Outpatient Treatment of Deep Vein Thrombosis
Authors: Gregory R. Wise, MD, FACP, Associate Professor of Medicine, Wright State University, Dayton, Ohio; and Suneil Kapur, MD, Resident, Kettering Medical Center, Kettering, Ohio.
Peer Reviewers: David W. Hawkins, MD, Professor and Chair of Pharmacy Practice, Mercer University, Atlanta, Ga; John A. Heit, MD, Associate Professor of Medicine, Director, Thrombophilia Center, Mayo Clinic and Foundation, Rochester, Minn; Thomas Hyers, MD, Clinical Professor of Medicine, St. Louis University School of Medicine, St. Louis, Mo; and Andrea R. Redman, PharmD, Clinical Assistant Professor, Mercer University, Clinical Pharmacist, Ambulatory Care, Atlanta VA Medical Center.
Editor’s Note—Since the introduction of low-molecular-weight heparins (LMWHs) to the U.S. market in 1993, their indications have continued to expand. Of most significance to primary care physicians is the recent Food and Drug Administration (FDA) approval of enoxaparin for the outpatient treatment of deep vein thrombosis (DVT). With the ever-increasing emphasis on cost-effective health care, primary care physicians need to be conversant with the role of LMWHs in shortening or even eliminating hospitalization for patients with uncomplicated DVT. This issue outlines the rationale and indications for outpatient therapy and provides an example of a clinical care pathway for ease of establishing treatment guidelines at local hospitals.
Introduction
Despite the recognition of risk factors and the availability of effective means for prophylaxis, DVT and pulmonary embolism (PE) remain common causes of morbidity and mortality. It is estimated that approximately 600,000 patients per year are hospitalized for DVT in North America.1 In the United States, symptomatic pulmonary embolism occurs in more than 600,000 patients and causes or contributes to death in up to 200,000 patients annually.2
PE is the most common cause of death in patients following total hip replacement, which is one of the top 10 diagnostic-related groups (DRGs) for almost every hospital in this country. PE has been touted as the most common cause of preventable hospital mortality. The postphlebitic syndrome with persistent leg pain, swelling, and ulcerations affects 15 million Americans and may be prevented if thrombosis prophylaxis were routinely used and DVT treated effectively.3 A recently published cohort analysis indicates that the mortality associated with venous thromboembolism (VTE) may be higher than previously thought.4
Traditional Approach to VTE Treatment
Since the clinical introduction of warfarin in the 1950s, the management of VTE in the United States has changed little. Patients with proximal and symptomatic distal DVT are customarily hospitalized and placed at bed rest. They are given a bolus of intravenous (IV) unfractionated heparin (UFH) with subsequent continuous IV infusion of UFH for 5-6 days until therapeutic anticoagulation with warfarin is achieved, which is defined as an International Normalized Ratio (INR) of 2.0-3.0. The heparin dose is adjusted to achieve an activated partial thromboplastin time (APTT) ratio of 1.5-2.5, which commonly correlates with a therapeutic heparin level of 0.2-0.4 IU/mL by protamine titration or an anti-Xa level of 0.3-0.6 IU/mL by a chromogenic assay.5 The concept of dosing UFH by body weight was introduced by Raschke et al in 1993. This approach resulted in a more rapid achievement of a therapeutic APTT.6
Although the complication rate during the hospitalization period for most patients is extremely low, only recently has the possibility of treating DVT on an outpatient or short-stay basis been explored. The need to give UFH by constant IV infusion guided by frequent APTT measurements precluded outpatient therapy or early discharge.
The opportunity to initiate outpatient or short-stay programs for DVT treatment has been made possible by the introduction of LMWHs. These LMWHs have significant pharmocokinetic advantages over UFH due to their differences in size and structure.
Structure of Heparins
LMWH and UFH are glycosaminoglycans made of chains of alternating residues of D-glucosamine and a uronic acid, which may be either glucoronic or iduronic acid.7 Heparins are commercially prepared most commonly from porcine intestinal mucosa. UFHs are treated by chemical or enzymatic depolymerization to form LMWHs. The mean molecular weight distribution of LMWH is 4000-6000 Daltons compared to about 12,000 Daltons for UFH.8 The majority of UFH molecules are greater than 18 saccharide units long; however, this is true in less than half of LMWH molecules. These differences in size and structure account for the distinct pharmacological actions of LMWHs.
Mechanism of Action
Heparins exhibit most of their antithrombotic effects by inactivating two important factors in the coagulation cascade: factor Xa and factor IIa (thrombin). Heparin acts as a template to which both antithrombin III and coagulation enzymes bind. The main difference between UFH and LMWH is that LMWH has greater activity against factor Xa than factor IIa (4:1 to 2:1), whereas UFH has similar effects against both. Approximately one-third of UFH and LMWH molecules have a unique pentasaccharide enabling them to bind to antithrombin III and subsequently inhibit factors IIa and Xa. However, only those heparin molecules with at least 18 saccharide units are capable of forming a ternary complex with antithrombin III and factor IIa.7 Since only about a third of LMWH molecules are large enough to form this ternary structure, they have less effect on factor IIa but retain their antifactor Xa activity.9 In addition, both UFH and LMWH stimulate the release of tissue factor pathway inhibitor (TFPI) from the endothelium. TFPI complexes with and inactivates factor Xa and factor VIIa and works independently of pentasaccharide binding. Yet another mechanism of action is that heparin inactivates factor IIa by heparin cofactor II.
Pharmacokinetics
The substantial pharmacokinetic advantage of LMWHs is their increased bioavailability resulting from their decreased affinity for circulating plasma proteins. UFHs bind readily to histidine-rich glycoprotein, polymeric vitronectin, platelet factor IV, multimers of von Willebrand factor, fibronectin, macrophages, and endothelial cells.10 In addition, UFHs exhibit unpredictable anticoagulant activity due to the wide inter-patient variability in plasma concentrations of these heparin-binding proteins. Some of these proteins are acute phase reactants while others are released during the clotting process. To compensate for this binding, higher doses of UFH are required. Frequent laboratory monitoring is also required for UFHs; however, lab monitoring is usually not required for LMWHs due to their superior bioavailability, more predictable dose response effect, and minimal effect on IIa. Exceptions would include patients with renal insufficiency (since both UFHs and LMWHs are eliminated renally) and patients who are markedly obese or underweight. Because LMWHs do not prolong the APTT, monitoring of the anticoagulant response in these patients can be achieved by following anti-Xa levels.
Variation in plasma protein concentrations results in unpredictable renal and hepatic clearance. Because LMWHs bind less to macrophages and endothelium, the renal and hepatic clearance is slower and results in a longer plasma half-life. The improved bioavailability and longer half-life of LMWHs allow them to be dosed conveniently once or twice daily. (See Table 1.)
| Table 1. Advantages of LMWH over UFH |
| • Less binding to heparin-binding proteins, endothelial cells, and matrix proteins |
| • More predictable antithrombotic dose response |
| • Better bioavailability at lower doses |
| • Less bleeding (possibly) |
| • Lower risk of heparin-induced thrombocytopenia |
| • Longer half-life |
| • No need for APTT monitoring |
| • Less risk of osteoporosis |
Indications for LMWH
LMWHs have been used in Europe and Canada for more than 10 years, during which a great deal of clinical experience has been gained. Enoxaparin was introduced in the United States in 1993. Currently, three LMWHs and one heparinoid are approved by the FDA in the United States. These agents are widely used in the prophylaxis of DVT, particularly in high-risk abdominal surgery patients and in those patients undergoing total hip and knee replacement. The value of extended DVT prophylaxis is supported by the results of a prospective, randomized, double-blind study demonstrating a 63% risk reduction with enoxaparin for 21 days post-discharge after total hip replacement for DVT prophylaxis compared to placebo.11 There was no significant difference in incidence of adverse events including bleeding. Enoxaparin is the only LMWH approved by the FDA for extended prophylaxis after hospital discharge in patients with total hip replacement. Even though LMWHs are more expensive than UFHs, they are more cost effective for DVT prophylaxis after major orthopedic surgery.12 Non-FDA-approved uses include DVT prophylaxis following hip fracture and multiple trauma.
The Fifth American College of Chest Physicians’ Consensus Conference on Antithrombotic Therapy has published recommendations for DVT prophylaxis and has identified LMWH as an acceptable pharmacological agent for most at-risk patients.13 (See Table 2.) In addition to VTE prophylaxis and treatment, two LMWHs (enoxaparin and dalteparin) are approved by the FDA for the prevention of thrombotic complications in acute non-Q-wave infarction and unstable angina. A recent study in patients with acute ischemic stroke showed a statistically significant improvement in favor of LMWH compared to placebo in terms of mortality and dependency in daily activities. Hemorrhagic complications during 10 days of treatment were similar between the groups.14 The use of LMWH has expanded to other clinical settings including pregnancy, vascular surgery grafts, trauma, and spinal cord injury.
| Table 2. Recommendations for DVT Prophylaxis13 | |
| Medical patients | |
| • General medical patients: | Low-dose unfractionated heparin (LDUH) or LMWH (grade A1*) |
| • Myocardial infarction: | LDUH or full-dose anticoagulation (grade A1); intermittent pneumatic compression (IPC), and elastic stockings (ES) may be useful if anticoagulation contraindicated (grade C1). |
| • Ischemic stroke: | LDUH or LMWH (grade A1) |
| • Long-term central lines: | warfarin 1 mg daily or LMWH (grade A1) |
| Surgery patients | |
| • General surgery patients: | Low risk: early ambulation Moderate risk: LDUH 2 hpreop and q 12 h, ES, IPC, LMWH (grade A1) |
| High risk: LDUH q 8 h or LMWH (grade A1). | |
| High risk prone to hematomas and infection: IPC (grade A1) | |
| Very high risk: LDUH or LMWH combined with IPC (grade B1) | |
| Selected very high risk: warfarin (grade A2)Aspirin not to be used in general surgery patients | |
| • Intracranial neurosurgery: | IPC with or without ES. LDUH or LMWH may be acceptable alternatives (grade A1). |
| • Acute spinal cord injury: | LWMW (grade B1) |
| • Multiple trauma: | LMWH should be started ASAP (grade A1) |
| Orthopedic patients | |
| • Total hip replacement: | LMWH* or warfarin or adjusted dose UFH (grade A1) |
| Adjuvant ES or IPC may provide additional efficacy. | |
| • Total knee replacement: | LMWH, warfarin, or IPC |
| • Hip fracture: | LMWH or warfarin (grade A2) |
| Adjuvant IPC may provide additional benefit | |
| IVC filters indicated only in high-risk patients in whom anticoagulant-based prophylaxis not feasible due to active bleeding | |
| * Grade A recommendations are more strongly supported by the literature than grade B and grade C recommendations. See reference for complete definitions. | |
| Emerging level I data suggest 29-31 day duration of LMWH prophylaxis may provide additional protection (grade A2). | |
Literature Support for LMWH in VTE Treatment
More than 20 published studies have evaluated the safety and efficacy of various LMWHs in the treatment of VTE. Leizorovicz performed a meta-analysis of the literature and found LMWHs to be at least as effective and safe as UFH.15 In a study of 500 patients, Levine et al compared outpatient enoxaparin at 1 mg/kg subcutaneously (SC) bid vs. inpatient UFH administered by IV infusion with APTT monitoring in the treatment of DVT.16 All patients received warfarin. Patients randomized to enoxaparin spent an average of only 1.1 days in the hospital compared to 6.5 days for UFH. One hundred twenty patients receiving enoxaparin were not hospitalized at all. There was no significant difference in major bleeds between the two groups. Similarly, Koopman et al randomized 400 patients to nadroparin (a LMWH not available in the U.S.) vs. UFH.17 Rates of recurrent VTE between the two groups were not significantly different but nearly 40% of the patients assigned to nadroparin did not require hospitalization. Bleeding complications were less frequent in the LMWH-treated patients. In their European multicenter trial, Fiessinger et al showed that 253 patients randomized to dalteparin administered once daily vs. UFH did not have statistical differences in progression of DVTs distal to the inguinal ligament.18 Hull et al compared the LMWH logiparin to intravenous UFH and demonstrated at least equal effectiveness and safety in the treatment of proximal DVT.19 In a review of the literature, Brewer concluded that LMWHs are clearly superior to UFH in the treatment of DVT based on efficacy, safety, convenience, and cost.20
Enoxaparin was found to be as safe and effective as UFH in a study of 900 patients in the treatment of DVT with or without PE.21 These results, combined with the study of Levine et al,16 led the FDA to approve enoxaparin for the inpatient treatment of DVT with or without PE and for outpatient treatment of patients with DVT. Yeager and Matheny have concisely summarized information on various LMWHs that have been successfully used in the treatment of DVT.22 This information is summarized in Table 3. Table 4 lists the results of four studies using various LMWHs.
| Table 3. Comparison of LMWH for DVT Treatment22 | |||||
| Generic Agent | Trade name | Treatment dose | Average MW (Dalton) | Anti Xa/IIa Ratio | Half-life (min) |
| Ardeparin | Normiflo | Not evalulated | 6000 | 2:1 | 200 |
| Dalteparin | Fragmin | 100 u/kg bid | 5000 | 2:1 | 119-139 |
| Danaparoid | Orgaran | 750 u bid | 5500 | 28:1 | 24 hrs |
| Enoxaparin | Lovenox | 100 u/kg bid | 4500 | 4:1 | 129-180 |
| Nadroparin | Fraxiparine | 225 u/kg bid | 4500 | 3.2:1 | 132-162 |
| Reviparin | Clivarine | 100 u/kg bid | 4300 | NA | |
| Tinzaparin | Logiparin, Innohep | 175 u/kg qd | 4900 | 2:1 | 111 |
| Table 4. Results of Randomized Clinical Trials of LMWH vs. UFH for DVT Treatment | |||||
| Study reference | Number of patients | Agents | Recurrence, LMWH/UFH | Bleeding, LMWH/UFH | Mortality, LMWH/UFH |
| Fiessenger18 | 253 | Dalteparin | 3.3/1.5 | 0/1.5 | 0.8/2.9 |
| Levine16 | 500 | Enoxaparin | 5.3/6.7 | 2/1.2 | 4.5/6.7 |
| Koopman17 | 400 | Nadroparin | 6.9/8.6 | 0.5/2.0 | 6.9/8.1 |
| Hull19 | 432 | Tinzaporin | 2.8/6.9 | 0.5/5.0 | 4.7/9.6 |
Outpatient or Short-Stay Treatment of VTE
The first step in treatment is accurate diagnosis. No patient should be subjected to the risk, expense, and inconvenience of anticoagulation therapy without an objective, diagnostic confirmation of VTE. With good technique, duplex ultrasonography is adequate to made the diagnosis of DVT. If the results of duplex ultrasonography are unclear, venography remains the gold standard for diagnosis. For PE, diagnostic tests include ventilation/perfusion scan, pulmonary angiography, spiral computerized tomography, and gadolinium magnetic resonance. D-dimer (a fibrin split product) testing is considered a sensitive but not specific test for the diagnosis of VTE. Therefore, normal plasma levels (< 500 µg/L by enzyme-linked immunosorbent assay) provide excellent negative predictive value in patients suspected of having PE and particularly in those with low clinical suspicion.
Baseline laboratory testing should include a complete blood count including platelet count, APTT, and PT/INR. The physician should evaluate the patient’s candidacy for thrombolytic therapy, especially in younger patients with acute symptomatic iliofemoral thrombosis. Patients should be considered for a work-up for a hypercoagulable state (e.g., protein C, protein S, anti-thrombin III deficiency, factor V Leiden, antiphospholipid antibodies). Patients who might benefit from a hypercoagulability work-up include those with family history of VTE, development of DVT in the upper extremities, or DVT occurring without obvious provoking factors such as immobility, trauma, or surgery. Treatment with heparin and/or warfarin may make the work-up difficult due to these agents’ interference with test results. For example, warfarin lowers protein C and S levels. Similarly, an acute VTE with comorbid conditions may falsely alter the levels due to the increase in acute phase reactants that accompany stress. Because the cost of testing for hypercoagulable states can be substantial and the results do not normally affect the acute treatment decision, it is suggested that the hypercoagulable work-up be done 2-3 weeks after the cessation of therapy. Consultation with the laboratory director or hematologist may be helpful in determining the scope and timing of any anticipated work-up.
Because cancer is a common cause of the hypercoagulable state, patients presenting with unprovoked VTE should be considered for a work-up for occult malignancy. At the very least, these patients should have a thorough history and physical examination and subsequent clinically appropriate cancer screening such as mammography and fecal occult blood testing.
Estrogen replacement therapy or oral contraceptives must be discontinued as they are absolutely contraindicated during the course of therapy for VTE. The dilemma is whether these agents can be safely reintroduced upon completion of therapy in patients who have no major continuing risk factors for DVT. If reintroduced, they should be done so at the lowest possible clinically effective dose.
Only those patients with uncomplicated DVT are eligible for outpatient treatment. (See Table 5.)
| Table 5. Contraindications to Outpatient Treatment |
| • Hypersensitivity to heparin or pork products |
| • Pulmonary embolism |
| • Significant comorbid conditions (e.g., congestive heart failure, chronic obstructive lung disease) |
| • Pediatric patients (safety and efficacy not established) |
| • Nursing mothers (not known if drug excreted in human milk and caution should be used in this patient population) |
| • Known hypercoagulable state and recurrent thromboembolism (relative contraindication) |
| • Active major bleeding |
| • History of heparin-induced thrombocytopenia |
| • Expected noncompliance |
The physician must confirm the diagnosis of DVT and determine that the patient is a candidate for LMWH treatment. Although several LMWHs have been successfully used in the treatment of DVT, currently only enoxaparin has gained FDA approval for the treatment indication. For in-hospital treatment of DVT with or without pulmonary embolism, the approved dose of enoxaparin is either 1 mg/kg SC q 12 hours or 1.5 mg/kg SC q day. For outpatient treatment, the only FDA-approved dosage is 1 mg/kg bid. Enoxaparin is available in 30, 40, 60, 80, and 100 mg prefilled disposable syringes. Multi-dose vials that will make more precise weight-based dosing easier to achieve should be available shortly.
Warfarin may be given 2-4 hours after the initial subcutaneous dose of enoxaparin. Warfarin can temporarily cause a hypercoagulable state due to its effect on depleting protein C and protein S, which both have short half-lives. A commonly used approach is to begin with a dose estimated to be the patient’s eventual maintenance dose. For most patients, this will be 5 mg daily with subsequent doses adjusted based on the results of the INR in order to achieve a goal INR of 2.0-3.0. Higher loading doses have not resulted in faster achievement of targeted INR and run the risk of increased bleeding and warfarin skin necrosis. Although not universally agreed upon, patients known to have a hypercoagulable state caused by the antiphospholipid antibody syndrome may require an INR of 3.0-3.5.23
The multiple drug-drug and drug-food interactions associated with warfarin warrant an attempt to keep the patient’s vitamin K intake and concomitant drug usage stable. Warfarin should be administered in the afternoon or evening to allow for morning INR results to return so that dosing can be appropriately adjusted.
There is no good supporting evidence for the value of routine bed rest, and bed rest with leg elevation would be appropriate for those patients with significant leg pain and swelling until such symptoms resolve.24
Patient education forms the cornerstone of outpatient anticoagulation management. The patient needs to be instructed on signs and symptoms of PE, bleeding, or extension of DVT. Also, the patient needs instruction on proper technique of LMWH administration as well as drug-drug and drug-food interactions with warfarin. Case managers are helpful in securing third-party reimbursement and arranging for home health agency (HHA) visits if required. Many HHAs are equipped today with portable finger-stick monitoring devices so that the PT/INR can be obtained immediately and the results called in to the pharmacist or physician for warfarin dosing changes. Platelet counts do not need to be routinely performed if the total course of LMWH administration is expected to be less than seven days. Once the INR is greater than 2.0 for two consecutive days, LMWH can be stopped and the patient continued on warfarin. Although there is some debate regarding the length of warfarin therapy, it is generally recommended that the minimum duration is three months—although recurrence rates are less when treatment is extended to at least six months for patients with idiopathic VTE.25
Patients who develop worsening signs and symptoms of DVT extension such as increasing swelling and pain, and those patients who show evidence of PE should be considered for hospital admission. The mortality rate of patients with DVT who are promptly and effectively anticoagulated is extremely low. A meta-analysis indicates the rate of fatal PE during 5-10 days of heparin and three months of oral anticoagulants is around 0.4%.26
The enclosed supplement provides a sample short-stay DVT clinical pathway that can be readily adapted to an outpatient protocol.
Important Considerations with LMWH Therapy
Bleeding. Hemorrhage is the most frequent and significant side effect of heparin. Animal studies have shown hemorrhage is more frequent with UFH than LMWH when given in equipotent doses.8 LMWHs have less inhibition of platelet function less and less interaction between platelets and endothelial walls than UFH. Animal studies have shown reduced bleeding in those LMWHs with higher anti-Xa:anti-IIa ratios. Although LMWHs theoretically might cause less bleeding than UFH, recent clinical experience suggests similar bleeding rates.
Patients at risk of bleeding include those with peptic ulcer disease and those who have had recent surgery. All patients should be screened at the time of VTE diagnosis and patients at excessive risk for bleeding should be excluded from consideration for outpatient management. Although the package insert for enoxaparin suggests urine analysis and fecal occult blood tests during the course of therapy, the need for such testing is uncertain.
Patients should be educated to promptly report any symptoms of bleeding, such as tarry stools, coffee-ground emesis, weakness, pallor, and fatigue. If bleeding is minor, holding LMWH is usually adequate. If bleeding is major, LMWH’s effect can be at least partially reversed with protamine sulfate, a basic protein that neutralizes heparin’s anti-IIa activity. It should be administered mg for mg and given slowly over 10 minutes as it may cause hypotension. The total dose should not exceed 50 mg. One study comparing the effects of protamine on UFH and LMWH showed near complete reversal of anti-Xa activity and APTT.27 However, in patients with prolonged APTT on LMWH, protamine had a minimal effect on anti-Xa.
Heparin-Induced Thrombocytopenia (HIT). There are two forms of thrombocytopenia associated with heparin use. The early form is benign and reverses despite continued heparin use. The severe form is called HIT. This typically does not occur until day 5 of heparin therapy and is an autoimmune reaction. The body forms heparin platelet factor 4-dependent IgG antibodies that bind with platelet antigens.7 This immune complex results in thrombocytopenia and/or paradoxical thrombosis. If a patient has been exposed to heparin within the last three months, HIT can occur within 24 hours.
There is evidence that the risk of HIT is less with LMWHs than with UFHs. In one large study, the incidence of HIT, defined as a platelet count (< 150 ´ 109/L) at more than four days post-initiation of therapy, was higher in the UFH group than the LMWH group (2.7% vs 0%). When thrombocytopenia is defined as a drop in platelets of greater than 50% in more than four days, the incidence was 5.7% and 0.9%, respectively.28 HIT is a clinicopathological diagnosis. Platelet activation assays using washed platelets have a sensitivity and specificity of 90% for detection of HIT antibodies. Antigen assays using enzyme-linked immunosorbent antibodies (ELISA) to detect antibodies against heparin/PF4 complexes yield sensitivities and specificities of 80% and 90%, respectively.
HIT rarely presents within five days of heparin administration and platelet counts are not routinely recommended if the duration of heparin administration is expected to be seven days or less and the patient has had no heparin exposure within the previous three months. If the platelet count falls more than 50% from baseline or if the absolute platelet count falls below 100 ´ 109/L, LMWH should be held pending laboratory confirmation of HIT. If the patient develops HIT and requires continuing anticoagulation, recombinant hirudin should be considered.
Lipid Effects. Heparins exert lipolytic activity and lipase enzymes including lipoprotein lipase. In one study, total cholesterol increased by about 20% in groups given UFH or LMWH for 3-6 months.29 HDL levels increased more in the UFH group, and LDL increased more than twice that in the LMWH group although this difference was not statistically significant. Since the duration of UFH or LMWH therapy for VTE is typically a few days, these lipid effects are not clinically important.
Osteoporosis. Heparins augment PTH-stimulated bone resorption and stimulate osteoclasts. Generally, increased molecular size and the degree of sulfation are major determinants of heparin’s ability to promote bone resorption. Animal studies have shown decreased calcium loss in fetal rat calvaria with LMWH compared to UFH.30 Also, spinal fractures occur less frequently in humans on long-term LMWH compared to UFH.31 From these data, it would be expected that LMWHs would result in lower risk of heparin-induced osteoporosis.
Other Side Effects. Skin lesions associated with heparin use include erythematous papules, skin necrosis, and urticaria. Reactions such as asthma, tachycardia, tachypnea, conjunctivitis, rhinitis, angioedema, and shock are less common. Long-term administration of heparin may rarely cause hypoaldosteronism due to the inhibition of aldosterone synthesis.7
Renal Insufficiency. LMWHs, like UFHs, are eliminated through the kidneys. It is prudent in patients with renal insufficiency to adjust the dosage accordingly. Data are scarce regarding dose modifications in patients with serum creatinine of greater than 2 mg/dL. LMWHs might be best administered at reduced doses or increased intervals and monitored with anti-Xa levels. If anti-Xa levels are not readily available, reduced doses of UFH should be given and the APTT monitored accordingly.
Obese Patients. In most studies, LMWH has been dosed on the basis of actual body weight. Data on pharmacokinetics and dosing guidelines in obese patients are scarce. In patients weighing more than 130 kg, consider using a modification toward ideal body weight (IBW). A commonly used formula to adjust for ideal body weight is found below:
IBW for men = 50 kg + (2.3 kg × [inches > 5 feet])
IBW for women = 45 kg + (2.3 kg × [inches > 5 feet])
If Actual Body Weight (ABW) < IBW, enoxaparin dosing weight = ABW
If ABW > IBW, enoxaparin dosing weight = IBW + 0.3 (ABW-IBW)
Economic Considerations. One of the major impediments to more widespread use of LMWH in the outpatient treatment of DVT is economics. Although LMWHs are more expensive than UFH, the total cost of care is reduced for each event. Currently, financial incentives are misaligned in many U.S. healthcare facilities. Physicians are commonly reimbursed by patient day, whereas hospitals are typically reimbursed by case rates or DRGs for Medicare patients. Thus, hospitals do not benefit from avoiding hospitalization because they do not receive DRG payment. Physicians do not have any financial incentive to discharge early as their daily revenues will decline. Shortening the hospital stay, however, would result in considerable reduction in cost for the hospital while maintaining the same DRG reimbursement. Hospitals should, therefore, be motivated to provide the necessary resources of infrastructure and personnel if overall cost savings can be achieved through a shortened hospital stay.
If hospitalization can be completely avoided, Medicare patients avoid the substantial out-of-pocket cost of the Part A deductible, which currently is $768 per hospitalization. As Medicare does not cover outpatient prescription medications, these savings would be reduced to a degree by the costs of LMWH. The clinician should keep these financial implications in mind and recognize that elderly patients without supplemental insurance may be at risk for noncompliance. The pharmaceutical company that manufactures enoxaparin has a mechanism to provide enoxaparin for indigent patients and can assist in facilitating home care coverage for eligible patients. Case managers, social workers, and HHAs play crucial roles in the coordinated management of these patients.
In areas of the country with highly penetrated managed care such as California, outpatient protocols have been in place for years with high success.32 In these setting, capitation payment arrangements often align incentives among physicians, hospitals, and health plans. A recent analysis has demonstrated that LMWHs are highly cost effective for management of VTE when even a relatively small percentage of patients are eligible for outpatient treatment.33
Patient Acceptance
Some patients may be hesitant to have an abbreviated hospitalization or outpatient treatment for a potentially life-threatening condition such as DVT. At least one clinical study investigated patient compliance, acceptance, and satisfaction with such a protocol. In a prospective cohort of 113 consecutive patients presenting with acute DVT, 89 were treated at home with LMWH.34 During the study, one patient died from a combination of PE and major bleeding. No other patient died during the three-month follow-up. One patient developed bleeding that required readmission to the hospital and five patients developed recurrent DVT. All had active malignant disease and developed their recurrence 2-12 weeks into their course of oral anticoagulation. Of the subjects who completed the satisfaction questionnaire, 75 of 82 (91%) were pleased with home treatment; 44 of 63 (70%) felt comfortable with the self-injection of LMWH; and 71 of 77 (92%) were satisfied with the support and instructions they received during their outpatient management.
Are LMWHs Interchangeable?
With the increasing introduction of LMWHs in the U.S. marketplace, there is interest as to whether these LMWHs are truly clinically distinct or whether they can be used interchangeably. Fareed et al have demonstrated distinct pharmacologic and biochemical profiles among LMWHs.35 The Fifth American College of Chest Physicians’ Consensus Conference on Antithrombotic Therapy states that although the various LMWHs have similar profiles, they may not be interchangeable clinically.7 Each is produced through a distinct depolymerization process resulting in products with varying molecular weights, anti Xa:anti IIa activity ratios, release of tissue factor pathway inhibitor, bioavailability, and plasma half-lives. For these reasons, the FDA has stated that LMWHs cannot be used interchangeably.36 It is recognized that other LMWHs, including ardeparin and dalteparin, have been used in abbreviated hospitalization and outpatient studies and are currently being used in DVT treatment, particularly in other countries.34,37 However, due to the ever-present threat of litigation and until more trials comparing LMWHs with each other are available, it would seem prudent to limit the use of LMWHs to those agents that are FDA approved for their respective indications (see Table 6). Nevertheless, the market must be sensitive to the enormous pressure placed on third-party payers, physicians, hospitals, and patients to continually seek cost-effective alternatives.
| Table 6. FDA-Approved Indications for LMWHs and Heparinoids |
| Ardeparin (Normiflo) |
| DVT prophylaxis in total knee replacement |
| Dalteparin (Fragmin) |
| DVT prophylaxis in abdominal surgery |
| DVT prophylaxis in total hip replacement |
| Unstable angina and non-Q-wave infarctions |
| Enoxaparin (Lovenox) |
| DVT prophylaxis in total hip and total knee replacement and in patients at risk in abdominal surgery |
| Unstable angina and non-Q-wave infarctions |
| Treatment of inpatient DVT with or without PE |
| Outpatient treatment of DVT |
| Danaparoid (Orgaran) |
| DVT prophylaxis in total knee replacement |
Summary
The introduction of LMWHs has provided a unique opportunity to improve outcomes and reduce cost in the management of selected patients with DVT. The FDA-approved enoxaparin for inpatient treatment of DVT with or without PE and for outpatient treatment of DVT. Managed care organizations and hospitals will embrace the use of LMWHs in short-stay or outpatient treatment protocols as a more cost-effective approach to the traditional but expensive inpatient management with UFH. Primary care physicians need to be familiar with outpatient protocols so that patients are selected appropriately and continuity of care is not jeopardized.
References
1. Turpie AGG. Management of venous thromboembolism: Optimization by clinical trials. Haemostasis 1996;26(4):220-226.
2. Dalen JE, Albert JS. Natural history of pulmonary embolism. Prog Cardiovasc Dis 1975;17:257-270.
3. Prevention of venous thromboembolism. International Consensus Statement. Int Angiol 1997;16(1):3-38.
4. Heit JA, et al. Predictors of survival after deep vein thrombosis and pulmonary embolism. Arch Intern Med 1999;159:445-453.
5. Hyers TM, et al. Antithrombotic therapy for venous thromboembolic disease. Chest 1998;114:561S-578S.
6. Raschke RA, et al. The weight-based heparin dosing nomogram compared with a "standard care" nomogram. A randomized controlled trial. Ann Intern Med 1993;119:874-881.
7. Hirsh J, et al. Heparin and low-molecular-weight heparin. Chest 1998;114:489S-510S.
8. Samama MM, et al. New data on the pharmacology of heparin and low molecular weight heparins. Drugs 1996;52(Suppl 7):8-15.
9. Thompson-Ford JK. Low-molecular-weight heparin for the treatment of deep vein thrombosis. Pharmacotherapy 1998;18(4):748-758.
10. Weitz JI. Low-molecular-weight heparins. N Engl J Med 1997;337: 688-698.
11. Planes A, et al. Efficacy and safety of postdischarge administration of enoxaparin in the prevention of deep venous thrombosis after total hip replacement: A prospective randomised double-blind placebo-controlled trial. Drugs 1996;52(Suppl 7):47-54.
12. Borris LC, Lassen MR. Thromboprophylaxis with low molecular weight heparin after major orthopaedic surgery is cost effective. Drugs 1996; 52(Suppl 7):42-46.
13. Clagett GP, et al. Prevention of venous thromboembolism. Chest 1998; 114:531S-560S.
14. Kay R, et al. Low-molecular-weight heparin for the treatment of acute ischemic stroke. N Engl J Med 1995;333:1588-1593.
15. Leizorovicz A. Comparison of the efficacy and safety of low molecular weight heparins and unfractionated heparin in the initial treatment of deep venous thrombosis: An updated meta-analysis. Drugs 1996;52 (Suppl 7):30-37.
16. Levine M, 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.
17. Koopman MMW, et al. Treatment of venous thromboembolism 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.
18. Fiessinger JN, et al. Once-daily subcutaneous dalteparin, a low molecular weight heparin, for the initial treatment of acute deep vein thrombosis. Thromb Haemost 1996;76:195-199.
19. Hull RD, et al. Subcutaneous low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis. N Engl J Med 1992;326:975-982.
20. Brewer D. Should low-molecular-weight heparins replace unfractionated heparin as the agent of choice for adults with deep venous thrombosis? J Fam Pract 1998;47:185-192.
21. Spiro TE. A multicenter clinical trial comparing once and twice-daily subcutaneous enoxaparin and intravenous heparin the treatment of acute deep vein thrombosis. Blood 1997;90(Suppl 1):295A.
22. Yeager BF, Matheny SC. Low-molecular-weight heparin in outpatient treatment of DVT. Am Fam Physician 1999;59(4):945-952.
23. Khamashta MA, et al. The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med 1995;332:993-997.
24. Opinions regarding the diagnosis and management of venous thromboembolic disease. Chest 1996;109:233-237.
25. Kearon C, et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med 1999;340:901-907.
26. Douketis JD, et al. Risk of fatal pulmonary embolism in patients with treated venous thromboembolism. JAMA 1998;279:458-462.
27. Wolz M, et al. Studies on neutralizing effects of protamine on unfractionated and low molecular weight heparin (Fragmin) at the site of activation of the coagulation system in man. Thromb Haemost 1993;73: 439-445.
28. Warkentin TE, et al. Heparin-induced thrombocytopenia in patients treated with low molecular weight heparin or unfractionated heparin. N Engl J Med 1995;332:1330-1335.
29. Monreal M, et al. Effects of long-term therapy with either heparin or low molecular weight heparin on serum lipid levels. A prospective study. Haemostasis 1995;25:283-287.
30. Shaughnessy SG, et al. The effects of low molecular weight heparin and standard heparin on calcium loss from fetal rat calvaria. Blood 1995; 86:1368-1373.
31. Monreal M, et al. 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.
32. Dedden P, et al. Pharmacy-managed program for home treatment of deep vein thrombosis with enoxaparin. Am J Health Syst Pharm 1997;54: 1968-1972.
33. Gould MK, et al. Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep vein thrombosis. Ann Intern Med 1999;130:789-799.
34. Harrison L, et al. Assessment of outpatient treatment of deep-vein thrombosis with low-molecular-weight heparin. Arch Intern Med 1998;158: 2001-2003.
35. Fareed J, et al. Are the available low-molecular-weight heparin preparations the same? Semin Thromb Hemost 1996;22(Suppl 1):77-91.
36. Nightingale SL. Appropriate use of low-molecular-weight heparins. JAMA 1993;270:1672.
37. Goldhaber SZ, et al. Abbreviated hospitalization for deep venous thrombosis with the use of ardeparin. Arch Intern Med 1998;158:2325-2328.
CME Questions
54. Which of the following would not be an advantage of low- molecular-weight heparin compared to unfractionated heparin?
a. Lower drug cost
b. Longer half-life
c. Less protein binding
d. No need for APTT monitoring
e. Less risk of heparin-induced thrombocytopenia
55. Which of the following is not a FDA-approved indication for LMWH?
a. Popliteal vein thrombosis
b. Symptomatic distal DVT
c. Outpatient therapy for pulmonary embolism
d. Non-Q-wave myocardial infarction
e. Prophylaxis of total knee replacement
You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content