J. Hirsh

Different Intensities of Oral Anticoagulant Therapy in the Treatment of Proximal-Vein Thrombosis

We have previously reported that long-term therapy with warfarin is effective for preventing recurrent venous thromboembolism in patients with proximal-vein thrombosis but that there is an appreciable risk of hemorrhage. To determine whether that risk could be reduced without a loss of effectiveness, we randomly allocated 96 patients with proximal-vein thrombosis to a group receiving less intense anticoagulant therapy, with a mean prothrombin time of 26.9 seconds using the Manchester comparative reagent (corresponding Simplastin time, 15 seconds), or a group given more intense therapy, with a mean Simplastin time of 19.4 seconds (corresponding prothrombin time 41 seconds with the Manchester comparative reagent) (P less than 0.001). Two of 47 patients (4 per cent) in the less intensely treated group had hemorrhagic complications, as compared with 11 of 49 patients (22 per cent) in the more intensely anticoagulated group (P = 0.015 by the two-tailed test). This difference was due to minor bleeding episodes. The frequency of recurrent venous thromboembolism was low in both groups (2 per cent). Our findings indicate that less intense anticoagulant therapy is associated with a low frequency of recurrent venous thromboembolism (2 per cent) and a reduced risk of hemorrhage.

Pulmonary Angiography, Ventilation Lung Scanning, and Venography for Clinically Suspected Pulmonary Embolism with Abnormal Perfusion Lung Scan

Inherent contradictions in current diagnostic recommendations for pulmonary embolism have created considerable confusion and controversy. To resolve these contradictions, we did a prospective study of ventilation-perfusion scanning, pulmonary angiography, and venography in consecutive patients with clinically suspected pulmonary embolism and abnormal perfusion scans. Ventilation scanning increased the probability of pulmonary embolism in patients with large perfusion defects and ventilation mismatch, but a ventilation-perfusion match was not helpful in ruling out pulmonary embolism. Small perfusion defects with mismatch had neither sufficiently high nor low probability to be of diagnostic value. The observed frequency of proximal vein thrombosis (19% to 51%) and its association with the range of ventilation-perfusion defects have important implications for management of pulmonary embolism. Pulmonary angiography is required in combination with venography in most patients with perfusion abnormalities because the probability of pulmonary embolism is neither sufficiently high nor low to confirm or exclude pulmonary embolism.

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.

Heparin kinetics in venous thrombosis and pulmonary embolism.

The response to a standard dose of heparin was studied in 20 patients with venous thromboembolism. The heparin regimen consisted of intravenous injection of 70 units per kg, followed after 90 minutes by a maintenance dose of 400 units per kg per 24 hours given by continuous infusion. Plasma heparin activity and the activated partial thromboplastin time (APTT) were measured at intervals to determine clearance of the initial injection and the response to maintenance dose. Large inter-individual variations were found in the anticoagulant effect and these were due in part to differences in heparin clearance and in part to differences in the APTT response to given amounts of heparin (heparin effect index). The heparin half-life was 63 ± 15 minutes when plasma heparin activities were used for this calculation and 84 ± 71.5 minutes when the APTT was used. These results are similar to values previously reported in normal volunteers. Four of the 20 patients had pulmonary embolism and in these heparin half-life was significantly shortened (P < 0.005).

Impedance plethysmography using the occlusive cuff technique in the diagnosis of venous thrombosis.

Impedance plethysmography using the cuff technique has been compared with venography in 346 consecutive patients with suspected venous thromboembolism. The limbs were classified according to the venographic results as no thrombosis, proximal (popliteal, femoral, or iliac) vein thrombosis, and calf thrombosis. A discriminant analysis was performed. The impedance plethysmographic result was normal in 386 of 397 limbs which were normal on venography, a specificity of 97%, and abnormal in 124 of 133 limbs which showed proximal vein thrombosis, a sensitivity of 93%. Seventy-three of 88 limbs with calf vein thrombi had a normal impedance plethysmographic result. The sensitivity in 29 limbs with asymptomatic proximal vein thrombosis was 83%. Impedance plethysmography is an accurate method for detecting proximal vein thrombosis but has limitations which include the possibility of false positive results due to arterial insufficiency and muscle tension.

Thrombogenic Effect of High-Dose Aspirin in Rabbits: RELATIONSHIP TO INHIBITION OF VESSEL WALL SYNTHESIS OF PROSTAGLANDIN I2-LIKE ACTIVITY

Aspirin is a promising antithrombogenic agent. It inhibits the generation of thromboxane A(2) by acetylating platelet cyclo-oxygenase. Aspirin also inhibits vessel wall production of PGI(2) which is an inhibitor of platelet aggregation, and therefore is potentially thrombotic. To investigate these two opposing effects we studied the effects of aspirin upon fibrin accretion onto experimentally induced venous thrombi in rabbits and on the PGI(2)-like activity of vessel wall using the thrombin-induced [(14)C]serotonin release assay. A 200-mg/kg dose of aspirin significantly augmented thrombus size when compared to (a) sodium salicylate administered in equal doses, (b) aspirin in a 10-mg/kg dose or (c) controls (P < 0.001). A 200-mg/kg dose of aspirin totally inhibited vessel wall PGI(2)-like activity whereas aspirin in a 10-mg/kg dose produced less inhibition, and 200 mg/kg sodium salicylate had no effect. Local instillation of tranylcypromine, an inhibitor of PGI(2) formation, also significantly augmented thrombus size compared to saline-treated controls and totally inhibited the production of PGI(2)-like activity. The thrombogenic effect of high dose aspirin was lost if an interval of 2.5 h or longer elapsed between vessel damage and drug administration, indicating that in contrast to the platelet, the effect of aspirin on vessel wall prostaglandin synthesis is relatively short-lived. It is concluded that aspirin, in doses higher than those used clinically, can augment experimental thrombosis, presumably by inhibiting the synthesis of vessel wall PGI(2).

Replacement of Venography in Suspected Venous Thrombosis by Impedance Plethysmography and 125I-Fibrinogen Leg Scanning: A Less Invasive Approach

Noninvasive diagnostic testing is gaining acceptance in the evaluation of patients with clinically suspected venous thrombosis. Although clinically useful, all these tests have limitations, and the safety of basing therapeutic decisions on their outcome has not been assessed. We have done a prospective study of 322 symptomatic patients to ascertain the safety of replacing venography with impedance plethysmography and leg scanning. To provide a diagnostic reference, we did venography in all patients but withheld anticoagulants if the noninvasive tests were negative irrespective of the results of venography. None of the 163 patients with negative noninvasive tests died or developed clinical pulmonary embolism during 3 months follow-up, confirming the safety of this approach. In two, clinically evident postvenographic venous thrombosis developed, confirmed by repetition of these objective tests. Also, the positive predictive values indicate that therapeutic decisions can be based on a positive noninvasive outcome in patients without clinical disorders known to produce false-positive results.

Adjusted subcutaneous heparin or continuous intravenous heparin in patients with acute deep vein thrombosis. A randomized trial.

STUDY OBJECTIVEnTo determine the efficacy and safety of adjusted subcutaneous calcium heparin compared with continuous intravenous calcium heparin as the initial treatment for acute deep vein thrombosis.nnnDESIGNnRandomized control trial.nnnSETTINGnUniversity-affiliated general hospital.nnnPATIENTSnOf 111 consecutive patients considered, 103 had acute proximal or calf vein thrombosis confirmed by ascending venography and met all other eligibility criteria.nnnINTERVENTIONSnPATIENTS were randomly assigned to receive subcutaneous or intravenous heparin. The subcutaneous regimen consisted of an initial dose of 15,000 U, adjusted thereafter to prolong the activated partial thromboplastin time to 50 to 70 seconds. The continuous intravenous regimen was begun as a bolus injection of 5000 U, followed by an infusion of 1250 U/h, adjusted to maintain the activated partial thromboplastin time at 50 to 70 seconds.nnnMEASUREMENTS AND MAIN RESULTSnThere was no significant difference in the rate of new pulmonary embolism between the two groups, as defined by new high-probability defect on repeat ventilation-perfusion scintigrams of the lung in 96 (93%) of the patients after 7 to 10 days of treatment. Five of forty-seven patients in the subcutaneous group and 5 of 49 in the intravenous group developed pulmonary embolism (95% confidence interval [CI] for the difference, -13.1% to 12.2%). Similarly, there was no significant difference in the frequency of hemorrhagic complications. Five of fifty-one patients in the subcutaneous group and 5 of 52 in the intravenous group had hemorrhagic complications (95% CI for the difference, -11.2% to 11.6%).nnnCONCLUSIONnAdjusted subcutaneous calcium heparin may be an effective and safe alternative to continuous intravenous calcium heparin in the initial treatment of acute proximal deep vein thrombosis.

Effectiveness of intermittent pulsatile elastic stockings for the prevention of calf and thigh vein thrombosis in patienis undergoing elective knee surgery

Abstract Intermittent calf compression (ICC) prevents postoperative venous thrombosis (VT) but has not been previously tested in patients who remain immobilized for prolonged periods. We have evaluated a pulsatile elastic stocking in a randomized trial of 61 patients who underwent elective knee surgery. The stockings were worn for up to 17 days or until patient discharge and did not produce patient discomfort. The patients were well matched for age, sex, type of operation and aspirin use. Bilateral venography was performed on all patients 14–17 days postoperatively or earlier if the 1251-fibrinogen scan became positive. Nineteen of the 29 patients (65.5%) in the control group and 2 of 32 patients (6.3%) in the stocking group developed deep VT (p