Clinical Evidence Handbook: Thromboembolism - August 1, 2002

August 1, 2002 Table of Contents

Clinical Evidcence: A Publication of BMJ Publishing Group

Thromboembolism

DAVID A. FITZMAURICE, M.D.; F.D. RICHARD HOBBS, M.B., Ch.B., FRCGP, FRCP; and RICHARD J. MCMANUS, MSc, MBBS, MRCGP, DRCOG

The Medical School University of Birmingham, Birmingham, United Kingdom

Am Fam Physician.�2002�Aug�1;66(3):475-477.

Questions Addressed

What are the effects of treatments for proximal deep venous thrombosis?
What are the effects of treatments for isolated calf vein thrombosis?
What are the effects of treatments for pulmonary embolism?
What are the effects of computerized decision support on oral anticoagulation management?

Summary of Interventions

Trade-off of benefits and harms

Oral anticoagulants in people with deep venous thrombosis

Unfractionated and low-molecular-weight heparin in people with deep venous thrombosis

Warfarin plus heparin in people with isolated calf vein thrombosis

Unfractionated and low-molecular-weight heparin in people with pulmonary embolism

Oral anticoagulants in people with pulmonary embolism

Unknown effectiveness

Computerized decision support in oral anticoagulation

To be covered in future updates of Clinical Evidence

Thrombolysis for pulmonary embolism

Compression stockings for deep venous thrombosis

Oral antithrombotic agents (such as glycoprotein IIb/IIIa antagonists)

Inferior vena cava filters

Aspirin

Thromboembolism in pregnancy

Definition	Venous thromboembolism is any thromboembolic event occurring within the venous system, including deep venous thrombosis and pulmonary embolism. Deep venous thrombosis is a radiologically confirmed partial or total thrombotic occlusion of the deep venous system of the legs sufficient to produce symptoms of pain or swelling. Proximal deep venous thrombosis affects the veins above the knee (popliteal, superficial femoral, common femoral, and iliac veins). Isolated calf vein thrombosis is confined to the deep veins of the calf and does not affect the veins above the knee. Pulmonary embolism is radiologically confirmed partial or total thromboembolic occlusion of pulmonary arteries, sufficient to cause symptoms of breathlessness, chest pain, or both. Post-thrombotic syndrome is edema, ulceration, and impaired viability of the subcutaneous tissues of the leg occurring after deep venous thrombosis. Recurrence refers to symptomatic deterioration caused by a further (radiologically confirmed) thrombosis, after a previously confirmed thromboembolic event, where there had been an initial, partial, or total symptomatic improvement. Extension refers to a radiologically confirmed new, constant, symptomatic intraluminal filling defect extending from an existing thrombosis.
Incidence/Prevalence	We found no reliable study of the incidence/prevalence of deep venous thrombosis or pulmonary embolism in the United Kingdom. A prospective Scandinavian study found an annual incidence of 1.6 to 1.8 per 1,000 people in the general population.1,2 One postmortem study estimated that 600,000 people develop pulmonary embolism each year in the United States, of whom 60,000 die as a result.3
Etiology/Risk Factors	Risk factors for deep venous thrombosis include immobility, surgery (particularly orthopedic), malignancy, smoking, pregnancy, older age, and inherited or acquired prothrombotic clotting disorders.4 Evidence for these factors is mainly observational. The oral contraceptive pill is associated with death caused by venous thromboembolism (absolute risk increase with any combined oral contraception: 1 to 3 per million women per year).5 The principal cause of pulmonary embolism is a deep venous thrombosis.4
Prognosis	The annual recurrence rate of symptomatic calf vein thrombosis in people without recent surgery is more than 25 percent.6,7 Proximal extension develops in 40 to 50 percent of people with symptomatic calf vein thrombosis.8 Proximal deep venous thrombosis may cause fatal or nonfatal pulmonary embolism, recurrent venous thrombosis, and the post-thrombotic syndrome. One observational study published in 1946 found 20 percent mortality from pulmonary emboli in people in the hospital with untreated deep venous thrombosis.9 One non-systematic review of observational studies found that, in people after recent surgery who have an asymptomatic calf vein deep venous thrombosis, the rate of fatal pulmonary embolism was 13 to 15 percent.10 The incidence of other complications without treatment is not known. The risk of recurrent venous thrombosis and complications is increased by thrombotic risk factors.11
Clinical Aims	To reduce acute symptoms of deep venous thrombosis and to prevent morbidity and mortality associated with thrombus extension, the post-thrombotic syndrome, and pulmonary embolization; to reduce recurrence; and to minimize any adverse effects of treatment.
Clinical Outcomes	Rates of symptomatic recurrence, post-thrombotic syndrome, symptomatic pulmonary embolism, and death. Proxy outcomes include radiologic evidence of clot extension or pulmonary embolism.

Evidence-Based Medicine Findings

SEARCH DATE: CLINICAL EVIDENCE UPDATE SEARCH AND APPRAISAL JULY 2001

Proximal Deep Venous Thrombosis

Warfarin versus placebo: We found no randomized controlled trials (RCTs). Combined warfarin plus intravenous unfractionated heparin versus warfarin alone for initial treatment: One RCT found reduced recurrence of proximal deep venous thrombosis. Longer versus shorter duration of anticoagulation: Systematic reviews have found significantly fewer deep venous thrombosis recurrences with longer anticoagulation. One nonsystematic review found limited evidence of significantly increased major hemorrhage, but another nonsystematic review found no significant increase. Low-molecular-weight heparin versus unfractionated heparin: Systematic reviews have found no significant difference in recurrence of thromboembolism but significantly decreased major hemorrhage. Long-term low-molecular-weight heparin versus oral anticoagulation: Systematic reviews and subsequent RCTs have found no significant difference in recurrent thromboembolism, major hemorrhage, or mortality. Heparin treatment at home versus in the hospital: One systematic review has found limited evidence of no significant difference in recurrence of thromboembolism.

Calf Vein Deep Venous Thrombosis

One RCT found that, in isolated calf vein thrombosis, warfarin plus intravenous unfractionated heparin versus heparin alone (International Normalized Ratio [INR] of 2.5 to 4.2) reduced rates of proximal extension. One unblinded RCT found no significant difference between shorter versus longer courses of anticoagulation in recurrent thromboembolism.

Pulmonary Embolism

We found no direct evidence in people with pulmonary embolism about the optimum intensity and duration of anticoagulation. Evidence for intensity and duration of treatment has been extrapolated from studies in people with proximal deep venous thrombosis and any venous thromboembolism. One small RCT found that heparin plus warfarin versus no anticoagulation significantly reduced mortality in people with pulmonary embolism. Two RCTs found no significant difference between low-molecular-weight heparin versus unfractionated heparin in mortality or new episodes of thromboembolism in people with pulmonary embolism.

Computerized Decision Support

We found no RCTs of computerized decision support versus usual management of oral anticoagulation that used clinically important outcomes (major hemorrhage or death). One systematic review and two subsequent RCTs have found that computerized decision support in oral anticoagulation improves time spent in the target INR range. Another subsequent RCT found no significant difference between computerized decision support and standard manual support in the time spent in the target INR range. A subsequent RCT of initiation of warfarin found no significant difference between computerized decision support versus usual care in the time taken to reach therapeutic levels of anticoagulation. Most RCTs were small and brief.

Adapted with permission from Fitzmaurice D, Hobbs FR, McManus R. Thromboembolism. Clin Evid 2002;7:199–213.

F. D. Richard Hobbs is a member of the European Society of Cardiology (ESC) Working Party on Heart Failure, Treasurer of the British Society for Heart Failure, and Chair of the British Primary Care Cardiovascular Society (PCCS). He has received travel sponsorship and honoraria from a number of multinational biotechnology and pharmaceutical companies with cardiovascular products for plenary talks and attendance at major cardiology scientific congresses and conferences.

David Fitzmaurice has received reimbursement for attendance at scientific meetings from Leo Laboratories who make tinzaparin, a low-molecular-weight heparin. The Department of Primary Care and General Practice at the University of Birmingham, where the authors work, has a computerized decision support program that is commercially available.

Richard McManus indicates that he does not have any conflicts of interest. Sources of funding: none reported.

REFERENCES

1. Nordstrom �M, Lindblad �B, Bergqvist �D, Kjellstrom �T. �A prospective study of the incidence of deep-vein thrombosis within a defined urban population. �J Intern Med. �1992;232:155–60.

2. Hansson �PO, Welin �L, Tibblin �G, Eriksson �H. �Deep vein thrombosis and pulmonary embolism in the general population. �Arch Intern Med. �1997;157:1665–70.

3. Rubinstein �I, Murray �D, Hoffstein �V. �Fatal pulmonary emboli in hospitalized patients: an autopsy study. �Arch Intern Med. �1988;148:1425–6.

4. Hirsh �J, Hoak �J. �Management of deep vein thrombosis and pulmonary embolism. �Circulation. �1996;93:2212–45.

5. Farley �TM, Meirik �O, Chang �CL, Marmot �MG, Poulter �NR. �Effects of different progestagens in low oestrogen oral contraceptives on venous thromboembolic disease. �Lancet. �1995;346:1582–8.

6. Lagerstedt �C, Olsson �C, Fagher �B, Oqvist �B, Albrechtsson �U. �Need for long-term anticoagulant treatment in symptomatic calf vein thrombosis. �Lancet. �1985;334:515–8.

7. Lohr �J, Kerr �T, Lutter �K, Cranley �R, Spirtoff �K, Cranley �J. �Lower extremity calf thrombosis: to treat or not to treat?. �J Vasc Surg. �1991;14:618–23.

8. Kakkar �VV, Howe �CT, Flanc �C, Clarke �MB. �Natural history of postoperative deep-vein thrombosis. �Lancet. �1969;ii:230–2.

9. Zilliacus �H. �On the specific treatment of thrombosis and pulmonary embolism with anticoagulants, with a particular reference to the post thrombotic sequelae. �Acta Med Scand. �1946;170:1–221.

10. Giannoukas �AD, Labropoulos �N, Burke �P, Katsamouris �A, Nicolaides �AN. �Calf deep vein thrombosis: a review of the literature. �Eur J Vasc Endovasc Surg. �1995;10:398–404.

11. Lensing �AW, Prandoni �P, Prins �MH, Buller �HR. �Deep-vein thrombosis. �Lancet. �1999;353:479–85.

This is one in a series of chapters excerpted from Clinical Evidence, published by the BMJ Publishing Group, Tavistock Square, London, United Kingdom. Clinical Evidence is published in print twice a year and is updated monthly online. The complete text for this topic, as well as additional information, is available to subscribers at www.clinicalevidence.com. This series is part of the AFP's CME. See “Clinical Quiz” on page 371.

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