Peter Powers

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 Randomized Controlled Trial of a Low-Molecular-Weight Heparin (Enoxaparin) to Prevent Deep-Vein Thrombosis in Patients Undergoing Elective Hip Surgery

There is experimental evidence that low-molecular-weight fractions of heparin are as effective as the standard form but cause less bleeding. We therefore performed a double-blind, randomized trial comparing PK10169 low-molecular-weight heparin with placebo for the prevention of venous thrombosis in patients undergoing elective hip surgery. Prophylactic treatment with a fixed dose was begun postoperatively and continued for 14 days. Fifty patients in each treatment group underwent surveillance with [125I]fibrinogen leg scanning and impedance plethysmography. In the first 24 patients, venography was performed only if either surveillance test was positive. Because the rate of venous thrombosis detected in those patients was unexpectedly low, venography was requested in the remaining 76 patients, even if the screening tests were negative. In this latter group, venous thrombosis occurred in 4 patients (10.8 percent) given PK10169 heparin and 20 patients (51.3 percent) given placebo (P = 0.0002); the corresponding rates for proximal-vein thrombosis were 5.4 percent and 23.1 percent, respectively (P = 0.029). In the entire group of 100 patients, venous thrombosis occurred in 12 percent of those given PK10169 heparin and 42 percent of those given placebo (P = 0.0007), and the corresponding rates for proximalvein thrombi were 4 percent and 20 percent, respectively (P = 0.014). The observed hemorrhagic rate was 4 percent in each treatment group. We conclude that prophylaxis with fixed-dose PK10169 heparin is effective and safe for patients undergoing elective hip replacement.

Diagnostic efficacy of impedance plethysmography for clinically suspected deep-vein thrombosis. A randomized trial.

Impedance plethysmography is an accurate noninvasive method to test for proximal vein thrombosis, but it is insensitive to calf-vein thrombi. We randomly assigned patients on referral with clinically suspected deep-vein thrombosis and normal impedance plethysmographic findings to either serial impedance plethysmography alone or combined impedance plethysmography and leg scanning (which has been shown to be essentially as sensitive as venography) and compared the long-term outcomes. During the initial surveillance, deep-vein thrombosis was detected in 6 of 311 patients (1.9%) tested by serial impedance plethysmography alone and in 30 of 323 patients (9.3%) (most with calf-vein thrombi) tested by the combined approach (p less than 0.001). During long-term follow-up, no patient died from pulmonary embolism; but 6 patients (1.9%; 95% confidence limits, 0.7% to 4.2%) tested by serial impedance plethysmography developed deep-vein thrombosis compared with 7 patients (2.2%; 95% confidence limits, 0.9% to 4.4%) tested by the combined approach. Serial impedance plethysmography used alone is an effective strategy to evaluate such symptomatic patients.

Clinical validity of a negative venogram in patients with clinically suspected venous thrombosis.

Although it is generally accepted that negative venography excludes deep vein thrombosis (DVT) in patients in whom it is clinically suspected, there is no evidence to support this conclusion. To test the correctness of withholding anticoagulant therapy in these patients, we followed 160 consecutive patients who had clinically suspected DVT and negative venograms to determine the frequency of postvenographic DVT. Anticoagulant therapy was withheld in all patients. No patient died or developed pulmonary embolism during 3 months of follow-up. Two of the 160 patients (1.3%) attended the clinic on an emergency basis during follow-up with new symptoms of DVT and in both patients, DVT was confirmed by objective testing. These events developed within 5 days of venography, which suggests that they were induced by venography. Nevertheless, the findings indicate it is safe to withhold treatment in patients with clinically suspected DVT and negative venograms.

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

OBJECTIVE To 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. DESIGN A double-blind, randomized, controlled trial. PATIENTS Six hundred sixty-five consecutive patients undergoing hip replacement at five participating hospitals. INTERVENTIONS Patients 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. MEASUREMENTS All 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. RESULTS Evaluable 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%. CONCLUSION Low 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.

Combined use of leg scanning and impedance plethysmography in suspected venous thrombosis. An alternative to venography.

Venography is the standard method for the diagnosis of venous thrombosis but is invasive and may cause discomfort. We evaluated the combination of impedance plethysmography and 125I-fibrinogen leg scanning as an alternative to venography in 200 symptomatic patients. One or both of these less invasive tests was positive in 81 of 86 patients with positive venograms (sensitivity of 94 per cent) and both were negative in 104 of 114 patients with negative venograms (specificity of 91 per cent). These two tests detected all 60 patients with popliteal or more proximal venous thrombosis and 21 of 26 patients with calf-vein thrombosis. In addition, this approach detected 21 of 22 patients with calf-vein thrombosis with symptoms for eight days or less. These results suggest that the combination of these two less invasive tests can be used as an alternative to venography in selected patients with clinically suspected venous thrombosis.

The diagnosis of acute, recurrent, deep-vein thrombosis: a diagnostic challenge.

Recurrent venous thrombosis presents a diagnostic challenge. Venography, impedance plethysmography and fibrinogen leg scanning all have potential limitations, and their role in this context has not been evaluated. We performed a prospective cohort study evaluating impedance plethysmography and leg scanning, plus venography, using outcome on long-term follow-up as the end point in 270 patients with clinically suspected recurrent deep-vein thrombosis. Anticoagulant treatment was withheld in the 181 patients negative by noninvasive testing and was given in patients positive by impedance plethysmography if leg scanning was positive or if intraluminal filling defects were detected by venography. The validity of this approach was tested by long-term follow-up. Three of 181 patients (1.7%) negative by noninvasive testing had a recurrence, compared with 18 of 89 (20%) with positive findings (p < 0.001). Our objective diagnostic approach has high clinical utility; an objective rationale for withholding or giving treatment was established in 95% of patients.

Impedance plethysmography: the relationship between venous filling and sensitivity and specificity for proximal vein thrombosis.

We investigated the hypothesis that the diagnostic accuracy of impedance plethysmography (IPG) for thrombosis of the popliteal or more proximal veins increases with enhanced venous filling. Venous filling was increased by prolonging cuff occlusion and by sequential testing. IPG and vengography were performed on 169 legs with and 317 legs without proximal vein thrombosis. The sensitivity and specificity of IPG rose significantly with increased venous filling. Changes in venous filling were associated with corresponding changes in emptying in normal legs, but not those with proximal vein thrombosis, so that the regression lines relating venous filling and emptying in normal and abnormal legs diverged significantly (P less than 0.001). If the IPG sequence had been terminated after only a single 45 second occlusion time test, sensitivity would have deteriorated by 10% and specificity by 20%. These observations indicate that the accuracy of IPG can be significantly enhanced if optimal venous filling is obtained.

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

BACKGROUND The 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. METHODS AND RESULTS Patients 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. CONCLUSIONS This 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

OBJECTIVE To 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. DESIGN Double-blind randomized trial. SETTING Seven Canadian university-affiliated hospitals. PARTICIPANTS Eighty-seven patients with acute ischemic stroke resulting in lower-limb paresis. INTERVENTION Patients 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. MEASUREMENTS Deep 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. RESULTS Venous 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. CONCLUSION Low-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.