Treating DVT: Answers to 7 key questions

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Applied Evidence

Treating DVT: Answers to 7 key questions

J Fam Pract. 2010 November;59(11):616-622a

By

Anne H. Metzger, PharmD, BCPS

Patricia R. Wigle, PharmD, BCPS

Complex recommendations for anticoagulant therapy raise questions for family physicians. Here are the evidence-based answers you need to manage DVT patients successfully.

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References

1. Minichiello T, Fogarty PF. Diagnosis and management of venous thromboembolism. Med Clin North Am. 2008;92:443-465.

2. Deitcher SR, Carman TL. Deep venous thrombosis and pulmonary embolism. Curr Treat Options Cardiovasc Med. 2002;4:223-238.

3. Kearon C, Kahn SR, Agnelli G, et al. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133(6 suppl):454S-545S.

4. Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133(6 suppl):160S-198S.

5. Bussey HL, Wittkowsky AK, Hylek EM, et al. Genetic testing for warfarin dosing? Not yet ready for prime time. Pharmacotherapy. 2008;28:141-143.

6. McWilliam A, Lutter R, Nardinelli C. Health care savings from personalizing medicine using genetic testing: the case of warfarin. American Enterprise Institute-Brookings Joint Center for Regulatory Studies. November 2006. Available at: www.reg-markets.org/publications/abstract.php?pid=1127&printversion=1. Accessed October 2, 2010.

7. Coumadin [package insert]. Princeton, NJ. Bristol-Myers Squibb; 2010.

8. Juurlink DN. Drug interactions with warfarin: what clinicians need to know. CMAJ. 2007;177:369-371.

9. Holmes DR, Kereiakes DJ, Kleiman NS, et al. Combining antiplatelet and anticoagulant therapies. J Am Coll Cardiol. 2009;54:95-109.

10. Hermosillo AJ, Spinler SA. Aspirin, clopidogrel and warfarin: Is the combination appropriate and effective or inappropriate and too dangerous? Ann Pharmacother. 2008;42:790-805.

11. Becker RC, Meade TW, Berger PB, et al. The primary and secondary prevention of coronary artery disease: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133(6 suppl):776S-814S.

12. Khurram Z, Chou E, Minutello R, et al. Combination therapy with aspirin, clopidogrel and warfarin following coronary stenting is associated with a significant risk of bleeding. J Invasive Cardiol. 2006;18:162-164.

13. Bauer KA. New anticoagulants. Hematology Am Soc Hematol Educ Program. 2006;450-456.

14. Fiessinger JN, Huisman MV, Davidson BL, et al. Ximelagatran vs low-molecular weight heparin and warfarin for the treatment of deep vein thrombosis. JAMA. 2005;293:681-689.

15. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361:2342-2352.

16. The RE-MOBILIZE Writing Committee. Oral thrombin inhibitor dabigatran etexilate versus the North American enoxaparin regimen for the prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty. 2009;24:1-9.

17. Eriksson BI, Dahl OE, Rosencher N, et al. Oral dabigatran etexilate vs subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost. 2007;5:2178-2185.

18. Eriksson BI, Dahl OE, Rosencher N, et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement. Lancet. 2007;370:949-956.

19. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Re-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-1151.

20. Hughes S. RECORD 1, 2 and 3 rivaroxaban trials published. Heartwire July 1, 2008. Available at: http://www.theheart.org/article/878097.do. Accessed November 24, 2008.

21. Fragmin [package insert]. Woodcliff Lake, NJ: Eisai; 2010.

22. Lovenox [package insert]. Greenville, NC: Sanofi-Aventis; 2009.

23. Innohep [package insert] Parsippany, NJ: LEO Pharmaceuticals Products; 2010.

24. Arixtra [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2010.

PRACTICE RECOMMENDATIONS

• Start patients with a new-onset venous thrombosis on a low-molecular-weight heparin (LMWH), unfractionated heparin (UFH), or fondaparinux as well as warfarin therapy. A

• Continue LMWH,UFH, or fondaparinux with warfarin for a minimum of 5 days until the international normalized ratio (INR) is ≥2 for 24 hours. A

• Educate patients about anticoagulant therapy, dietary and medication interactions with warfarin, and signs and symptoms of bleeding. A

Strength of recommendation (SOR)

A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series

Arterial and venous thromboses are major causes of morbidity and mortality in the United States. Each year, about 100 out of 100,000 Americans (0.1%) experience a venous thromboembolism (VTE), and the incidence is considerably higher among hospitalized patients.¹ Incidence and early mortality after a first-time event increase with age. Mortality and the potential for a pulmonary embolism (PE) to occur after a deep vein thrombosis (DVT) depend on the location of the DVT and how well the DVT is managed. Proximal DVTs are more likely to develop into a PE. Mortality rates for patients with PE are as high as 17% 3 months after diagnosis.²

Anticoagulant therapy is the foundation for prevention and treatment of thromboembolic disease, and family physicians are on the front line of management when patients with DVT are discharged from the hospital. There are many therapeutic options to choose from: unfractionated heparin (UFH), low-molecular-weight heparins (LMWHs), the factor Xa inhibitor fondaparinux, direct thrombin inhibitors, or vitamin K antagonists (VKAs). All of these agents are effective, but you’ll need to keep clinical considerations and drug limitations in mind to use them properly.

The salient details for optimal use of these agents are set out in the 8th edition of the American College of Chest Physicians (ACCP) Evidence-based Clinical Practice Guidelines, released in 2008.³ But following these complex guidelines to maximize patient safety and minimize both cost and inconvenience raises many questions for the busy family physician. This article provides the answers you need to maximize your care.

1. What therapies can be used in the outpatient setting to treat acute DVT or PE?

FAST TRACK

LMWH and fondaparinux are not approved by the US Food and Drug Administration for the outpatient treatment of PE.

You can manage DVT with LMWH—dalteparin (Fragmin), enoxaparin (Lovenox), or tinzaparin (Innohep)—or the factor Xa inhibitor fondaparinux (Arixtra) overlapped with warfarin (Coumadin). UFH is generally not recommended in the outpatient setting. Patients who are obese or have a creatinine clearance <30 mL/min will need inpatient treatment with UFH in most cases.

Outpatient management of PE based on clinical prediction rules that stratify patients by risk factors has been attempted, although the safety and efficacy of this practice have not been conclusively demonstrated. Prediction rules are available at http://www.medicalcriteria.com/criteria/car_thrombosis.htm. Note that LMWH and fondaparinux are not approved by the US Food and Drug Administration (FDA) for the outpatient treatment of PE.

Dosing guidelines for LMWH agents and fondaparinux are given in TABLE 1, and recommendations for treatment of DVT are summarized in TABLE 2.

TABLE 1
Low-molecular-weight heparins and fondaparinux dosing for DVT

Agent	Dose
Dalteparin (Fragmin)²¹	100 units/kg SQ every 12 h or 200 units/kg SQ every 24 h
Enoxaparin (Lovenox)²²	1 mg/kg SQ every 12 h or 1.5 mg/kg every 24 h
Tinzaparin (Innohep)²³	175 anti-Xa IU/kg SQ every 24 h
Fondaparinux (Arixtra)²⁴	Weight <50 kg: 5 mg SQ every 24 h Weight 50-100 kg: 7.5 mg SQ every 24 h Weight >100 kg: 10 mg SQ every 24 h
DVT, deep vein thrombosis; SQ, subcutaneously.

TABLE 2
Treating DVT: Recommended options^3,4,21-24

Warfarin	UFH	LMWH
Starting dose 5-10 mg/d for first 1-2 days. Lower starting dose for patients with liver impairment, malnourishment, heart failure, or recent major surgery; for debilitated and elderly patients; and for patients on medications known to inhibit CYP-450 enzyme. Initial monitoring after the first 2-3 doses. Maintenance monitoring at least every 4 weeks. For acute DVT, overlap with LMWH, UFH, or fondaparinux for at least 5 days and until INR is ≥2 for 24 hours. Continue therapy for ≥3 months for patients with upper extremity DVT.	UFH is recommended for patients who are obese or have a creatinine clearance <30 mL/min; UFH is generally an inpatient treatment option, and patients may need to be admitted for therapy.	For acute DVT, LMWH daily or twice daily is recommended over UFH. Exceptions include patients who are obese or have a creatinine clearance <30 mL/min. Anti-factor Xa levels should be monitored in pregnant patients on therapeutic doses of LMWH.
DVT, deep vein thrombosis; INR, international normalized ratio; LMWH, low-molecular-weight heparin; UFH, unfractionated heparin.