Sulodexide in venous disease.

Sulodexide is a glycosaminoglycan extracted from porcine intestinal mucosa. The purpose of this review is to discuss sulodexide's complex pharmacological profile and its clinical applications for venous disease. Sulodexide has wide-ranging biological effects on the vascular system, including antithrombotic, profibrinolytic, anti-inflammatory, endothelial protective and vasoregulatory effects. Sulodexide has emerged as a potential therapeutic option for the management of chronic venous insufficiency, including venous ulceration, and the prevention of recurrent venous thromboembolism, with a low rate of major bleeding complications. Sulodexide's pleiotropic vascular effects may facilitate the management of common venous disorders.

Effect of extended-duration thromboprophylaxis on venous thromboembolism and major bleeding among acutely ill hospitalized medical patients: a bivariate analysis.

Essentials Anticoagulants prevent venous thromboembolism but may be associated with greater bleeding risks. Bivariate analysis assumes a non-linear relationship between efficacy and safety outcomes. Extended full-dose betrixaban is favorable over standard enoxaparin in bivariate endpoint. Clinicians must weigh efficacy and safety outcomes in decision-making on thromboprophylaxis. SUMMARY: Background Among acutely ill hospitalized medical patients, extended-duration thromboprophylaxis reduces the risk of venous thromboembolism (VTE), but some pharmacologic strategies have been associated with greater risks of major bleeding, thereby offsetting the net clinical benefit (NCB). Methods To assess the risk-benefit profile of anticoagulation regimens, a previously described bivariate method that does not assume a linear risk-benefit tradeoff and can accommodate different margins for efficacy and safety was performed to simultaneously assess efficacy (symptomatic VTE) and safety (major bleeding) on the basis of data from four randomized controlled trials of extended-duration (30-46 days) versus standard-duration (6-14 days) thromboprophylaxis among 28 227 patients (EXCLAIM, ADOPT, MAGELLAN and APEX trials). Results Extended thromboprophylaxis with full-dose betrixaban (80 mg once daily) was superior in efficacy and non-inferior in safety to standard-duration enoxaparin, and showed a significantly favorable NCB, with a risk difference of - 0.51% (- 0.89% to - 0.10%) in the bivariate outcome. Extended enoxaparin was superior in efficacy and inferior in safety (bivariate outcome: 0.03% [- 0.37% to 0.43%]), whereas apixaban and rivaroxaban were non-inferior in efficacy and inferior in safety (- 0.20% [- 0.49% to 0.17%] and 0.23% [- 0.16% to 0.69%], respectively). Reduced-dose betrixaban did not show a significant difference in either efficacy or safety (0.41% [- 0.85% to 1.94%]). Conclusions In a bivariate analysis that assumes non-linear risk-benefit tradeoffs, extended prophylaxis with full-dose betrixaban was superior to standard-duration enoxaparin, whereas other regimens failed to simultaneously achieve both superiority and non-inferiority with respect to symptomatic VTE and major bleeding in the management of acutely ill hospitalized medical patients.

Treatment of venous thromboembolism in cancer patients with dalteparin for up to 12 months: the DALTECAN Study.

BACKGROUND: Treatment of venous thromboembolism (VTE) in patients with cancer has a high rate of recurrence and bleeding complications. Guidelines recommend low-molecular-weight heparin (LMWH) for at least 3-6 months and possibly indefinitely for patients with active malignancy. There are, however, few data supporting treatment with LMWH beyond 6 months. The primary aim of the DALTECAN study (NCT00942968) was to determine the safety of dalteparin between 6 and 12 months in cancer-associated VTE. METHODS: Patients with active cancer and newly diagnosed VTE were enrolled in a prospective, multicenter study and received subcutaneous dalteparin for 12 months. The rates of bleeding and recurrent VTE were evaluated at months 1, 2-6 and 7-12. FINDINGS: Of 334 patients enrolled, 185 and 109 completed 6 and 12 months of therapy; 49.1% had deep vein thrombosis (DVT); 38.9% had pulmonary embolism (PE); and 12.0% had both on presentation. The overall frequency of major bleeding was 10.2% (34/334). Major bleeding occurred in 3.6% (12/334) in the first month, and 1.1% (14/1237) and 0.7% (8/1086) per patient-month during months 2-6 and 7-12, respectively. Recurrent VTE occurred in 11.1% (37/334); the incidence rate was 5.7% (19/334) for month 1, 3.4% (10/296) during months 2-6, and 4.1% (8/194) during months 7-12. One hundred and sixteen patients died, four due to recurrent VTE and two due to bleeding. CONCLUSION: Major bleeding was less frequent during dalteparin therapy beyond 6 months. The risk of developing major bleeding complications or VTE recurrence was greatest in the first month of therapy and lower over the subsequent 11 months.

Comparison of three-factor and four-factor prothrombin complex concentrates regarding reversal of the anticoagulant effects of rivaroxaban in healthy volunteers.

BACKGROUND: Four-factor prothrombin complex concentrates (PCCs), which contain factor II, FVII, FIX, and FX, have shown the potential to reverse the anticoagulant effect of rivaroxaban in healthy volunteers. The purpose of this study was to determine whether a three-factor PCC, which contains little FVII, has a similar effect. METHODS AND RESULTS: We performed an open-label, single-center, parallel-group study comparing the effect of a three-factor PCC (Profilnine SD) with that of a four-factor PCC (Beriplex P/N) on the pharmacodynamics of rivaroxaban in 35 healthy volunteers. After receiving 4 days of rivaroxaban 20 mg twice daily to obtain supratherapeutic steady-state concentrations, volunteers were randomized to receive a single 50 IU kg(-1) bolus dose of four-factor PCC, three-factor PCC or saline 4 h after the morning dose of rivaroxaban on day 5, and the effects of these interventions on prothrombin time and thrombin generation were determined. Within 30 min, four-factor PCC reduced mean prothrombin time by 2.5-3.5 s, whereas three-factor PCC produced only a 0.6-1.0-s reduction. In contrast, three-factor PCC reversed rivaroxaban-induced changes in thrombin generation more than four-factor PCC. CONCLUSIONS: This study demonstrates the potential of both three-factor and four-factor PCCs to at least partially reverse the anticoagulant effects of rivaroxaban in healthy adults. The discrepant effects of the PCC preparations may reflect differences in the procoagulant components present in each.

Neutrophil extracellular traps form predominantly during the organizing stage of human venous thromboembolism development.

BACKGROUND: A growing health problem, venous thromboembolism (VTE), including pulmonary embolism (PE) and deep vein thrombosis (DVT), requires refined diagnostic and therapeutic approaches. Neutrophils contribute to thrombus initiation and development in experimental DVT. Recent animal studies recognized neutrophil extracellular traps (NETs) as an important scaffold supporting thrombus stability. However, the hypothesis that human venous thrombi involve NETs has not undergone rigorous testing. OBJECTIVE: To explore the cellular composition and the presence of NETs within human venous thrombi at different stages of development. PATIENTS AND METHODS: We examined 16 thrombi obtained from 11 patients during surgery or at autopsy using histomorphological, immunohistochemical and immunofluorescence analyses. RESULTS: We classified thrombus regions as unorganized, organizing and organized according to their morphological characteristics. We then evaluated them, focusing on neutrophil and platelet deposition as well as micro-vascularization of the thrombus body. We observed evidence of NET accumulation, including the presence of citrullinated histone H3 (H3Cit)-positive cells. NETs, defined as extracellular diffuse H3Cit areas associated with myeloperoxidase and DNA, localized predominantly during the phase of organization in human venous thrombi. CONCLUSIONS: NETs are present in organizing thrombi in patients with VTE. They are associated with thrombus maturation in humans. Dissolution of NETs might thus facilitate thrombolysis. This finding provides new insights into the clinical development and pathology of thrombosis and provides new perspectives for therapeutic advances.

Prevention and treatment of venous thromboembolism--International Consensus Statement.

The aim of this document is to provide a clear and concise account of the evidence regarding efficacy or harm for various methods available to prevent and manage venous thromboembolism (VTE).

Multi-screen electronic alerts to augment venous thromboembolism prophylaxis.

Venous thromboembolism (VTE) prophylaxis in high-risk patients is frequently underutilised. We previously devised a one-screen computer alert program that identified hospitalised patients at high risk for VTE who were not receiving prophylaxis and advised their physicians to prescribe prophylaxis. While this strategy reduced the 90-day incidence of symptomatic VTE by 41%, the majority of electronic alerts were ignored. We have now developed a serial three-screen alert computer program designed to educate physicians who initially declined to order prophylaxis after a single screen alert. Of a total cohort of 880, the responsible physicians for 425 patients received a single electronic alert, whereas 455 who declined prophylaxis after the first screen received the second and third screens of the novel three-screen alert. Our enhanced serial three-screen alert program generated VTE prophylaxis orders for 58.4% of the 455 patients whose physicians initially declined to order prophylaxis following the one-screen alert. There was no significant difference in symptomatic 90-day VTE rates between the two cohorts (2.8% for the one-screen vs. 2.2% for the three-screen, p=0.55). We conclude that our three-screen computer alert program can markedly increase prophylaxis among physicians who decline an initial single screen alert.

Ability of VKORC1 and CYP2C9 to predict therapeutic warfarin dose during the initial weeks of therapy.

BACKGROUND: CYP2C9 and VKORC1 genotypes predict therapeutic warfarin dose at initiation of therapy; however, the predictive ability of genetic information after a week or longer is unknown. Experts have hypothesized that genotype becomes irrelevant once international normalized ratio (INR) values are available because INR response reflects warfarin sensitivity. METHODS: We genotyped the participants in the Prevention of Recurrent Venous Thromboembolism (PREVENT) trial, who had idiopathic venous thromboemboli and began low-intensity warfarin (therapeutic INR 1.5-2.0) using a standard dosing protocol. To develop pharmacogenetic models, we quantified the effect of genotypes, clinical factors, previous doses and INR on therapeutic warfarin dose in the 223 PREVENT participants who were randomized to warfarin and achieved stable therapeutic INRs. RESULTS: A pharmacogenetic model using data from day 0 (before therapy initiation) explained 54% of the variability in therapeutic dose (R(2)). The R(2) increased to 68% at day 7, 75% at day 14, and 77% at day 21, because of increasing contributions from prior doses and INR response. Although CYP2C9 and VKORC1 genotypes were significant independent predictors of therapeutic dose at each weekly interval, the magnitude of their predictive ability diminished over time: partial R(2) of genotype was 43% at day 0, 12% at day 7, 4% at day 14, and 1% at day 21. CONCLUSION: Over the first weeks of warfarin therapy, INR and prior dose become increasingly predictive of therapeutic dose, and genotype becomes less relevant. However, at day 7, genotype remains clinically relevant, accounting for 12% of therapeutic dose variability.

Advanced treatment strategies for acute pulmonary embolism, including thrombolysis and embolectomy.

The optimal treatment strategy for acute pulmonary embolism relies upon a multidisciplinary team that rapidly assesses available data, performs additional testing if necessary, weighs treatment options, and recommends an appropriate therapeutic plan to the patient and family. Round-the-clock availability is imperative. Centers that specialize in pulmonary embolism management offer a wide range of therapeutic options. Hospitals with more limited facilities should establish pulmonary embolism patient referral and transfer contingency plans that can be activated at a moment's notice. Management options include anticoagulation alone, thrombolysis plus anticoagulation, insertion of an inferior vena caval filter, catheter embolectomy, or surgical embolectomy. The decision-making process requires accurate risk stratification, which is comprised of several crucial components: clinical evaluation that includes history and physical examination, biomarker measurement especially of troponin, as well as assessment of right ventricular size and function based upon chest CT scanning and echocardiography. The 'old school' approach of declaring a benign prognosis based solely upon the presence of normal systemic arterial pressure can delay advanced therapy until after the onset of irreversible cardiogenic shock. We have now formulated a more contemporary, comprehensive, and multifaceted strategy to prognosticate. Our 'new approach' uses advanced treatment strategies in addition to anticoagulation for those pulmonary embolism patients deemed to be at high risk for a poor outcome.

Cost benefit of intermittent pneumatic compression for venous thromboembolism prophylaxis in general surgery.

AIM: In moderate to high-risk general surgical patients, the cost effectiveness of mechanical prophylaxis for venous thromboembolism (VTE) is uncertain. Therefore, we determined the costs and savings of intermittent pneumatic compression (IPC) plus graduated compression stockings (GCS). METHODS: Postoperative VTE events in the absence of prophylaxis, efficacy of prophylaxis and costs of prophylaxis have been obtained from the English literature and Medicare 2004 reimbursement schedule. RESULTS: In 1000 moderate to high risk general surgical patients, in the absence of prophylaxis, the cost of investigating and treating 72 patients with clinical suspicion of DVT and 32 with PE is calculated to be $263,779. This corresponds to a cost of $263 per surgical patient. The cost of IPC combined with TED stockings in 1000 similar patients would be $66 760, and the cost of diagnosis and treatment of the reduced numbers (69% reduction) of clinical VTE is $ 83,574 making a total of $150 344. This means a saving of $133,435 ($263,779 - $150,344) per 1000 patients. This corresponds to a saving of $113 per surgical patient. Sensitivity analysis demonstrates that despite variation in costs or efficacy for IPC plus GCS, marked savings persist. CONCLUSIONS: Prophylaxis with IPC not only prevents VTE but also saves money.

Hormonal factors and risk of recurrent venous thrombosis: the prevention of recurrent venous thromboembolism trial.

BACKGROUND: In some but not all studies, men with venous thrombosis had a higher risk of recurrence than women. Information on women with initial hormone-related thrombosis is scant. OBJECTIVE: We assessed the incidence of recurrent thrombosis by gender, and among women using exogenous hormones or pregnant/postpartum at the time of index thrombosis. PATIENTS/METHODS: A total of 508 men and women with one or more previous venous thrombosis episodes were observed while participating in a randomized trial of low-intensity warfarin or placebo for 2.1 years. Index thrombosis events during treatment with postmenopausal hormones, oral contraceptives, or during pregnancy, or the puerperium were considered to be hormone-related events. RESULTS: Among 268 men the 3-year probability of recurrent thrombosis was 18.4% (95% confidence intervals; CI 12.3-24.4). Among 109 women without hormone-related thrombosis, the rate was 15.0% (95% CI 6.3-23.8). Among 129 women with hormone-related thrombosis, the rate was 5.0% (95% CI 1.1-8.9). Adjusting for other risk factors and treatment assignment, women had a 39% lower thrombosis recurrence risk than men: hazard ratio (HR) 0.61 (95% CI 0.34-1.08). Women with hormone-related thrombosis had a 58% lower risk than men: HR 0.42 (95% CI 0.19-0.97); and a 46% lower recurrence risk than other women; HR 0.54 (95% CI 0.19-1.54). Women without hormone-related index events had a recurrence rate similar to men; HR 0.83 (95% CI 0.42-1.66). CONCLUSIONS: In this trial population, women had a lower risk of recurrent venous thrombosis than men. This difference was explained by a low risk of recurrence among women with hormone-related index thrombosis.

Rationale and design of ACTIVE: the atrial fibrillation clopidogrel trial with irbesartan for prevention of vascular events.

BACKGROUND: Atrial fibrillation (AF) is the most frequently occurring cardiac arrhythmia with often serious clinical consequences. Many patients have contraindications to anticoagulation, and it is often underused in clinical practice. The addition of clopidogrel to aspirin (ASA) has been shown to reduce vascular events in a number of high-risk populations. Irbesartan is an angiotensin receptor-blocking agent that reduces blood pressure and has other vascular protective effects. METHODS AND RESULTS: ACTIVE W is a noninferiority trial of clopidogrel plus ASA versus oral anticoagulation in patients with AF and at least 1 risk factor for stroke. ACTIVE A is a double-blind, placebo-controlled trial of clopidogrel in patients with AF and with at least 1 risk factor for stroke who receive ASA because they have a contraindication for oral anticoagulation or because they are unwilling to take an oral anticoagulant. ACTIVE I is a partial factorial, double-blind, placebo-controlled trial of irbesartan in patients participating in ACTIVE A or ACTIVE W. The primary outcomes of these studies are composites of vascular events. A total of 14000 patients will be enrolled in these trials. CONCLUSIONS: ACTIVE is the largest trial yet conducted in AF. Its results will lead to a new understanding of the role of combined antiplatelet therapy and the role of blood pressure lowering with an angiotensin II receptor blocker in patients with AF.

D-dimer, factor VIII coagulant activity, low-intensity warfarin and the risk of recurrent venous thromboembolism.

BACKGROUND: Elevated plasma D-dimer and factor VIII coagulant activity (FVIIIc) may be associated with the risk of recurrent venous thromboembolism (VTE). OBJECTIVES: To evaluate D-dimer and FVIIIc as risk factors for recurrent VTE and assess the efficacy of extended low-intensity warfarin (target International Normalized Ratio 1.5-2.0) in preventing recurrence by biomarker level. PATIENTS AND METHODS: In the Prevention of Recurrent Venous Thromboembolism trial, 508 idiopathic VTE patients treated for > or = 3 months with full-intensity warfarin, and who had stopped warfarin for 7 weeks on average, were randomized to low-intensity warfarin or placebo and followed for 2.1 years for recurrent VTE. Prerandomization blood samples were analysed for D-dimer and FVIIIc. RESULTS: One-third of participants had elevated baseline D-dimer (> or = 500 ng mL(-1)) and one-fourth, elevated FVIIIc (> or = 150 IU dL(-1)). Adjusting for other risk factors, the hazard ratios (HRs) for recurrent VTE with elevated D-dimer or FVIIIc were 2.0 [95% confidence interval (CI) 1.2-3.4] and 1.5 (95% CI 0.8-2.8), respectively. The association of elevated D-dimer with recurrence was larger among patients with one prior VTE (HR 3.2, 95% CI 1.3-8.0) than in patients with more than one event (HR 1.4, 95% CI 0.7-2.2). For patients with one prior VTE on placebo, the annual recurrence incidence was 10.9% with elevated D-dimer and 2.9% with normal values. Low-intensity warfarin was equally effective in recurrence risk reduction in those with normal or elevated biomarkers. CONCLUSIONS: Among patients with idiopathic VTE, measurement of D-dimer, but not FVIIIc, might be useful for risk stratification. The efficacy of extended low-intensity warfarin therapy did not vary by biomarker level.

Modern treatment of pulmonary embolism.

Modern treatment of acute pulmonary embolism requires rapid and accurate diagnosis followed by risk stratification to devise an optimal management strategy. Patients at low risk have good outcomes simply with intensive anticoagulation treatment. Higher-risk patients may require more aggressive intervention with thrombolysis or embolectomy. Clinical risk factors for an adverse outcome include increasing age, cancer, congestive heart failure, systemic arterial hypotension, chronic obstructive pulmonary disease and right ventricular dysfunction. A promising approach is the Geneva Prognostic Score, which is based upon a rapid clinical assessment. On physical examination, signs of right ventricular failure, including distended jugular veins and a right-sided S3 gallop, should be looked for. The electrocardiogram may show evidence of right ventricular strain with a new right bundle branch block or T wave inversion in leads V1-V4. The troponin level may be elevated as a marker of cardiac injury and right ventricular microinfarction, even in the absence of coronary artery disease. The most useful imaging marker of high risk is the presence of moderate or severe right ventricular dilatation and hypokinesis on the echocardiogram, especially with progressively worsening right ventricular function despite intensive anticoagulation treatment. Patients at high risk should be considered for thrombolytic therapy or embolectomy rather than management with anticoagulation therapy alone. Special care must be taken to avoid thrombolytic therapy among patients who might be susceptible to intracranial haemorrhage. Intracranial haemorrhage reached a surprisingly high rate of 3.0% in the International Cooperative Pulmonary Embolism Registry of 2,454 prospectively evaluated acute pulmonary embolism patients at 52 hospitals in seven countries. An alternative approach to patients at high risk is a catheter-based or open surgical embolectomy. It is crucial to refer these patients as quickly as possible, rather than delaying intervention until cardiogenic shock has ensued. Fortunately the current tools for risk stratification provide an "early window" for prognostication and can help the coordination of a definitive treatment plan with optimal results.

Rationale and design of a clinical trial of a low-molecular-weight heparin in preventing clinically important venous thromboembolism in medical patients: the prospective evaluation of dalteparin efficacy for prevention of venous thromboembolism in immobilized patients trial (the PREVENT study).

The utility of low-molecular-weight heparin (LMWH) in the prophylaxis of venous thromboembolic disease has been examined using the surrogate endpoint of venographically identified thrombi. The largest portion of these thrombi were asymptomatic calf-vein thrombi. The clinical relevance of this observation is a matter of debate. The present study is designed to evaluate the impact of an LMWH on clinically important endpoints. The current study is a randomized, prospective, double-blinded, multicenter, multinational, controlled clinical trial comparing dalteparin with placebo in moderately high-risk hospitalized medical patients. A total of 3300 patients will be randomized to receive either 5,000 IU per day of dalteparin or placebo for 14 days. Patients will undergo appropriate evaluation for any symptomatic episodes and all patients will undergo a bilateral compression ultrasound (CUS) on day 21 to search for asymptomatic proximal thrombi. The primary endpoint is the combination of objectively confirmed symptomatic deep vein thrombi (DVT), fatal or non-fatal pulmonary emboli, all proximal DVT, and sudden death. This study will be the first study to examine clinically important endpoints in evaluating the effect of a LMWH in hospitalized medical patients. This study also is the first study to use CUS rather than venography in concordance with contemporary medical practice. This trial is thus designed to address this important question in a clinically relevant manner.

Isolated calf vein thrombosis: comparison of MR venography and conventional venography after initial sonography in symptomatic patients.

RATIONALE AND OBJECTIVES: The authors performed this study to compare magnetic resonance (MR) venography and conventional venography in the diagnosis of deep venous thrombosis (DVT) in the calf after sonography. MATERIALS AND METHODS: Sonography was performed in 595 patients who were suspected of having lower-extremity DVT. Patients with positive above-knee duplex sonograms, allergy to iodinated contrast material, renal insufficiency, or cardiac pacemakers and patients who were obese were excluded. The remaining 73 patients were asked to undergo MR venography and conventional venography. All studies were to be performed within 48 hours of the clinical diagnosis and according to standard clinical practice. Images were interpreted by radiologists who were blinded to the results of other modalities. Two separate analyses were performed: one in which conventional venography was used as the standard of reference, and one in which the presence of at least two positive studies for thrombus was considered diagnostic. RESULTS: Although 36 patients agreed to participate in the study, only 14 underwent MR venography and conventional venography within 48 hours of the clinical diagnosis. With use of any two positive studies for confirmation, acute DVT was diagnosed in three patients. Conventional venography depicted two of the three cases, whereas sonography and MR venography each depicted all three. The findings were concordant in only five of the 14 patients. CONCLUSION: Moderate discrepancy among modalities was demonstrated. This suggests radiologists should undertake comparisons among these three modalities for the detection of calf DVT. In patients with a high clinical suspicion, a second modality may be useful if the initial study is negative.

Rescue percutaneous coronary intervention immediately following coronary artery bypass grafting.

Perioperative graft failure after coronary artery bypass graft (CABG) can result in acute myocardial infarction with dire clinical consequences. We report a case of rescue percutaneous coronary intervention immediately after unsuccessful CABG. This approach salvaged the patient from cardiogenic shock and should be recognized as a viable alternative to immediate reoperation for certain patients.