Jacques R. Leclerc

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

BACKGROUNDnPatients 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.nnnMETHODSnPatients 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.nnnRESULTSnThirteen 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.nnnCONCLUSIONSnLow-molecular-weight heparin can be used safely and effectively to treat patients with proximal deep-vein thrombosis at home.

Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis.

We performed a randomized double-blind trial comparing continuous intravenous heparin with intermittent subcutaneous heparin in the initial treatment of 115 patients with acute proximal deep-vein thrombosis. Intermittent subcutaneous heparin as administered in this trial was inferior to continuous intravenous heparin in preventing recurrent venous thromboembolism. The subcutaneous heparin regimen induced an initial anticoagulant response below the target therapeutic range in the majority of patients and resulted in a high frequency of recurrent venous thromboembolism (11 of 57 patients, 19.3 percent), which was virtually confined to patients with a subtherapeutic anticoagulant response. In contrast, continuous intravenous heparin induced a therapeutic anticoagulant response in the majority of patients and a low frequency of recurrent events (3 of 58 patients, 5.2 percent; P = 0.024); the recurrences were limited to patients with an initial subtherapeutic anticoagulant response. The results of this trial establish the efficacy of intravenous heparin in the treatment of proximal venous thrombosis and suggest a relation between the effectiveness of heparin and the levels of anticoagulation achieved; such a relation could explain the observed failure of the subcutaneous regimen.

Prevention of deep vein thrombosis after elective hip surgery. A randomized trial comparing low molecular weight heparin with standard unfractionated heparin.

OBJECTIVEnTo determine the relative efficacy and safety of low molecular weight (LMW) heparin (Enoxaparin) compared with standard calcium heparin for the prevention of postoperative deep vein thrombosis in patients undergoing elective hip surgery.nnnDESIGNnA double-blind, randomized, controlled trial.nnnPATIENTSnSix hundred sixty-five consecutive patients undergoing hip replacement at five participating hospitals.nnnINTERVENTIONSnPatients received either fixed-dose LMW heparin, 30 mg subcutaneously twice daily, or fixed-dose standard calcium heparin, 7500 units subcutaneously twice daily; both regimens were started 12 to 24 hours after surgery and continued for 14 days or until discharge if sooner.nnnMEASUREMENTSnAll patients had postoperative I-125-fibrinogen leg scanning and impedance plethysmography. If results of one or both tests were positive, then venography was done. Otherwise, venography was done between day 10 and day 14, or sooner if the patient was ready for discharge.nnnRESULTSnEvaluable venograms were obtained in 258 of the 333 patients randomly assigned to receive LMW heparin and in 263 of the 332 patients assigned to receive calcium heparin. For patients with evaluable venograms, thrombosis was detected in 50 patients (19.4%) who received LMW heparin compared with 61 patients (23.2%) who received standard heparin (difference, -3.8%; 95% CI, -11.1% to 3.6%) (P greater than 0.2). Proximal deep vein thrombosis was detected in 5.4% of the patients receiving LMW heparin and in 6.5% of the patients receiving standard heparin (difference, -1.1%; CI, - 5.2% to 3.3%) (P greater than 0.2). For the entire group of 665 patients, venous thrombosis occurred in 17.1% given LMW heparin and in 19.0% given standard heparin. Hemorrhagic complications occurred in 31 patients (9.3%) given standard heparin and in 17 patients (5.1%) given LMW heparin (difference, 4.2%; CI, 0.3% to 8.2%) (P = 0.035). The relative risk reduction was 45%. The rate of major bleeding in the standard heparin group was 5.7% compared with 3.3% in the LMW heparin group (difference, 2.4%; CI, -1.0% to 5.4%) (P = 0.13). The relative risk reduction was 42%.nnnCONCLUSIONnLow molecular weight heparin is significantly less hemorrhagic than standard unfractionated heparin; the difference in the rate of deep vein thrombosis, although not statistically significant (P greater than 0.2), favors the use of LMW heparin.

Prevention of Venous Thromboembolism after Knee Arthroplasty: A Randomized, Double-Blind Trial Comparing Enoxaparin with Warfarin

Despite modern surgical techniques and early patient mobilization, venous thromboembolism remains a major complication of knee arthroplasty [1-3]. Without prophylaxis, the reported incidences of venographically verified deep venous thrombosis and proximal venous thrombosis have ranged from 55% to 70% and from 10% to 30%, respectively [2, 4-8]. Fatal pulmonary embolism, allegedly uncommon (incidence less than 1% [9]), remains an avoidable cause of perioperative death in these patients. The burden of postoperative venous thromboembolism must also be assessed in terms of the morbidity from the acute event, the risk for long-term postphlebitic complications [10, 11], and the effect of venous thromboembolism on the cost of health care delivery [12, 13]. Preventing venous thromboembolism after knee arthroplasty is difficult because of the relative resistance of this type of surgery to the effects of most thromboprophylaxis options [6, 14-18], the substantial hemorrhagic risk associated with the surgical procedure [19], and the lack of consensus on the safest and most effective method. The main hemorrhagic threat of thromboprophylaxis in knee surgery is hemarthrosis, which may require surgical drainage or may compromise the result of the reconstruction. Less intense warfarin and low-molecular-weight heparins have been evaluated as prophylaxis after knee surgery [8, 20-24]. Warfarin has the advantage of oral administration, and low-molecular-weight heparins do not require laboratory monitoring. In previous studies comparing warfarin with low-molecular-weight heparins, patients having either hip or knee surgery were evaluated together [20, 21], interventions were unblinded [21, 22], or unilateral venography was done [21-23]. We thus conducted a double-blind, randomized trial with bilateral venographic assessment of the effectiveness and safety of postoperative, adjusted-dose warfarin compared with those of postoperative, fixed-dose enoxaparin in patients having knee arthroplasty. Methods Patients Eight hundred sixty-five consecutive adult patients having knee arthroplasty at eight hospitals were evaluated. Sixty-eight patients were excluded for the following reasons: allergy to contrast material (20 patients); need for oral anticoagulant or antiplatelet agents (18 patients); bleeding diathesis (9 patients); gastrointestinal hemorrhage within 3 months of surgery (7 patients); renal or hepatic insufficiency (4 patients); uncontrolled hypertension (3 patients); illicit drug use or alcohol abuse (3 patients); participation in the present study within the last 3 months (1 patient); hemorrhagic stroke within 3 months of surgery (1 patient); receipt of other investigational drugs in the past month (1 patient); and warfarin allergy (1 patient). Of the 797 patients eligible for the study, 670 (84%) gave informed consent. Interventions The 670 eligible and consenting patients were randomly allocated after surgery to receive either warfarin sodium (334 patients) or enoxaparin (336 patients) in a 1:1 ratio in blocks of four. A computer generated the randomization schedule. We stratified randomization by study center, history of venous thromboembolism, and use of a cemented or uncemented prosthesis. Patients in the warfarin group also received subcutaneous saline placebo every 12 hours. The treatment goal was to maintain the international normalized ratio between 2.0 and 3.0 using a prespecified nomogram. Patients in the enoxaparin group received 30 mg of enoxaparin subcutaneously every 12 hours and warfarin placebo once daily. Therapy with oral medications began on the evening of the day on which surgery was done (day 1), and therapy with subcutaneous medications began on the morning of the first day after surgery (day 2). Study medications were administered for 14 days or until hospital discharge, whichever occurred first. No other thromboprophylactic agents or antiembolic stockings were used. Patient Surveillance and Outcome Measures The primary end point was the incidence of deep venous thrombosis in patients with adequate bilateral venograms and symptomatic pulmonary embolism. Venography was done on day 14 or earlier if the patient was discharged or if patients developing clinically suspected deep venous thrombosis had abnormal noninvasive test results. The diagnostic criterion for thrombosis was a constant intraluminal filling defect seen on two or more views. Venograms were considered adequate if the entire deep venous system could be seen to at least the level of the common femoral vein. Bilateral compression ultrasonography of the tibioperoneal trunk, popliteal vein, superficial femoral vein in at least two sites, and common femoral vein was routinely done before venography. A positive venous ultrasound was defined as the noncompressibility of a vein segment. Patients with clinically suspected venous thrombosis had either compression ultrasonography or impedance plethysmography when symptoms developed. Venography was done immediately if the noninvasive test result was abnormal. Symptomatic patients with a normal noninvasive test result had repeated testing every other day until predischarge venography was done. Patients with suspected pulmonary embolism had lung scanning. Pulmonary embolism was excluded on the basis of a normal perfusion scan and was confirmed by a high-probability scan; the latter was defined as showing one or more segmental perfusion defects with normal or near-normal ventilation. Patients with abnormal lung scans that did not show a high probability of embolism subsequently had pulmonary angiography. Patients with proven venous thromboembolism received heparin treatment followed by oral anticoagulant agents as per local practice. Patients who did not develop venous thromboembolism received no further thromboprophylaxis after hospital discharge. Secondary end points were clinically overt hemorrhage and postoperative blood loss. Major hemorrhage was defined as overt bleeding that 1) decreased the hemoglobin level by 20 g/L or more or 2) necessitated transfusion of 2 or more units of packed red cells, hemarthrosis requiring evacuation, discontinuation of prophylaxis, or interruption of physiotherapy for at least 24 hours. Minor hemorrhage was defined as overt bleeding that did not meet the criteria for major hemorrhage. All patients were followed for 6 months. During this interval, patients were instructed to contact the investigator if they developed symptoms suggestive of venous thromboembolism. Blinding Oral medications were monitored by an independent physician who was aware of the randomization schedule but was not otherwise involved in the study. Dosage adjustments were based on the measured international normalized ratios in patients receiving warfarin and on phantom international normalized ratios, generated a priori, in patients receiving warfarin placebo. Patients receiving warfarin placebo also had daily blood sampling for sham measurements of the international normalized ratio. International normalized ratios were not recorded in the patients charts. All diagnostic tests and bleeding episodes were adjudicated by a central committee that was unaware of treatment allocation or clinical findings. Statistical Analysis The rates of deep venous thrombosis in the two treatment groups were compared using the chi-square test with Yates correction. Blood loss was analyzed using one-way analysis of variance. The rates of pulmonary embolism and the proportion of patients receiving packed red cells were analyzed using the Fisher exact test. We used the statistical package S-PLUS version 3.1 (StatSci, Seattle, Washington). Estimation of Sample Size On the basis of the assumption that the incidence of deep venous thrombosis in enoxaparin recipients would be approximately 20% [8] and with an value of 0.05 (two-tailed) and a value of 0.20, we determined that 200 patients with adequate venograms per group would be required to show at least a 50% reduction in the rate of thrombosis in the enoxaparin group compared with the warfarin group. Interim Analysis We did a preplanned interim analysis after 200 patients with adequate venograms were enrolled. An independent committee reviewed the results without breaking the code. We formally used an OBrien-Fleming stopping boundary [25] but also analyzed the overall rate of thrombosis and bleeding complications to arrive at a conclusion. We decided to continue the trial until 400 patients had adequate venograms. Study Logistics The investigators independently designed the study and interpreted the results. The research coordinators at each site collected the data, and the sponsoring pharmaceutical firm monitored the quality of the data at each study center. Biostatisticians from the Division of Clinical Epidemiology of the Montreal General Hospital designed the database, and the clinical research firm Biopharmaceutical Research Consultants (Ann Arbor, Michigan) independently analyzed the data. Results The two treatment groups had similar important baseline characteristics (Table 1). Adequate venographic outcomes were obtained in 417 of 670 patients (62%). Adequate venograms were not obtained in the remaining patients for the following reasons: technically inadequate venogram (129 patients), failed venous access (94 patients), refusal of the patient (24 patients), pulmonary embolism (3 patients), refusal of the treating physician (2 patients), and unavailable films (1 patient). These reasons were equally balanced between the two groups. All technically inadequate venograms resulted from incomplete opacification of the deep venous system. In many instances, radiologists were uncomfortable administering additional contrast material, particularly because the protocol required bilateral venography. An additional complicating factor was the overshadowing of the popliteal vein by the knee prosthesis, despite the protocol requirement to obtain lateral views of this area. The re

Low-Molecular-Weight Heparinoid Orgaran Is More Effective Than Aspirin in the Prevention of Venous Thromboembolism After Surgery for Hip Fracture

BACKGROUNDnThe study objective was to determine the relative efficacy and safety of a low-molecular-weight heparinoid (Orgaran) compared with aspirin for the prevention of postoperative venous thromboembolism in patients undergoing surgery for fractured hips. A double-blind, randomized, controlled trial was used to study 251 consecutive eligible and consenting patients undergoing surgery for hip fracture in seven participating hospitals.nnnMETHODS AND RESULTSnPatients received either fixed-dose Orgaran by subcutaneous injection every 12 hours in a dose of 750 anti-Factor Xa units or aspirin 100 mg orally twice daily; both regimens were started 12 to 24 hours after surgery and continued for 14 days or until discharge, if sooner. All patients had postoperative 125I-fibrinogen leg scanning and impedance plethysmography. If the results of one or both tests were positive, then venography was performed. Otherwise, venography was done at day 14, or sooner if the patient was ready for discharge. Pulmonary embolism in symptomatic patients was diagnosed on the basis of a high probability perfusion/ventilation lung scan, a positive angiogram, or a clinically significant embolism detected at autopsy. Evaluable venograms were obtained in 90 of the 125 patients randomly assigned to receive Orgaran and in 87 of the 126 patients assigned to receive aspirin. Venous thromboembolism was detected in 25 (27.8%) patients in the Orgaran group and in 39 (44.3%) patients in the aspirin group. Thus, there was a relative risk reduction of 37% with Orgaran (P=.028; 95% confidence interval, 3.7% to 59.7%). Six (6.8%) of 88 patients in the Orgaran group and 12 (14.3%) of 84 patients in the aspirin group developed proximal deep vein thrombosis or pulmonary embolism, a relative risk reduction of 52% with Orgaran (P=.137; 95% confidence interval, -30.7% to 84.6%). Hemorrhagic complications occurred in 2 (1.6%) patients given Orgaran and 8 (6.4%) patients given aspirin (P=.10). There was one major bleed in the Orgaran group compared with four in the aspirin group.nnnCONCLUSIONSnThis study demonstrates that Orgaran is significantly more efficacious than aspirin in preventing postoperative venous thromboembolism in patients undergoing surgery for fractured hips, with no evidence of any increase in hemorrhagic complications.

A Low-Molecular-Weight Heparinoid Compared with Unfractionated Heparin in the Prevention of Deep Vein Thrombosis in Patients with Acute Ischemic Stroke: A Randomized, Double-Blind Study

OBJECTIVEnTo compare the relative safety and efficacy of a low-molecular-weight heparinoid (ORG 10172) with unfractionated heparin in the prevention of deep vein thrombosis in patients with acute ischemic stroke.nnnDESIGNnDouble-blind randomized trial.nnnSETTINGnSeven Canadian university-affiliated hospitals.nnnPARTICIPANTSnEighty-seven patients with acute ischemic stroke resulting in lower-limb paresis.nnnINTERVENTIONnPatients received either low-molecular-weight heparinoid, 750 anti-factor Xa units twice daily, or unfractionated heparin, 5000 units subcutaneously twice daily. Treatment was continued for 14 days or until hospital discharge if sooner.nnnMEASUREMENTSnDeep vein thrombosis was diagnosed using 125I-labeled fibrinogen leg scanning and impedance plethysmography. Venography was indicated if either test was positive. Overt hemorrhage, major or minor, was assessed clinically.nnnRESULTSnVenous thrombosis occurred in four patients (9%) given low-molecular-weight heparinoid and in 13 patients (31%) given heparin (relative risk reduction, 71%; 95% CI, 16% to 93%. The corresponding rates for proximal vein thrombosis were 4% and 12%, respectively (relative risk reduction, 63%; P greater than 0.2). The incidence of hemorrhage was 2% in both groups.nnnCONCLUSIONnLow-molecular-weight heparinoid, given in a fixed dose of 750 anti-factor Xa units subcutaneously twice daily, is more effective than subcutaneous low-dose heparin for the prevention of deep vein thrombosis in patients with acute ischemic stroke.

Venous and arterial thromboembolism in severe sepsis

The burden of thromboembolism (TE) in severe sepsis is largely unknown. We assessed the prevalence of venous and arterial TE in patients with severe sepsis over a four-week period. We performed a retrospective analysis of a pooled database of three randomized, placebo-controlled trials of two novel pharmacological agents for the treatment of severe sepsis, drotrecogin alfa (activated) (DrotAA) and secretory phospholipase A2 inhibitor (sPLA(2)I). The study was conducted at intensive care units of the participating institutions. A total of 2,649 patients with known or suspected infection and sepsis-associated acute organ dysfunction were enrolled in the three trials and were assigned to treatment groups (DrotAA=850; sPLA2I=578; placebo=1221). The database was queried for venous and arterial TE, using investigator reports of serious adverse events. Eighty-four of 2,649 patients (3.2%; 95% confidence interval, 2.5% to 3.9%) developed at least one thromboembolic event over 28 days. Nearly three-quarters of episodes were atheroembolic (n=62); 25% involved the deep venous system (n=25). Ischemic stroke (n=30) and venous thromboembolism (n=25) each occurred in about 1% of patients. Ischemic stroke and acute coronary syndrome had a higher peak incidence during the first five days compared to venous TE onset, which was more constant over the 28-day period. Subgroup analysis by pooled treatment groups yielded TE rates of 2.0% (DrotAA), 3.5% (placebo), and 4.0% (sPLA2I), respectively. Clinically manifest TE occurred in about 3% of severe sepsis patients treated in the intensive care unit over a 28-day period. Arterial TE may be more common than previously recognized. More accurate estimates of TE prevalence and relationship to sepsis await future studies.

Management of anti-thrombin III deficiency during pregnancy without administration of anti-thrombin III

We report a patient with hereditary antithrombin III deficiency who was successfully treated with heparin throughout pregnancy. Functional antithrombin III levels fell to 0.32 U/ml during heparin treatment, but it was possible to achieve a heparin effect, measured by the activated partial thromboplastin time, thrombin clotting time and heparin assay with subcutaneous heparin in doses of 30,000 U to 35,000 U/24 hours. This achieve an long term heparin effect was obtained without the need for antithrombin III infusions.

Thromboneurosis: A New Term for Postphlebitic Neurosis?-Reply

Thank you for having these facts brought to our attention. I would agree with you that the sentence we have coined the term thromboneurosis to describe this syndrome should read we and others have coined the term thromboneurosis to describe this syndrome. However, with objective testing the clinician can now have a more rational approach to differentiate thromboneurosis from recurrent deep venous thrombosis.