introduced that require no laboratory monitoring in order to maintain safe levels of anticoagulation and it may be that these prove to be a solution to this problem [11-14]. As with any new intervention, the financial and clinical implications of such an approach must be carefully considered prior to widespread implementation. Therefore, despite extensive study of the subject and the publication of multiple guidelines, understanding of post-operative VTE is far from complete and opinion as to the optimum prophylactic regime remains divided. Attempts to introduce national protocols have proved controversial with some parties feeling that the suggested treatments are excessively expensive and introduce a disproportionate risk of complication given the actual clinical risk presented by VTE [15, 16]. This special supplement is intended as an update on current concepts in this field. It contains review articles, original data and meta-analysis including papers discussing the use of fondaparinux, evidence for the use of low molecular weight heparins in orthopaedic practice, the timing of chemical thromboprophylaxis, potential targets for a new generation of anti-coagulants as well as current evidence for thromboprophylaxis following bilateral total hip replacement, total knee replacement, pelvic trauma and noncardiac vascular surgery. It should provide evidence to support decision making in this area and useful information regarding potential future avenues of development.

Strategies for prevention of venous thromboembolism in orthopaedic patients undergoing major lower limb surgery include pharmacological prophylaxis. Over the last three decades, the search for new safe and effective approaches for the prevention of venous thromboembolism in these patients has continued. Increased understanding of the haemostatic process has led to a clearer appreciation of the mechanisms of action of antithrombotic drugs already in use as well as the identification of new targets for novel drug development. As a result, the development of new anticoagulants has advanced rapidly over recent years. The molecular targets of several novel anticoagulants, and their effectiveness in early Phase II and Phase III trials are reviewed.

Patients undergoing major orthopaedic surgery of the lower extremities or spine are at increased risk of venous thromboembolism (VTE). Although consensus exists as to the need for routine thromboprophylaxis in high risk patients, some aspects of this approach, such as the timing of the first dose and overall duration of the anticoagulation regimen, are subject to debate. Reviewing the available literature, there appears to be little evidence to support initiation of thromboprophylaxis more than 12 hours before surgery. Perioperative thromboprophylaxis (2 hours pre to 6 hours post -op) has been associated with an increased risk of bleeding complications whilst initiating prophylaxis more than 12 hours after surgery appears to increase the incidence of subsequent thromboembolic complications. Overall evidence would appear to support initiation of thromboprophylaxis 6 to 9 hours postoperatively, though further confirmatory studies investigating this variable in isolation would be useful to guide clinical decision making. Although evidence exists supporting extended duration thromboprophylaxis after major orthopaedic procedures, further evidence is required, using clinically important end points, prior to adoption of such an approach in all patients. Stratification of prophylaxis duration, based on risk factors for thromboembolic or bleeding complications, would seem a more rational approach than strict adherence to guidelines.

Low molecular weight heparin (LMWH) is used in orthopaedic surgery largely for prophylaxis of venous thromboembolism (VTE). The purpose of this study was to review the available evidence to better define its role. The most recent American College of Chest Physicians Evidence-Based Practice guidelines for the most current recommendations for the application of LMWH to orthopaedic surgery are reviewed. A systematic review of the literature was undertaken using MEDLINE database and manual searches. The terms low molecular weight heparin, orthopaedic procedures, venous thromboembolism, and thromboprophylaxis were used as keywords. A total of 34 studies were identified, including prospective, randomised controlled clinical studies comparing LMWH with other treatment methods in orthopaedic surgery patients, meta-analysis and health economic related studies. There is clear supporting evidence for the application of LMWH for DVT prophylaxis in orthopaedic surgery. Although newer agents such as oral thrombin inhibitors are being developed for DVT prophylaxis, it will take some time to adequately assess the clinical efficacy, safety, and costeffectiveness of these newer agents. Whether these agents will ultimately supplant the widespread application of LMWH to orthopaedic surgery remains to be seen.

We conducted a thorough search of all the English language literature and carried out a meta-analysis in an attempt to reveal potential differences on the incidence of deep vein thrombosis (DVT) and pulmonary embolism (PE) between one stage bilateral and unilateral total hip replacements, and to provide, if possible, recommendations on thromboembolic prophylaxis. We identified 37 citations eligible for inclusion. A total of 5868 bilateral simultaneous THR patients were identified. Analysis of data was performed with the Mantel-Haenszel method. Meta-analysis of homogeneous data revealed no statistically significant differences in the rates of deep vein thrombosis (p = 0.40) and pulmonary embolism (p = 0.39) when comparing staged with bilateral simultaneous THR procedures as well as the rates of pulmonary embolism when comparing bilateral simultaneous THR with unilateral procedures (p = 0.69). However, deep vein thrombosis rate was in favor of bilateral two-stage compared to unilateral THR (p = 0.00001). Definite recommendations regarding the prevention of thromboembolic events in bilateral simultaneous THR could not be produced as the literature was limited and the data heterogenic. Conclusively, deep vein thrombosis and pulmonary embolism is not increased in bilateral simultaneous THR, provided that appropriate prophylactic measures are taken. More data are needed in order to clarify if additional measures or altered protocols of thromboembolic prophylaxis should be followed.

Thromboembolic disease remains one of the most devastating and potentially lethal complications after elective total knee replacement (TKR) surgery. Studies have shown that 40-85% of patients undergoing TKR will develop venographically confirmed deep vein thrombosis (DVT) if they are not given any type of post-operative thromboprophylaxis and approximately 0.1 to 1.7% will suffer fatal pulmonary embolism (PE). Consequently, there is a general consensus that patients undergoing elective TKR require adequate antithrombotic prophylaxis. The following article reviews current evidence regarding chemical thromboprophylaxis after total knee replacement. Clinical guidelines as described by the American Academy of Orthopaedic Surgeons (AAOS), the American College of Chest Physicians (ACCP) and the UK's National Institute for Health and Clinical Excellence (NICE) are summarized along with the differences between the recommendations. The results of the new oral anticoagulants are reviewed as well as the most recent developments in the search for the most effective venous thromboembolism (VTE) prophylaxis after TKR surgery.

Surgery for pelvic or acetabular fractures carries a high risk of deep-vein thrombosis (DVT). Reports indicate that fondaparinux is a more effective thromboprophylactic agent than low molecular weight heparin (LMWH) after major orthopaedic surgery. The safety and efficacy of fondaparinux was evaluated in a new protocol used for DVT prophylaxis. One hundred and twenty seven patients with pelvic or acetabular fractures received either fondaparinux or enoxaparin and were analysed in a historical non-concurrent study. Specific review points included clinical deep-vein thrombosis (DVT) or pulmonary embolism (PE) and evidence of adverse effects such as bleeding or allergic reactions. Two patients that received enoxaparin were found to have a DVT and one patient had a PE. There was no documented DVT or PE in patients that received fondaparinux. The mean number of units of blood transfused postoperatively was higher in the enoxaparin group; however, multivariate regression modelling demonstrated no significant difference between the groups. The most current large randomised controlled studies investigating the administration of fondaparinux following joint arthroplasty or hip fracture surgery, have demonstrated a slight increase or a similar number of bleeding events in patients treated with fondaparinux when compared to those treated with enoxaparin. The current report supports that fondaparinux, in patients with pelvic and acetabular fractures, can be equally effective as enoxaparin and not associated with adverse bleeding events.

Patients undergoing non-cardiac vascular surgery (NCVS) are at high risk of developing perioperative venous and arterial thrombotic complications. Effective thromboprophylaxis is an essential part of the perioperative management of patients undergoing surgical procedures. To ensure appropriate delivery of antithrombotic agents and standardise clinical practice, numerous national and international guidelines have been developed in recent years. Very few of these recommendations are designed specifically for patients undergoing NCVS. This review aims to highlight the relevant guidelines and novel recommendations that are available for patients undergoing NCVS while noting their limitations and providing suggestions for specific subsets.

For decades, parenteral drugs, such as the low molecular weight heparins and unfractionated heparins or vitamin K antagonists, have been used as anticoagulants for prevention of venous thromboembolism following major lower limb surgery. However, these regiments have limitations that rendered the quest for new anticoagulants mandatory. Recently, research has been focused on the development of orally active small molecules that directly target thrombin or activated factor X (FXa). These regiments exhibit a number of characteristics that an “ideal” anticoagulant should possess. Currently, two agents, dabigatran etexilate and rivaroxaban, which inhibit thrombin and FXa, respectively have been approved in the European Union and Canada for venous thromboprophylaxis in patients undergoing elective hip- or kneereplacement surgery. Other agents are at an early or late stage of clinical evaluation. In this study, we summarize the current evidence for these new developed or under development drugs regarding their applications in the filed of lower limb orthopaedic surgery.

Atherosclerosis is known to increase the prevalence of metabolic disorders such as dyslipidemia, diabetes, and metabolic syndrome. Dyslipidemia, especially elevated levels of low-density lipoprotein (LDL)-cholesterol, is central to the management of patients at risk of atherosclerosis [1]. Traditional LDL-cholesterol lowering-therapy has focused on modifying the endogenous lipid pathway using HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors, statins. Intensive LDLcholesterol reduction with statins is associated with improved clinical outcomes in the setting of coronary artery disease [2-4], but is sometimes associated with an increased incidence of adverse drug reactions when traditional agents are used [5]. Ezetimibe (Zetia®), is a comparatively new discovered selective inhibitor of cholesterol absorption, has proved to be highly effective in lowering LDL-cholesterol with both monotherapy and combination therapy with statins [6]. Ezetimibe is expected to be the best pharmacological option for the treatment of patients unable to achieve ideal LDL-cholesterol goals with statins [7]. In recent studies, ezetimibe improved not only lipoprotein profiles but also metabolic disorder and fatty liver disease by suppressing intestinal chylomicrons production in patients with hypercholesterolemia [8, 9]. Although much evidence has revealed preventive effects of ezetimibe on atherosclerosis in several animal models, there is currently little evidence proving that treatment with ezetimibe is effective against cardiovascular events or death in humans; therefore, choosing ezetimibe to lower LDL-cholesterol is currently controversial [5]. This special issue of Current Vascular Pharmacology (CVP) is dedicated to vascular protective effects of ezetimibe focused on the recent findings of ezetimibe in vascular system. Moreover, known and proposed mechanisms of how ezetimibe may improve various vascular functions are discussed; these effects may be helpful to explain the mechanisms by which ezetimibe may protect vascular from atherosclerosis. The purpose of this special issue of CVP is to remind readers of the evidence-based therapeutic possibility of ezetimibe and of its clinical relevance. Reviews have been written by forefront experts on data obtained from experimental animal models and/or clinical studies. A variety of excited topics are covered including ezetimibe: an update after 4 years (Chapter 1), effects of ezetimibe on: vascular endothelial function (Chapter 2), vascular inflammation from the view of immune response (Chapter 3), reactive oxygen species (Chapter 4), hepatic metabolism (Chapter 5), and vascular calcification and metabolism (Chapter 6). We hope this special issue will help investigators in the field of prevention for cardiovascular disease and atherosclerosis to understand recent ezetimibe-related studies and find new aspects.

Ezetimibe (EZE), a selective inhibitor of intestinal cholesterol absorption, is mostly used in combination with statins across various patient populations. Besides its low-density lipoprotein cholesterol (LDL-C) lowering, EZE exerts different effects on several other variables. In an earlier review, we discussed the effects of EZE on lipid parameters other than LDL-C [e.g. C-reactive protein (CRP) levels, insulin sensitivity and endothelial function]. In the present review, we consider recent evidence regarding these topics as well as data reporting novel EZE actions. EZE may protect from cholelithiasis and non-alcoholic fatty liver disease (NAFLD) and appears as an effective lipid-lowering treatment option for human-immunodeficiency virus (HIV)-positive patients, transplant recipients and children with familial hypercholesterolaemia (FH). Studies with EZE that raised concern about its effects on atherosclerosis are also discussed. The potential clinical benefit of these actions with respect to vascular events and overall mortality remains to be established in appropriately designed trials.

Hypercholesterolemia is a major risk factor for cardiovascular diseases that has been managed mostly with 3- hydroxy-3-methyl glutaryl coenzyme A reductase inhibitors (statins) that suppress de novo cholesterol synthesis in the liver. Statins also have beneficial pleiotropic effects on the atherosclerotic process that are independent of their ability to lower lipid values. However, the levels of low-density lipoprotein cholesterol (LDL-C) in most hypercholesterolemic patients at high risk for cardiovascular disease do not reach the goals proposed by guidelines even when prescribed with statins. Ezetimibe is a new lipid-lowering agent that blocks the intestinal absorption of dietary and biliary cholesterol and reduces LDL-C levels, especially when combined with statins. However, its effect on cardiovascular events remains unknown. We reviewed the effects of ezetimibe on cardiovascular diseases, in particular, vascular endothelial function, which is initially impaired during the atherogenetic process and is an important predictor of cardiovascular events. The simultaneous inhibition of cholesterol synthesis by statin and of cholesterol absorption by ezetimibe might retard the atherogenetic process. These effects are considered to be mainly mediated by lipid lowering. However, further studies should elucidate the mechanism of the anti-atherosclerotic effects induced by ezetimibe; for instance, whether or not it directly affects atherogenesis independently from its lipid-lowering effects.

Atherosclerosis is an inflammation-based complex vascular disorder which causes coronary artery disease, stroke and peripheral artery disease. Its pathophysiological process consists of endothelial dysfunction, monocyte adhesion to endothelial cells, lipid and inflammatory cell accumulation in the vascular wall, and migration and proliferation of smooth muscle cells. Both hyperlipidemia and inflammation are profoundly involved in each step. Cholesterol lowering by HMG-CoA reductase (statin) is beneficial for treating atherosclerotic coronary artery disease and stroke, together with reducing a surrogate-marker of inflammation, C-reactive protein (CRP). Another recently established cholesterol lowering tool using an intestinal cholesterol absorption inhibitor, ezetimibe, has been applied for clinical treatment of hypercholesterolemia for several reasons. First, hypercholesterolemia is associated with increased intestinal cholesterol absorption. Second, low cholesterol absorption prevents cardiovascular events. Third, cholesterol metabolism analysis provides evidence that the long-term use of statin increases cholesterol absorption. In terms of low-density lipoprotein cholesterol (LDL-C) and CRP reductions, the more powerful effect of ezetimibe has been seen when the agent is combined with statins. However, the effect of ezetimibe monotherapy on CRP reduction has not been well defined. This review provides information on recently described clinical trials of ezetimibe monotherapy, stain monotherapy, and combined therapy for LDL-C lowering and vascular inflammation.

Ezetimibe is a potent inhibitor of cholesterol absorption that has been approved for the treatment of hypercholesterolemia. Statin, 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, is an inhibitor of cholesterol synthesis. Statin is the first-choice drug to reduce low-density lipoprotein (LDL)-cholesterol for patients with hypercholesterolemia, due to its strong effect to lower the circulating LDL-cholesterol levels. Because a high dose of statins causes concern about rhabdomyolysis, it is sometimes difficult to achieve the guideline-recommended levels of LDLcholesterol in patients with high LDL-cholesterol treated with statin monotherapy. Ezetimibe has been reported to reduce LDL-cholesterol safely with both monotherapy and combination therapy with statins. Ezetimibe is especially expected to be the best pharmacological option for the treatment of patients unable to achieve LDL-cholesterol goals with statins. Reactive oxygen species (ROS) are produced at low levels to maintain physiological redox balance. Oxidative stress results when ROS production exceeds the ability of cells to detoxify ROS. Overproduction of ROS damages cellular components, including lipids, leading to decline in physiological function and cell death. Oxidative stress exacerbates atherosclerosis, the major risk factor for coronary artery disease and ischemic stroke, at every step involves the accumulation of oxidized LDL in the arteries, leading to foam cell formation, plaque development, and plaque rupture. This review focuses on the recent findings of ezetimibe-related atheroprotective effects in vasculature. Moreover, known and proposed mechanisms of how ezetimibe could improve ROS-induced pro-atherosclerotic conditions in vasculature are discussed; these effects may help to explain the mechanisms by which ezetimibe may protect vascular from atherosclerosis.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries and also in other parts of the world. NAFLD encompasses a histological spectrum ranging from simple steatosis to steatohepatitis, advanced fibrosis and inflammatory changes. It frequently occurs with features of the metabolic syndrome including obesity, type 2 diabetes mellitus, dyslipidemia and hypertension. In fact, the metabolic syndrome is a strong predictor of NAFLD. Recently, Niemann-Pick C1-like 1 (NPC1L1) has been shown to play a pivotal role in cholesterol absorption. Unlike mouse NPC1L1 protein, predominantly expressed in the intestines, human and rat NPC1L1 is also abundantly expressed in the liver. Though the exact functions of hepatic NPC1L1 remain unknown, NPC1L1 may facilitate the hepatic accumulation of cholesterol. This raises a potential possibility that ezetimibe may improve fatty liver formation. In this review, potential role of lipid metabolism in NAFLD and its possible modulation through NPC1L1 blockade is discussed.

Vascular calcification is recently considered as one of the major complications and an independent risk factor of cardiovascular diseases. Although vascular calcification was commonly regarded as a passive process of mineral adsorption or precipitation, it tends to be an active process associated with the expression of growth factors, matrix proteins, and other bone-related proteins. There are 2 main types of vascular calcification. Intimal calcification is found in atherosclerotic plaques and is associated with the vascular events such as myocardial infarction. Medial calcification is usually associated with age and chronic kidney disease patients, which leads to increased vascular stiffness and reduced vascular compliance. Interestingly, our vascular calcification model using ApoE deficient mice showed intima calcification at sites of atherosclerotic plaques under high fat diet with ovariectomy. Thus, lipid metabolism is one of the therapeutic targets to prevent intima calcification of aorta. Previously we reported that ezetimibe significantly prevented atherosclerosis through lipid-lowering effects in ApoE-deficient mice. Based on these findings, we speculate that ezetimibe might prevent aortic intima calcification, which may give us the benefits to decrease vascular events.