Carl-Gustav Olsson

A COMPARISON OF ENOXAPARIN WITH PLACEBO FOR THE PREVENTION OF VENOUS THROMBOEMBOLISM IN ACUTELY ILL MEDICAL PATIENTS

BACKGROUND The efficacy and safety of thromboprophylaxis in patients with acute medical illnesses who may be at risk for venous thromboembolism have not been determined in adequately designed trials. METHODS In a double-blind study, we randomly assigned 1102 hospitalized patients older than 40 years to receive 40 mg of enoxaparin, 20 mg of enoxaparin, or placebo subcutaneously once daily for 6 to 14 days. Most patients were not in an intensive care unit. The primary outcome was venous thromboembolism between days 1 and 14, defined as deep-vein thrombosis detected by bilateral venography (or duplex ultrasonography) between days 6 and 14 (or earlier if clinically indicated) or documented pulmonary embolism. The duration of follow-up was three months. RESULTS The primary outcome could be assessed in 866 patients. The incidence of venous thromboembolism was significantly lower in the group that received 40 mg of enoxaparin (5.5 percent [16 of 291 patients]) than in the group that received placebo (14.9 percent [43 of 288 patients]) (relative risk, 0.37; 97.6 percent confidence interval, 0.22 to 0.63; P< 0.001). The benefit observed with 40 mg of enoxaparin was maintained at three months. There was no significant difference in the incidence of venous thromboembolism between the group that received 20 mg of enoxaparin (43 of 287 patients [15.0 percent]) and the placebo group. The incidence of adverse effects did not differ significantly between the placebo group and either enoxaparin group. By day 110, 50 patients had died in the placebo group (13.9 percent), 51 had died in the 20-mg group (14.7 percent), and 41 had died in the 40-mg group (11.4 percent); the differences were not significant. CONCLUSIONS Prophylactic treatment with 40 mg of enoxaparin subcutaneously per day safely and effectively reduces the risk of venous thromboembolism in patients with acute medical illnesses.

Subcutaneous Enoxaparin Once or Twice Daily Compared with Intravenous Unfractionated Heparin for Treatment of Venous Thromboembolic Disease

Venous thromboembolic disease causes significant morbidity and mortality in both hospitalized and nonhospitalized patients. The mean annual incidence in the United States is 48 per 100 000 for deep venous thrombosis and 23 per 100 000 for pulmonary embolism, according to an epidemiologic study conducted in Massachusetts (1). A similar study in Sweden showed an annual incidence of 160 new cases of deep venous thrombosis per 100 000 inhabitants (2). Five to 10 days of unfractionated heparin is a common recommended initial treatment for deep venous thrombosis. This treatment maintains the activated partial thromboplastin time above 1.5 times its control value (3, 4), as calibrated by protamine titration or an antifactor Xa assay. Another recommended initial treatment is 5 to 10 days of weight-adjusted low-molecular-weight heparin followed by at least 3 months of oral anticoagulant therapy (3-7). Low-molecular-weight heparins are now frequently being used in place of unfractionated heparin for both prevention and treatment of venous thromboembolism (3, 8). Randomized trials and meta-analyses have shown subcutaneously administered low-molecular-weight heparins to have antithrombotic efficacy equal to (9-12) or greater than (13-16) that of continuously infused unfractionated heparin in the initial treatment of deep venous thrombosis and equal to that of unfractionated heparin in the treatment of pulmonary embolism (17, 18). However, many of these studies enrolled small numbers of patients (9-13, 15, 16), used primarily venographic plethysmographic or scintigraphic end points (9-11, 13, 16), and sometimes excluded patients with pulmonary embolism (11, 15). Most trials of twice-daily low-molecular-weight heparin adjusted treatment regimens according to patient weight without laboratory monitoring. However, several studies suggest that once-daily weight-adjusted dosage of a low-molecular-weight heparin is as effective in the treatment of proximal deep venous thrombosis as adjusted dosages of intravenous unfractionated heparin (14, 19) or twice-daily low-molecular-weight heparin (20). Since low-molecular-weight heparins differ in their physicochemical and pharmacologic characteristics, study results that apply to one cannot be extended to another (21, 22). We conducted the present study to determine whether enoxaparin administered subcutaneously once or twice per day is as effective as continuously infused unfractionated heparin in the treatment of patients with acute, symptomatic venous thromboembolic disease. Methods Study Description This parallel-group, randomized, partially blinded, international, multicenter clinical trial compared continuously infused unfractionated heparin (adjusted to maintain activated partial thromboplastin time within a defined range) with two weight-adjusted dosages of enoxaparin administered subcutaneously once or twice daily. The study was conducted in 74 hospitals in 16 countries, including the United States, several European countries, Australia, and Israel, and was approved by the institutional review board or ethics committees at each location. Written informed consent was obtained from each patient. Four committees participated in this study: an Advisory Committee; an Outcome Adjudication Committee, which provided blinded outcome assignments for incidence of recurrent venous thromboembolic disease, major or minor hemorrhage, immune thrombocytopenia, and cause of death; an independent Safety Committee; and a Vascular Imaging Committee, which reviewed all baseline venograms and all vascular imaging studies in a blinded manner to determine whether deep venous thrombosis was present at baseline and whether objective evidence of recurrence existed. Patient Characteristics Patients were required to be at least 18 years of age and willing to remain hospitalized during randomized therapy. The primary inclusion criteria were symptomatic lower-extremity deep venous thrombosis confirmed by venography or ultrasonography (if venography was inconclusive), symptomatic pulmonary embolism confirmed by high-probability ventilationperfusion scanning, or positive pulmonary angiography with confirmation of lower-extremity deep venous thrombosis. All eligible patients underwent baseline lung scanning or angiography. Exclusion criteria were more than 24 hours of previous treatment with heparin or warfarin; need for thrombolytic therapy; known hemorrhagic risk, including active hemorrhage, active intestinal ulcerative disease, known angiodysplasia, or eye, spinal, or central nervous system surgery within the previous month; renal insufficiency (serum creatinine concentration>180 mol/L [2.03 mg/dL]); severe hepatic insufficiency; allergy to heparin, protamine, porcine products (both heparin and enoxaparin are derived from pork intestinal mucosa), iodine, or contrast media; history of heparin-associated thrombocytopenia or heparin- or warfarin-associated skin necrosis; treatment with other investigational therapeutic agents within the previous 4 weeks; inferior vena cava interruption; or known pregnancy or lactation. Treatments Within each center, consecutive eligible patients were randomly assigned sequentially to one of three treatment groups. Randomization was done without stratification in blocks of six, according to ascending randomization number. The numbers were affixed to sealed treatment kits that contained study medication and were provided by the study sponsor. Patients assigned to enoxaparin received a weight-adjusted subcutaneous dose. Two blinded regimens were tested: 1.0 mg/kg of body weight twice daily or 1.5 mg/kg once daily. Several clinical trials have shown the twice-daily regimen to be effective and safe (16, 23, 24). The once-daily dosage was chosen on the basis of results of pharmacokinetic studies that showed it to have a suitable pharmacokinetic profile in healthy volunteers and to be well tolerated in the treatment of patients with venous thromboembolism (25, 26). In these previous studies, therapeutic antifactor Xa levels were present for up to 18 hours in both volunteers and patients, and measurable levels were present for up to 24 hours. A total of three injections, study drug and placebo, were given each day to maintain blinding for volume of solutions and frequency of administration. Patients assigned to the nonblinded unfractionated heparin group received an intravenous bolus dose and infusion on the basis of an approved institution-specific nomogram. In most cases, administration was as follows: Six hours after the initial bolus, the activated partial thromboplastin time was measured and the dose was adjusted to maintain the specified value, which was between 55 and 80 seconds in most centers (4-7). Activated partial thromboplastin time was measured at least daily during unfractionated heparin treatment. Enoxaparin and heparin treatments were continued for at least 5 days, and warfarin was started within 72 hours of initial study drug administration. Forty-three patients received phenprocoumon in place of warfarin sodium. Prothrombin time was measured daily, and patients could be discharged from the hospital after the international normalized ratio was found to be between 2.0 and 3.0 on 2 consecutive days. Oral anticoagulation was continued for at least 3 months. Study Assessments Observers who were aware of treatment assignment assessed patients daily and monthly during the 3-month follow-up for worsening or recurrence of deep venous thrombosis or pulmonary embolism, hemorrhage, adverse events, changes in concomitant medications and adequacy of warfarin use, and warfarin adherence. For patients receiving unfractionated heparin, adherence was defined as an activated partial thromboplastin time within or above the therapeutic range on the second day of treatment. For patients receiving enoxaparin, adherence was defined as at least 10 doses of study medication given with no dosing errors. Adherence to warfarin therapy was defined as having at least one international normalized ratio value greater than or equal to 2.0 between day 4 and the last dose of study treatment during the initial treatment period. These definitions of treatment adherence were established before the analysis of the study outcomes. Efficacy Analysis The efficacy analysis was performed on two study samples: all treated patients, who received at least one dose of study medication, and evaluable patients, which excluded all patients who met at least one of the criteria for nonevaluability. These criteria were no confirmed deep venous thrombosis at baseline, insufficient study therapy, placement of an inferior vena cava filter, two random assignments, and no 3-month follow-up. Insufficient study therapy was defined as one or more missed enoxaparin doses among at least eight consecutive enoxaparin doses or less than 4 consecutive days of heparin infusion. The definition of insufficient study therapy was established before analysis of study outcomes. These two study samples were analyzed to strengthen the conclusion of equivalence among the treatment groups. The homogeneity of the results of the two analyses is considered to be more supportive of the conclusion of equivalence than the results of either analysis alone. Primary clinical end points were recurrent deep venous thrombosis or pulmonary embolism within 3 months of randomization. Patients with symptoms of recurrent thrombosis underwent confirmatory testing with venography, ultrasonography, or both. Patients presenting with signs or symptoms of pulmonary embolism underwent lung perfusion scanning, pulmonary angiography, or both. Clinical symptoms and supportive findings on objective tests; extension of existing thrombi or new thrombi for venography, angiography, or ultrasonography; or high-probability defect patterns on perfusion scans were required to confirm recurrent thrombosis. Prespecified subgroup analyses were performed on the basis of patient demog

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.

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 ≥ 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.

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.