Use of Low-Molecular-Weight Heparin in the Treatment of Venous Thromboembolic Disease: Answers to Frequently Asked Questions

Transcription

1 Concise Review for Primary-Care Physicians Use of Low-Molecular-Weight Heparin in the Treatment of Venous Thromboembolic Disease: Answers to Frequently Asked Questions SCOTT C. LITIN, M.D., JOHN A. HEIT, M.D., AND KARLA A. MEES, R.N., FOR THE THROMBOPHILIA CENTER INVESTIGATORS* Low-molecular-weight heparins (LMWHs) represent an important therapeutic advance in the treatment of patients with venous thromboembolism. The use of LMWH has potential advantages in comparison with the use of standard unfractionated heparin (UH), including decreased binding to nonanticoagulant-related plasma proteins, greater bioavailability, longer half-life, and lower incidence of the heparin-induced thrombocytopenia syndrome. Because of the predictable anticoagulant response of LMWH when administered subcutaneously, laboratory monitoring is unnecessary, and the drug can be used to treat selected patients with venous thromboembolism in the outpatient setting. Numerous studies have shown that the treatment of venous thromboembolism with LMWH is as safe and effective as that with standard UH when both are used appropriately. Allied health personnel can easily teach most patients to self-administer LMWH subcutaneously for home use. Transition of the treatment regimen to oral warfarin anticoagulation necessitates an overlap with heparin (UH or LMWH) for at least 4 to 5 days, and the international normalized ratio should ideally be 2.0 or higher for 2 consecutive days before heparin therapy is discontinued. A practical understanding of the pharmacology, risks, and benefits of LMWH in the treatment of venous thromboembolism will enhance the primary-care physician's ability to care for patients safely and costeffectively. Mayo Clin Proc 1998;73: aptt = activated partial thromboplastin time; DVT = deep venous thrombosis; FDA = Food and Drug Administration; INR = international normalized ratio; LMWHs = low-molecular-weight heparins; UH = unfractionated heparin; VTE = venous thromboembolism; Xa = activated factor X Venous thromboembolism (VTE) is commonly diagnosed and managed by primary-care physicians. Standard treatment of patients has consisted of hospitalization and constant infusion of unfractionated heparin (UH), with frequent adjustments to maintain a therapeutic activated partial thromboplastin time (aptt) while the regimen is converted to oral anticoagulant therapy with warfarin. The development of low-molecular-weight heparins (LMWHs) has been an important new refinement in the treatment of patients with VTE. When administered subcutaneously, these heparins have properties that allow a predictable anticoagulant response without laboratory monitoring; thus, selected patients can be treated for VTE as outpatients. Although LMWHs are not yet approved by the Food and Drug Administration (FDA) for this indication, several studies have shown that LMWHs are at least From the Division of Area General Internal Medicine (S.C.L.), Division of Hematology and Internal Medicine (J.A.H.), and Thrombophilia Center (S.C.L., J.A.H., K.A.M.), Mayo Clinic Rochester, Rochester, Minnesota. *The members of the Thrombophilia Center are listed in the Appendix. Address reprint requests to Dr. S. C. Litin, Division of Area General Internal Medicine, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN as safe and effective as UH in the treatment of VTE. Many clinicians have questions about LMWHs, including how to use these drugs and when to consider their use in patients with VTE. The purpose of this article is to answer these commonly asked questions. FREQUENTLY ASKED QUESTIONS ABOUT LMWHs 1. How Does LMWH Differ From UH in Structure and Mechanism of Action? UH is a heterogeneous mixture of polysaccharide chains ranging in molecular weight from about 3,000 to 30,000 d (mean, 15,000). LMWHs are fragments of standard UH created by enzymatic or chemical depolymerization. The mean molecular weight of LMWH is about 5,000 d. 1 Recall that the ultimate purpose of the coagulation cascade is to generate thrombin (factor Ha), which subsequently acts on fibrinogen to generate a fibrin clot. The thrombin is generated from prothrombin by the action of activated factor X (Xa). Both UH and LMWH exert anticoagulation activity by activating antithrombin (previously known as antithrombin III). Once heparins interact with antithrombin, the antithrombin has substantially accelerated activity in inactivating the coagulation enzymes thrombin (factor Ha) and factor Xa. Mayo Clin Proc 1998;73: Mayo Foundation for Medical Education and Research

2 546 Low-Molecular-Weight Heparin The major difference in the mechanism of action between UH and LMWH is in their relative inhibitory activity against factor Xa and thrombin. Any size heparin chain can inhibit the action of factor Xa by simply binding to antithrombin and causing a conformational change. In contrast, in order to inactivate thrombin, the heparin molecule must be long enough to bind both antithrombin and thrombin, an outcome that forms a ternary complex. Although most of the chains of UH are long enough to form this ternary complex, fewer than half the chains of LMWH are of sufficient length. Therefore, unlike UH, which has equivalent activity against factor Xa and thrombin, LMWHs have greater activity against factor Xa.2 2. What Are the Potential Advantages of LMWH in Comparison With Standard UH for Anticoagulation? LMWH has several practical advantages in comparison with UH. The pharmacokinetics of UH are influenced by its binding to plasma proteins, endothelial cell surfaces, macrophages, and other acute phase reactants. This property contributes to "heparin resistance," which may occur shortly after initiation of anticoagulant therapy during the acute thromboembolic state when acute phase reactant proteins are increased. In contrast, LMWH has decreased binding to nonanticoagulant-related plasma proteins. Therefore, the LMWH anticoagulant response is unaffected by individual variation in acute phase reactant plasma protein levels.1 3 When the dosage of LMWH is given on a weight-adjusted basis, the LMWH anticoagulant response is predictable and reproducible. Thus, laboratory monitoring is unnecessary. In addition, in comparison with UH, LMWH has a substantially higher bioavailability after subcutaneous injection (90% versus 30%) and a longer plasma half-life (4 to 6 hours versus 0.5 to 1 hour). Therefore, it has ideal properties for subcutaneous administration twice daily. Because LMWHs have reduced binding to macrophages, they are not cleared by the liver to the same extent as UH. They are cleared by the kidney (slower than hepatic clearance), an outcome that accounts for the longer plasma half-life. LMWHs interact less with platelets than does UH and therefore cause less inhibition of platelet function. Because of this and other factors, LMWH theoretically has a slight advantage in regard to bleeding risks, although this advantage has not been shown to be substantial in many clinical studies. UH does have pronounced interactions with platelets, including an affinity to bind with platelet factor 4. Investigators have suggested that the platelet-activating antibodies that are responsible for the development of heparininduced thrombocytopenia are specific not for heparin but Mayo Clin Proc, June 1998, Vol 73 for heparin-platelet factor 4 complexes. Because LMWH has much less propensity to react with platelet factor 4, it would be less likely to cause antibody-associated thrombocytopenia.2 This proposed advantage was proved by Warkentin and associates,4 who reported a randomized, doubleblind clinical trial of 665 patients receiving UH or LMWH as prophylaxis after a hip operation. Heparin-induced thrombocytopenia (defined as a decrease in platelet count to less than 150 x 109/L beginning 5 days or more postoperatively and a positive test result for heparin-dependent IgG antibodies) occurred in 9 of 332 patients who received UH and in 0 of 333 patients who received LMWH (2.7% versus 0%; P = ). Of importance, eight of the nine patients with heparin-induced thrombocytopenia also experienced one or more thrombotic events. In a subgroup of 387 patients tested for heparin-dependent IgG antibodies (regardless of platelet count), 7.8% of those treated with UH had development of heparin-dependent antibodies in comparison with only 2.2% who received LMWH (P = 0.02).4 Thus, the use of LMWH is associated with a lower incidence of both thrombocytopenia and thrombosis. 3. How Can the Anticoagulant Effect of LMWH Be Monitored? When patients receive anticoagulant therapy with UH, the aptt test can be used to monitor their response. When LMWH is used, the aptt test is less useful because it reflects anti-iia activity, which is typically low during LMWH use. Administration of LMWH will prolong the aptt test result but not to the extent that it can be monitored for therapeutic efficacy.5 The anticoagulant response to LMWH is more predictable than that to UH because of better bioavailability and decreased affinity in binding to plasma proteins or macrophages. Because of the predictable anticoagulant response, laboratory monitoring is unnecessary in a vast majority of patents. Some consultants, however, recommend laboratory monitoring of LMWH in specific patients,3 including those with renal insufficiency (creatinine, greater than 2.0 mg/dl) because the drug is excreted through the kidney and could accumulate in such patients. Other situations include obese patients in whom the pharmacokinetics of drug distribution might be in question and perhaps patients who have other major bleeding risk factors. The plasma anti-factor Xa assay, which measures inhibition of Xa activity, would be the most appropriate test if one wanted to assess whether LMWH administration was in the therapeutic anticoagulant range. The therapeutic range will vary depending on heparin type. In most of the studies on acute deep venous thrombosis (DVT) in which

3 Mayo Clin Proc, June 1998, Vol 73 Low-Molecular-Weight Heparin 547 LMWH was used, routine monitoring was not performed, and bleeding complications were not increased over those associated with UH; however, patients at highest risk were excluded from these studies. In summary, because of the predictable anticoagulant response of LMWH, laboratory monitoring is rarely necessary. In special instances, the plasma anti-factor Xa activity could be monitored. 5 Currently, however, this test is not widely available, and clinical experience with its use is limited. 4. Is LMWH Safe and Effective for Patients With VTE? Numerous published studies have shown that the treatment of VTE with LMWH is as safe and effective as that with standard UH when both are used in appropriate dosages. 611 Several large randomized trials have shown that LMWH can be safely administered subcutaneously to outpatients in comparison with UH administration to hospitalized patients with proximal DVT. In one such study by Levine and colleagues, 7 eligible patients with proximal DVT were randomized to receive standard UH while in the hospital or the LMWH enoxaparin sodium, 1 mg/kg administered subcutaneously twice daily primarily in the home setting. Results at 90-day follow-up revealed that 13 of 247 patients with LMWH (5.3%) had development of recurrent thromboembolism in comparison with 17 of 253 patients (6.7%) who received UH. Major bleeding occurred in five patients who received LMWH in comparison with three who were treated with UH. After randomization, the patients treated with LMWH stayed in the hospital a mean of 1.1 days in comparison with 6.5 days for the patients who received UH. Thus, LMWH has a decided advantage relative to patient convenience and costs of medical care. Other studies have confirmed these findings for DVT, and recent studies have verified the efficacy and safety of LMWH in treating patients with submassive pulmonary emboli (who have adequate cardiopulmonary reserve) primarily at home; a major advantage was noted in the cost of care as well as patient satisfaction. Even when patients must receive anticoagulant therapy with heparin while in the hospital, LMWH can have a cost advantage because of efficacy, ease of administration, and ability to be administered without frequent laboratory monitoring. 5. Should All Patients With VTE Now Be Treated With LMWH in the Outpatient Setting? A review of the studies comparing LMWH to UH in the treatment of patients with VTE revealed that approximately 50% were not eligible because of factors that were believed to preclude outpatient therapy (for example, major bleeding risks, compliance problems, inaccessibility for follow-up, and renal failure). Thus, not all patients with VTE should be treated with LMWH in the outpatient setting. With increased experience in the use of LMWH, however, the number of absolute contraindications for outpatient therapy is decreasing. In patients with comorbid conditions who might need initial inpatient management, the duration of their hospitalization may be decreased considerably by a change to outpatient LMWH therapy while they wait for oral anticoagulation to be adjusted into the therapeutic range. 6. Because LMWH Has Not Been Approved by the FDA for the Treatment of VTE, Is Its Use Associated With Medicolegal Risks? FDA approval is not necessary for the "off-label" use of a drug as long as appropriate literature supports its use and especially if the scientific community agrees on the appropriateness of the use of the drug for the off-label indication. Both these factors are true for the use of LMWH as outpatient therapy for acute VTE. As with any treatment, patients must be informed of the risks and alternatives, and their consent must be documented. An additional support is endorsement by the hospital practice committee for the use of LMWH for this purpose. Finally, although physicians should not be at risk if LMWH is used appropriately in the treatment of VTE, malpractice is a possible risk if the drug is used inappropriately. 7. What LMWH Preparations Are Currently Available in the United States, and What Are the Dosage Regimens for Anticoagulant Treatment of DVT? Three LMWH preparations are currently being marketed in the United States for VTE prophylaxis. The dosages differ substantially for prophylaxis versus DVT treatment. DVT prophylaxis after total knee or total hip replacement is as follows: ardeparin, 50 U/kg administered subcutaneously every 12 hours; dalteparin, 2,500 U administered subcutaneously every 12 hours; or enoxaparin, 30 mg administered subcutaneously every 12 hours. The treatment of DVT is as follows: ardeparin, 130 U/kg administered subcutaneously every 12 hours; dalteparin, 100 U/kg administered subcutaneously every 12 hours; or enoxaparin, 1 mg/kg administered subcutaneously every 12 hours. 8. Is One LMWH "Better" Than the Others? Several LMWH preparations are available in the United States, Canada, and Europe. Their molecular weights differ as do their anti-xa/anti-iia potency ratios (Table l). 1 Dosing regimens also differ for various conditions. Unfor-

4 548 Low-Molecular-Weight Heparin Mayo Clin Proe, June 1998, Vol 73 Table 1. Comparison of Low-Molecular-Weight Heparins in the Treatment of Venous Thromboembolism* Agent Enoxaparin Dalteparin Ardeparin Trade name Lovenox Fragmin Normiflo Xa:IIa 2.7:1 2.0:1 2.0:1 Mean molecular weight (d) 4,500 5,000 6,000 *b.i.d. = twice daily; Xa = activated factor X. tadministered subcutaneously. Doset 100 U/kg b.i.d. 100 U/kg b.i.d. 130 U/kg b.i.d. tunately, no clinical trials have compared one LMWH drug to another in DVT treatment, and no such trials are likely in the foreseeable future. In the absence of such data, determining whether one LMWH drug is superior to another is impossible. Additional well-designed large clinical studies must be performed to establish the safety and efficacy of each LMWH preparation versus UH and warfarin for prophylaxis and treatment in various scenarios. The Mayo Clinic Thrombophilia Center is maintaining a detailed registry of all patients treated with LMWH for DVT in an attempt to obtain outcome measures and comparative data on the preparations used. Our assumption has been that, if the drug-specific dose and dosing schedules are correct, LMWH drugs have similar efficacy and safety for outpatient treatment of VTE. On the basis of this assumption, the Mayo Clinic formulary uses the competitive bidding process to determine which LMWH drug will be placed in the formulary. 9. Is the Cost of Outpatient LMWH Treatment Covered by Insurance Carriers? Currently, most major insurance carriers (including Medicare) will not cover the cost of outpatient self-administered injectable medication other than insulin. We have successfully lobbied our part B Medicare carrier to cover the cost of outpatient LMWH prescribed through a healthcare provider. Most major insurance carriers will cover outpatient LMWH prescribed in this manner as well. With this approach, however, patients must have access to a service that can accommodate twice-daily dosing schedules 7 days a week (usually an outpatient hospital or emergency department setup). This arrangement can be inconvenient for the patient because of the need to return twice daily for at least 5 days to receive injections. Many insurance carriers and especially managed-care organizations will cover the cost of the use of LMWH at home (as they begin to realize that this is a cost-effective approach). Of note, if the physician or the patient does not know whether the insurance company covers outpatient LMWH therapy, telephone the company. Depending on the LMWH selected and its dose, treatment can cost more than $80 per day. 10. What Details Are Involved in Teaching Patients to Self-Administer LMWH Subcutaneously? Several issues must be addressed with the patient, including education about the drug, injection technique, and follow-up care (for example, monitoring the international normalized ratio [INR]). At the Mayo Clinic Thrombophilia Center, we calculate the appropriate dose for the patient and have our pharmacy express the correct drug volume into a group of syringes for the patient to use on a twice-daily dosing regimen. The patient is taught to attach the cover-protected needle to the syringe before use. We tell our patients not to worry if a small air bubble is in the syringe because it is not a safety issue when the drug is administered subcutaneously. Furthermore, by trying to "push" the bubble out of the syringe, patients may "squirt out" some of the drug. Theoretically, if some of the drug is on the needle at the time of administration, the risk of subcutaneous hematoma formation may be increased. A nurse at our thrombophilia center is experienced in educating patients about anticoagulant therapy and the technique of subcutaneous injection. We have been able to manage a large number of outpatients successfully. Patients are taught to select a site, usually in the anterior aspect of their abdomen. They clean the site appropriately with an alcohol swab and then inject the syringe at a 90 angle into the "pinched" subcutaneous tissue of the lower part of the abdomen (Fig. 1). After the drug has been delivered, the syringe is appropriately discarded. Patients practice the technique on a teaching device in the office before they are dismissed. We ensure that appropriate follow-up has been arranged with their primary-care physician or with us to monitor for any complications and to determine their INR values. 11. What Is Involved in the Transition from LMWH to Oral Anticoagulation? No matter which type of heparin is used (UH or LMWH) in the treatment of VTE, heparin anticoagulation should overlap with warfarin for a minimum of 4 to 5 days. Recall that the early prolongation of the INR after warfarin has been initiated reflects a reduction in factor VII activity. Prevention of thrombus formation or propagation of clot primarily depends on decreasing factor II (prothrombin) and, probably, factor X activities. These factors have plasma half-lives of about 60 hours and 40 hours, respectively. Therefore, the INR could be increased early while the patient still has a risk of clotting. Consequently, a minimum of 4 to 5 days of overlapping heparin therapy with warfarin anticoagulation is needed to lower all these

5 Mayo Clin Proc, June 1998, Vol 73 Low-Molecular-Weight Heparin 549 factors into the therapeutic range In addition to 4 to 5 days of overlapping heparin therapy, the INR should ideally be 2.0 or higher for 2 consecutive days before heparin use is discontinued. Warfarin can be instituted on the same day that heparin is initiated; however, because the natural anticoagulant protein C has a short plasma half-life (6 hours), theoretically, a "hypercoaguable state" could be induced shortly after the first dose of warfarin is administered if the patient has not received adequate anticoagulant therapy with heparin. Therefore, heparin should initially be administered before warfarin, or, theoretically, clot propagation is a risk in patients with VTE. In patients receiving warfarin for stroke prevention in atrial fibrillation, numerous studies have shown that initiation of warfarin in the outpatient setting without concurrent heparin coverage is safe. A recent report suggests that initiation of warfarin at the estimated daily maintenance dose (5 mg) is associated with less frequent "overshoot" of the target INR (2.0 to 3.0) and produces less of an early decrease in protein C in comparison with a larger initial dose (for example, 10 mg). 14 Although this initial warfarin dosing schedule is appealing, clinical experience suggests that a substantial proportion of patients may require a longer time to achieve a therapeutic INR. In patients receiving outpatient LMWH therapy, this is not as important. Although doses of warfarin to attain a therapeutic INR (2.0 to 3.0) vary substantially among patients, lessons from the SPAF (Stroke Prevention in Atrial Fibrillation) database can sometimes prove helpful in selecting a "usual" anticoagulant dose (Kopecky SL. Personal communication). On average, patients younger than 60 years old required 6 mg/day of warfarin to maintain an INR between 2.0 and 3.0; for patients 60 to 69 years old, the average dose was 4 mg/day; for patients 70 to 79 years old, the average dose was 3.5 mg/day; and for patients older than 80 years, the average dose was 3.0 mg/day. 12. Is Bed Rest or a Compression Stocking Necessary if the Patient Is Treated For DVT at Home? A review of the studies on outpatient LMWH therapy revealed that patients were treated with comfort measures only and that bed rest was unnecessary. No increased incidence of early thromboemboli was noted in comparison with patients randomized to hospitalization (UH) and bed rest. In general, if patients do not have a massively swollen leg, we allow them to remain completely ambulatory, and many continue their regular work schedule, although we advise against prolonged standing or prolonged sitting with feet in the dependent position. We fit almost all patients with a knee-high compression stocking (30 to 40 mm Hg) for comfort measures and because, on the basis of a welldone randomized trial, appropriately fitted knee-high Fig. 1. Photograph of patient demonstrating correct technique of injection of low-molecular-weight heparin into subcutaneous tissue of anterior abdominal wall. graded compression stockings reduced the occurrence of postthrombotic syndrome in patients with a first episode of proximal DVT What Is the Duration of Oral Anticoagulant Treatment in a Patient With VTE? Traditionally, patients with VTE have received appropriate doses of anticoagulant therapy with warfarin for at least 3 months to prolong the INR to 2.0 to 3.0. Several recent studies have addressed this issue If a patient has reversible risk factors for VTE (operation, trauma, pregnancy, or temporary complete immobilization), 3 months of treatment (or less) seems adequate. If a patient has a first episode of idiopathic DVT and does not have a high risk of bleeding, longer treatment (6 months) is reasonable. Some investigators suggest an even longer duration of treatment based on the study by Prandoni and associates, 17 who showed a 30% incidence of recurrence after treatment for a first episode of DVT in patients monitored for 8 years. Patients with two or more episodes of recurrent VTE (not related to transient clinical risk factors) should receive anticoagulant therapy indefinitely if they do not have an unacceptably high risk of bleeding. 18 Patients with VTE in the setting of metastatic cancer should either receive anticoagulant therapy indefinitely or be treated with an inferior vena caval filter placement (without anticoagulation). 19 Accumulated evidence suggests that symptomatic, isolated deep calf venous thrombosis should be treated with anticoagulation for 3 months Can the Effect of LMWH Anticoagulation Be Reversed? When administered in equimolar concentrations, protamine sulfate neutralizes the anti-iia activity of LMWH

6 550 Mayo Clin Proc, June 1998, Vol 73 Low-Molecular-Weight Heparin but only partially reverses the anti-factor Xa activity. Although protamine sulfate has been shown to block bleeding induced by LMWH in laboratory animals,20 published reports of the use of protamine sulfate to reverse bleeding associated with subcutaneously administered LMWH are not available. The package insert of the manufacturer recommends that a dose of 1 mg of protamine sulfate be administered intravenously for each 100 U of LMWH for reversal of the anticoagulant effect Is LMWH Safe During Pregnancy? No randomized trials have analyzed the use of LMWH in pregnant women; however, retrospective analyses have indicated that LMWHs are well tolerated and effective during pregnancy.21 They do not pass through the placenta during the second and third trimesters, and detection of LMWH in breast milk is not substantial. 16. Other Than Bleeding, What Complications Have Been Associated With LMWH? Mild increases in hepatic enzymes have been observed with both LMWH and UH treatment but without clinical sequelae. Moderate or pronounced increases in hepatic enzymes should trigger a search for other causes.3 As previously stated, heparin-induced thrombocytopenia is rarely associated with LMWHs. Because crossreactivity may occur, however, substitution of LMWH is not recommended when heparin-induced thrombocytopenia occurs with use of UH.2 In patients receiving long-term LMWH therapy, monitoring the complete blood cell count by obtaining a weekly platelet count seems reasonable for surveillance for bleeding or thrombocytopenia. Both LMWH and UH may be accompanied by a slight increase in serum potassium levels due to an interference with aldosterone synthesis. This is usually mild and asymptomatic, but monitoring of electrolytes is suggested in patients whose renin-angiotensin-aldosterone axis is inhibited by medication, age, or disease. CONCLUSION A large body of evidence now shows that LMWH preparations are as effective and safe as UH in the treatment of patients with VTE. Because of the favorable bioavailability characteristics of LMWH, it can be used safely in patients, and no laboratory monitoring is necessary; therefore, it can be used to treat patients with VTE in the outpatient setting. A practical understanding of the pharmacology, risks, and benefits of LMWH used for this purpose will enhance the primary-care physician's ability to care for patients safely and cost-effectively. APPENDIX The following are members of the Thrombophilia Center: Denise M. Dupras, M.D., John A. Heit, M.D., Scott C. Litin, M.D., Robert D. McBane, M.D., George W. Petty, M.D., Rajiv K. Pruthi, M.D., Thorn W. Rooke, M.D., and Karla A. Mees, R.N. REFERENCES Weitz Jl. Low-molecular-weight heparins. N Eng! J Med 1997;337: Rosenberg RD. Biochemistry and pharmacology of low molecular weight heparin. Semin Hematol 1997;34(Suppl 4):2-8 Kessler CM. Low molecular weight heparins: practical considerations. Semin Hematol 1997;34(Suppl 4):35-42 Warkentin TE, Levlne MN, Hirsh J, Horsewood P, Roberts RS, Gent M, et al. Heparin-induced thrombocytopenia in patients treated with lowmolecular-weight heparin or unfractionated heparin. N Engl J Med 1995;332: Kessler CM, Esparraguera IM, Jacobs HM, Druy E, Fortune WP, Holloway DS, et al. Monitoring the anticoagulant effects of a low molecular weight heparin preparation: correlation of assays in orthopedic surgery patients receiving ardeparin sodium for prophylaxis of deep venous thrombosis. Am J Clin Pathol 1995;103: Lenslng AW, Prlns MH, Davidson BL, Hirsh J. Treatment of deep venous thrombosis with low-molecular-weight heparins: a meta-analysis. Arch Intern Med 1995;155: Levlne M, Gent M, Hirsh J, Leclerc J, Anderson D, Weitz 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 EnglJ Med 1996;334: Koopman MMW, Prandonl P, Piovella F, Ockelford PA, Brandjes DPM, van der Meer J, 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: Hirsh J. Comparison of the relative efficacy and safety of low molecular weight heparin and unfractionated heparin for the treatment of deep venous thrombosis. Semin Hematol 1997;34(Suppl 4):20-25 Columbus Investigators. Low-molecular-weight heparin in the treatment of patients with venous thromboembolism. N Engl J Med 1997;337: Slmonneau G, Sors H, Charbonnier B, Page Y, Laaban JP, Azarlan R, et al (THÉSÉE Study Group). A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism. N EnglJ Med 1997;337: Lltln SC, Gastineau DA. Current concepts in anticoagulant therapy. Mayo Clin Proc 1995;70: Ginsberg JS. Management of venous thromboembolism. N EnglJ Med 1996;335: Harrison L, Johnston M, Masslcotte MP, Crowther M, Moffat K, Hirsh J. Comparison of 5-mg and 10-mg loading doses in initiation of warfarin therapy. Ann Intern Med 1997;126: Brandjes DP, Buller HR, Heijboer H, Huisman MV, de Rijk M, Jagt H, et al. Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet 1997;349: Schulman S, Rhedin A-S, Lindmarker P, Carlsson A, Lärfars G, Nicol P, et al. A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. N Engl J Med 1995;332: Prandonl P, Lenslng AW, Cogo A, Cuppini S, Villalta S, Carta M, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med 1996;125:1-7 Schulman S, Granqvist S, Holmström M, Carlsson A, Lindmarker P, Nlcol P, et al. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. N Engl J Med 1997;336: Cohen JR, Grella L, Citron M. Greenfield filter instead of heparin as primary treatment for deep venous thrombosis or pulmonary embolism in patients with cancer. Cancer 1992;70: Van Ryn-McKenna J, Cai L, Ofosu FA, Hirsh J, Buchanan MR. Neutralization of enoxaparine-induced bleeding by protamine sulfate. Thromb Haemost 1990;63: Gillis S, Shushan A, Eldor A. Use of low molecular weight heparin for prophylaxis and treatment of thromboembolism in pregnancy. Int J Gynaecol Obstet 1992;39:

7 Mayo CHn Proc, June 1998, Vol 73 Low-Molecular-Weight Heparin 551 Questions About Use of Low-Molecular-Weight Heparin (See article, pages 545 to 550) 1. Which one. of the following is not a practical advantage of low-molecular-weight heparin (LMWH) in comparison with standard unfractionated heparin (UH)? a. Greater bioavailability b. Laboratory monitoring is usually unnecessary c. Lower incidence of heparin-induced thrombocytopenia d. Increased binding to nonanticoagulant-related proteins e. A longer circulating half-life 2. Which one of the following statements regarding the use of LMWH in patients with venous thromboembolism (VTE) is not correct! a. In selected cases, patients may be treated entirely as outpatients without the need for hospitalization b. Many clinical studies have shown substantially decreased bleeding complication rates when LMWH was used in comparison with UH c. Studies have shown that selected patients with submassive pulmonary emboli have been treated safely and effectively with LMWH d. Not all patients with VTE are candidates for outpatient therapy with LMWH e. LMWH has been shown to be as effective as standard UH when both are used in appropriate dosages 3. Which one of the following statements is true regarding teaching patients to self-administer LMWH subcutaneously for the treatment of VTE? a. The therapeutic LMWH dose is the same for all patients regardless of weight b. The appropriate dose of LMWH comes prepackaged from the manufacturer in a needle-attached syringe c. Removal of any air bubbles from the syringe before subcutaneous administration is important d. Because complications are rare, follow-up appointments are not important e. The patient is instructed to inject the syringe at a 90 angle into a "pinched" area of subcutaneous fatty tissue 4. Which one of the following is not true in the transition of the treatment regimen from LMWH to oral anticoagulation? a. Heparin should overlap with warfarin for a minimum of 4 to 5 days b. Warfarin may be instituted on the same day that heparin is initiated c. Investigators have shown that institution of warfarin at 10 mg daily in all patients is associated with less frequent "overshoot" of the target international normalized ratio (INR) d. The INR should ideally be 2.0 or greater for 2 consecutive days before heparin therapy is discontinued e. Frequent INR determinations are necessary during the first 2 weeks of initiation of warfarin anticoagulation 5. Which one of the following is not a complication associated with LMWH or UH therapy? a. Diarrhea b. Bleeding c. Osteoporosis d. Hyperkalemia e. Increased hepatic enzymes Correct answers: \.d, 2.b, 3.e, A. c, 5. a