Thromboprophylaxis with dalteparin in medical patients: which patients benefit?

It is unclear whether thromboprophylaxis produces a consistent risk reduction in different subgroups of medical patients at risk from venous thromboembolism. We performed a retrospective, post hoc analysis of 3706 patients enrolled in the PREVENT study. Patients were at least 40 years old with an acute medical condition requiring hospitalization for at least 4 days and had no more than 3 days of immobilization prior to enrolment. Patients received either subcutaneous dalteparin (5000 IU) or placebo once daily. The primary end point was the composite of symptomatic deep vein thrombosis (DVT), pulmonary embolism, asymptomatic proximal DVT, or sudden death. Primary diagnosis subgroups were acute congestive heart failure, acute respiratory failure, infectious disease, rheumatological disorders, or inflammatory bowel disease. All patients, except those with congestive heart or respiratory failure, had at least one additional risk factor for venous thromboembolism. A risk reduction was shown in patients receiving dalteparin versus placebo. The relative risk (RR) was 0.73 in patients with congestive heart failure, 0.72 for respiratory failure, 0.46 for infectious disease, and 0.97 for rheumatological disorders. The RR was 0.52 in patients aged > or = 75 years, 0.64 in obese patients, 0.34 for patients with varicose veins, and 0.71 in patients with chronic heart failure. No subgroup had a significantly different response from any other. Importantly, multivariate analysis showed that all patient groups benefited from thromboprophylaxis with dalteparin. Our findings, therefore, support the broad application of thromboprophylaxis in acutely ill hospitalized medical patients.

Outpatient tinzaparin therapy in pulmonary embolism quantified with ventilation/perfusion scintigraphy.

BACKGROUND: Out-of-hospital treatment of patients with deep-vein thrombosis (DVT) is routine in many countries regardless of frequent concomitant asymptomatic pulmonary embolism (PE) in this group. However, patients with symptoms and verified PE are still regularly treated in hospital. The objectives were to test a model for outpatient tinzaparin therapy and to evaluate its safety and efficacy in patients with symptomatic, small or medium-sized PE using quantitative ventilation/perfusion scintigraphy (qV/P SCINT) for patient selection and follow up. MATERIAL/METHODS: This prospective study included 102 patients treated with tinzaparin and warfarin for 5 days at a patient hotel. PE was quantified scintigraphically as loss of perfusion with preserved ventilation at segmental or subsegmental levels (mismatch). Points were attributed to segments of reduced ventilation (RoVent) and perfusion (RoPer). A holistic principle of interpretation was applied. Patients were excluded if they had >14 RoPer points (7 segments) or >7 RoVent points. Clinical follow-up and scintigraphy were repeated at discharge in 100 patients and after 13 months on average. RESULTS: Embolism diminished by 44% after 5 days and demanding symptoms declined. There was no thromboembolic mortality in the trial. At late follow-up, PE had not recurred in patients with resolution after 5 days. In those with insufficient early response, persistent perfusion defects were usually observed. CONCLUSIONS: The results indicate the safety and efficacy of outpatient treatment of PE according to our model and merit larger, multicenter, controlled studies.

Efficacy and safety of fixed low-dose dalteparin in preventing venous thromboembolism among obese or elderly hospitalized patients: a subgroup analysis of the PREVENT trial.

BACKGROUND: We were concerned that a fixed rather than a weight-based dosing regimen of dalteparin sodium to prevent venous thromboembolism (VTE) might result in decreased efficacy in obese patients and decreased safety in elderly patients. METHODS: We retrospectively performed subgroup analyses using the database from the Prospective Evaluation of Dalteparin Efficacy for Prevention of VTE in Immobilized Patients (PREVENT) Trial, a study of 3706 hospitalized, medically ill patients randomized to receive either dalteparin sodium, 5000 U/d, or placebo. The primary end point was a composite of symptomatic VTE, fatal pulmonary embolism, sudden death, or asymptomatic proximal deep venous thrombosis by day 21. Obesity was defined as a body mass index (calculated as weight in kilograms divided by the square of height in meters) of 30 or greater for men and 28.6 or greater for women. RESULTS: Overall, 1118 patients (30.4%) were obese and 1226 (33.3%) were 75 years or older. In obese patients, the primary end point occurred in 2.8% of the dalteparin and in 4.3% of the placebo groups (relative risk, 0.64; 95% confidence interval [CI], 0.32-1.28). In patients 75 years or older, the primary end point was reported in 4.2% of the dalteparin and in 8.0% of the placebo groups (relative risk, 0.52; 95% CI, 0.31-0.87). The dalteparin effect for the primary end point (odds ratio, 0.51; 95% CI, 0.32-0.82) was not attenuated when adjusted for age, sex, obesity, history of VTE, and varicose veins. Dalteparin was not associated with an increase in major hemorrhage by day 21 in obese (0% vs 0.7% placebo; P>.99) and in elderly (1.1% vs 0.7%; P=.12) patients. CONCLUSION: Our findings suggest that a fixed low dose of dalteparin sodium of 5000 U/d is effective and safe in preventing VTE in obese and elderly hospitalized medical patients.

Mortality rates and risk factors for asymptomatic deep vein thrombosis in medical patients.

The clinical importance of asymptomatic proximal and distal deep vein thrombosis (DVT) remains uncertain and controversial. The aim of this retrospective, post-hoc analysis was to examine mortality and risk factors for development of proximal DVT in hospitalized patients with acute medical illness who were recruited into a randomized, prospective clinical trial of thromboprophylaxis with dalteparin (PREVENT). We analyzed 1738 patients who had not sustained a symptomatic venous thromboembolic event by Day 21 and who had a complete compression ultrasound of the proximal and distal leg veins on Day 21. We examined the 90-day mortality rates in patients with asymptomatic proximal DVT (Group I, N=80), asymptomatic distal DVT (Group II, N=118) or no DVT (Group III, N=1540). The 90-day mortality rates were 13.75%, 3.39%, and 1.92% for Groups I-III, respectively. The difference in mortality between Group I and Group III was significant (hazard ratio 7.63, 95% CI=3.8-15.3; p <0.0001), whereas the difference between Groups II and III did not reach significance (hazard ratio 1.36, 95% CI=0.41-4.45). The association of asymptomatic proximal DVT with increased mortality remained highly significant after adjusting for differences in baseline demographics and clinical variables. Risk factors significantly associated with the development of proximal DVT included advanced age (p=0.0005), prior DVT (p=0.001), and varicose veins (p=0.04). In conclusion, the high mortality rate in patients with asymptomatic proximal DVT underscores its clinical relevance and supports targeting of asymptomatic proximal DVT as an appropriate endpoint in clinical trials of thromboprophylaxis.

Diagnostic evaluation of planar and tomographic ventilation/perfusion lung images in patients with suspected pulmonary emboli.

Planar lung ventilation/perfusion scintigraphy (V/P(PLANAR)) is a standard method for diagnosis of pulmonary embolism (PE). The goals of this study were to test whether the diagnostic information of ventilation/perfusion tomography (V/P(SPET)) applied in clinical routine might enhance information compared with V/P(PLANAR) and to streamline data processing for the demands of clinical routine. This prospective study includes 53 patients suspected for PE referred for lung scintigraphy. After inhalation of (99m)Tc-DTPA planar ventilation imaging was followed by tomography, using a dual-head gamma camera. (99m)Tc-MAA was injected i.v. for perfusion tomography followed by planar imaging. Patients were examined in supine position, unchanged during V/P tomography. Two reviewers evaluated V/P(PLANAR) and V/P(SPET) images separately and randomly. Mismatch points were calculated on the basis of extension of perfusion defects with preserved ventilation. Patients were followed up clinically for at least 6 months. With V/P(SPET) the number of patients with PE was higher and 53% more mismatch points were found. In V/P(SPET) interobserver variation was less compared with V/P(PLANAR). Ancillary findings were observed by both techniques in half of the patients but more precisely interpreted with V/P(SPET). V/P(SPET) shows more and better delineated mismatch defects, improved quantification and less interobserver variation compared with V/P(PLANAR). V/P(SPET) is amenable to implementation for clinical routine and suitable even when there is demand for a high patient throughput.

Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients.

BACKGROUND: Considerable variability exists in the use of pharmacological thromboprophylaxis among acutely ill medical patients, partly because clinically relevant end points have not been fully assessed in this population. We undertook an international, multicenter, randomized, double-blind, placebo-controlled trial using clinically important outcomes to assess the efficacy and safety of dalteparin in the prevention of venous thromboembolism in such patients. METHODS AND RESULTS: Patients (n=3706) were randomly assigned to receive either subcutaneous dalteparin 5000 IU daily or placebo for 14 days and were followed up for 90 days. The primary end point was venous thromboembolism, defined as the combination of symptomatic deep vein thrombosis, symptomatic pulmonary embolism, and asymptomatic proximal deep vein thrombosis detected by compression ultrasound at day 21 and sudden death by day 21. The incidence of venous thromboembolism was reduced from 4.96% (73 of 1473 patients) in the placebo group to 2.77% (42 of 1518 patients) in the dalteparin group, an absolute risk reduction of 2.19% or a relative risk reduction of 45% (relative risk, 0.55; 95% CI, 0.38 to 0.80; P=0.0015). The observed benefit was maintained at 90 days. The overall incidence of major bleeding was low but higher in the dalteparin group (9 patients; 0.49%) compared with the placebo group (3 patients; 0.16%). CONCLUSIONS: Dalteparin 5000 IU once daily halved the rate of venous thromboembolism with a low risk of bleeding.

Risk factors for venous thromboembolism in hospitalized patients with acute medical illness: analysis of the MEDENOX Study.

BACKGROUND: There is limited information about risk factors for venous thromboembolism (VTE) in acutely ill hospitalized general medical patients. METHODS: An international, randomized, double-masked, placebo-controlled trial (MEDENOX) has previously been conducted in 1102 acutely ill, immobilized general medical patients and has shown the efficacy of using a low-molecular-weight heparin, enoxaparin sodium, in preventing thrombosis. We performed logistic regression analysis to evaluate the independent nature of different types of acute medical illness (heart failure, respiratory failure, infection, rheumatic disorder, and inflammatory bowel disease) and predefined factors (chronic heart and respiratory failure, age, previous VTE, and cancer) as risk factors for VTE. RESULTS: The primary univariate analysis showed that the presence of an acute infectious disease, age older than 75 years, cancer, and a history of VTE were statistically significantly associated with an increased VTE risk. Multiple logistic regression analysis indicated that these factors were independently associated with VTE. CONCLUSIONS: Several independent risk factors for VTE were identified. These findings allow recognition of individuals at increased risk of VTE and will contribute to the formulation of an evidence-based risk assessment model for thromboprophylaxis in hospitalized general medical patients.

Correlation of plasma coagulation parameters with thromboprophylaxis, patient characteristics, and outcome in the MEDENOX study.

CONTEXT: Plasma anti-Xa and anti-IIa activities correlate with the dose of low-molecular-weight heparin, and D-dimer and thrombin-antithrombin complexes are markers of procoagulant activity. OBJECTIVE: To investigate the relationship between plasma coagulation parameters and patient characteristics, including renal function, thromboprophylaxis, and incidence of venous thromboembolism (VTE) in the MEDENOX study population. DESIGN: Controlled, multicenter, double-blind, randomized study. PATIENTS: Two hundred twenty-four acutely ill medical patients. INTERVENTIONS: Either 20 or 40 mg of enoxaparin administered subcutaneously or a placebo once daily for 10 (+/-4) days. MAIN OUTCOME MEASURES: VTE and plasma anti-Xa and anti-IIa activities, D-dimer, and thrombin-antithrombin levels in blood collected before prophylaxis was given (day 0) and after the last injection of the study drug. RESULTS AND CONCLUSIONS: Anti-Xa activity correlated with the dose of enoxaparin. In patients with mild or moderate renal impairment, there was no significant relationship between anti-Xa activity and the creatinine clearance rate. D-dimer concentrations were lower at day 10 (+/-4) in the 40-mg group, which had a 63% lower VTE incidence, than at day 0. No venographically confirmed thromboses were found in patients with a normal D-dimer concentration (<0.5 microg/mL [0.5 mg/L]). D-dimer levels were higher in patients with VTE than in those without VTE, but no predictive value could be demonstrated for individual patients.

Prevention of venous thromboembolism in medical patients with enoxaparin: a subgroup analysis of the MEDENOX study.

The Medical Patients with Enoxaparin (MEDENOX) trial was a randomized, placebo-controlled study that defined the risk of venous thromboembolism (VTE) in acutely ill, immobilized, general medical patients and the efficacy of the low-molecular-weight heparin, enoxaparin, in preventing thrombosis. We performed a post-hoc analysis to evaluate the effect of 40 mg enoxaparin once daily on MEDENOX patient outcome in different types of acute medical illness (heart failure, respiratory failure, infection, rheumatic disorder and inflammatory bowel disease) and pre-defined risk factors (chronic heart and chronic respiratory failure, age, immobility, previous VTE and cancer). The primary outcome was the occurrence of documented VTE between days 1 and 14. The relative risk reduction [95% confidence intervals (CI)] for VTE comparing 40 mg enoxaparin with placebo in the subgroups were: acute heart failure, 0.29 (95% CI, 0.10-0.84); acute respiratory failure, 0.25 (95% CI, 0.10-0.65); acute infectious disease, 0.28 (95% CI, 0.09-0.81); and acute rheumatic disorder, 0.48 (95% CI, 0.11-2.16). The relative risk reduction for VTE in the pre-defined risk factor subgroups were: chronic heart failure, 0.26 (95% CI, 0.08-0.92); chronic respiratory failure, 0.26 (95% CI, 0.10-0.68); age, 0.22 (95% CI, 0.09-0.51); immobility, 0.53 (95% CI, 0.14-1.72); previous VTE, 0.49 (95% CI, 0.15-1.68); and cancer, 0.50 (95%o CI, 0.14-1.72). The beneficial effects of enoxaparin extend to a wide range of acutely ill medical patients.

MR venography using an intravascular contrast agent: results from a multicenter phase 2 study of dosage.

OBJECTIVE: The objective of this study was to determine the optimal dose of the iron oxide contrast agent feruglose for contrast-enhanced MR venography of the abdominopelvic and lower extremity veins and to evaluate its safety and tolerability in patients with deep venous thrombosis. SUBJECTS AND METHODS: We enrolled in our study a total of 45 patients at six centers who had lower extremity deep venous thrombosis documented on radiographic venography. Forty-four patients received the study drug; 39 completed the study. Each patient received three sequential IV injections of feruglose at doses of 0.75, 1.25, and 3.0 mg Fe/kg body weight. MR venography at 1.5 T was repeated at three levels after each dose. Safety was evaluated. RESULTS: The agreement between contrast-enhanced MR venography and radiographic venography with regard to deep venous thrombosis above the knee was zero at the lowest dose (0.75 mg Fe/kg body weight), 43% at the dose 2.0 mg Fe/kg body weight, and 49% at the dose 5.0 mg Fe/kg body weight. No significant difference was seen between the two highest doses. The highest cumulative dose provided the greatest diagnostic usefulness score. No serious adverse events occurred. CONCLUSION: The two highest doses of feruglose showed the best agreement between contrast-enhanced MR venography and radiographic venography for deep venous thrombosis above the knee. The safety and tolerability of feruglose were confirmed.

Comparison of ventilation/perfusion scintigraphy and helical CT for diagnosis of pulmonary embolism; strategy using clinical data and ancillary findings.

STUDY OBJECTIVE: To address the question whether ventilation/perfusion scintigraphy (SCINT) or helical computed tomography (CT) should be the first hand method for diagnosis of pulmonary embolism (PE). SETTING: Departments of radiology, nuclear medicine and internal medicine of a large university hospital. PATIENTS: During 3 years all 128 patients examined for PE with both methods were analysed. The strategy of interpretation behind original clinical reports, i.e. clinical CT and clinical SCINT, was based upon basic criteria for PE, ancillary findings and information from the referring doctor and from previous examinations. Reviewed SCINT and CT reports were obtained from experts in each field blinded to clinical and laboratory data. The findings with respect to PE were classified as no PE, PE or non-diagnostic. Other pathology than PE was described. A final diagnosis serving as reference was based upon CT, SCINT and other information including clinical follow for 6-24 months. METHODS: Planar SCINT was made with ventilation always preceding perfusion. CT was made with contrast injection using 3 mm collimation and table feed of 3 mm s-1. RESULTS: PE was diagnosed in 32 patients. For clinical and reviewed SCINT sensitivity was 91 and 97%, specificity 96 and 100% and rate of non-diagnostic findings 10 and 9%, respectively. For clinical and reviewed CT sensitivity was 81 and 78%, specificity 99 and 100% and non-diagnostic findings was observed in 8 and 1%, respectively. In patients with PE, concordant positive results were obtained with both modalities in 23 of 32 patients (72%). CONCLUSION: SCINT remains the first hand method because its high sensitivity, general feasibility, low radiation burden and low rate of non-diagnostic findings in our setting. CT is indispensable when SCINT is not available or its result non-diagnostic.

Pharmacokinetics, pharmacodynamics and clinical effects of the oral direct thrombin inhibitor ximelagatran in acute treatment of patients with pulmonary embolism and deep vein thrombosis.

INTRODUCTION: Ximelagatran is a novel, oral direct thrombin inhibitor that is currently being investigated for the prophylaxis and treatment of thromboembolic events. This study evaluated the pharmacokinetics, pharmacodynamics, and clinical effects of melagatran, the active form of ximelagatran, in patients with both deep vein thrombosis (DVT) and pulmonary embolism (PE). MATERIALS AND METHODS: In this open-label study, 12 patients received a fixed dose of 48 mg oral ximelagatran twice daily for 6-9 days. Plasma samples were collected for determination of melagatran concentrations and scintigraphic changes and adverse events were recorded. RESULTS: Peak plasma concentrations of melagatran were attained approximately 2 h after administration of ximelagatran. Melagatran plasma concentration profiles were similar on Days 1, 2, and 6-9. Plasma activated partial thromboplastin time increased following administration of ximelagatran and reached a peak that was approximately twofold higher than the predose activated partial thromboplastin time and correlated with melagatran plasma concentrations (R(2) = 0.69). All but one patient (with malignancy) showed regressed or unchanged lung scintigraphic findings, and six of these demonstrated no, or only minor, perfusion defects at central evaluation after 6-9 days of ximelagatran treatment. Clinical symptoms, including chest pain, dyspnoea, cough, and oedema, and pain in the affected leg, were improved. Ximelagatran was well tolerated with no deaths or severe bleeding events reported during treatment. CONCLUSION: Treatment with a fixed dose of oral ximelagatran, used without routine coagulation monitoring, showed reproducible pharmacokinetics and pharmacodynamics with a rapid onset of action and promising clinical results in patients with pulmonary embolism.