Clinical Investigations

Low-Molecular-Weight Heparin versus Unfractionated Heparin in the Treatment of Patients with Acute Pulmonary Thromboembolism
Serhat Findik^a, M. Levent Erkan^a, M. Bekir Selçuk^b, Selahattin Albayrak^c, Atilla G. Atici^a, Fatma Doru<sup>a

a</sup>Department of Pulmonary Medicine,
^bDepartment of Radiology,
^cDepartment of Nuclear Medicine, 19 Mays University, Samsun, Turkey

Address of Corresponding Author

Respiration 2002;69:440-444 (DOI: 10.1159/000064023)

 Outline

• Key Words
• Abstract
• Introduction
• Material and Methods
• Treatment Regimens
• Surveillance and Follow-Up
• Outcome Measures
• Statistical Analysis
• Results
• Study Patients
• Outcome Events and Primary End Points
• Perfusion Lung Scans
• Discussion
• References

• Author Contacts
• Article Information
• Publication Details
• Drug Dosage / Copyright

  Key Words

• Pulmonary thromboembolism
• Unfractionated heparin
• Low-molecular-weight heparin
• Enoxaparin

  Abstract

Background: Low-molecular-weight heparin (LMWH) appears to be as effective as unfractionated heparin (UFH) for both treatment and prophylaxis of deep vein thrombosis (DVT), but limited data are available for its use in acute pulmonary thromboembolism (PTE). Objective: To determine whether enoxaparin, a LMWH, was clinically as efficient and safe as UFH in patients with a diagnosis of acute PTE. Material and Methods: After exclusion of those with massive forms, 59 patients with acute PTE were randomly assigned to either subcutaneous enoxaparin given twice daily (1 mg/kg/dose) or adjusted dose intravenous UFH. Oral anticoagulant treatment was begun on the second day and was given for at least 6 months. We compared the treatment regimens at day 8 and day 90 with respect to a combined end point of major bleeding, recurrent venous thromboembolism (VTE), and death. Results: In the first 8 days of treatment, 1 of 30 patients assigned to receive UFH (3.3%) reached one of the end points (recurrence), as compared with none of 29 patients assigned to enoxaparin. Statistically this difference was not significant (p = 0.508). By day 90, 3 patients assigned to UFH (10%) had symptomatic recurrent VTE, as compared with 1 patient assigned to enoxaparin (3.4%). There was neither major bleeding nor death in the study groups. There was an absolute difference of 6.4 percentage points between the two treatment groups, but the difference was statistically not significant (p = 0.318). Conclusion: Initial subcutaneous treatment with enoxaparin appeared to be as effective and safe as UFH in acute PTE.

Copyright © 2002 S. Karger AG, Basel

 Introduction

Low-molecular-weight heparins (LMWH), like unfractionated heparin (UFH), are glycosaminoglycans consisting of chains of alternating residues of D-glucosamine and uronic acid [1]. LMWH preparations are fragments of UFH produced by enzymatic or chemical depolymerization processes resulting in chains with a mean molecular weight of 5,000 D. Like UFH, LMWHs exert anticoagulant activity via activation of antithrombin. The advantage of LMWH preparations arises from their increased bioavailability and longer half-life as well as the simplicity of subcutaneous administration once or twice daily without a need for monitoring activated partial thromboplastin time (aPTT), in contrast to UFH treatment.

LMWH is known to be effective and safe for the initial treatment of deep vein thrombosis (DVT) [2, 3, 4, 5], but only limited data are available on the use of LMWHs, tinzaparin and reviparin, for the treatment of acute pulmonary thromboembolism (PTE) [6, 7, 8]. To our knowledge, our study was the first to compare enoxaparin with UFH for the treatment of patients with acute PTE.

Therefore, we conducted a randomized trial in which patients with acute PTE were given either continuous intravenous UFH or a twice-daily subcutaneous injection of enoxaparin. We aimed to determine whether enoxaparin was clinically as efficient and safe as UFH with regard to the combined outcome of major bleeding, recurrent venous thromboembolism (VTE), and death within both 8 and 90 days of diagnosis.

 Material and Methods

Consecutive patients over 18 years of age with clinically suspected acute PTE were considered for enrollment in the study. Before their inclusion, PTE had to be objectively documented by ventilation/perfusion lung scanning showing a high probability of PTE [9], or by scanning with indeterminate results that was accompanied by DVT confirmed by compression ultrasonography.

Patients who met these criteria for inclusion were ineligible for the study if they had massive PTE (mPTE) requiring thrombolytic therapy or pulmonary embolectomy; if they had active bleeding or hematologic disorders contraindicating anticoagulant therapy; if they had received anticoagulant therapy at a therapeutic dose for more than 24 h before the study; if life expectancy was less than 3 months; if they had severe hepatic or renal failure; if they were pregnant; if noncompliance was likely. After the patient gave informed consent, randomization was performed.

In order to diagnose mPTE, the patient must have hemodynamic instability (systolic blood pressure <90 mm Hg, syncope, and/or shock) plus 1 of the following: high probability ventilation-perfusion lung scanning for PTE; multiple filling defects and/or cut-off signs in proximal pulmonary arterial bed by conventional pulmonary angiography; acute right ventricular hypokinesis and dilatation causing a leftward shift of the interventricular septum on echocardiography that was accompanied by DVT confirmed by compression ultrasonography.

 Treatment Regimens

Enoxaparin (LMWH) Group: The patients received enoxaparin sodium (Clexane^®), administered subcutaneously in 1 mg/kg, 100 international anti-factor Xa units per kg of body weight twice daily.

UFH Group: The patients received an initial bolus dose of 5,000 IU, followed by a dose of 1,000 IU/h given by continuous intravenous infusion. The UFH dose was adjusted so that the aPTT would be 1.5-2.5 times the control value.

Oral anticoagulant treatment was begun on the second day and continued for a total of 6 months.

During treatment with the study drug, all patients were followed up in the hospital. Prothrombin times were measured every day, with the dose adjusted to achieve an international normalized ratio (INR) that was maintained between 2.0 and 3.0 for 2 consecutive days and the patient had received the study drug for at least 5 days.

 Surveillance and Follow-Up

All patients were examined daily within 10 days of therapy and symptoms and signs of recurrent VTE or bleeding were sought. For all patients, compression ultrasonography of the lower limbs was planned at enrollment.

Complete blood counts were obtained daily during the initial 8 days and whenever there was any bleeding.

Perfusion lung scans and compression ultrasonography were repeated in all patients on day 8 and day 90.

 Outcome Measures

For evaluation of the therapeutic regimens, criteria and strategies of the THESEE study [6] were used.

Recurrent VTE. Patients in whom recurrent VTE was suspected on the basis of clinical signs or symptoms underwent ventilation/perfusion scanning or angiography if needed. Recurrent PTE was diagnosed if there was a new perfusion defect, segmental or larger, on the lung scan. If the lung scan was inconclusive, pulmonary angiography would be performed. Patients with suspected new or recurrent DVT on the basis of the clinical findings underwent ultrasonography. The criterion for DVT was a lack of compressibility on ultrasonography when it represented a change from the baseline test.

Major Bleeding. (1) Overt bleeding associated either with a decrease in the hemoglobin concentration by at least 2.0 g/dl or with the need for the transfusion of 2 or more units of blood, or (2) if the bleeding was intracranial or retroperitoneal.

Death. Classified as due to PTE, hemorrhage, cancer, or other causes including unknown ones.

Thrombocytopenia. If the platelet count fell below 50,000/mm³ or if it was between 50,000 and 100,000/mm³ and accompanied by clinical signs of bleeding.

We compared the treatments at day 8 and day 90 with respect to a combined end point of recurrent VTE, major bleeding and death.

 Statistical Analysis

Data were analysed using SPSS version 8.0 for Windows. ² and Fisher's exact tests were used. Significance levels were set at p < 0.05.

 Results

 Study Patients

The recruitment of patients began in August 1998 and ended in January 2000. The follow-up of the patients was completed in July 2000. Of 87 consecutive patients who met the criteria for enrollment, 28 (32%) were excluded from the study for the following reasons: previous treatment with an anticoagulant drug for more than 24 h (11 patients), contraindications to anticoagulant treatment (8 patients), mPTE requiring thrombolytic therapy (7 patients), short life expectancy due to stage IV lung cancer (2 patients).

Among 59 eligible patients, 30 were randomly assigned to UFH and 29 to enoxaparin. The baseline characteristics of the treatment groups were similar (tables 1, 2).

Table 1. Baseline characteristics of the study patients

Table 2. Selected characteristics of the study patients

The doses and duration of the study drugs are shown in table 3. The mean time to reach the target aPTT range, which was 1.5-2.5 times the control value, in patients treated with UFH was 24 ± 8.2 h.

Table 3. Dose and duration of anticoagulant therapy

 Outcome Events and Primary End Points

During the 8 days after randomization, 1 patient assigned to receive UFH (3.3%) had symptomatic recurrent VTE. In the enoxaparin group there was no occurrence of an outcome event (0%) (table 4). There was an absolute difference of 3.3 percentage points between the two groups, but it was not statistically significant (p > 0.05).

Table 4. Outcome events in the study group within 8 and 90 days

During the 90 days after randomization, 3 patients assigned to receive UFH (10%) had symptomatic recurrent VTE, as compared with 1 patient assigned to receive enoxaparin (3.4%, odds ratio: 0.32) (table 4). There was neither major bleeding nor death in the study group. There was an absolute difference of 6.4 percentage points between the two groups but it was not statistically significant (p > 0.05).

Thrombocytopenia with or without heparin was observed in neither group.

 Perfusion Lung Scans

Among the patients assigned to UFH, the perfusion lung scans improved in 22 (73%), remained the same in 7 (23%), and worsened in 1 (3%) from day 1 to day 8. Among the patients assigned to enoxaparin, the perfusion scans improved in 21 patients (72%), remained unchanged in 8 (28%), worsened in none from day 1 to day 8.

On day 90, among the patients assigned to UFH, the perfusion lung scans improved in all patients except 2, who developed symptomatic recurrent VTE on days 86 and 88, respectively. In the enoxaparin group, all the perfusion lung scans improved on day 90.

 Discussion

PTE remains a leading cause of morbidity and mortality. Its incidence in the United States has been estimated at over 500,000 patients per year [10]. Untreated PTE carries a mortality rate as high as 30%, although it has been reported that when diagnosed and treated on time, this mortality falls to below 3% [11]. There are very few conditions in medicine where correct diagnosis and treatment have such a substantial impact on prognosis.

The standard anticoagulant therapy of VTE (DVT or PTE, except massive form) is a combination of continuous intravenous UFH and oral warfarin sodium. In the literature, there are lots of studies demonstrating the efficiency of LMWH for the initial treatment of DVT [5]. Although DVT and PTE are considered to be different expressions of the same disease, there is limited information on the use of LMWH for the initial treatment of PTE [6, 7, 8].

Our study shows that enoxaparin, an LMWH, can be used safely and effectively when given twice daily to treat patients with acute symptomatic PTE. During the first 8 days of treatment, although we detected 1 significant event, recurrent VTE, in 1 patient (3.3%) assigned to UFH, there was no detectable significant event in the enoxaparin group (p = 0.508; table 4). During the 90 days of follow-up, 3 patients (10%) in the UFH group and 1 patient (3.4%) in the enoxaparin group developed a recurrence of VTE (p = 0.318; table 4). There was neither major bleeding nor death in both study arms, nor was there any episode of thrombocytopenia in either group. Thus, by day 90, 3 patients (10%) assigned to UFH and 1 patient (3.4%) assigned to enoxaparin developed significant events (p = 0.318; table 4).

The relative efficacy and safety of LMWH and UFH in acute PTE have been studied in the THESEE study [6] in a larger population than ours: 612 patients with submassive PTE were randomized to regimens of LMWH (tinzaparin, 175 anti-Xa U/kg s.c. q.d.) or UFH (50 U/kg i.v. bolus followed by an infusion of 500 U/kg/day) adjusted to an aPTT ratio of 2.0-3.0, for the prevention of recurrent VTE, major bleeding, and death. By day 8, 9 of 308 patients (2.9%) assigned to UFH and 9 of 304 patients (3.0%) assigned to tinzaparin developed primary events; by day 90, 22 patients (7.1%) assigned to UFH and 18 patients (5.9%) assigned to tinzaparin developed events (p = 0.54). The rate of major bleedings was similar in both groups (2.6 and 2%, respectively; not significant). There were 3 deaths at 8 days and 14 deaths (4.5%) at 90 days in the UFH group, and 4 deaths at 8 days and 12 deaths (3.9%) at 90 days in the tinzaparin group. As a result, they suggested that the use of tinzaparin may be extended to patients with acute PTE after those with hemodynamic instability are excluded.

American-Canadian Thrombosis Study Group [8] compared a fixed-dose subcutaneous LMWH (tinzaparin sodium) given once daily with a dose-adjusted intravenous UFH using objective documentation of clinical outcomes for treatment of acute PTE, that was documented by the presence of high-probability lung scan findings. Of 200 patients, none of the 97 who received tinzaparin had any new episodes of VTE compared with 7 (6.8%) of 103 patients who received UFH (95% confidence interval for the difference, 1.9-11.7%; p = 0.01). Major bleeding associated with initial therapy occurred in 1 patient (1%) who was given tinzaparin and in 2 patients (1.9%) given UFH (95% confidence interval for the difference, -2.4 to 4.3%). And the study group concluded that tinzaparin administered once daily subcutaneously was no less effective and probably more effective than dose-adjusted intravenous UFH for preventing recurrent VTE in patients with PTE and associated proximal DVT and suggested extension of the use of LMWH without anticoagulant monitoring to patients with submassive PTE.

The Colombus investigators [7] compared a fixed-dose, subcutaneous LMWH (reviparin) with adjusted dose, intravenous UFH in 1,021 patients with symptomatic VTE, of which approximately one third had associated PTE. The outcome events studied over the 12 weeks were symptomatic recurrent VTE, major bleeding, and death. Of the patients assigned to LMWH 53.3% had recurrent VTE events, as compared with 4.9% of the patients assigned to UFH (p > 0.05). Sixteen patients assigned to LMWH (3.1%) and 12 patients assigned to UFH (2.3%) had episodes of major bleeding (p = 0.63), and the mortality rates in both groups were 7.1 and 7.6%, respectively (p = 0.89). And the study group concluded that LMWH is as effective and safe as adjusted-dose, intravenous UFH for the initial management of VTE, regardless of whether the patient has PTE or a history of VTE.

The low subject numbers in both LMWH and UFH arms (29 and 30, respectively) and, also, low event rates reduced the statistical power of our study to detect a significant difference between the arms. However, our results showed that enoxaparin was as effective and safe as UFH in the treatment of PTE with regard to the combined outcome of symptomatic recurrent VTE, major bleeding, and death in patients with acute PTE.

In conclusion, we suggest that enoxaparin is as effective and safe as UFH in the treatment of acute PTE.

  References

1.

Weitz JI: Low-molecular-weight heparins. N Engl J Med 1997;337:688-698.

2.

Leizorovicz A, Simonneau G, Decousus H, Boissel JP: Comparison of efficacy and safety of low molecular weight heparins and unfractionated heparin in initial treatment of deep venous thrombosis: A meta-analysis. BMJ 1994;309:299-304.

3.

Lensing AWA, Prins MH, Davidson BL, Hirsh J: Treatment of deep venous thrombosis with low-molecular-weight heparins: A meta-analysis. Arch Intern Med 1995;155:610-607.

4.

Siragusa S, Cosmi B, Piovella F, Hirsh J, Ginsberg JS: Low-molecular-weight heparins and unfractionated heparin in the treatment of patients with acute venous thromboembolism: Results of a meta-analysis. Am J Med 1996;100:269-277.

5.

Gould MK, Dembitzer AD, Doyle RL, et al: Low molecular weight heparins compared with unfractionated heparin for the treatment of acute deep venous thrombosis: A meta-analysis of randomised controlled trials. Ann Intern Med 1999;130:800-809.

6.

Simonneau G, Sors H, Charbonnier B, et al, for the THESEE Study Group: A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism. N Engl J Med 1997;337:663-669.

7.

The Colombus Investigators: Low-molecular-weight heparin in the treatment of patients with venous thromboembolism. N Engl J Med 1997;337:657-662.

8.

American-Canadian Thrombosis Study Group: Low-molecular-weight heparin versus heparin in the treatment of patients with pulmonary embolism. Arch Intern Med 2000;160:229-236.

9.

The PIOPED Investigators: Value of the ventilation/perfusion scan in acute pulmonary embolism: Results of the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED). JAMA 1990;263:2753-2759.

10.

Goldhaber SZ, Morpurgo M (for the WHO/ISFC Task Force on Pulmonary Embolism): Diagnosis, treatment, and prevention of pulmonary embolism. JAMA 1992;268:1727-1733.

11.

Carson JL, Kelley MA, Duff A, et al: The clinical course of pulmonary embolism. N Engl J Med 1992;326:1240-1245.

  Author Contacts

Assist. Prof. Dr. Serhat Findik
Department of Pulmonary Medicine, 19 Mays University
TR-55139 Kurupelit, Samsun (Turkey)
Tel. +90 362 4576000, ext. 3124, Fax +90 362 4576041
E-Mail serhatf@omu.edu.tr

  Article Information

Received: Received: December 3, 2001
Accepted after revision: May 29, 2002
Number of Print Pages : 5
Number of Figures : 0, Number of Tables : 4, Number of References : 11

  Publication Details

Respiration (International Review of Thoracic Diseases)
Founded 1944 as 'Schweizerische Zeitschrift für Tuberkulose und Pneumonologie' by E. Bachmann, M. Gilbert, F. Häberlin, W. Löffler, P. Steiner and E. Uehlinger, continued 1962-1967 as 'Medicina Thoracalis' as of 1968 as 'Respiration', H. Herzog (1962-1997)
Official Journal of the European Association for Bronchology and Interventional Pulmonology

Vol. 69, No. 5, Year 2002 (Cover Date: September-October 2002)

Journal Editor: C.T. Bolliger, Cape Town
ISSN: 0025-7931 (print), 1423-0356 (Online)

For additional information: http://www.karger.com/journals/res

  Drug Dosage / Copyright

Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.