Medical management of venous thromboembolic disease

Medical Management of Venous Thromboembolic Disease Steven Deitelzweig, MD and Michael R. Jaff, DO

Venous thromboembolic disease (deep vein thrombosis and pulmonary embolism) are common disorders with serious morbid and mortal complications. Given the varied modes of presentation, a high clinical index of suspicion in patients at risk must exist among physicians. Standard therapy has consisted of intravenous unfractionated heparin and overlapping administration of an oral Vitamin K antagonist, commonly Warfarin. Although an effective strategy, many practical limitations exist, including the need for prolonged hospitalization, frequent laboratory monitoring for anticoagulant effect, and erratic dose-response curves. Recently, subcutaneous low-molecular-weight heparins have emerged as safe and effective alternatives for unfractionated heparin. Appropriate patients may be treated with low-molecular-weight heparins and oral Warfarin entirely as outpatients, with similar efficacy and risk of recurrent thromboembolic events and hemorrhage. Thrombolytic therapy is a reasonable alternative in patients with iliofemoral venous thrombosis and/or pulmonary embolism resulting in hemodynamic compromise or obstructing significant pulmonary vasculature. Risks of serious hemorrhagic side effects including intracranial hemorrhage, along with the added economic burden, have limited widespread acceptance of thrombolytic therapy as primary treatment. Emerging oral direct thrombin inhibitors and other novel agents stand to move the treatment of patients with venous thromboemboli to even greater levels of safety and efficacy. © 2004 Elsevier Inc. All rights reserved.

eep vein thrombosis (DVT) and pulmonary embolism (PE) are generally considered to represent two clinical manifestations of the same disease. Venous thromboembolism (VTE) remains an important cause of morbidity and mortality in the United States. PE afflicts over 500,000 American lives annually, causes 10% of all in-hospital deaths, and remains the single most important medical cause of maternal deaths associated with live births in the United States. Given that only one-third of proximal DVT is clinically recognized, actual DVT rates may be as high as two million per year. It is also estimated that 60,000 people die of PE annually.1-5 Although older age patients are at increased risk of VTE, VTE is not bound by any age restriction, and anyone from infants to the elderly has a 10.7% probability of VTE by age 80. Unfortunately, autopsy studies continue to show that most cases of fatal PE are unrecognized and undiagnosed.6

D

Pathogenesis Venous thrombi typically form along valve cusps within the soleal sinuses of the calf as a result of platelet aggregation and From the Ochsner Clinic Foundation, New Orleans, Louisiana, and the Section of Vascular Medicine, Lenox Hill Hospital, New York, NY. Address reprint requests to Michael R. Jaff, DO, Section of Vascular Medicine, Lenox Hill Hospital, 130 East 77 Street, New York, NY, 10021. © 2004 Elsevier Inc. All rights reserved. 1089-2516/04/0702-0004$30.00/0 doi:10.1053/j.tvir.2004.02.003

local hypercoagulability, altered venous flow dynamics, and endothelial damage, and can overwhelm the endogenous fibrinolytic system in minutes. The propensity of the thrombus to embolize is greatest in the early or “loose” phase (first 7 days) when the thrombus is comprised of red blood cells, white blood cells, and platelets within a fibrin mesh. The clot is infiltrated by histiocytes and fibroblasts, becoming “adherent” and the organizational process continues through collateralization or retraction, ultimately leading to an irregular, often irreversible, intimal damage in the recanalization phase. The risk of development of a VTE is directly related to three pathologic factors first identified by Rudolph Virchow in the 19th century and now known as Virchow’s triad: venous endothelial damage, localized or systemic hypercoagulability, and stasis of venous blood. It is now recognized that stasis primarily plays the role of a permissive factor and most research has concentrated on hypercoagulability, which can be acquired or congenital.

Treatment Various pharmacologic options have been studied with different efficacy and safety results including unfractioned heparins (UFH), low molecular weight heparins (LMWH), warfarin, and several new agents. The goals of DVT treatment are not just limited to prevention of thrombus propagation, embolization, and recurrence. Today’s management must consider re-establishment of venous patency and the prevention of postthrombotic (chronic venous insufficiency) syndrome. There are two phases in the treatment of patients with symptomatic venous thromboembolism: acute or initial treatment and chronic or secondary prophylaxis. Acute phase treatment options include continuous IV UFH infusion, subcutaneous (SC) low molecular weight heparin (LMWH), the use of an inferior vena caval filter, and thrombolytic therapy. Historically, one early question that was answered by Barritt and Jordan, who completed the first prospective randomized anticoagulation trial in patients with acute venous thrombolism in 1960, was the need for anticoagulation in patients with acute PE. In a trial stopped prematurely after only 35 patients enrolled, the mortality rate from PE in the untreated group was ⬎25% compared with no deaths from PE in the anticoagulated group.7 Standard of care dictates aggressive anticoagulation in patients with acute PE.

Acute VTE Management Unfractionated Heparin (UH) Anticoagulants approved for use by the Food and Drug Administration (FDA) are shown in Table 1;8 therapeutic goals and treatment options are indicated in Table 2.

Techniques in Vascular and Interventional Radiology, Vol 7, No 2 (June), 2004: pp 63-67

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TABLE 1. Anticoagulants Approved for Use by the FDA Mechanism of Anticoagulation

Generic Name

Trade Name

1

Warfarin

Vitamin K antagonism

2

Anisindione

Coumadin and generic brands Miradon

3

Unfractionated heparin

Various agents

4

Fractionated heparin

Fragmin, Innohep, Lovenox, Normiflo

Thrombin and factor Xa inhibitor Factor Xa and thrombin inhibitor

5

Antithrombin

Thrombate iii

6

Danaparoid

Orgaran

7 8 9 10

Argatroban Lepirudin Bivalirudin Fondaparinux

Argatroban Refludan Angiomax Arixtra

11

Drotrecogin alfa (activated protein C)

Xigris

Indications

Vitamin K antagonism

Thrombin and factor Xa inhibitor Factor Xa and thrombin inhibitor Direct thrombin inhibitor Direct thrombin inhibitor Direct thrombin inhibitor Xa inhibitor Inhibitor of factor Va and VIIIa

Application

Arterial and venous thromboembolic disorders Arterial and venous thromboembolic disorders Arterial and venous thromboembolic disorders VTE prophylaxis and treatment, acute coronary syndrome Antithrombin deficiency

Oral

IV

VTE prophylaxis

IV

HIT HIT PCI VTE prophylaxis in orthopedic patients Severe sepsis

IV IV IV SC

Oral IV, SC IV, SC

IV

Abbreviations: VTE ⫽ venous thromboembolism; HIT ⫽ heparin-induced thrombocytopenia; PCI ⫽ percutaneous coronary intervention; SC ⫽ subcutaneous; IV ⫽ intravenous. Used with permission: Moll, Roberts: Semin Hematol 39:145-57, 2002.

All heparins are heterogeneous mixtures of glycosaminoglycans derived from animal products that catalyze the blood enzyme antithrombin (AT). UFH has a narrow therapeutic window and has been cited as a common cause of drug-related deaths in hospitalized patients. Significant bleeding occurs in 7% to 30% of patients on IV UFH, and complication rates of 1% to 2% per day have been reported.9 From a pathophysiological perspective, heparin prevents extension of thrombus and reduces the risk of embolism. The importance of achieving an adequate intensity of initial and maintenance anticoagulation with heparin was emphasized by noting a recurrent VTE rate of at least 29% without therapeutic anticoagulation.10,11 Raschke and co-workers reported a weight-based dosing protocol that resulted in a 95% likelihood of therapeutic heparin effect with an intravenous bolus of 80 U/kg followed by continuous IV infusion of 18 U/kg/hr.11 Using the activated partial thromboplastin time (APTT), the dosage of heparin should be adjusted to maintain an anticoagulant intensity above the lower limit of a defined therapeutic range.12 Despite physicians’ being most comfortable with an APTT of 1.5 to 2.5 times the control as a therapeutic range for heparin, there are alternatives, such as heparin levels via either thrombin/protamine titration with a target of 0.2 to 0.4 U/mL, or an anti-Xa level of 0.5 to 1.1 U/mL. Warfarin may be initiated within the first 24 to 48 hours at a dose of 5.0 mg to 7.5 mg a day. The disadvantages of “loading doses” of warfarin of 10 mg per day have been well described, including a high incidence of overanticoagulation (36% over-

shoot phenomenon) at 60 hours, requiring correction.13 This occurs as a result of an increased sensitivity to warfarin because of poor dietary status and concomitant use of other anticoagulants (ie, broad spectrum antibiotics) which decrease vitamin K absorption from enteric flora. Both heparin and warfarin must be used concomitantly for at least 4 days until the international normalized ratio (INR) is within the target therapeutic range (INR 2.0-3.0), preferably for two consecutive days, at which time heparin administration can be discontinued.14 This is important because heparin’s mechanism of action depends on activating antithrombin (antithrombin III previously) to inactivate both factors IIa and Xa. There are several methods whereby this occurs. Heparin can bind both antithrombin and IIa (thrombin), thereby creating a physical bond inactivating IIA. Another mechanism occurs when the heparin chain binds with antithrombin inducing a conformational change. Factors II and X have plasma half-lives of 60 hours and 40 hours, respectively. In addition, when Coumadin is initiated, factor VII is the first factor reduced with a half-life of 6 hours, leading to an early prolongation of the INR. Therefore, the INR could be increased early when the patient actually has an increased risk of thrombosis. Therefore, 4 to 5 days of overlapping heparin and warfarin is critical to avoid early prothrombotic conditions.15 The most common and serious adverse effects of any anticoagulant is bleeding. The risk of major hemorrhage with UFH is higher with intermittent compared with continuous IV infusion. No difference in major bleeding was detected between continuous IV and subcutaneous heparin.16

TABLE 2. Therapeutic Goals and Treatment Options for DVT Goals of Therapy Prevent embolization Prevent extension Reduce recurrence Restore patency Prevent postthrombotic syndrome

Supportive Care

IVC Filter

Heparin

LMWH

Thrombolysis

✽

✽ ✽ ✽

✽ ✽ ✽ ? ?

? ✽ ✽ ✽ ?

?

Current Concepts in Thrombosis II. DVT ⫽ deep vein thrombosis; IVC ⫽ inferior venal caval; LMWH ⫽ low molecular weight heparin.

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DEITELZWEIG AND JAFF

TABLE 3. Pharmacokinetic comparison of unfractionated heparin and LMWH

Low dose bioavailability High dose bioavailability Elimination Low dose High dose (nonsaturable) Half life

Unfractionated Heparin

LMWH

80% 90%

90% 90%

Cellular uptake (saturable) Renal elimination Dose dependent (30 min to 4 hr)

Renal elimination (nonsaturable) Renal elimination Dose independent (2-4 hr)

LMWH is less often associated with major hemorrhage, likely a result of the complexities of UFH administration which involves pump infusion, varying techniques, laboratory reagents, and dosing manipulation. Patient characteristics associated with increased major bleeding include age ⬎70 years and multiple severe comorbid conditions. Those who are healthy have a 2% incidence, while debilitated severely ill patients have a 25% risk of bleeding. Aspirin is known to increase the hemorrhagic risk when combined with heparin but has been administered commonly without serious bleeding.17,18 Minor bleeding with UFH can be managed by observation, as the half-life is only 90 minutes. In situations requiring prompt reversal of heparin effect, reversal with 1 mg per 100 U of UFH of protamine sulfate is appropriate. The concerns with protamine sulfate administration are anaphylaxis, hypotension, and possibly bleeding. Equimolar concentrations of protamine sulfate neutralize anti-IIa activity but only partial anti-Xa activity of LMWHs probably because protamine sulfate does not bind to very low molecular weight components. The protamine effect for LMWH reversal remains uncertain. One of the problems most often confronted clinically with UFH is heparin resistance. Heparin binds to various plasma proteins, endothelial cells, and monocytes during IV infusion. The amount of binding is unpredictable and the proportion may be higher in patients with inflammatory states where the binding proteins are acute phase reactants. Another problem is the need for recurrent phlebotomy, which should be performed every 6 hours after the initial bolus to repetitively assay the aPTT.

A serious adverse effect with all forms of heparin is heparininduced thrombocytopenia (HIT). HIT occurs at an incidence of 3.5% with UH and 0.6% with LMWH.13 Typically after at least 5 days of heparin administration, a 50% reduction in the platelet count when compared with pretreatment platelet counts, or an absolute reduction to 100,000 per cubic millimeter suggests the development of HIT. This is an antigen-antibody reaction between heparin and platelet factor 4.19 If this complication occurs or is suspected, a direct thrombin inhibitor such as hirudin or argatroban needs to be administered because of the potential for cross reactivity with other heparins and LMWHs. Finally, because of an increase in osteoclast activating factor, heparin-induced osteoporosis can be a serious complication, especially with long-term administration. The risk of osteoporosis occurs less frequently with prolonged administration of LMWH than with UFH.20 The absolute contraindications to anticoagulant therapy include intracranial hemorrhage, active internal bleeding, peptic ulcer disease with hemorrhage, malignant hypertension, intracranial neoplasm, recent and significant trauma or surgery, and history of heparin-induced thrombocytopenia.

LMWH Another primary option available for the acute management of VTE are LMWHs, which are chemical or enzymatic depolymerizations of UFH. LMWHs possess a number of significant advantages over UFH. LMWHs have favorable pharmacokinetics with 90% bioavailability at both low (prophylaxis) and high (treatment) doses (Table 3). A prolonged half-life, independent of dose between 2 hours and 4 hours, allows for subcutaneous injection once or twice daily with a predictable dose response, most often without monitoring (anti-Xa level). The response is so predictable that, with the exception of certain high-risk situations, no dose monitoring is necessary. A host of these products are available in the United States and Europe (Table 4). Several major randomized prospective multicenter trials and meta-analyses in the mid-1990s demonstrated a (nonstatistically significant) advantage of LMWH over UFH in the treatment of VTE when comparing VTE recurrence, hemorrhage, and death. Leizorovicz examined 2,045 patients in 16 con-

TABLE 4. Product profiles for available LMWHs

Anti-Xa to Anti-IIa Ratio

Molecular Wt. (Range) [saccharide units]

Plasma Half-Life (min)

Enoxaparin (RhonePoulenc Rorer)

2.7:1

4500 (3000-8000) [10-27]

Fragmin (Kabl)

2.0:1

Fraxiparin (Sanoff)

Recommended Dose Converted Into International Anti-Xa Units General Surgery

Orthopedic Surgery

129-180

2000 U SC

5000 (2000-9000) [7-30]

119-139

2500 U SC

4000 U SC OD or 3000 U SC BID 2500 U SC BID or 5000 U SC OD

3.2:1

4500 (2000-8000) [7-27]

132-162

Logiparin (Novo)

1.9:1

4500 (3000-6000) [10-20]

111

7500 U/IC SC OD 3500 U SC OD

Normiflo (Wyeth)

2.0:1

6000 (2000-15,000) [7-50]

200

Lomoparan* (Organon)

2:1

6500

1100

Agent (manufacturer)

50 U/kg SC OD 50 U/kg SC BID 750 U SC BID

Treatment 7000 U SC (70 kg) BID 8400 U SC (70 kg) BID 31,500 U IC OD 12,250 OD

*Lomoparan is a heparinoid; weight-adjusted dose ⬃ stated dose for 70 kg patient; 3ICU ⫽ 1 International Unit; SC ⫽ subcutaneously; BID ⫽ twice daily; OD ⫽ once daily. MANAGING VT DISEASE

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trolled trials and found the trend for VTE recurrence, bleeding, and mortality favoring LMWH, with respective relative risk ratios of 0.66, 0.65, and 0.72.21-23 In addition, several clinical studies have shown significantly less thrombus progression in patients treated with LMWH when compared with UFH.24 For acute PE, several randomized trials have demonstrated that LMWHs are at least as safe and effective as UFHs in preventing recurrent emboli.25-27 Simonneau randomized 612 patients with acute symptomatic PE not requiring thrombolytic therapy to the LMWH tinzaparin SQ and UFH IV26 There was no difference in the primary endpoints of death, recurrent VTE, or major hemorrhage at 8 days or 3 months. LMWHs have been used as primary therapy for acute venous thromboemboli in the outpatient setting. Two large randomized trials comparing outpatient LMWHs to UFH IV demonstrated LMWH safety and efficacy in this specific low-risk patient group.28,29 Patients in the LMWH group were discharged from the hospital after a mean of 1.1 days while the UFH patients were hospitalized for a mean of 6.5 days. This study suggests that LMWH can significantly alter the current therapeutic approach to DVT, allowing patients to be safely and effectively managed at home, potentially increasing patient convenience and markedly reducing health care costs. Currently, enoxaparin (Lovenox) is approved by the United States FDA at a 1.5 mg/kg once daily to inpatients with DVT with or without PE, and to outpatients at a dosage of 1 mg/kg twice daily for DVT without PE. Dalteparin (Fragmin) is not yet approved for the treatment of VTE but has been used in dosages of 100 antifactor Xa units/kg given subcutaneously twice daily and 200 anti-Xa units/kg given once daily for the management of DVT. Tinzaparin is FDA-labeled at a dosage of 175 IU/kg for DVT with or without PE, but data have been established only in hospitalized patients (Table 2). LMWHs have a significant cost and patient convenience advantage over UFH, but not all patients with VTE should be treated with LMWH in the outpatient setting. Certainly, with increasing experience, there appear to be fewer absolute contraindications, and many institutions have implemented outpatient treatment protocols. Only patients with low bleeding risk and without criteria requiring hospital admission should be considered candidates for outpatient treatment with LMWHs. Careful patient selection is the most important component to a successful outpatient treatment program. Inclusion criteria require an objectively documented proximal DVT or symptomatic distal DVT in a low-risk patient. The patient must be medically and hemodynamically stable. The patient and family will need verbal and written education regarding VTE, complications of anticoagulation therapy, as well as hands-on teaching for subcutaneous self-injection. For outpatient acute VTE management, warfarin should be instituted on the first or second day of LMWH therapy. Combination therapy with both LMWH and warfarin must continue for at least 4 days with an INR ⬎2.0 for two consecutive days. Some investigators have suggested that the 10 mg “loading dose” nomogram was superior to the 5 mg dose because it allowed more rapid achievement (1.4 days earlier) of a therapeutic INR without significant differences in recurrent events, major bleeding, and survival.30

Chronic VTE Management Recurrent VTE is common, suggesting that longer term anticoagulation may reduce this risk. However, prolonged anticoag-

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TABLE 5. FDA-Approved Thrombolytic Regimens for Pulmonary Embolism Streptokinase 250,000 IU loading dose over 30 min followed by 100,000 IU/24 hr IV Urokinase 4400 IU/kg loading dose over 10 min followed by 4440 IU/kg/hr for 12-24 hr IV rt-PA 100 mg continuous IV infusion over 2 hr FDA ⫽ Food and Drug Administration; IU ⫽ international unit.

ulation increases the risk of anticoagulant-related hemorrhage. Individualization remains the rule for both duration and intensity of oral anticoagulant therapy. Current guidelines recommend 3 months of oral anticoagulant therapy with warfarin at an INR of 2 to 3 if a reversible or temporary risk factor is present. Such reversible risk factors include orthopedic conditions, temporary immobility, and a major medical illness (ie, pneumonia). Otherwise, at least 6 months of warfarin therapy is recommended as the risk of recurrence is higher if thrombosis was unprovoked (idiopathic) or associated with a nonreversible risk factor. The optimal intensity of anticoagulation remains an INR of 2 to 3. We recommend a duration of therapy of at least 2 years at an intensity of 2 to 3 INR for idiopathic VTE patients with acceptable low risk of hemorrhagic complications. Currently, the indications for lifelong warfarin include: two or more episodes of recurrent VTE, proven idiopathic VTE and hypercoagulable disorders, and continuing underlying risk factors (cancer).31

Thrombolysis Catheter-directed and systemic thrombolytic therapy with agents that activate plasminogen to form plasmin, resulting in thrombolysis, have been investigated. There are three FDAapproved thrombolytic agent regimens for PE utilizing weightbased monograms (Table 5). For DVT, a catheter-directed dissolution of the thrombus is performed by an interventional physician; however, this route of administration and dosing strategy has not yet been approved by the FDA. Thrombolysis should be considered in acute venous thrombi (less than 28 days old) as Bjarnason and co-workers32 reported a 66% to 100% lysis rate compared with only 33% if the thrombus was present for more than 4 weeks. Theoretically, this will result in preservation of venous valvular function and a reduced incidence of postthrombotic syndrome. Therefore, thrombolytic therapy may be considered for those patients with iliofemoral DVT, phlegmasia cerulea dolens, young patients with increased risk for postthrombotic syndrome, and patients with upper extremity venous thrombosis.33 Mechanical thrombectomy devices have recently been evaluated for therapy of large occlusive acute venous thrombi either in the lower extremities or pulmonary vasculature.

Future Newer designer anticoagulants target individual components of the coagulation cascade and now include direct and indirect Factor Xa inhibitors, heparinoids, oral and parenteral direct thrombin inhibitors, oral SNAC/SNAD heparins, tissue factor pathway inhibitors, and nematode anticoagulant peptide C2. DEITELZWEIG AND JAFF

All these agents have the potential of replacing UFH and LMWH for VTE management.

Conclusion The field of venous thromboembolism continues to evolve at a rapid pace. The focus needs to be one of prevention of this prevalent disorder, maintaining a high degree of suspicion for VTE in high-risk patients, as VTE often remains unrecognized and undiagnosed. The initial or recurrent diagnosis needs to be made in the most rapid, safe, reliable, cost-effective fashion. Therapy must be instituted immediately, often before the established diagnosis in high-risk patients, thereby minimizing the likelihood of developing significant sequelae, such as chronic thromboembolic pulmonary hypertension or postthrombotic syndrome. Therapy with an anticoagulant (UFH or LMWH), thrombolysis, or other interventional maneuvers (catheter-based or surgical) must be initiated with an evidence-based approach. The LMWHs have been revolutionary, especially with patients who may be treated in the outpatient setting. This promotes patient satisfaction and potentially reduces cost to the health care system. Novel therapies will continue to revolutionize our management of VTE with effective and safe oral agents.

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