Oral rivaroxaban for symptomatic venous thromboembolism.

BACKGROUND: Rivaroxaban, an oral factor Xa inhibitor, may provide a simple, fixed-dose regimen for treating acute deep-vein thrombosis (DVT) and for continued treatment, without the need for laboratory monitoring. METHODS: We conducted an open-label, randomized, event-driven, noninferiority study that compared oral rivaroxaban alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with subcutaneous enoxaparin followed by a vitamin K antagonist (either warfarin or acenocoumarol) for 3, 6, or 12 months in patients with acute, symptomatic DVT. In parallel, we carried out a double-blind, randomized, event-driven superiority study that compared rivaroxaban alone (20 mg once daily) with placebo for an additional 6 or 12 months in patients who had completed 6 to 12 months of treatment for venous thromboembolism. The primary efficacy outcome for both studies was recurrent venous thromboembolism. The principal safety outcome was major bleeding or clinically relevant nonmajor bleeding in the initial-treatment study and major bleeding in the continued-treatment study. RESULTS: The study of rivaroxaban for acute DVT included 3449 patients: 1731 given rivaroxaban and 1718 given enoxaparin plus a vitamin K antagonist. Rivaroxaban had noninferior efficacy with respect to the primary outcome (36 events [2.1%], vs. 51 events with enoxaparin-vitamin K antagonist [3.0%]; hazard ratio, 0.68; 95% confidence interval [CI], 0.44 to 1.04; P<0.001). The principal safety outcome occurred in 8.1% of the patients in each group. In the continued-treatment study, which included 602 patients in the rivaroxaban group and 594 in the placebo group, rivaroxaban had superior efficacy (8 events [1.3%], vs. 42 with placebo [7.1%]; hazard ratio, 0.18; 95% CI, 0.09 to 0.39; P<0.001). Four patients in the rivaroxaban group had nonfatal major bleeding (0.7%), versus none in the placebo group (P=0.11). CONCLUSIONS: Rivaroxaban offers a simple, single-drug approach to the short-term and continued treatment of venous thrombosis that may improve the benefit-to-risk profile of anticoagulation. (Funded by Bayer Schering Pharma and Ortho-McNeil; ClinicalTrials.gov numbers, NCT00440193 and NCT00439725.).

Idraparinux versus standard therapy for venous thromboembolic disease.

BACKGROUND: Venous thromboembolism is treated with unfractionated heparin or low-molecular-weight heparin, followed by a vitamin K antagonist. We investigated the potential use of idraparinux, a long-acting inhibitor of activated factor X, as a substitute for standard therapy. METHODS: We conducted two randomized, open-label noninferiority trials involving 2904 patients with deep-vein thrombosis and 2215 patients with pulmonary embolism to compare the efficacy and safety of idraparinux versus standard therapy. Patients received either subcutaneous idraparinux (2.5 mg once weekly) or a heparin followed by an adjusted-dose vitamin K antagonist for either 3 or 6 months. The primary efficacy outcome was the 3-month incidence of symptomatic recurrent venous thromboembolism (nonfatal or fatal). RESULTS: In the study of patients with deep venous thrombosis, the incidence of recurrence at day 92 was 2.9% in the idraparinux group as compared with 3.0% in the standard-therapy group (odds ratio, 0.98; 95% confidence interval [CI], 0.63 to 1.50), a result that satisfied the prespecified noninferiority requirement. At 6 months, the hazard ratio for idraparinux was 1.01. The rates of clinically relevant bleeding at day 92 were 4.5% in the idraparinux group and 7.0% in the standard-therapy group (P=0.004). At 6 months, bleeding rates were similar. In the study of patients with pulmonary embolism, the incidence of recurrence at day 92 was 3.4% in the idraparinux group and 1.6% in the standard-therapy group (odds ratio, 2.14; 95% CI, 1.21 to 3.78), a finding that did not meet the noninferiority requirement. CONCLUSIONS: In patients with deep venous thrombosis, once-weekly subcutaneous idraparinux for 3 or 6 months had an efficacy similar to that of heparin plus a vitamin K antagonist. However, in patients with pulmonary embolism, idraparinux was less efficacious than standard therapy. (ClinicalTrials.gov numbers, NCT00067093 [ClinicalTrials.gov] and NCT00062803 [ClinicalTrials.gov].).

Extended prophylaxis of venous thromboembolism with idraparinux.

BACKGROUND: The extended use of vitamin K antagonists for prophylaxis against venous thromboembolism is often constrained by risk-benefit limitations and inconvenience. We evaluated the efficacy and safety of a 6-month extension of prophylaxis against recurrent venous thromboembolism with idraparinux in patients who had initially received 6 months of prophylaxis with an anticoagulant. METHODS: We randomly assigned patients who had completed 6 months of prophylaxis with idraparinux or a vitamin K antagonist and in whom extended anticoagulation was warranted to receive once-weekly injections of 2.5 mg of idraparinux or placebo for 6 months without monitoring. The primary efficacy and safety outcomes were recurrent venous thromboembolism and major bleeding. RESULTS: Of 1215 patients, 6 of 594 (1.0%) in the idraparinux group and 23 of 621 (3.7%) in the placebo group had recurrent venous thromboembolism (P=0.002). Major bleeding occurred in 11 patients (1.9%) in the idraparinux group and in none in the placebo group (P<0.001). Of these 11 episodes, 3 were fatal intracranial hemorrhages. As compared with patients whose initial treatment was a vitamin K antagonist, patients whose initial treatment was idraparinux who were assigned to 6 months in the placebo group had a lower incidence of recurrent thromboembolism (0.7% vs. 5.9%); patients who received 6 additional months of idraparinux therapy had a higher incidence of major bleeding (3.1% vs. 0.9%). CONCLUSIONS: During a 6-month extension of thromboprophylaxis, idraparinux was effective in preventing recurrent thromboembolism but was associated with an increased risk of a major hemorrhage. (ClinicalTrials.gov number, NCT00071279 [ClinicalTrials.gov].).

Treatment of venous thromboembolism in patients with cancer: subgroup analysis of the Matisse clinical trials.

In the initial treatment of venous thromboembolism (VTE) fondaparinux, a pentasaccharide, is a good alternative to heparin. Whether this is also true for cancer patients is unknown. We performed two post-hoc analyses of two randomized studies to compare efficacy, safety and overall survival of fondaparinux to standard initial (low-molecular-weight) heparin (LMWH) treatment in cancer patients with venous thromboembolism. Two hundred thirty-seven cancer patients with deep venous thrombosis (DVT) were initially treated with fondaparinux or enoxaparin. Two hundred forty cancer patients with pulmonary embolism (PE) received fondaparinux or unfractionated heparin. The initial treatment was followed by vitamin K antagonists. In DVT patients, the three-month recurrence rate was 5.4% in the enoxaparin recipients compared to 12.7% in those treated with fondaparinux [absolute difference 7.3%, 95% CI 0.1, 14.5]. A recurrence was observed in 8.9% of the PE patients treated with fondaparinux compared to 17.2% in the unfractionated heparin recipients [absolute difference -8.3, 95% CI -16.7, 0.1]. In both studies no difference in bleeding and overall survival was observed. Regarding overall survival and bleeding fondaparinux is comparable to enoxaparin and unfractionated heparin in cancer patients. No significant differences in recurrent VTE were observed when comparing fondaparinux with unfractionated or LMWH. Because of study limitations these results should be considered hypothesis-generating.

Venous thromboembolism prophylaxis in acutely ill hospitalized medical patients: findings from the International Medical Prevention Registry on Venous Thromboembolism.

BACKGROUND: Evidence-based guidelines recommend that acutely ill hospitalized medical patients who are at risk of venous thromboembolism (VTE) should receive prophylaxis. Our aim was to characterize the clinical practices for VTE prophylaxis in acutely ill hospitalized medical patients enrolled in the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE). METHODS: IMPROVE is an ongoing, multinational, observational study. Participating hospitals enroll the first 10 consecutive eligible acutely ill medical patients each month. Patient management is determined by the treating physicians. An analysis of data on VTE prophylaxis practices is presented. RESULTS: From July 2002 to September 30, 2006, 15,156 patients were enrolled from 52 hospitals in 12 countries, of whom 50% received in-hospital pharmacologic and/or mechanical VTE prophylaxis. In the United States and other participating countries, 52% and 43% of patients, respectively, should have received prophylaxis according to guideline recommendations from the American College of Chest Physicians (ACCP). Only approximately 60% of patients who either met the ACCP criteria for requiring prophylaxis or were eligible for enrollment in randomized clinical trials that have shown the benefits of pharmacologic prophylaxis actually received prophylaxis. Practices varied considerably. Intermittent pneumatic compression was the most common form of medical prophylaxis utilized in the United States, although it was used very rarely in other countries (22% vs 0.2%, respectively). Unfractionated heparin was the most frequent pharmacologic approach used in the United States (21% of patients), with low-molecular-weight heparin used most frequently in other participating countries (40%). There was also variable use of elastic stockings in the United States and other participating countries (3% vs 7%, respectively). CONCLUSIONS: Our data suggest that physicians' practices for providing VTE prophylaxis to acutely ill hospitalized medical patients are suboptimal and highlight the need for improved implementation of existing evidence-based guidelines in hospitals.

The safety and efficacy of extended thromboprophylaxis with fondaparinux after major orthopedic surgery of the lower limb with or without a neuraxial or deep peripheral nerve catheter: the EXPERT Study.

BACKGROUND: The benefit-risk ratio of extended fondaparinux therapy has not been assessed in patients undergoing major lower limb joint arthroplasty. Few data on the concomitant use of fondaparinux and continuous neuraxial or deep peripheral nerve blockade are available. We performed a prospective intervention study in patients undergoing major orthopedic surgery primarily designed to assess the efficacy of fondaparinux when drug administration was withheld for 48 h to permit removal of a neuraxial or deep peripheral nerve catheter. The safety and efficacy of extended fondaparinux therapy for the prevention of venous thromboembolism were also evaluated. METHODS: Patients received a daily subcutaneous injection of 2.5 mg fondaparinux for 3 to 5 wk postoperatively. In patients with a neuraxial or deep peripheral nerve catheter, the catheter was removed 36 h after the last fondaparinux dose. The next fondaparinux dose was administered 12 h after catheter removal. The primary end points were symptomatic venous thromboembolism and major bleeding up to 4-6 wk after surgery. RESULTS: We recruited 5704 patients. A neuraxial or deep peripheral nerve catheter was inserted in 1553 (27%) patients and 78 (1.4%) patients, respectively. The rate of venous thromboembolism was 1.0% (54 of 5387). There was no difference between patients without (1.1%) or with (0.8%) a catheter (the upper limit of the 95% confidence interval of the odds ratio, 1.49, being below the predetermined noninferiority margin of 1.75). The incidence of major bleeding was 0.8% (42 of 5382). No neuraxial or perineural hematoma was reported. CONCLUSIONS: Once-daily subcutaneous injection of 2.5 mg fondaparinux given for 3 to 5 wk was effective and safe for prevention of venous thromboembolism after major orthopedic surgery. Temporary discontinuation of fondaparinux for 48 h permitted safe removal of a neuraxial or deep peripheral nerve catheter without decreasing thromboprophylatic efficacy.

Extended non-vitamin K antagonist oral anticoagulation therapy for prevention of recurrent venous thromboembolism.

Evidence from the use of traditional therapy (low-molecular-weight heparin/vitamin K antagonists) for venous thromboembolism (VTE) treatment and prevention suggests that extending treatment beyond the acute phase reduces recurrence. More recently, several non-vitamin K antagonist oral anticoagulants (NOACs) have been approved in the acute setting; accumulating evidence suggests continuing treatment with these agents beyond 12months offers additional benefits to patients with VTE. This review examines the evidence for NOAC use in longer-duration anticoagulation treatment, and discusses guidelines from major societies. Clinical data from the phase III extension studies for apixaban, dabigatran and rivaroxaban are presented, and the clinical and economic costs and benefits are examined. Evidence from other therapy areas utilising extended treatment regimens highlights the possible impact of factors relevant to extended anticoagulation therapy. Phase IV studies of NOACs are presented. US and European guidelines advise long-term therapy in certain instances, taking into account evidence on NOAC use in VTE accumulated recently. They support NOAC use where they have been selected as the initial therapy choice and therapy needs to be extended beyond 3months. The phase III extension studies demonstrate the benefits of extended NOAC use versus treatment cessation, with reduced recurrence rates versus placebo, although associated with a potential moderate increase in bleeding risk. Phase IV data are also emerging, with the recent XALIA study showing that a broad range of patients with VTE can benefit from continued rivaroxaban treatment; ongoing research will yield data on long-term use of the other NOACs in routine clinical practice.

The effect of low molecular weight heparin on survival in patients with advanced malignancy.

PURPOSE: Studies in cancer patients with venous thromboembolism suggested that low molecular weight heparin may prolong survival. In a double-blind study, we evaluated the effect of low molecular weight heparin on survival in patients with advanced malignancy without venous thromboembolism. METHODS: Patients with metastasized or locally advanced solid tumors were randomly assigned to receive a 6-week course of subcutaneous nadroparin or placebo. The primary efficacy analysis was based on time from random assignment to death. The primary safety outcome was major bleeding. RESULTS: In total, 148 patients were allocated to nadroparin and 154 patients were allocated to placebo. Mean follow-up was 1 year. In the intention-to-treat analysis the overall hazard ratio of mortality was 0.75 (95% CI, 0.59 to 0.96) with a median survival of 8.0 months in the nadroparin recipients versus 6.6 months in the placebo group. After adjustment for potential confounders, the treatment effect remained statistically significant. Major bleeding occurred in five (3%) of nadroparin-treated patients and in one (1%) of the placebo recipients (P = .12). In the a priori specified subgroup of patients with a life expectancy of 6 months or more at enrollment, the hazard ratio was 0.64 (95% CI, 0.45 to 0.90) with a median survival of 15.4 and 9.4 months, respectively. For patients with a shorter life expectancy, the hazard ratio was 0.88 (95% CI, 0.62 to 1.25). CONCLUSION: A brief course of subcutaneous low molecular weight heparin favorably influences the survival in patients with advanced malignancy and deserves additional clinical evaluation.

Acute pulmonary embolism: risk assessment, risk stratification and treatment options.

INTRODUCTION: Pulmonary embolism (PE) is a potentially life-threatening cardiovascular emergency with a high mortality rate. Rapid diagnosis and treatment are important in optimising clinical outcomes in patients with PE, and anticoagulants are the mainstay of treatment. Traditionally, anticoagulant therapy involves parenteral anticoagulants, overlapping with and followed by oral vitamin K antagonists. Direct oral anticoagulants (DOACs), including the factor Xa inhibitors rivaroxaban, apixaban and edoxaban, and the direct thrombin inhibitor dabigatran etexilate, have been developed to address limitations associated with traditional anticoagulant therapy. Apixaban, dabigatran and rivaroxaban have recently been approved for the treatment of acute deep vein thrombosis (DVT) and PE and prevention of recurrent DVT or PE. Edoxaban is approved in the United States but not currently in the European Union for the treatment of DVT and PE; approval of edoxaban in Europe is anticipated in the near future. OBJECTIVE: To summarise the management of patients with suspected PE in accordance with recent guidelines, and to discuss the evidence behind the recent approvals of the DOACs for the treatment of PE. DISCUSSION: Diagnosis and treatment of PE is guided by clinical probability scoring systems and tools for prognostic stratification and early mortality risk evaluation. Anticoagulants remain the mainstay of treatment. Successful phase III trials have demonstrated the efficacy of the DOACs for the treatment of DVT and PE, with a potentially improved safety profile, leading to their recent approval in this indication, and giving the clinician greater choice of anticoagulant therapies in this setting. CONCLUSIONS: DOACs offer an alternative and potentially simplified option for anticoagulation therapy in patients with PE compared with traditional anticoagulants and are likely to assist physicians in optimising management of patients with PE and improve clinical outcomes.

European Union-28: An annualised cost-of-illness model for venous thromboembolism.

Annual costs for venous thromboembolism (VTE) have been defined within the United States (US) demonstrating a large opportunity for cost savings. Costs for the European Union-28 (EU-28) have never been defined. A literature search was conducted to evaluate EU-28 cost sources. Median costs were defined for each cost input and costs were inflated to 2014 Euros (€) in the study country and adjusted for Purchasing Power Parity between EU countries. Adjusted costs were used to populate previously published cost-models based on adult incidence-based events. In the base model, annual expenditures for total, hospital-associated, preventable, and indirect costs were €1.5-2.2 billion, €1.0-1.5 billion, €0.5-1.1 billion and €0.2-0.3 billion, respectively (indirect costs: 12 % of expenditures). In the long-term attack rate model, total, hospital-associated, preventable, and indirect costs were €1.8-3.3 billion, €1.2-2.4 billion, €0.6-1.8 billion and €0.2-0.7 billion (indirect costs: 13 % of expenditures). In the multiway sensitivity analysis, annual expenditures for total, hospital-associated, preventable, and indirect costs were €3.0-8.5 billion, €2.2-6.2 billion, €1.1-4.6 billion and €0.5-1.4 billion (indirect costs: 22 % of expenditures). When the value of a premature life-lost increased slightly, aggregate costs rose considerably since these costs are higher than the direct medical costs. When evaluating the models aggregately for costs, the results suggests total, hospital-associated, preventable, and indirect costs ranging from €1.5-13.2 billion, €1.0-9.7 billion, €0.5-7.3 billion and €0.2-6.1 billion, respectively. Our study demonstrates that VTE costs have a large financial impact upon the EU-28's healthcare systems and that significant savings could be realised if better preventive measures are applied.

Simplification of the diagnostic management of suspected deep vein thrombosis.

BACKGROUND: The standard diagnostic approach in patients with suspected deep vein thrombosis is to repeat the compression ultrasonography after 1 week in all patients with an initial normal result. We hypothesized that a normal finding of a D-dimer assay safely obviates the need for repeated ultrasonography. In addition, we evaluated the potential value of a pretest probability assessment for this purpose. METHODS: At presentation, consecutive outpatients with suspected thrombosis underwent independent assessment by means of ultrasonography of the proximal veins, a whole-blood D-dimer assay, and a pretest clinical model. Patients with normal ultrasonographic findings and an abnormal D-dimer assay result were scheduled for repeated ultrasonography. We evaluated the incidence of symptomatic venous thromboembolic complications during a 3-month follow-up, and the value of clinical pretest probability with ultrasonography or D-dimer assay in scenario analyses. RESULTS: We studied 1756 patients with prevalence of thrombosis of 22%. At entry, results of the D-dimer assay and ultrasonography were normal in 828 patients (47%). Of these, 6 returned with confirmed symptomatic venous thromboembolism (complication rate, 0.7%; 95% confidence interval [CI], 0.3%-1.6%). Repeated ultrasonography was avoided in 61% of the patients with an initial normal test result. Scenario analyses disclosed that the complication rate was 1.6% (95% CI, 0.8%-2.6%) in those with a low clinical pretest probability and a normal result of ultrasonography at referral, whereas this figure was 1.8% (95% CI, 0.9%-3.3%) in patients with a low clinical probability result and a normal result of the D-dimer assay at referral. CONCLUSIONS: It is safe to withhold repeated ultrasonography in patients with suspected deep vein thrombosis who have normal results of ultrasonograpy and the SimpliRED D-dimer assay at presentation. The combination of a low clinical pretest probability with a normal result of compression ultrasonography or the D-dimer assay appears to be equally safe in refuting the diagnosis of deep vein thrombosis.

Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis: a randomized trial.

BACKGROUND: The current standard initial therapies for deep venous thrombosis are low-molecular-weight heparin and unfractionated heparin. In a dose-ranging study of patients with symptomatic deep venous thrombosis, fondaparinux had efficacy and a safety profile similar to those of low-molecular-weight heparin (dalteparin). OBJECTIVE: To evaluate whether fondaparinux has efficacy and safety similar to those of enoxaparin in patients with deep venous thrombosis. DESIGN: Randomized, double-blind study. SETTING: 154 centers worldwide. PATIENTS: 2205 patients with acute symptomatic deep venous thrombosis. INTERVENTION: Fondaparinux, 7.5 mg (5.0 mg in patients weighing <50 kg and 10.0 mg in patients weighing >100 kg) subcutaneously once daily, or enoxaparin, 1 mg/kg of body weight, subcutaneously twice daily for at least 5 days and until vitamin K antagonists induced an international normalized ratio greater than 2.0. MEASUREMENTS: The primary efficacy outcome was the 3-month incidence of symptomatic recurrent venous thromboembolic complications. The main safety outcomes were major bleeding during initial treatment and death. An independent, blinded committee adjudicated all outcomes. RESULTS: 43 (3.9%) of 1098 patients randomly assigned to fondaparinux had recurrent thromboembolic events compared with 45 (4.1%) of 1107 patients randomly assigned to enoxaparin (absolute difference, -0.15 percentage point [95% CI, -1.8 to 1.5 percentage points]). Major bleeding occurred in 1.1% of patients receiving fondaparinux and 1.2% of patients receiving enoxaparin. Mortality rates were 3.8% and 3.0%, respectively. LIMITATIONS: Follow-up was incomplete in 0.4% of fondaparinux-treated patients and 1.0% of enoxaparin-treated patients. CONCLUSIONS: Once-daily subcutaneous fondaparinux was at least as effective (not inferior) and safe as twice-daily, body weight-adjusted enoxaparin in the initial treatment of patients with symptomatic deep venous thrombosis.

New anticoagulants in the management of venous thromboembolism in women.

Objective diagnosis and treatment are important in optimizing clinical outcomes in patients with venous thromboembolism (VTE), and anticoagulants are the mainstay of treatment. Traditionally, anticoagulant therapy involves parenteral anticoagulants, overlapping with and followed by oral vitamin K antagonists. Recently, direct oral anticoagulants (DOACs), including the Factor Xa inhibitors rivaroxaban, apixaban and edoxaban, and the direct thrombin inhibitor dabigatran etexilate, have been developed to address limitations associated with traditional anticoagulant therapy. DOACs have recently been approved for the treatment of acute deep vein thrombosis (DVT) and pulmonary embolism (PE). Successful phase III trials have demonstrated their efficacy for the treatment of DVT and PE, with a potentially improved safety profile. Recent evidence suggests that women bleed more compared to men when treated with DOACs for VTE without differences in treatment efficacy. Future clinical trials should include outcomes stratified by sex, and should investigate the clinical impact of this sex-related safety difference.

Usefulness and limits of transthoracic echocardiography in the evaluation of patients with primary and chronic thromboembolic pulmonary hypertension.

The aim of the study was to evaluate the potential usefulness of transthoracic echocardiography in differentiating patients with primary or chronic thromboembolic pulmonary hypertension and to define the capability of echocardiography to assess right-heart performance in such patients. Right-heart catheterization and ultrasound examination were performed in 111 patients with chronic thromboembolic pulmonary hypertension and in 31 patients with primary pulmonary hypertension. All echocardiographic and Doppler parameters were similar in primary and chronic thromboembolic pulmonary hypertension. A significant correlation was found between the tricuspid annular plane systolic excursion and the right ventricular fractional area change and thermodilution-derived right ventricular ejection fraction (P <.001 for both). Furthermore, different patterns of the pulsed Doppler flow velocity curve into the superior vena cava were associated with different right-heart hemodynamic profiles. In conclusion, in patients with chronic pulmonary hypertension transthoracic echocardiography portends meaningful information on the capability of the right heart to confront the increased afterload but it does not permit etiologic differentiation.

Epoprostenol in chronic thromboembolic pulmonary hypertension with distal lesions.

BACKGROUND: Although patients with primary pulmonary hypertension and patients with chronic thromboembolic pulmonary hypertension with distal lesions may share similar pathophysiological characteristics, scarce information is available on the usefulness of epoprostenol in this form of secondary pulmonary hypertension. The aim of this study was to evaluate the feasibility, safety and efficacy of epoprostenol therapy in surgically untreatable patients with chronic thromboembolic pulmonary hypertension. METHODS: Continuous infusive therapy with epoprostenol was undertaken in 16 patients with primary pulmonary hypertension and in 11 surgically untreatable thromboembolic pulmonary hypertension patients. The median follow-up was 12.4 months (range 6-23 months). Patients underwent clinical, echocardiographic and hemodynamic evaluation at baseline and a 6-min walk test every 3 months after beginning epoprostenol; ultrasound evaluations were repeated in a subgroup of patients. RESULTS: Epoprostenol therapy improved the clinical status, exercise tolerance and NYHA functional class. A greater left ventricular end-diastolic volume was recorded at echocardiography in both groups. CONCLUSIONS: Epoprostenol therapy may be feasible, safe and clinically effective in patients with surgically untreatable chronic thromboembolic pulmonary hypertension.

The effect of prothrombotic blood abnormalities on risk of deep vein thrombosis in users of hormone replacement therapy: a prospective case-control study.

BACKGROUND: Few studies have assessed the effect of prothrombotic blood abnormalities on the risk of deep vein thrombosis (DVT) with hormone replacement therapy (HRT). METHODS: We studied postmenopausal women with suspected DVT in whom HRT use and prothrombotic blood abnormalities were sought. Cases had unprovoked DVT and controls had no DVT and without DVT risk factors. The risk of DVT was determined in women with and without prothrombotic abnormalities. RESULTS: A total of 510 postmenopausal women with suspected DVT were assessed; 57 cases and 283 controls were identified. Compared to HRT, nonusers without the factor V Leiden mutation, the risk of DVT was increased in estrogen-progestin HRT users (odds ratio [OR], 3.2; 95% confidence interval [CI]: 1.2-8.6) and in nonusers with the factor V Leiden mutation (OR, 5.3; 1.9-15.4) and appears multiplied in users of estrogen-progestin HRT with the factor V Leiden mutation (OR, 17.1; 3.7-78). Compared to HRT, nonusers with normal factor VIII, the risk of DVT was increased in estrogen-progestin HRT users with normal factor VIII (OR, 2.8; 1.0-7.9) and in HRT nonusers with the highest factor VIII quartile (OR, 6.0; 2.1-17), and appears to be multiplied in women who are users of estrogen-progestin HRT with the highest factor VIII quartile (OR, 17.0; 3.6-80). CONCLUSIONS: In postmenopausal women who are estrogen-progestin HRT users, the presence of the factor V Leiden mutation or an elevated factor VIII level appears to have a multiplicative effect on their overall risk of DVT, increasing it 17-fold compared to women without these blood abnormalities who are HRT nonusers.

Prevalence and risk of preexisting heparin-induced thrombocytopenia antibodies in patients with acute VTE.

BACKGROUND: Some patients with acute VTE who may previously have been exposed to heparin products have unrecognized antibodies implicated in heparin-induced thrombocytopenia (HIT). Antibody prevalence and patient consequences upon exposure to heparin, low-molecular-weight heparin, and fondaparinux are uncertain. METHODS: In this secondary analysis, we tested patients in the Matisse VTE studies at study entry for heparin-dependent antibodies and further tested patients with enzyme-linked immunosorbent assay (ELISA)-positive results for platelet-activating antibodies. We compared the risk of HIT (> 50% fall in platelet count, heparin-dependent antibodies, no contradicting features) between patients treated with heparin (either unfractionated or low molecular weight [enoxaparin]) vs those who received fondaparinux. Comparison groups for thrombocytopenia occurrence comprised patients with ELISA-positive, platelet-activating, antibody-positive results; ELISA-positive, but platelet-activating antibody-negative results; and randomly selected antibody-negative results. RESULTS: A total of 127 of 3,994 patients (3.2%) had ELISA-positive results at baseline, but only 14 (0.4%; 95% CI, 0.2%-0.6%) had platelet-activating antibodies. Among these 14, four treated with unfractionated or low-molecular-weight heparin developed HIT compared with zero of 10 fondaparinux-treated patients (OR, 95; 95% CI, 8-1,123; P < .001). This frequency (four of four, 100%) significantly differed from that of both heparin-treated patients whose results were ELISA positive but platelet-activating antibody negative and from heparin-treated antibody-negative control subjects (zero of 15 and zero of 27, respectively; P < .001 for both). CONCLUSIONS: Of patients with VTE, 0.4% had pathologic platelet-activating heparin-dependent antibodies rather than the 3.2% detected by the recommended cutoff of the commercial ELISA. Among study patients with acute VTE who had platelet-activating antibodies, treatment with fondaparinux reduced the risk of precipitating rapid-onset HIT.

Factors at admission associated with bleeding risk in medical patients: findings from the IMPROVE investigators.

BACKGROUND: Acutely ill, hospitalized medical patients are at risk of VTE. Despite guidelines for VTE prevention, prophylaxis use in these patients is still poor, possibly because of fear of bleeding risk. We used data from the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) to assess in-hospital bleeding incidence and to identify risk factors at admission associated with in-hospital bleeding risk in acutely ill medical patients. METHODS: IMPROVE is a multinational, observational study that enrolled 15,156 medical patients. The in-hospital bleeding incidence was estimated by Kaplan-Meier analysis. A multiple regression model analysis was performed to identify risk factors at admission associated with bleeding. RESULTS: The cumulative incidence of major and nonmajor in-hospital bleeding within 14 days of admission was 3.2%. Active gastroduodenal ulcer (OR, 4.15; 95% CI, 2.21-7.77), prior bleeding (OR, 3.64; 95% CI, 2.21-5.99), and low platelet count (OR, 3.37; 95% CI, 1.84-6.18) were the strongest independent risk factors at admission for bleeding. Other bleeding risk factors were increased age, hepatic or renal failure, ICU stay, central venous catheter, rheumatic disease, cancer, and male sex. Using these bleeding risk factors, a risk score was developed to estimate bleeding risk. CONCLUSIONS: We assessed the incidence of major and clinically relevant bleeding in a large population of hospitalized medical patients and identified risk factors at admission associated with in-hospital bleeding. This information may assist physicians in deciding whether to use mechanical or pharmacologic VTE prophylaxis.

Predictive and associative models to identify hospitalized medical patients at risk for VTE.

BACKGROUND: Acutely ill hospitalized medical patients are at risk for VTE. We assessed the incidence of VTE in the observational International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) study and derived VTE risk assessment scores at admission and associative VTE scores during hospitalization. METHODS: Data from 15,156 medical patients were analyzed to determine the cumulative incidence of clinically observed VTE over 3 months after admission. Multiple regression analysis identified factors associated with VTE risk. RESULTS: Of the 184 patients who developed symptomatic VTE, 76 had pulmonary embolism, and 67 had lower-extremity DVT. Cumulative VTE incidence was 1.0%; 45% of events occurred after discharge. Factors independently associated with VTE were previous VTE, known thrombophilia, cancer, age > 60 years, lower-limb paralysis, immobilization ≥ 7 days, and admission to an ICU or coronary care unit (first four were available at admission). Points were assigned to each factor identified to give a total risk score for each patient. At admission, 67% of patients had a score ≥ 1. During hospitalization, 31% had a score ≥ 2; for a score of 2 or 3, observed VTE risk was 1.5% vs 5.7% for a score ≥ 4. Observed and predicted rates were similar for both models (C statistic, 0.65 and 0.69, respectively). During hospitalization, a score ≥ 2 was associated with higher overall and VTE-related mortality. CONCLUSIONS: Weighted VTE risk scores derived from four clinical risk factors at hospital admission can predict VTE risk in acutely ill hospitalized medical patients. Scores derived from seven clinical factors during hospitalization may help us to further understand symptomatic VTE risk. These scores require external validation.