Christine Demers

A Comparison of Low-Molecular-Weight Heparin with Unfractionated Heparin for Unstable Coronary Artery Disease

BACKGROUND Antithrombotic therapy with heparin plus aspirin reduces the rate of ischemic events in patients with unstable coronary artery disease. Low-molecular-weight heparin has a more predictable anticoagulant effect than standard unfractionated heparin, is easier to administer, and does not require monitoring. METHODS In a double-blind, placebo-controlled study, we randomly assigned 3171 patients with angina at rest or non-Q-wave myocardial infarction to receive either 1 mg of enoxaparin (low-molecular-weight heparin) per kilogram of body weight, administered subcutaneously twice daily, or continuous intravenous unfractionated heparin. Therapy was continued for a minimum of 48 hours to a maximum of 8 days, and we collected data on important coronary end points over a period of 30 days. RESULTS At 14 days the risk of death, myocardial infarction, or recurrent angina was significantly lower in the patients assigned to enoxaparin than in those assigned to unfractionated heparin (16.6 percent vs. 19.8 percent, P=0.019). At 30 days, the risk of this composite end point remained significantly lower in the enoxaparin group (19.8 percent vs. 23.3 percent, P=0.016). The need for revascularization procedures at 30 days was also significantly less frequent in the patients assigned to enoxaparin (27.1 percent vs. 32.2 percent, P=0.001). The 30-day incidence of major bleeding complications was 6.5 percent in the enoxaparin group and 7.0 percent in the unfractionated-heparin group, but the incidence of bleeding overall was significantly higher in the enoxaparin group (18.4 percent vs. 14.2 percent, P=0.001), primarily because of ecchymoses at injection sites. CONCLUSIONS Antithrombotic therapy with enoxaparin plus aspirin was more effective than unfractionated heparin plus aspirin in reducing the incidence of ischemic events in patients with unstable angina or non-Q-wave myocardial infarction in the early phase. This benefit of enoxaparin was achieved with an increase in minor but not in major bleeding.

A COMPARISON OF LOW-MOLECULAR-WEIGHT HEPARIN ADMINISTERED PRIMARILY AT HOME WITH UNFRACTIONATED HEPARIN ADMINISTERED IN THE HOSPITAL FOR PROXIMAL DEEP-VEIN THROMBOSIS

BACKGROUND Patients with acute proximal deep-vein thrombosis are usually treated first in the hospital with intravenous standard (unfractionated) heparin. However, the longer plasma half-life, better bioavailability after subcutaneous administration, and more predictable anticoagulant response of low-molecular-weight heparins make them attractive for possible home use. We compared these two approaches. METHODS Patients with acute proximal deep-vein thrombosis were randomly assigned to receive either intravenous standard heparin in the hospital (253 patients) or low-molecular-weight heparin (1 mg of enoxaparin per kilogram of body weight subcutaneously twice daily) administered primarily at home (247 patients). The study design allowed outpatients taking low-molecular-weight heparin to go home immediately and hospitalized patients taking low-molecular-weight heparin to be discharged early. All the patients received warfarin starting on the second day. RESULTS Thirteen of the 247 patients receiving low-molecular-weight heparin (5.3 percent) had recurrent thromboembolism, as compared with 17 of the 253 patients receiving standard heparin (6.7 percent; P=0.57; absolute difference, 1.4 percentage points; 95 percent confidence interval, -3.0 to 5.7). Five patients receiving low-molecular-weight heparin had major bleeding, as compared with three patients receiving standard heparin. After randomization, the patients who received low-molecular-weight heparin spent a mean of 1.1 days in the hospital, as compared with 6.5 days for the standard-heparin group; 120 patients in the low-molecular-weight- heparin group did not need to be hospitalized at all. CONCLUSIONS Low-molecular-weight heparin can be used safely and effectively to treat patients with proximal deep-vein thrombosis at home.

A COMPARISON OF THREE MONTHS OF ANTICOAGULATION WITH EXTENDED ANTICOAGULATION FOR A FIRST EPISODE OF IDIOPATHIC VENOUS THROMBOEMBOLISM

BACKGROUND Patients who have a first episode of venous thromboembolism in the absence of known risk factors for thrombosis (idiopathic thrombosis) are often treated with anticoagulant therapy for three months. Such patients may benefit from longer treatment, however, because they appear to have an increased risk of recurrence after anticoagulant therapy is stopped. METHODS In this double-blind study, we randomly assigned patients who had completed 3 months of anticoagulant therapy for a first episode of idiopathic venous thromboembolism to continue receiving warfarin, with the dose adjusted to achieve an international normalized ratio of 2.0 to 3.0, or to receive placebo for a further 24 months. Our goal was to determine the effects of extended anticoagulant therapy on rates of recurrent symptomatic venous thromboembolism and bleeding. RESULTS A prespecified interim analysis of efficacy led to the early termination of the trial after 162 patients had been enrolled and followed for an average of 10 months. Of 83 patients assigned to continue to receive placebo, 17 had a recurrent episode of venous thromboembolism (27.4 percent per patient-year), as compared with 1 of 79 patients assigned to receive warfarin (1.3 percent per patient-year, P<0.001). Warfarin resulted in a 95 percent reduction in the risk of recurrent venous thromboembolism (95 percent confidence interval, 63 to 99 percent). Three patients assigned to the warfarin group had nonfatal major bleeding (two had gastrointestinal bleeding and one genitourinary bleeding), as compared with none of those assigned to the placebo group (3.8 vs. 0 percent per patient-year, P=0.09). CONCLUSIONS Patients with a first episode of idiopathic venous thromboembolism should be treated with anticoagulant agents for longer than three months.

Compression stockings to prevent post-thrombotic syndrome: a randomised placebo-controlled trial.

BACKGROUND Post-thrombotic syndrome (PTS) is a common and burdensome complication of deep venous thrombosis (DVT). Previous trials suggesting benefit of elastic compression stockings (ECS) to prevent PTS were small, single-centre studies without placebo control. We aimed to assess the efficacy of ECS, compared with placebo stockings, for the prevention of PTS. METHODS We did a multicentre randomised placebo-controlled trial of active versus placebo ECS used for 2 years to prevent PTS after a first proximal DVT in centres in Canada and the USA. Patients were randomly assigned to study groups with a web-based randomisation system. Patients presenting with a first symptomatic, proximal DVT were potentially eligible to participate. They were excluded if the use of compression stockings was contraindicated, they had an expected lifespan of less than 6 months, geographical inaccessibility precluded return for follow-up visits, they were unable to apply stockings, or they received thrombolytic therapy for the initial treatment of acute DVT. The primary outcome was PTS diagnosed at 6 months or later using Ginsbergs criteria (leg pain and swelling of ≥1 month duration). We used a modified intention to treat Cox regression analysis, supplemented by a prespecified per-protocol analysis of patients who reported frequent use of their allocated treatment. This study is registered with ClinicalTrials.gov, number NCT00143598, and Current Controlled Trials, number ISRCTN71334751. FINDINGS From 2004 to 2010, 410 patients were randomly assigned to receive active ECS and 396 placebo ECS. The cumulative incidence of PTS was 14·2% in active ECS versus 12·7% in placebo ECS (hazard ratio adjusted for centre 1·13, 95% CI 0·73-1·76; p=0·58). Results were similar in a prespecified per-protocol analysis of patients who reported frequent use of stockings. INTERPRETATION ECS did not prevent PTS after a first proximal DVT, hence our findings do not support routine wearing of ECS after DVT. FUNDING Canadian Institutes of Health Research.

Randomized trial of low molecular weight heparin (enoxaparin) versus unfractionated heparin for unstable Coronary artery disease : One-year results of the ESSENCE study

OBJECTIVES We sought to determine whether the observed benefits of enoxaparin were maintained beyond the early phase; a one-year follow-up survey was undertaken for patients enrolled in the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q wave Coronary Events (ESSENCE) study. BACKGROUND We have previously reported a significant benefit of low molecular weight as compared with unfractionated heparin (UFH) in the 14- and 30-day incidence of a composite end point of death, myocardial infarction (MI) or recurrent angina in patients with unstable angina or non-Qwave MI. METHODS The study recruited 3,171 patients with recent-onset rest angina and underlying ischemic heart disease. All patients received oral aspirin daily and were randomized to receive enoxaparin subcutaneously every 12 h or UFH (intravenous bolus followed by continuous infusion) in a double-blind, double-dummy fashion for a median of 2.6 days. RESULTS The incidence of the composite triple end point at one year was lower among patients receiving enoxaparin as compared with those receiving UFH (32.0% vs. 35.7%, p = 0.022), with a trend toward a lower incidence of the secondary composite end point of death or MI (11.5% vs. 13.5%, p = 0.082). At one year, the need for diagnostic catheterization and coronary revascularization was lower in the enoxaparin group (55.8% vs. 59.4%, p = 0.036 and 35.9% vs. 41.2%, p = 0.002, respectively). CONCLUSIONS In patients with unstable angina or non-Qwave MI, enoxaparin therapy significantly reduced the rates of recurrent ischemic events and invasive diagnostic and therapeutic procedures in the short term with sustained benefit at one year.

Predictors of the post‐thrombotic syndrome during long‐term treatment of proximal deep vein thrombosis

Summary.  Background: The post‐thrombotic syndrome is a chronic, poorly understood complication of deep venous thrombosis (DVT). Objectives: To evaluate predictors of the post‐thrombotic syndrome, including intensity of long‐term anticoagulation, and to assess the impact of the post‐thrombotic syndrome on quality of life. Patients and methods: The setting was 13 Canadian hospitals and one US hospital. One hundred and forty‐five patients with an unprovoked episode of proximal DVT who were initially treated with 3 months of conventional‐intensity warfarin [target International Normalized Ratio (INR) of 2.5] then participated in a trial comparing two intensities of long‐term warfarin therapy (target INR 2.5 vs. INR 1.7). Post‐thrombotic syndrome was assessed at the end of the trial using a validated clinical scale. Generic and venous disease‐specific quality of life was compared in patients with and without the post‐thrombotic syndrome. Multivariable regression analyses were performed to identify predictors of the post‐thrombotic syndrome and of its severity. Results: After an average follow‐up of 2.2 years, the prevalence of post‐thrombotic syndrome was 37% and of severe post‐thrombotic syndrome was 4%. Quality of life was worse in patients with the post‐thrombotic syndrome compared with patients who did not have it. The presence of factor (F)V Leiden or the prothrombin gene mutation was an independent predictor of both a lower risk (P = 0.006) and reduced severity (P = 0.045) of the post‐thrombotic syndrome. Intensity of anticoagulation did not influence the risk of developing the post‐thrombotic syndrome. Conclusions: The post‐thrombotic syndrome is a frequent and burdensome complication of proximal DVT, even among patients maintained on long‐term oral anticoagulation. While the presence of FV Leiden or prothrombin gene mutation appears to be associated with a reduced risk of post‐thrombotic syndrome, this finding requires further evaluation in prospective studies.

Thrombosis in Antithrombin-III-deficient Persons: Report of a Large Kindred and Literature Review

PURPOSE To estimate the prevalence of objectively proven thrombotic complications in antithrombin-III-deficient persons. STUDY DESIGN Cross-sectional study and a critical review of the literature. DATA SOURCES AND EXTRACTION The prevalence of thrombosis in antithrombin III-deficient and -nondeficient family members of a large kindred was estimated by history, review of diagnostic tests, and examination for venous reflux by Doppler ultrasonography, as an indicator of previous venous thrombosis. A MEDLINE search and literature review of the published English- and French-language literature from 1966 to 1990 that described antithrombin-III-deficient families was done, and the following information was obtained: the prevalence of thrombosis in deficient and nondeficient family members, the presence or absence of risk factors for thrombosis (surgery, pregnancy, the postpartum state, use of oral contraceptives, immobilization, metastatic cancer, major trauma) at the time of the thrombotic event, and age of onset of the first episode of thrombosis. The validity of the studies was assessed according to predetermined criteria. RESULTS Sixty-seven research subjects were evaluated. Six of 31 (19.4%) antithrombin-III-deficient subjects compared with none of 36 (0%) nondeficient subjects had had one or more thrombotic events. The initial episode in five of six subjects had occurred in association with risk factors for thrombosis. The literature search indicated that the pooled prevalence of symptomatic venous thrombosis among the deficient subjects was 51%, but objective testing was done in only 17% of these subjects at the time of presentation. CONCLUSION Based on the data from this antithrombin-III-deficient kindred, lifelong anticoagulant prophylaxis does not appear to be warranted in asymptomatic carriers, and prophylaxis could be limited to periods of high risk for thrombosis.

Comparison of 1 month with 3 months of anticoagulation for a first episode of venous thromboembolism associated with a transient risk factor

Summary.  Background: The risk of recurrence is lower after treatment of an episode of venous thromboembolism associated with a transient risk factor, such as recent surgery, than after an episode associated with a permanent, or no, risk factor. Retrospective analyses suggest that 1 month of anticoagulation is adequate for patients whose venous thromboembolic event was provoked by a transient risk factor. Methods: In this double‐blind study, patients who had completed 1 month of anticoagulant therapy for a first episode of venous thromboembolism provoked by a transient risk factor were randomly assigned to continue warfarin or to placebo for an additional 2 months. Our goal was to determine if the duration of treatment could be reduced without increasing the rate of recurrent venous thromboembolism during 11 months of follow‐up. Results:  Of 84 patients assigned to placebo, five (6.0%) had recurrent venous thromboembolism, compared with three of 81 (3.7%) assigned to warfarin, resulting in an absolute risk difference of 2.3%[95% confidence interval (CI) − 5.2, 10.0]. The incidence of recurrent venous thromboembolism after discontinuation of warfarin was 6.8% per patient‐year in those who received warfarin for 1 month and 3.2% per patient‐year in those who received warfarin for 3 months (rate difference of 3.6% per patient‐year; 95% CI − 3.8, 11.0). There were no major bleeds in either group. Conclusion: Duration of anticoagulant therapy for venous thromboembolism provoked by a transient risk factor should not be reduced from 3 months to 1 month as this is likely to increase recurrent venous thromboembolism without achieving a clinically important decrease in bleeding.

Influence of thrombophilia on risk of recurrent venous thromboembolism while on warfarin: results from a randomized trial

We sought to determine whether thrombophilic defects increase recurrent venous thromboembolism (VTE) during warfarin therapy. Six hundred sixty-one patients with unprovoked VTE who were randomized to extended low-intensity (international normalized ratio [INR], 1.5-1.9) or conventional-intensity (INR, 2.0-3.0) anticoagulant therapy were tested for thrombophilia and followed for a mean of 2.3 years. One or more thrombophilic defects were present in 42% of patients. The overall rate of recurrent VTE was 0.9% per patient-year. Recurrent VTE was not increased in the presence of factor V Leiden (hazard ratio [HR], 0.7; 95% CI, 0.2-2.6); the 20210G>A prothrombin gene mutation (HR, 0); antithrombin deficiency (HR, 0); elevated factor VIII (HR, 0.7; 95% CI, 0.1-5.4); elevated factor XI (HR, 0.7; 95% CI, 0.1-5.0), or elevated homocysteine (HR, 0.7; 95% CI, 0.1-5.3), but showed a trend to an increase with an antiphospholipid antibody (HR, 2.9; 95% CI, 0.8-10.5). Compared with patients with no thrombophilic defects, the rate of recurrence was not increased in the presence of one (HR, 0.7; 95% CI, 0.2-2.3) or more than one (HR, 0.7; 95% CI, 0.2-3.4) defect. We conclude that single or multiple thrombophilic defects are not associated with a higher risk of recurrent VTE during warfarin therapy.

Low-molecular-weight heparins in non–ST-segment elevation ischemia: the ESSENCE trial

Combination antithrombotic therapy with heparin plus aspirin decreases the risk of recurrent ischemic events in patients with acute coronary syndromes without persistent ST-segment elevation. Compared with standard unfractionated heparin, low-molecular-weight heparin (LMWH) has a more predictable antithrombotic effect, is easier to administer, and does not require coagulation monitoring. At 176 hospitals in 3 continents, 3,171 patients with rest unstable angina or non–Q-wave myocardial infarction were randomly assigned to either enoxaparin (a LMWH), 1 mg/kg twice daily subcutaneously, or to continuous intravenous unfractionated heparin, for a minimum of 48 hours to a maximum of 8 days. Trial medication was administered in a double-blind, placebo-controlled fashion. At 14 days, the primary endpoint, the composite risk of death, myocardial infarction, or recurrent angina with electrocardiographic changes or prompting intervention, was significantly lower in patients assigned to enoxaparin compared with heparin (16.6% vs 19.8%; odds ratio [OR] 1.24; 95% confidence interval [CI] 1.04–1.49; p = 0.019). At 30 days, the composite risk of death, myocardial infarction, or recurrent angina remained significantly lower in the enoxaparin group compared with the unfractionated heparin group (19.8% vs 23.3%, OR 1.23; 95% CI 1.0–1.46, p = 0.016). The rate of revascularization procedures at 30 days was also significantly lower in patients assigned to enoxaparin (27.1% vs 32.2%, p = 0.001). The 30-day incidence of major bleeding complication was 6.5% versus 7.0% (p = not significant), but the incidence of minor bleeding was significantly higher in the enoxaparin group (13.8% vs 8.8%, p <0.001) due primarily to injection-site ecchymosis. Thus, combination antithrombotic therapy with enoxaparin plus aspirin is more effective than unfractionated heparin plus aspirin in decreasing ischemic outcomes in patients with unstable angina or non–Q-wave myocardial infarction in the early (30 days) phase. The lower recurrent ischemic event rate seen with the LMWH, enoxaparin, is achieved without an increase in major bleeding, but with an increase in minor bleeding complications due mainly to injection-site ecchymosis.