Prevention Of Thromboembolic Disease Research Articles

The Multimodal Approach for the Prevention of Thromboembolic Disease After Total Joint Arthroplasty

Total hip and knee arthroplasties carry an increased risk for thromboembolic disease. A multimodal prophylaxis protocol developed at the Hospital for Special Surgery and fully implemented since 1995, consists of stratifying the individual patient's risk and implementing a series of safe preventive measures before, during, and after surgery to reduce the risk of venous thromboembolism and bleeding. The measures include discontinuation of procoagulant medication and autologous blood donation before surgery; the use of hypotensive epidural anesthesia and intraoperative intravenous heparin after acetabular work during total hip arthroplasty; the use of pneumatic compression devices, elastic stockings, and frequent, vigorous dorsiflexion of the ankles; and prompt mobilization of the patient after surgery to diminish venous stasis. If these safe measures are observed, postoperative pharmacologic prophylaxis does not need to be aggressive in the patients without predisposing factors for venous thromboembolism and who mobilize promptly, thus diminishing the morbidity and mortality associated with the routine use of potent anticoagulants and the overall cost of care. Our clinical experience with close to 10,000 total hip and knee replacements demonstrates that this multimodal prophylaxis is safe and effective, resulting in a very low prevalence of thromboembolism, bleeding, and all-cause mortality.

Prevention of Venous Thromboembolism in the Cancer Surgical Patient

Venous thromboembolism is a common complication in patients with malignant disease. One of the environments in which patients can present with symptomatic thromboembolic disease is in the postoperative period. Operation in the patient with cancer increases the risk of thromboembolic complications some two to three fold. A variety of methods have been evaluated for the prevention of thromboembolic disease in cancer surgical patients. The most extensively investigated are the pharmacologic methods, including low-dose unfractionated heparin and low molecular weight heparin. These agents are recommended for the prevention of thromboembolic disease during hospital stay. For selected high-risk populations, extended thromboprophylaxis into the postdischarge period is also recommended.

Dabigatran Etexilate: Future Directions in Anticoagulant Treatment

Dabigatran etexilate is a novel, oral reversible direct thrombin inhibitor in the clinical development for the treatment and prevention of thromboembolic diseases. Clinical data indicate that dabigatran etexilate has immediate onset of effect, no need for monitoring, predictable and consistent pharmacokinetics and pharmacodynamics-all features that differentiate it from oral vitamin K antagonists (VKAs). Completed phase III studies demonstrated a comparable efficacy and safety profile to enoxaparin in the prevention of venous thromboembolism (VTE) after orthopedic surgery. Ongoing phase III trials are now evaluating the long-term use of dabigatran etexilate for the treatment and secondary prevention of VTE and for prevention of stroke in patients with atrial fibrillation, as a replacement for VKAs. With an immediate, reliable, and predictable anticoagulant effect without the need for coagulation monitoring and the lack of long-term safety concerns, dabigatran etexilate may be a prospective candidate that offers additional benefit over VKAs and parenteral anticoagulants in these settings.

Rivaroxaban: A Novel, Oral, Direct Factor Xa Inhibitor

Thromboembolic disorders such as deep vein thrombosis, pulmonary embolism, myocardial infarction, and stroke often result in long-term disability and/or mortality. The anticoagulants currently available have been effective in the treatment and prevention of these disorders; however, parenteral administration, variable pharmacokinetics and pharmacodynamics, drug and dietary interactions, and a requirement for frequent monitoring of efficacy and safety limit use of these drugs. Rivaroxaban is a novel, oral factor Xa inhibitor in clinical development for the treatment and prevention of thromboembolic diseases. Rivaroxaban is a small molecule directed at active sites, and the agent mechanistically differs from traditional anticoagulants, such as heparins and fondaparinux, in that its activity is independent of antithrombin and its ability to inhibit prothrombinase bound factor Xa. In addition, preclinical and clinical trial data indicate that rivaroxaban has predictable pharmacokinetics and pharmacodynamics, which are features that differentiate it from oral vitamin K antagonists. Phase II studies showed that rivaroxaban is safe and well tolerated across a wide range of doses. Furthermore, completed phase III studies demonstrated its efficacy in the prevention of venous thromboembolism after orthopedic surgery. Additional studies are now under way to evaluate the use of rivaroxaban in the treatment and prevention of other venous and arterial thromboembolic conditions.

Paeonol Attenuates High-Fat-Diet-Induced Atherosclerosis in Rabbits by Anti-Inflammatory Activity

Cortex Moutan (Paeonia suffruticosa Andrews, Ranunculaceae) has several uses in traditional medicine, such as analgesic, antipyretic, and anti-inflammatory applications and use in the prevention of thromboembolic diseases. Paeonol, a main active component in Cortex Moutan, possesses various pharmacological activities, particularly an anti-atherosclerosis effect. However, so far there have been no reports evaluating the anti-inflammatory action of paeonol in atherosclerosis therapy. The purpose of this study was to investigate the association of the therapeutic effect of paeonol on atherosclerotic rabbits with its anti-inflammatory action. The atherosclerotic model was developed in 24 rabbits fed a high-fat diet for 12 weeks. Twelve rabbits on the high-fat diet then were administered with paeonol (p.o) for a subsequent 6 weeks at the doses of 75 mg/kg and 150 mg/kg. Histological analysis showed significant improvement in atherosclerosis plaque in the paeonol groups. Moreover, the blood levels of TNF- alpha, IL-1 beta, and CRP and the translocation of NF- kappaB to the nucleus were significantly suppressed in paeonol groups, as was the inhibition of lipid peroxidation. In conclusion, these findings suggest that the anti-inflammatory action of paeonol may contribute to its anti-atherosclerosis effect.

Effects of CYP2C9 and VKORC1 on INR Variations and dose Requirements During Initial Phase of Anticoagulant Therapy

Anticoagulants of the coumarin type are effective drugs for the treatment and prevention of thromboembolic diseases. However, they have a narrow therapeutic range and show inter- and intra-individual variability in dose requirement, largely conditioned by both environmental and genetic factors. This prospective study investigated, during the initial phase of acenocoumarol therapy, the effect of CYP2C9 variant alleles and VKORC1 haplotypes, single and in combination, in 220 Italians. CYP2C9*3 was associated with a 25% dose reduction and an increased risk of over-anticoagulation (International Normalized Ratio [INR] > 6) on day 4. Two copies of the VKORC1*2 haplotype were associated with a 45% dose reduction and an increased risk of over-anticoagulation. Homozygosity for VKORC1*3 and VKORC1*4 was associated with an increased dose requirement and a reduced risk of over-anticoagulation. The VKORC1*3 or *4 plus CYP2C9*1 genotype combination was associated with the highest dose requirement and the lowest INR on day 4; VKORC1*2 plus CYP2C9*3 was associated with the lowest dose requirement, the highest INR and an increased risk of over-anticoagulation. Even though they spent approximately 50% of the time within the target therapeutic range, VKORC1*3 or *4 plus CYP2C9*1 carriers spent a large percentage of the remaining time below and carriers of VKORC1*2 plus CYP2C9*3 above the target range. The determination of VKORC1*3 and VKORC1*4 haplotypes may be an important addition to CYP2C9 and VKORC1*2 genotyping to identify patients at risk of being outside the target range during initial anticoagulation with acenocoumarol.

Fondaparinux : mise au point et perspectives

The development of new antithrombotic molecules which induced an inhibition of activated factor X (fondaparinux, Arixtra) shows effectiveness and safety in prevention of thromboembolic disease in surgery, but also in the treatment of the pulmonary embolism and major venous thromboses and acute myocardial infarction. Recent clinical trials show that new anti-Xa inhibitors also have interesting properties in antithrombotic therapy. Fondaparinux could offer new therapeutic possibilities that could simplify the management of patients under anticoagulant treatment.

369: B-2 gycoprotein-1 antibodies in the initial assessment of antiphospholipid antibody syndrome: A cost analysis for prevention of thromboembolic disease

PHOSPHOLIPID ANTIBODY SYNDROME: A COST ANALYSIS FOR PREVENTION OF THROMBOEMBOLIC DISEASE KIMBERLY DESTEFANO, ZOI RUSSELL, AARON DEUTSCH, RUBEN QUINTERO, University of South Florida, Tampa, Florida OBJECTIVE: B-2 Glycoprotein-1(B2GP1) antibodies are recommended as a potential secondary test for patients in whom a diagnosis of antiphospholipid antibody (APA) syndrome is suspected but not confirmed by anti-cardiolipin(ACA) or lupus anti-coagulant testing. This may result in delay of diagnosis and missed opportunity for preventative care, especially in patients already pregnant. Our objective was to use a decision analysis to assess whether inclusion of this test in the initial work-up could prove cost-effective in the prevention of thromboembolic(TE) disease in our population. STUDY DESIGN: Cost of screening for B2GP1 antibodies and number of patients screened was obtained from Tampa General Hospital (TGH) data. Probability of TE and cost of diagnosis and management was determined by literature review. Cost of thromboprophylaxis for patients with positive testing was based on average pharmaceutical prices. This information was then incorporated into a cost assessment model to determine the potential benefit. RESULTS: Seventy patients were tested at a total cost of $8610. Four were positive for B2GP1 and no other thrombophilic factor. The cost for prophylaxis in these 4 women is $1172-39508 depending on anticoagulant choice. The overall cost of screening in our study is approximately $10000-50000. The reported cost for TE diagnosis and management ranges from $17500-33100. Assuming a 50% TE rate based on literature review, 2 women in our population would be expected to have an event at a cost of $35000-66200. CONCLUSION: In our analysis, screening with B2GP1 does appear to be costeffective in prevention of TE.While there is overlap in the cost of each strategy we did not include costs of lost productivity, recurrent TE, or pregnancy complications. A larger sample size, as well as consideration of the aforementioned variables is likely to show a significant cost benefit of including B2GP1 in initial assessment of APA syndrome.

Treatment of Post-Influenza Pneumonia in Health Care Workers

Treatment of Post-Influenza Pneumonia in Health Care Workers

Foot pumps without graduated compression stockings for prevention of deep-vein thrombosis in total joint replacement: efficacy, safety and patient compliance

Mechanical prophylaxis with foot pumps provides an interesting alternative to chemical agents in the prevention of thromboembolic disease following major orthopaedic surgical procedures. Recent studies have suggested that the simultaneous use of graduated compression stockings (GCS) may hinder the pneumatic compression effect of foot pumps. The hypothesis of this prospective study was that the use of foot pumps without GCS does not affect the efficacy of deep-vein thrombosis (DVT) prophylaxis and improves patient compliance. A total of 846 consecutive patients admitted at a single institution undergoing total hip (THR) or knee replacement (TKR) were included in the study. The A-V Impulse System foot-pump unit (Orthofix Vascular Novamedix, Andover, UK) was used in all patients. Of these 846 patients, 46 discontinued the use of foot pumps, leaving 400 patients who received foot pumps in combination with GCS and 400 patients with foot pumps alone. Eleven patients of the stocking group (2.7%) and nine patients of the no-stocking group (2.3%) developed postoperative symptomatic DVT (p=0.07). DVT was more frequent in TKR (10/364; 2.7%) than in THR (10/436; 2.3%). Non-fatal pulmonary embolism occurred in four of the 20 patients with symptomatic DVT, two patients each of the stocking and no-stocking groups. The foot-pump discontinuation rate of patients treated with stockings was 7% versus 4% of the patients treated without stockings (p<0.05). In conclusion, management of patients with foot pumps without GCS does not reduce the efficacy of DVT prophylaxis after THR and TKR and improves patient compliance.

Fondaparinux is a safe alternative in case of heparin intolerance during pregnancy

Heparin is the drug of choice for the treatment or the prevention of thromboembolic disease during pregnancy. However, treatment options are limited when heparin cannot be used because of hypersensitivity skin reactions. Despite the recent availability of new anticoagulant agents, data relating to their use during pregnancy are lacking. This report describes the successful management with fondaparinux, during 150 days, of a pregnant patient with protein S deficiency and prior deep vein thrombosis (DVT) who developed heparin and danaparoid hypersensitivity.

The Pharmocogenomics of Warfarin: Closing in on Personalized Medicine

Warfarin, a coumarin anticoagulant, is used worldwide for the treatment and prevention of thromboembolic disease. Warfarin therapy, however, can be difficult to manage because of the drug's narrow therapeutic index and the wide interindividual variability in patient response. It is now clear that genetic polymorphisms in genes influencing metabolism (CYP2C9) and pharmacodynamic response (VKORC1) are strongly associated with warfarin responsiveness. Optimal warfarin dosing in turn drives other positive anticoagulation-related outcomes. Therefore, a strong basic science argument is emerging for prospective genotyping of warfarin patients. Effective clinical translation would establish warfarin pharmacogenomics as a heuristic model for personalized medicine.

Les nouveaux antithrombotiques : une thérapeutique en mutation, des perspectives d'avenir

The development of new antithrombotic molecules which induced an inhibition of activated factor X (fondaparinux), or a direct inhibition of thrombin, transforms the antithrombotic treatment. Fondaparinux (Arixtra ®) shows an effectiveness and a safety as well as low weight molecular heparin in prevention of thromboembolic disease in orthopedic surgery and in the treatment of the pulmonary embolism and major venous thromboses. The lack of interaction shown in vitro and observed during clinical trials makes this molecule a product particularly easy-to-use in antithrombotic therapy. The introduction of an active direct antithrombin (Exanta ®) per oral way opened very promising prospects in the replacement of the antivitamines K treatment. Its effectiveness and its tolerance appear very acceptable and the absence of food and drug interaction contributes to make it the ideal antithrombotic ambulatory treatment for tomorrow. Only its biological hepatic toxicity, not yet elucidated, currently delays a wider application.

Update in the prevention and treatment of deep vein thrombosis and pulmonary embolism

Thromboembolic events have a major impact on outcome of surgical and medical patients. This review is focused on standards and recent advances in antithrombotic strategies for prevention and therapy of venous thromboembolism and pulmonary embolism. Alert programs improve prophylactic strategies to prevent venous thromboembolism. Evidenced-based guidelines are available on antithrombotic and thrombolytic therapy outweighing the benefits, risks, burdens and costs. Selective factor Xa and direct thrombin inhibitors are at least as effective as low-molecular-weight heparin in prevention of venous thromboembolism and treatment of pulmonary embolism, but have fewer side effects and will not need routine monitoring. In high-risk orthopaedic patients but not in general surgery patients fondaparinux is superior to low-molecular-weight heparin in the prevention of thromboembolic disease. Ximelagatran, the first oral direct thrombin inhibitor, is as effective and well tolerated as warfarin. Long-term treatment is uncertain, however, because of elevation in alanine transaminase levels. In high-risk patients with contraindication for anticoagulation, retrievable vena cava filters may be an option to prevent pulmonary embolism. Permanent cava filters do not improve long-term survival and are associated with relevant side effects. Thrombolytics should be reserved for deep venous thrombosis complicated by limb gangrene and for life threatening pulmonary embolism. There is currently sufficient information based on guidelines available on preventive and therapeutic strategies for venous thromboembolism and pulmonary embolism. Antithrombotics are the therapeutic backbone. In high-risk orthopedic surgery and venous thromboembolism the new antithrombotics fondaparinux, idraparinux and ximelagatran are superior to standard treatment. Temporary caval filters may be a therapeutic option in high-risk patients with contraindication for antithrombotics.

Prophylaxis with Vena-Flow and Enoxaparin vs Vena-Flow and Aspirin for Thromboembolic Disease Prevention in Total Knee Arthroplasty

Prophylaxis with Vena-Flow and Enoxaparin vs Vena-Flow and Aspirin for Thromboembolic Disease Prevention in Total Knee Arthroplasty

New Oral Antithrombotic Drugs

New oral antithrombotic drugs are currently used for several indications, but mostly for the long-term treatment or prevention of thromboembolic disease in situations such as high-risk orthopedic surgery, deep vein thrombosis and myocardial infarction. They are also used in atrial fibrillation for the prevention of stroke. This family of drugs includes anti-platelet agents, eg. ticlopidine and clopidogrel, antithrombin agents, eg. ximelagatran and several others with various mechanisms of action. Oral intake has to fulfill certain conditions regarding absorption, efficacy and safety.

Population Pharmacokinetics of Melagatran, the Active Form of the Oral Direct Thrombin Inhibitor Ximelagatran, in Atrial Fibrillation Patients Receiving Long-Term Anticoagulation Therapy

Ximelagatran is an oral direct thrombin inhibitor for the prevention of thromboembolic disease. After oral administration, ximelagatran is rapidly absorbed and bioconverted to its active form, melagatran. To characterise the pharmacokinetics of melagatran in patients with nonvalvular atrial fibrillation (NVAF) receiving long-term treatment for prevention of stroke and systemic embolic events. A population pharmacokinetic model was developed based on data from three phase II studies (1177 plasma concentration observations in 167 patients, treated for up to 18 months) and confirmed by including data from two phase III studies (8702 plasma concentration observations in 3188 patients, treated for up to 24 months). The impact of individualised dosing on pharmacokinetic variability was evaluated by simulations of melagatran concentrations based on the pharmacokinetic model. Melagatran pharmacokinetics were consistent across the studied doses and duration of treatment, and were described by a one-compartment model with first-order absorption and elimination. Clearance of melagatran was correlated to creatinine clearance, which was the most important predictor of melagatran exposure (explained 54% of interpatient variance in clearance). Total variability (coefficient of variation) in exposure was 45%; intraindividual variability in exposure was 23%. Concomitant medication with the most common long-term used drugs in the study population had no relevant influence on melagatran pharmacokinetics. Simulations suggested that dose adjustment based on renal function or trough plasma concentration had a minor effect on overall pharmacokinetic variability and the number of patients with high melagatran exposure. The pharmacokinetics of melagatran in NVAF patients were predictable, and consistent with results from previously studied patient populations. Dose individualisation was predicted to have a low impact on pharmacokinetic variability, supporting the use of a fixed-dose regimen of ximelagatran for long-term anticoagulant therapy in the majority of NVAF patients.

Generation of “Neoheparin” from E. coli K5 Capsular Polysaccharide

Heparin remains a major drug in prevention of thromboembolic disease. Concerns related to its animal source have prompted search for heparin analogues. The anticoagulant activity of heparin depends on a specific pentasaccharide sequence that binds antithrombin. We report the generation of a product with antithrombin-binding, anticoagulant, and antithrombotic properties similar to those of heparin, through combined chemical and enzymatic modification of a bacterial (E. coli K5) polysaccharide. The process is readily applicable to large-scale production.

Current Options in the Prevention of Thromboembolic Disease

Significant advances in the pharmacological prophylaxis of venous thromboembolism have occurred since warfarin and unfractionated heparin were introduced for this indication nearly 60 years ago. Despite these advances, coumarin derivatives such as warfarin remain the only orally active anticoagulants available for prophylaxis in venous thromboembolism. Although administered orally, coumarin derivatives are not convenient to use, because they have narrow therapeutic indexes and require routine coagulation monitoring and dose adjustment. This is inconvenient for patients and physicians and costly for the healthcare system. Low-molecular-weight heparins, which are administered in fixed or weight-adjusted doses and do not require monitoring, are widely used for the prevention of venous thromboembolism in patients in both the hospital and the outpatient setting. However, these drugs must be given subcutaneously, which can be difficult for outpatients and resource-intensive for in-hospital use. Likewise, fondaparinux, the synthetic pentasaccharide, must be administered subcutaneously. Consequently, there remains a need for new orally active anticoagulants that can be given in fixed doses and do not have a narrow therapeutic index, so that coagulation monitoring is unnecessary. Because such agents would be more convenient for patients and physicians, they would probably expand the use of prophylaxis in venous thromboembolism in those at risk, and would simplify treatment of patients with established venous thromboembolism.

THE CHARACTERIZATION OF POTENT NOVEL WARFARIN ANALOGS

Racemic sodium warfarin, Coumadin,® is widely used in the prevention of thromboembolic disease. The present study was undertaken to characterize three novel classes of warfarin analogs, and to compare them with the warfarin enantiomers. All three classes of compounds inhibit vitamin K epoxide reductase, the enzyme inhibited by racemic warfarin. The alcohol and the ester analogs have reduced protein binding compared with R-(+)-warfarin 1 1 R-(+)-warfarin will be designated as R-warfarin; S-(−)-warfarin will be designated as S-warfarin . The ester and the fluoro-derivatives have similar in vivo anticoagulant activity in the rat to that of S-(−)-warfarin 1 . Thus, it is possible to synthesize novel warfarin analogs that differ from racemic warfarin or its enantiomers in certain selected properties. © 1997 Elsevier Science Ltd