Correspondence
Unfractionated versus Low-Molecular-Weight Heparin for Deep Venous Thrombosis
N Engl J Med 1996; 335:670-672August 29, 1996
- Article
To the Editor:
The studies on low-molecular-weight heparin by Levine et al. and by Koopman et al. (March 14 issue)1,2 addressed the safety and efficacy of low-molecular-weight heparin given at home, as compared with standard heparin given in the hospital, for acute proximal deep venous thrombosis. There did not appear to be any differences between the two treatment groups in terms of bleeding, pulmonary embolism, recurrent thromboembolic events, or death. The cost savings to the health care system could be substantial. I have several reservations about these studies, since many of the short-term and long-term problems that develop from deep-vein thrombosis were not addressed.
Although venography and ultrasound examinations were used to establish the diagnosis at the time of entry into the study, no data were provided on the extent of the disease other than the statement that there was involvement of the proximal veins. No further studies were done on the patients who did “well.” Some patients underwent plethysmography to monitor the deep-venous system. Unfortunately, impedance plethysmography is a very poor method for documenting changes in the deep-venous system. It will show a change to normal with no change in the venous thrombi as venous collaterals develop.
No data are presented on the status of the thrombi, the extent of recanalization, the status of the venous valves, or the extent of residual venous obstruction in the two groups of patients. In addition, no attempt was made to stratify the severity of the venous involvement with regard to the form of therapy. Do the authors suggest that iliofemoral venous thrombosis be treated at home? Patients with this condition have a great deal of pain and swelling and are most prone to serious and fatal pulmonary embolism.
I am also concerned that some patients may be deprived of ancillary therapy that could be of great value in preventing the development of the post-thrombotic syndrome. For example, there is increasing interest and apparent success in the use of catheter-directed thrombolysis in patients with proximal venous thrombosis. We know that with rapid lysis, preservation of valve function and restoration of patency may be possible.3-5 How do we know that the two forms of therapy are indeed similar in terms of even short-term outcome?
5 ReferencesD. Eugene Strandness, Jr., M.D.
University of Washington School of Medicine, Seattle, WA 98195-64101
Levine M ,Gent M ,Hirsh J , et al. A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med 1996;334:677-681
Full Text | Web of Science | Medline2
Koopman MMW ,Prandoni P ,Piovella F , et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. N Engl J Med 1996;334:682-687
Full Text | Web of Science | Medline3
Meissner MH ,Manzo RA ,Bergelin RO ,Markel A ,Strandness DE Jr . Deep venous insufficiency: the relationship between lysis and subsequent reflux. J Vasc Surg 1993;18:596-608
CrossRef | Web of Science | Medline4
Meissner MH ,Caps MT ,Bergelin RO ,Manzo RA ,Strandness DE Jr . Propagation, rethrombosis and new thrombus formation after acute deep venous thrombosis. J Vasc Surg 1995;22:558-567
CrossRef | Web of Science | Medline5
Johnson BF ,Manzo RA ,Bergelin RO ,Strandness DE Jr . Relationship between changes in the deep venous system and the development of the postthrombotic syndrome after an acute episode of lower limb deep vein thrombosis: a one- to six-year follow-up. J Vasc Surg 1995;21:307-313
CrossRef | Web of Science | Medline
To the Editor:
The articles by Levine et al. and by Koopman et al. supporting the therapeutic use of low-molecular-weight heparin for venous thrombosis imply advantages over unfractionated heparin with respect to convenience and the opportunity to treat patients in a home setting. There is also an advantage in a lower incidence of heparin-induced thrombocytopenia — believed to be approximately 1 to 2 percent, as compared with the 4 percent observed in healthy men receiving porcine heparin, and 17 percent in those receiving bovine heparin.1
Overlooked, perhaps, is the fact that heparin concentrate (40,000 units per milliliter) can also provide therapeutic levels of anticoagulant activity when administered subcutaneously, at a dosage of 250 units per kilogram of body weight every 12 hours. Daily monitoring is usually unnecessary after the second or third day.2 In addition, the therapeutic dose of the concentrate can be provided in smaller volume and is well tolerated for long-term treatment. A comparison of subcutaneous unfractionated (not concentrated) heparin with low-molecular-weight heparin showed similar therapeutic responses,3 and our experience with concentrated heparin would indicate equal benefit for the two products. The cost factor should therefore be considered, inasmuch as concentrates of unfractionated heparin cost several dollars a day, whereas low-molecular-weight heparin costs 10 times as much.
3 ReferencesJohn Penner, M.D.
Michigan State University, East Lansing, MI 48824-13151
Schwartz KA ,Royer G ,Kaufman DB ,Penner JA . Complications of heparin administration in normal individuals. Am J Hematol 1985;19:355-363
CrossRef | Web of Science | Medline2
Penner JA ,Hiss RG . Heparin therapy in the 70's. Univ Mich Med Cent J 1974;40:57-613
Monreal M ,Lafoz E ,Olive A ,del Rio L ,Vedia C . Comparison of subcutaneous unfractionated heparin with a low molecular weight heparin (Fragmin) in patients with venous thromboembolism and contraindications to coumarin. Thromb Haemost 1994;71:7-11
Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Dr. Strandness raises several points for discussion. In our study, impedance plethysmography was not used to monitor venous valvular function. It was used as one of three tests to confirm a diagnosis of clinically suspected recurrent deep-vein thrombosis. The change from a negative to a positive impedance plethysmogram is a validated method of diagnosing recurrence.1
The most clinically relevant outcome measures — recurrent deep-vein thrombosis, pulmonary embolism, and bleeding — were used in the trial. The extent of recanalization, the status of the venous valves, or the extent of residual venous obstruction may be of physiologic interest, but they are not important clinical outcomes.
Patients with iliofemoral-vein thrombosis were not excluded from our trial provided that their symptoms and family circumstances did not preclude home treatment. There were no deaths from pulmonary embolism in the patients who received low-molecular-weight heparin.
There is no evidence that thrombolytic therapy prevents the post-thrombotic syndrome. We limit the use of thrombolytic therapy to young patients with marked phlegmasia cerulea dolens who are at low risk of bleeding.
In response to Dr. Penner, no difference was detected in the incidence of heparin-associated thrombocytopenia between groups in our trial, and the rates in both groups were extremely low.
We do not agree with Dr. Penner that unfractionated heparin administered in a fixed dose subcutaneously should be considered a standard regimen in patients with acute proximal deep-vein thrombosis, either in the hospital or at home. There have been no randomized trials comparing fixed-dose unfractionated heparin administered subcutaneously with continuous intravenous heparin in patients with acute deep-vein thrombosis. There have been a number of randomized trials comparing continuous intravenous unfractionated heparin with subcutaneous unfractionated heparin adjusted to achieve a therapeutic activated partial-thromboplastin time in hospitalized patients.2 It should be noted that in one double-blind trial, a starting dose of 15,000 units of heparin subcutaneously every 12 hours was associated with a high rate of recurrent venous thrombosis.3 Dr. Penner uses the trial reported by Monreal and colleagues to support the use of fixed-dose subcutaneous standard heparin.4 However, all the patients in that study initially received intravenous unfractionated heparin in doses adjusted to achieve a therapeutic activated partial-thromboplastin time, and then immediately before discharge from the hospital they were randomly assigned to receive subcutaneous fixed-dose heparin or low-molecular-weight heparin. This is a different question from the one we addressed.
4 ReferencesMark Levine, M.D.
Jack Hirsh, M.D.
Michael Gent, D.Sc.
Hamilton Regional Cancer Centre, Hamilton, ON L8V 5C2, Canada1
Hull RD ,Carter CJ ,Jay RM , et al. The diagnosis of acute, recurrent, deep-vein thrombosis: a diagnostic challenge. Circulation 1983;67:901-906
CrossRef | Web of Science | Medline2
Hirsh J . Heparin. N Engl J Med 1991;324:1565-1574
Full Text | Web of Science | Medline3
Hull RD ,Raskob GE ,Hirsh J , et al. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis. N Engl J Med 1986;315:1109-1114
Full Text | Web of Science | Medline4
Monreal M ,Lafoz E ,Olive A ,del Rio L ,Vedia C . Comparison of subcutaneous unfractionated heparin with a low molecular weight heparin (Fragmin) in patients with venous thromboembolism and contraindications to coumarin. Thromb Haemost 1994;71:7-11
Web of Science | Medline
Author/Editor Response
We thank Drs. Strandness and Penner for their comments. Dr. Strandness was concerned about the documentation of the extent of the thrombus and the course of the disease. The study population consisted of consecutive symptomatic ambulatory patients with a diagnosis of deep-vein thrombosis made by ultrasonography or venography. Both methods are generally accepted as very accurate techniques for diagnosing venous thrombosis and allow anticoagulant therapy to be initiated independently of the extent of the thrombus. About 70 percent of the patients in the study had at least femoral-vein involvement consistent with data on the distribution of thrombi on venography.1 This indicates that our study population was representative of the average ambulatory patient with deep-vein thrombosis.
We did not have data on the extent of recanalization or the status of the venous valves because the main goal of our study was to compare the standard treatment of deep-vein thrombosis (intravenous standard heparin given in the hospital) with a more convenient therapy (subcutaneous low-molecular-weight heparin given at home) in terms of efficacy, safety, quality of life, and costs. On the other hand, the recurrence rate of venous thromboembolism was low in both treatment groups (8.6 percent in the standard-heparin group and 6.9 percent in the low-molecular-weight–heparin group) and seems to reflect adequately the resolution of the clot. Since the great majority of our patients had iliofemoral-vein thrombosis, our findings indeed indicate that it is possible to treat these patients outside the hospital. No fatal pulmonary embolism was recorded during the initial treatment period.
We cannot imagine what kind of ancillary therapy was withheld from our patients to prevent the post-thrombotic syndrome, because to our knowledge such a therapy has not been evaluated in well-designed clinical studies.
Dr. Penner wonders if it is not possible to treat patients with subcutaneous unfractionated heparin instead of low-molecular-weight heparin, because of the higher costs of the latter. Indeed, the subcutaneous administration of standard heparin is as effective and safe as the intravenous route,2 but the monitoring of activated partial-thromboplastin time remains necessary during the entire treatment period. The total costs of the low-molecular-weight–heparin therapy, therefore, must be compared with all the costs of unfractionated heparin, including the costs of laboratory measurements, infusion systems, nursing time, and the costs associated with the higher prevalence of recurrent venous thromboembolism and bleeding.
2 ReferencesMaria M.W. Koopman, M.D.
Harry R. Büller, M.D.
Academic Medical Center, 1105 AZ Amsterdam, the Netherlands1
Cogo A ,Lensing AW ,Prandoni P ,Hirsh J . Distribution of thrombosis in patients with symptomatic deep vein thrombosis: implications for simplifying the diagnostic process with compression ultrasound. Arch Intern Med 1993;153:2777-2780
CrossRef | Web of Science | Medline2
Hommes DW ,Bura A ,Mazzolai L ,Buller HR ,ten Cate JW . Subcutaneous heparin compared with continuous intravenous heparin administration in the initial treatment of deep vein thrombosis: a meta-analysis. Ann Intern Med 1992;116:279-284
Web of Science | Medline
- Citing Articles (1)
Citing Articles
1
P. Hölper, A. Hyhlik-Dürr, H. Schumacher, T. Heye, D. Böckler. (2009) Venöse Hybridoperation zur Therapie einer symptomatischen kongenitalen Hypoplasie der Vena cava inferior. Gefässchirurgie 14:6, 512-515
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