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).

Venous Ulcers.

Venous leg ulcers are the most frequent form of wounds seen in patients. This article presents an overview on some practical aspects concerning diagnosis, differential diagnosis and treatment. Duplex ultrasound investigations are essential to ascertain the diagnosis of the underlying venous pathology and to treat venous refluxes. Differential diagnosis includes mainly other vascular lesions (arterial, microcirculatory causes), hematologic and metabolic diseases, trauma, infection, malignancies. Patients with superficial venous incompetence may benefit from endovenous or surgical reflux abolition diagnosed by Duplex ultrasound. The most important basic component of the management is compression therapy, for which we prefer materials with low elasticity applied with high initial pressure (short-stretch bandages and Velcro-strap devices). Local treatment should be simple, absorbing and not sticky dressings keeping adequate moisture balance after debridement of necrotic tissue and biofilms are preferred. After the ulcer is healed compression therapy should be continued in order to prevent recurrence.

Can combined (mechanical and pharmacological) modalities prevent fatal VTE?

AIM: The aim of this paper was to perform a systemic review and meta-analysis of the efficacy of combined modalities (intermittent pneumatic leg compression and pharmacological prophylaxis, treatment group) against single modalities alone (control group) in preventing pulmonary embolism (PE), including fatal PE and deep-vein thrombosis (DVT) in high-risk patients. METHODS: Databases searched included the Cochrane Central Register of Controlled Trials, the Specialized Register of the Peripheral Vascular Diseases Group, MEDLINE and EMBASE. RESULTS: Seventeen studies, six of them randomized controlled trials (RCTs), which enrolled a total of 9998 patients in a variety of specialties were identified. Sixteen of the included studies evaluated the role of combined modalities on the incidence of symptomatic PE. These showed a reduction in symptomatic PE from 2.83% (122/4313) in the control group to 0.86% (33/3838) in the treatment group. Odds ratio was 0.34, 95% Confidence interval (CI) 0.23 to 0.50. Fatal PE was reduced from 0.56% (11/1972) in the control group to 0.07% (1/1377) in the treatment group (results were available in 10 studies). Odds ratio was 0.37 (95% CI; 0.09 to 1.48). Fourteen studies investigated the role of combined modalities on the incidence of DVT. These showed a reduction in DVT from 6.18% (200/3238) in the control group to 2.05% (63/3074) in the treatment group. Odds ratio was 0.31, 95% CI 0.23 to 0.43. CONCLUSION: Combined prophylactic modalities decrease significantly the incidence of PE and DVT, compared to single modalities, but the reduction seen in fatal PE did not reach statistical significance. Further research on the role of combined modalities in reducing DVT and PE is necessary.

Dabigatran versus enoxaparin for prevention of venous thromboembolism after hip or knee arthroplasty: a pooled analysis of three trials.

BACKGROUND: Three randomized, double-blind trials compared dabigatran, an oral direct thrombin inhibitor, with enoxaparin for the primary prevention of venous thromboembolism (VTE) in patients undergoing elective total hip and knee arthroplasty. OBJECTIVES AND METHODS: We conducted a pre-specified pooled analysis of these trials. 8,210 patients were randomized, of whom 8,135 were treated (evaluable for safety) with dabigatran 220 mg or 150 mg once-daily, or subcutaneous enoxaparin (40 mg once-daily or 30 mg twice-daily). Efficacy analyses were based on the modified intention-to-treat population of 6,200 patients with an evaluable outcome. The common risk difference (RD) of treatment effect between each dabigatran dose and enoxaparin was estimated using fixed-effects models, and statistical heterogeneity was estimated using the I2 statistic. RESULTS: The composite outcome of major VTE (proximal deep vein thrombosis and/or pulmonary embolism) and VTE-related mortality occurred in 3.3% of the enoxaparin group versus 3.0% of the dabigatran 220 mg group (RD vs. enoxaparin -0.2%, 95% CI -1.3% to 0.9%, I2=37%) and 3.8% of the 150 mg group (RD vs. enoxaparin 0.5%, -0.6% to 1.6%, I2=0%). Major bleeding occurred in 1.4% of the enoxaparin group versus 1.4% of the dabigatran 220 mg group (RD vs. enoxaparin -0.2%, -0.8% to 0.5%, I2=40%) and 1.1% of the 150 mg group (RD vs. enoxaparin -0.4%, -1.0% to 0.2%, I2=0%). CONCLUSIONS: Oral dabigatran was as effective as subcutaneous enoxaparin in reducing the risk of major VTE and VTE-related mortality after hip or knee arthroplasty and has a similar bleeding profile.

Combined intermittent pneumatic leg compression and pharmacological prophylaxis for prevention of venous thrombo-embolism in high-risk patients.

BACKGROUND: It has been suggested that combined modalities (methods of treatment) are more effective than single modalities in preventing venous thrombo-embolism (defined as deep vein thrombosis and pulmonary embolism, or both) in high-risk patients. OBJECTIVES: To assess the efficacy of intermittent pneumatic leg compression combined with pharmacological prophylaxis versus single modalities in preventing venous thrombo-embolism in high-risk patients. SEARCH STRATEGY: The Cochrane Peripheral Vascular Diseases (PVD) Group searched the reference lists of their Specialised Register (last searched 17 July 2007) and the Cochrane Central Register of Controlled Trials (CENTRAL) (last searched The Cochrane Library 2008, issue 3) for relevant articles to identify additional trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) of combined intermittent pneumatic leg compression and pharmacological interventions used to prevent venous thrombo-embolism in high-risk patients. DATA COLLECTION AND ANALYSIS: Data extraction was undertaken independently by two review authors using data extraction sheets.

Major joint replacement. A model for antithrombotic drug development: from proof-of-concept to clinical use.

AIM: Development of antithrombotic compounds has traditionally been performed in patients undergoing total hip and knee replacement surgery. A high number of asymptomatic deep-vein thromboses are radiologically detectable, and bleeding and other adverse events (AE) are easy to observe. However, standardization of study procedures and endpoints in early proof-of-concept studies and late pure clinical endpoint studies has been lacking. This has made comparison between studies difficult, economic analyses speculative and potential benefits of applying the drug regimen in non-selected patients uncertain. In this paper, the International Surgical Thrombosis Forum proposes a strategy for the clinical investigation of new pharmacological agents for the prophylaxis of postoperative thrombotic events. METHODS: First, dose titration safety studies of short duration, in highly selected patients using objective venographic endpoints are recommended. Bleeding should be divided into the quantified volume of surgical bleeding and other adjudicated clinical bleeding events. The number of AE should be described for each dose step and classified according to International Coding of Diagnoses (ICD). Second, a dose confirmatory study of moderate exposure period and sufficient follow-up time is recommended. The exclusion criteria should be restricted to contraindications of the compared drugs and technical procedure. RESULTS: The efficacy, bleeding and AE should be similar to those used in dose-titration studies. In addition, the failure rate of the drug to exert its effect and the net clinical benefit should be calculated. CONCLUSION: Finally, trials with simple clinical endpoints and long follow-up should be conducted to evaluate the potential benefits of the drug-regimen in non-selected populations.

Fondaparinux combined with intermittent pneumatic compression vs. intermittent pneumatic compression alone for prevention of venous thromboembolism after abdominal surgery: a randomized, double-blind comparison.

BACKGROUND: The benefit of combined mechanical and pharmacologic methods for venous thromboembolism prevention after abdominal surgery has not been clearly established. OBJECTIVES: To compare the efficacy and safety of fondaparinux in conjunction with intermittent pneumatic compression vs. intermittent pneumatic compression alone in this context. PATIENTS AND METHODS: This was a randomized, double-blind, placebo-controlled superiority trial. Patients aged at least 40 years undergoing abdominal surgery were randomized to receive either fondaparinux 2.5 mg or placebo s.c. for 5-9 days, starting 6-8 h postoperatively. All patients received intermittent pneumatic compression. The primary efficacy outcome was venous thromboembolism up to day 10. The main safety outcomes were major bleeding and all-cause mortality. Follow-up lasted 32 days. RESULTS: Of the 1309 patients randomized, 842 (64.3%) were evaluable for efficacy. The venous thromboembolism rate was 1.7% (7/424) in the fondaparinux-treated patients and 5.3% (22/418) in the placebo-treated patients (odds ratio reduction 69.8%; 95% confidence interval 27.9-87.3; P = 0.004). Fondaparinux significantly reduced the proximal deep vein thrombosis rate from 1.7% (7/417) to 0.2% (1/424; P = 0.037). Major bleeds occurred in 1.6% (10/635) and 0.2% (1/650) of fondaparinux-treated and placebo-treated patients, respectively (P = 0.006), none being fatal or involving a critical organ. By day 32, eight patients (1.3%) receiving fondaparinux and five (0.8%) receiving placebo had died. CONCLUSIONS: In patients undergoing abdominal surgery and receiving intermittent pneumatic compression, fondaparinux 2.5 mg reduced the venous thromboembolism rate by 69.8% as compared to pneumatic compression alone, with a low bleeding risk as compared to placebo.

Thrombophilia testing in patients with venous thrombosis.

BACKGROUND: Routine thrombophilia testing is controversial because of the low yield of positive tests, costs involved, and debate about the clinical usefulness of the data obtained from testing. Laboratory investigations are rarely done for those with superficial venous thrombosis (SVT) or isolated calf vein thrombosis (CVT) which are often not treated with anticoagulants. OBJECTIVE: To identify the incidence of markers of thrombophilia in patients with deep vein thrombosis (DVT), SVT, isolated CVT or a history of thrombosis in a referral practice. METHODS: One hundred and sixty-six patients were referred to our thrombosis unit for consultation, including patients with SVT, DVT, and preoperative patients with a previous history of SVT or DVT. Patients underwent thrombophilia screening and patients with a diagnosis of SVT or DVT were confirmed by bilateral duplex ultrasonography of all lower limb veins. Thrombophilia testing included factor V Leiden (FVL), prothrombin 20210A mutation (P2), methylene tetrahydrofolate reductase deficiency (MTHFR), fasting serum homocysteine (HC), lupus anticoagulant (LA), anticardiolipin antibodies (ACA), antithrombin deficiency (AT), protein S deficiency (PS), and protein C deficiency (PC). RESULTS: The incidence of any significant abnormality in patients with DVT was 27/44 (61%; 95% Confidence interval [CI], 47-76%) and 10 of these patients were positive for FVL (23%; 95% CI, 10-35%). Twelve patients with isolated CVT were seen and five had at least one abnormality (42%; 95% CI, 14-70%) including one with FVL (8%; 95% CI, 0-24%). Thirty-nine patients with isolated SVT were seen including 14 with at least one abnormality (36%; 95% CI, 21-51%) and five of these patients with SVT had FVL (13%; 95% CI, 2-23%). Nine patients with recurrent DVT were seen and five of these had at least one abnormal test (56%; 95% CI, 23-88%). Finally, 18 of the 166 patients had more than one abnormality (11%; 95% CI, 6-16%). CONCLUSION: The presence of one or more markers of thrombophilia was significantly higher in this patient population compared to reports from other centres. This study identified 18/166 (10.8%; 95% CI, 6-16%) with more than one defect where life-long anticoagulation might be considered. The results in this subset of patients as well as the serious defects found in some patients with provoked DVT, isolated CVT or isolated SVT demonstrate the value of this screening program to both these patients and their blood relatives. On the other hand, this is a small series from a referral practice where the incidence of these defects is greater than one would expect in the general population. These studies are preliminary and it is not recommended that all VTE patients should be screened on the basis of the current report.

The outcome after treatment of venous thromboembolism is different in surgical and acutely ill medical patients. Findings from the RIETE registry.

BACKGROUND: The history of venous thromboembolism (VTE), and the rationale for thromboprophylaxis in surgical patients are well understood. The situation is less clear for acutely ill medical patients. OBJECTIVES: To compare the clinical presentation of VTE and clinical outcomes of immobile acutely ill medical patients with surgical patients. PATIENTS: RIETE (Registro Informatizado de la Enfermedad TromboEmbolica) is a Spanish registry of consecutively enrolled patients with objectively confirmed, symptomatic acute VTE. In this analysis, clinical characteristics of patients, details of anticoagulant therapy, and outcomes of all enrolled acutely ill medical patients with immobility >/= 4 days, and surgical patients are included. RESULTS: Of 6160 patients enrolled up to December 2003, 756 (12%) were acutely ill medical patients with immobility >/= 4 days, and 884 (14%) were surgical patients who developed VTE within 2 months of surgical intervention. Only 28% of acutely ill medical patients had received thromboprophylaxis, compared with 67% of surgical patients. During the 3-month follow-up period, both fatal pulmonary embolism (PE) and fatal bleeding occurred more frequently in acutely ill medical patients. Immobility in acutely ill medical patients, cancer, and PE were associated with a significantly higher risk of fatal PE or bleeding. CONCLUSIONS: In patients treated for VTE, the incidences of fatal PE, fatal bleeding, and major bleeding were significantly higher in acutely ill medical patients compared with surgical patients. Given the low percentage of acutely ill medical patients who had received thromboprophylaxis, increasing its use appropriately may reduce the incidence of VTE and associated complications.

The use of low molecular weight heparins for the prevention of postoperative venous thromboembolism in general surgery. A survey of practice in the United States.

BACKGROUND: Even though low molecular weight heparins (LMWHs) have become the standard for venous thromboembolism (VTE) prophylaxis in most European countries and Canada, it was not until recently that LMWHs were approved for use in the United States. The main objective of this study was to assess the current preferences and attitudes of United States surgeons toward the prevention of VTE with particular reference to LMWH. METHODS: A survey with questions relative to VTE awareness, risk factors, and prevention practices was mailed to 10,000 Fellows of the American College of Surgeons. RESULTS: A total of 1,145 (11.45%) usable questionnaires were returned. The vast majority (96%) of respondents use prophylaxis against VTE. Although LMWHs were rated first regarding efficacy and second regarding simplicity of use, conventional unfractionated heparin at fixed doses remains the preferred pharmacological agent for VTE prevention (74%), followed by 2 LMWHs: enoxaparin (34%) and dalteparin (16%). Overall, 52% of surgeons preferred physical methods over pharmacological methods when used separately and 26% of surgeons utilize combined physical-pharmacological modalities. CONCLUSIONS: North American general surgeons have substantially modified their approach to VTE prevention in the last 4 years. Physical methods and unfractionated heparin remain the preferred prophylactic modalities, but LMWHs have gained rapid acceptance since their approval for use for VTE prevention in North America. Even though the results of this survey must be interpreted with caution because of the limited response rate and possible sampling bias, they still reflect the current preferences and attitudes of North American surgeons toward prophylaxis.

Home use of impulse compression of the foot and compression stockings in the treatment of chronic venous insufficiency.

PURPOSE: The use of intermittent pneumatic compression, in addition to elastic bandages or stockings, accelerates the healing of leg ulcers in patients with severe chronic venous insufficiency (CVI). There is recent evidence that impulse compression of the plantar venous plexus reduces post-traumatic ankle swelling and prevents postoperative venous thromboembolism. The purpose of this study was to evaluate the clinical and hemodynamic responses after home use of impulse foot compression for 3 months in patients already using therapeutic compression stockings for the management of CVI. METHODS: Twelve extremities from 9 patients with documented CVI, class 4 to 5 according to the Clinical, Etiology, Anatomy, Pathophysiology classification system, were included in this prospective cohort study. All patients were instructed to use a foot pump device at home for 2 hours a day for 3 months in addition to therapeutic compression stockings (30-40 mm Hg) worn during the day. The device was set to three cycles (3 seconds) of compression (120 mm Hg) per minute. A clinical scoring system was completed before foot compression and 1, 2, and 3 months thereafter. In addition, all patients underwent air plethysmography studies at the same time intervals, including venous volume, venous filling index, ejection fraction, and residual volume fraction. RESULTS: Patients reported significant improvement in their scores for swelling (P <.05) and pain (P <.04). Air plethysmography showed a reduction in venous volume and venous filling index, although these differences were not significant. Ejection fraction remained unchanged and residual volume fraction was significantly reduced (P <.05) compared with baseline. The foot compression devices were well tolerated by all the patients in the study. CONCLUSIONS: The use of home foot impulse compression plus elastic stockings significantly reduced the residual volume fraction as measured by air-plethysmography in a group of patients with severe CVI. This favorable hemodynamic response could, in part, explain the clinical improvement achieved by this combined treatment. However, this represents a preliminary pilot study that needs to be confirmed in future randomized controlled studies with more patients included.

Effective risk stratification of surgical and nonsurgical patients for venous thromboembolic disease.

Effective and safe methods of preventing venous thromboembolism (VTE) are now widely available, but a significant proportion of patients develop VTE either because thromboprophylaxis has not been used or because the intensity of thromboprophylaxis is not matched to the level of risk. Thromboembolic risk varies widely according to the clinical setting and presence of underlying risk factors, but VTE may not be suspected even in high-risk patients. Clinical risk factors for VTE include recent surgery, cancer, stroke, previous VTE, immobilization, and advanced age. Recent attention has focused on the role of inherited and acquired molecular factors in determining overall thromboembolic risk. These factors include the classic thrombophilias-deficiencies of antithrombin III, protein C, and protein S-and several newly described molecular risk factors: factor V Leiden, the prothrombin 20210A gene mutation, and hyperhomocysteinemia. Based on emerging knowledge of risk factors, several risk assessment models (RAMs) have been devised that stratify patients according to overall VTE risk, allowing thromboprophylaxis to be tailored appropriately. Compared with older risk assessment formulas, current RAMs are simpler and include specific recommendations for thromboprophylaxis based on the available scientific evidence. Consensus documents on VTE prevention classify patients into low-, moderate-, and high-risk categories. More recently, a new risk group, very high risk, has been described. Very-high-risk patients are especially prone to thromboembolic complications and need intensive and in some cases prolonged thromboprophylaxis.

Evaluation of oxygen extraction ratio as a physiologic transfusion trigger in coronary artery bypass graft surgery patients.

BACKGROUND: Approximately 20 percent of all allogeneic blood transfusions are administered in connection with coronary artery bypass graft (CABG) operations. Transfusion practices vary across the country. The whole-body oxygen extraction ratio (O2 ER) reflects the adequacy of the patient's response to acute normovolemic anemia with an O2 ER of approximately 50 percent being shown to be an appropriate transfusion trigger. The present study monitored the O2 ER in patients undergoing CABG and determined if transfusion practices would have been different if an O2 ER > or = 45 percent were used as a transfusion trigger. STUDY DESIGN AND METHODS: Seventy patients with a postoperative Hct < = 25 percent were the test subjects. Arterial and mixed venous contents were determined before the operation, in the intensive care unit after the operation, and 12 hours after the operation. RESULTS: There were no deaths. Forty-one patients received allogeneic transfusion. These patients were older, weighed less, and had a preoperative Hct lower than the nontransfused patients. There were no significant differences between transfused and nontransfused patients with respect to postoperative Hct (21.0 +/- 0.4 vs. 22.2 +/- 0.4), cardiac index (2.5 +/- 0.1 vs. 2.7 +/- 0.1), O2 delivery (6.4 +/- 0.3 vs. 6.7 +/- 0.3), O2 consumption (2.5 +/- 0.1 vs. 2.5 +/- 0.1), and O2 ER (38.3 +/- 1.7 vs. 37.5 +/- 1.5). In the transfusion group, 7 of 21 patients had a postoperative O2 ER > or = 45 percent, while 3 of 35 in the nontransfused group had that result. CONCLUSION: The use of O2 ER as a transfusion trigger as part of a transfusion algorithm could lead to a reduction in allogeneic blood transfusion.

Finding the right fit: effective thrombosis risk stratification in orthopedic patients.

Patients undergoing orthopedic surgery are at increased risk of venous thromboembolic events. Proven prophylactic measures are available but are generally underused. However, even one of the most effective therapies available, low-molecular-weight heparin, fails to prevent deep vein thrombosis in approximately 15% of patients undergoing total hip replacement. Clinical outcomes and cost-effectiveness of venous thromboembolism prophylaxis may be optimized by tailoring the treatment to the level of risk of each patient. Overall thromboembolic risk depends on the interactions among multiple factors, such as those that relate to the current clinical status and underlying susceptibility of the patient. Presently, risk assessment models that consider these factors may be of practical assistance in stratifying patients. Improving identification of patients with additional risk factors is a goal of future models. Novel therapies, such as the recombinant hirudin desirudin, or strategies, such as prolonged postoperative prophylaxis, may provide improved protection in these patients and should be considered in the future.

Risk factor assessment in the management of patients with suspected deep venous thrombosis.

BACKGROUND: To evaluate the prevalence of thrombosis risk factors in a group of patients undergoing venous duplex scanning (VDS) and to design a risk factor stratification model with the ability to improve the diagnostic yield of VDS. METHODS: Risk factor assessment and VDS were performed on 1,000 patients with clinically suspected lower extremity deep vein thrombosis (DVT) and patients were divided into two groups based upon the outcome of their scan: those with and those without confirmed DVT. Univariate and multivariate logistic regression analyses were performed in order to determine the significance of each risk factor in relation to having a confirmed DVT. RESULTS: There were 181 patients (18.1%) with confirmed DVT. A prior history of DVT/pulmonary embolism, malignancy, prior immobilization, and age over 70 were the most important risk factors associated with having a DVT confirmed on VDS. A novel risk factor stratification model was created utilizing the odds ratios of those factors found to be significant and the prevalence of DVT was found to be 92.4% in the high risk category, 11.5% in the moderate risk category, and 3.2% in the low risk category using this model. CONCLUSIONS: Venous duplex scanning is established as the screening test of choice when one suspects the diagnosis of DVT despite the significant cost of performing and interpreting the test. We suggest that a better clinical model utilizing risk factor assessment may be the key to increasing the yield rate and cost-effectiveness of VDS by excluding low-risk patients from undergoing unnecessary testing.

The use of a Bayesian forecasting model in the management of warfarin therapy after total hip arthroplasty.

This study was performed to compare the computer-based and physician-based management of warfarin therapy after total hip arthroplasty (THA). The computer-assisted and control groups of patients were placed on warfarin postoperatively and followed for a 1-month period. A significant difference (P<.05) was found between the mean number of days needed to reach therapeutic anticoagulation in the control group (4.7+/-3.0 days) and the experimental group (2.8+/-1.4 days) and the proportion of patients in each group who were discharged with a subtherapeutic international normalized ratio (INR) (INR <1.5). The computer-based management of warfarin therapy was more efficient than unaided physician-based management and therefore may lead to improved, cost-effective patient care by reducing length of hospital stay and complications attributable to nontherapeutic anticoagulation in THA patients.