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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 59:M34-M41 (2004)
© 2004 The Gerontological Society of America

REVIEW ARTICLE

The Management of Venous Thromboembolic Disease in Older Adults

Michael W. Rich

Cardiovascular Division, Washington University School of Medicine, St. Louis, Missouri.


   Abstract
Top
 Abstract
Clinical Features
 Pharmacotherapy
 Additional Therapeutic Options
 References
 
The incidence and prevalence of venous thromboembolic disease (VTED) increase progressively with age. Although the clinical features, diagnosis, and treatment of VTED are generally similar in older and younger adults, prevalent comorbidities often complicate the management of VTED in the elderly. The Sixth American College of Chest Physicians Consensus Conference on Antithrombotic Therapy provides comprehensive recommendations for the management of VTED. This article summarizes these recommendations as they apply to older adults and highlights factors that may modulate the diagnosis and treatment of VTED in the elderly patient.

VENOUS thromboembolism (VTE), a disorder encompassing deep venous thrombosis (DVT) and pulmonary embolism (PE), usually occurs as a result of stasis of blood in the venous circulation, abnormalities of the blood vessel wall, alterations in coagulation, or a combination of these factors (1). Older adults are at increased risk for VTE due to physical inactivity, enforced immobilization (e.g., following hip fracture), and the high prevalence of chronic illnesses that predispose to VTE, including cardiovascular disease and cancer (2–4). As a result, the incidence of VTE increases with age in men and women in both the hospital and community settings (Figures 1 and 2) (5). This article reviews current recommendations for the management of VTE as they apply to older adults. Therapeutic options for the treatment of VTE include unfractionated heparin (UFH), low molecular weight heparins (LMWH), warfarin, direct thrombin inhibitors, fibrinolytic agents, inferior vena caval procedures, and surgical or catheter-based embolectomy. Although each of these therapies will be discussed, the primary focus of this review is the pharmacological treatment of VTE. The recommendations discussed herein are based on the Sixth American College of Chest Physicians Consensus Conference on Antithrombotic Therapy, as reported in Chest. 2001;119:176S–193S. Each recommendation is graded according to the strength and quality of evidence supporting the recommendation (see Table 1) (6). Patients with isolated calf DVT are at low risk for developing PE and can be managed conservatively unless there is evidence for proximal extension or significant symptoms, in which case antithrombotic therapy is warranted (1). Superficial thrombophlebitis should be treated with local measures and nonsteroidal antiinflammatory drugs (1).



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  		Figure 1. Annual incidence of venous thromboembolism among hospitalized residents of Olmsted County, Minnesota, 1980–1990. [From: Heit JA, et al. Mayo Clin Proc. 2001;76:1102–1110. With permission.]

 


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  		Figure 2. Annual incidence of venous thromboembolism among community residents of Olmsted County, Minnesota, 1980–1990. [From: Heit JA, et al. Mayo Clin Proc. 2001;76:1102–1110. With permission.]

 

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  		Table 1. Recommendation Categories Based on Strength and Quality of Evidence*.

 

   CLINICAL FEATURES
Top
 Abstract
 Clinical Features
Pharmacotherapy
 Additional Therapeutic Options
 References
 
General Considerations
Clinical studies indicate that proximal DVT and PE frequently coexist. In addition, current pharmacotherapy of DVT and PE is similar; therefore, these conditions are considered together. Note, however, that patients presenting with PE have an approximately fourfold greater risk of dying due to recurrent VTE during the subsequent year than patients presenting with DVT (7). Importantly, with the exception of fibrinolytic therapy, all antithrombotic regimens used in the treatment of VTE are prophylactic, in that they act principally by reducing formation of new thrombus rather than by promoting resolution of existing thrombus.

Diagnosis
Both DVT and PE are frequently asymptomatic, and clinical symptoms and signs of VTE are insensitive and nonspecific (8). The most common symptoms of lower extremity DVT include unilateral pain and swelling. Erythema, warmth, and tenderness may be present, and differentiation from cellulitis is often difficult. Homan's sign (calf pain with manual dorsiflexion of the ipsilateral foot) is a nonspecific finding. The most common symptom of PE is the sudden onset of shortness of breath (9). Hemoptysis and pleuritic chest pain due to pulmonary infarction occur less frequently (9). Occasionally, patients with PE present with arrhythmias or syncope. Physical findings associated with PE may include tachypnea, tachycardia, and a focal area of dry pulmonary crackles (9). Respiratory distress, hypotension, and signs of pulmonary hypertension (augmented P2, right ventricular heave) may be present in patients with massive PE.

Routine laboratory tests are not helpful in the diagnosis of DVT. In patients with PE, arterial blood gases may demonstrate a respiratory alkalosis with reduced oxygen saturation and increased alveolar–arterial oxygen gradient (2). The chest radiograph may demonstrate pleural effusion, atelectasis, volume loss (elevated hemidiaphragm), signs of hypoperfusion, or a pleural-based wedge-shaped density suggesting pulmonary infarction (9,10). The electrocardiogram often demonstrates sinus tachycardia and may demonstrate a right ventricular strain pattern. A prominent S-wave in lead I, in conjunction with a small Q-wave and inverted T-wave in lead III (S1Q3T3 pattern), is suggestive of PE but is infrequently present (11).

Due to the lack of sensitivity and specificity of symptoms, signs, and routine laboratory tests for the diagnosis of VTE, additional confirmatory tests are usually required. D-dimer is a fibrin degradation product released into the circulation during endogenous fibrinolysis. Plasma D-dimer levels measured by enzyme-linked immunosorbent assay (ELISA) are highly sensitive for detecting DVT or PE, and an ELISA plasma D-dimer level <500 ng/ml has an almost 100% negative predictive value for excluding active VTE (8,12,13). The specificity of D-dimer is low, however, and it also declines with age, so that the value of measuring D-dimer in older patients with suspected VTE is uncertain (14).

Lower extremity venous compression Doppler ultrasonography is a safe and noninvasive test that is over 95% sensitive and specific for detecting proximal DVT (8). Impedance plethysmography is an alternative technique for diagnosing DVT, but it is less sensitive than ultrasonography (8,14). If intraabdominal or pelvic DVT is suspected, contrast computed tomography (CT), abdominopelvic ultrasonography, or magnetic resonance imaging is indicated (2,8,14).

Ventilation/perfusion (V/Q) lung scanning remains the initial procedure of choice to evaluate for suspected PE, but the diagnostic accuracy of this test is only moderate (15). High-resolution computed CT (helical or spiral CT) of the chest provides an excellent alternative to the V/Q scan but requires intravenous contrast administration (16). Pulmonary angiography should be performed when the diagnosis of PE remains in doubt based on the results of less-invasive tests (9,12,14).


   PHARMACOTHERAPY
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 Abstract
 Clinical Features
 Pharmacotherapy
Additional Therapeutic Options
 References
 
Heparin
Heparin potentiates the effects of antithrombin III, a plasma inhibitor that inactivates thrombin (factor IIa) and clotting factors IXa and Xa. Heparin also inhibits activation of factors V and VIII by thrombin. Importantly, heparin clearance is relatively unaffected by hepatic or renal disease.

Observational studies and clinical trials indicate that UFH at therapeutic dosages is efficacious in the treatment of VTE. In the United States, UFH is most often administered as a continuous intravenous infusion for treatment of VTE, although evidence that this approach is associated with enhanced efficacy (fewer VTE recurrences) or safety (fewer bleeding complications) compared to intermittent intravenous infusions or subcutaneous injections is inconclusive (17–19).

Intravenous UFH therapy should be initiated with a loading dose of 80 IU/kg followed by a maintenance dose of 18 IU/kg/hr. An activated partial thromboplastin time (aPTT) should be measured after 6 hours, and the dosage should be adjusted (Table 2) to maintain the aPTT in the range of 46–70 seconds (1.5–2.3 x normal control). The recommended therapeutic range for aPTT is based on evidence that levels <=1.5 x control are associated with reduced efficacy and levels >2.3 x control are associated with increased bleeding risk (17,20,21). Since studies consistently show that failure to achieve and maintain an aPTT >=1.5 x control is associated with an unacceptably high rate of recurrent VTE, aPTT levels below this threshold should be avoided (21,22). UFH may also be administered subcutaneously at dosages of 35,000 to 40,000 units over 24 hours, adjusted to maintain the aPTT within the therapeutic range.


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  		Table 2. Weight-Based Adjustment of Intravenous Unfractionated Heparin Dosage*.

 
An alternative approach to monitoring heparin therapy is to measure plasma heparin levels, for which the therapeutic range, determined by protamine sulfate titration, is 0.2–0.4 IU/ml (23). Although less widely used, plasma heparin levels correlate more closely with antithrombotic activity than does the aPTT. A third alternative is the thrombin clotting time (TCT), which correlates linearly with plasma heparin levels in the range of 0.2–0.6 IU/ml; in addition, TCT is more reproducible than aPTT and less affected by concomitant warfarin therapy (24–26). Whether using aPTT, plasma heparin, or TCT to monitor therapy, levels should be checked every 6 hours for the first 24 hours, 6 hours after each dosage adjustment, and once daily when stable.

A common clinical problem occurring during the course of heparin therapy is inadequate dosing with resultant subtherapeutic aPTTs or heparin levels. This problem may be more prevalent in elderly individuals, since physicians may reduce the dosage due to concerns about bleeding (27). However, it is important to recognize that the frequency of recurrent VTE in patients with subtherapeutic heparin dosages greatly exceeds the risk of serious bleeding complications due to excessive anticoagulation (21,22,28). In addition, heparin requirements are often highest during the first few days of therapy (29), and it is therefore essential that adequate heparin dosages are administered during this critical period.

The most common complication associated with heparin therapy is bleeding, and there is evidence that older adults are at increased risk for heparin-related bleeding complications (30). In one study of patients receiving UFH for treatment of proximal DVT, the incidence of major bleeding complications increased from 3.1% in patients <=71 years of age, to 11.1% in patients >=72 years of age, and older age was an independent risk factor for both minor and major bleeding (30). Additional risk factors for major bleeding include concomitant use of aspirin, renal failure, and recent surgery or trauma (31). In most cases, adjusting the heparin dose to maintain levels within the therapeutic range is sufficient to reduce the risk of further bleeding. However, heparin therapy should be discontinued in patients with life-threatening hemorrhage, and alternative therapies for VTE should be considered (e.g., placement of an inferior vena caval filter).

Heparin-induced thrombocytopenia (HIT) is an uncommon but serious complication of heparin therapy caused by antibody-mediated injury to platelets and vascular endothelium (32). HIT occurs in <1% of patients receiving short-term heparin therapy (i.e., fewer than 5–7 days). HIT is manifested by a precipitous or progressive decline in platelet count, and may be associated with arterial thromboembolism or recurrent VTE (32). To evaluate for HIT, a platelet count should be measured upon initiation of heparin therapy, and repeated at 3–5 days, 7–10 days, and 14 days of treatment. If the platelet level drops below 100,000/µl from a normal level at baseline, consideration should be given to discontinuing heparin therapy (including subcutaneous heparin and heparin flushes, if appropriate). If HIT-related thrombotic complications develop, recombinant hirudin (lepirudin) should be administrated for anticoagulation (33,34) and warfarin therapy should be deferred until the platelet count has risen to >100,000/µl. In addition, further administration of heparin should be avoided.

For most patients with VTE, heparin should be continued for a minimum of 5–7 days. In the absence of contraindications, warfarin should be initiated simultaneously with heparin, and heparin should be continued for at least 4–5 days and until the international normalized ratio (INR) is >=2.0 (grade 1A).

Low-Molecular-Weight Heparins
Low-molecular-weight heparins such as enoxaparin, dalteparin, tinzaparin, and nadroparin have mean molecular weights of 4000 to 5000 daltons, as compared to 15,000 daltons for UFH. Weight-adjusted subcutaneous LMWH administration provides a more reliable and stable level of anticoagulation than UFH, obviating the need for routine laboratory monitoring or subsequent dosage adjustment (35,36). LMWHs are cleared by the kidneys, and these drugs should be used with caution in patients with creatinine clearances <30 cc/min. In the United States, enoxaparin and tinzaparin are approved for the treatment of DVT. Enoxaparin is administered subcutaneously in a dose of 1 mg/kg every 12 hours or 1.5 mg/kg once daily. The dose of tinzaparin is 175 IU/kg once daily for patients weighing 40–100 kg.

Several studies have shown that LMWHs are at least as effective as UFH in preventing recurrent VTE, and the risk of bleeding complications also tends to be lower with LMWHs (37,38). HIT occurs less frequently with LMWHs than with UFH (39), and patients with VTE in the setting of malignancy may derive a modest survival benefit when treated with LMWHs rather than UFH (37,38).

The favorable efficacy and safety profiles of LMWH coupled with their relative ease of use permits outpatient treatment of VTE in selected patients, and two studies have now documented that such treatment is associated with equivalent clinical outcomes compared with hospital-based care and results in substantial cost savings (40,41). Candidates for outpatient treatment of VTE should be clinically and hemodynamically stable with normal vital signs, have a low risk of bleeding, have an estimated creatinine clearance of >=30 cc/min, and have a practical means for administering LMWH and warfarin (42). In addition, a system for surveillance and treatment of recurrent VTE and bleeding complications must be in place. Enlisting the services of a visiting nurse or qualified home health aide to provide drug administration and surveillance may be appropriate to facilitate proper care for older persons who are otherwise suitable candidates for outpatient VTE management. As with intravenous UFH, warfarin should be initiated concomitantly with LMWH, and LMWH should be continued for 5–7 days and until the INR has been therapeutic for 24–48 hours. Despite the low risk of HIT, platelet counts should be monitored periodically in patients receiving LMWH therapy for periods longer than 5–7 days.

Coumarin Derivatives
Coumarin derivatives act in the liver to inhibit the synthesis of four vitamin K-dependent coagulation proteins, factors II, VII, IX, and X, as well as two vitamin K-dependent anticoagulant factors, proteins C and S. In North America, racemic warfarin sodium is the predominant coumarin derivative in use.

Coumarins require several days to achieve their full anticoagulant effect because time is required to clear normal coagulation factors from plasma. In addition, protein C levels decline early after initiating coumarin therapy; as a result, there may be a net procoagulant rather than anticoagulant effect in the first 24–48 hours of treatment (43). Therefore, in treating VTE, heparin therapy in the form of UFH or LMWH must be administered prior to or concomitantly with the initiation of coumarin. Furthermore, "loading" doses of coumarin (warfarin) should be avoided, as this practice may potentiate the procoagulant effect resulting from reduced protein C levels (44).

The therapeutic range for most patients receiving warfarin for treatment of VTE is an INR in the range of 2.0–3.0. Multiple studies indicate that the risk of recurrent VTE increases with INRs less than 2.0, and the risk of bleeding increases progressively with INRs greater than 3.0 (45–47).

Warfarin is metabolized by the hepatic microsomal enzyme pathway, and an important consideration in monitoring the use of warfarin is that numerous drugs, both prescription and over-the-counter preparations (including dietary supplements and herbal products), as well as alcohol, foods rich in vitamin K, and other foodstuffs can substantially alter the anticoagulant response to warfarin (Table 3) (47). Older patients may be particularly prone to adverse drug interactions with warfarin due to the high use of multiple medications, frequent medication changes, and, in some cases, lack of direct control over dietary intake. In general, patients treated with warfarin should be receiving as few other medications as possible, maintain a stable intake of dietary vitamin K, and minimize or avoid alcohol use. Patients should also be advised to notify the physician about any medication changes, as such changes may necessitate closer monitoring of the INR and appropriate adjustment of warfarin dosage.


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  		Table 3. Drug and Food Interactions with Warfarin.

 
The most important complication during long-term warfarin therapy is bleeding. Older age is a risk factor for bleeding (48,49), and concomitant use of nonsteroidal antiinflammatory drugs (NSAIDs) increases the risk of both major and minor bleeding in older adults. In addition, bleeding risk increases progressively with INRs greater than 3.0 (46). To minimize bleeding risk, the INR should be carefully regulated and maintained in the therapeutic range (i.e., 2.0–3.0), and NSAIDs should be avoided whenever feasible. In the absence of bleeding, mildly elevated INRs should be managed by adjusting the warfarin dosage. Marked elevations of the INR (>=5.0), with or without bleeding, should be managed by withholding one or more doses of warfarin and administering 1–2 mg of vitamin K orally or subcutaneously (50). Serious bleeding can be treated with fresh frozen plasma in addition to withholding warfarin and administering vitamin K.

Recommendations for Treatment of Acute VTE
Patients with acute DVT or PE should be treated with intravenous UFH, subcutaneous LMWH, or adjusted dose subcutaneous UFH (all grade 1A), with subcutaneous LMWH being preferred over UFH (grade 2B). When UFH is used, the dose should be sufficient to prolong the aPTT to a range that corresponds to a plasma heparin level of 0.2–0.4 IU/ml by protamine sulfate or 0.3–0.6 IU/ml by an amiodolytic anti-Xa assay (grade 1C+). Treatment with UFH or LMWH should continue for at least 5 days, overlapping with oral anticoagulation for at least 4–5 days (grade 1A) and until the INR has been therapeutic for 24–48 hours. Patients with massive PE or severe iliofemoral thrombus should receive UFH or LMWH for approximately 10 days (grade 1C).

Duration of Treatment
Table 4 summarizes current recommendations for the duration of therapy for VTE. Patients with isolated symptomatic calf vein thrombosis should be treated for at least 6–12 weeks (grade 1A). If antithrombotic therapy is not given, serial noninvasive testing should be performed to assess for proximal extension of thrombus (grade 1C). Patients with a first event (i.e., proximal DVT or PE) associated with a reversible or time-limited risk factor (e.g., surgery or immobilization) should be treated for a period of 3–6 months (grade 1A). Patients with a first event without a modifiable risk factor or other identifiable precipitant (i.e., idiopathic VTE) should be treated for at least 6 months (grade 1A), and patients with recurrent VTE, underlying malignancy, antiphospholipid syndrome, or antithrombin III deficiency should be treated for at least 12 months and may require life-long therapy (grade 1C). Increased age is a risk factor for both recurrent events and hemorrhagic complications. As a result, the duration of therapy should be individualized in older patients, taking into consideration the overall prognosis and goals of treatment (e.g., quality vs quantity of life).


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  		Table 4. Duration of Therapy for Venous Thromboembolism*.

 

   ADDITIONAL THERAPEUTIC OPTIONS
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 Abstract
 Clinical Features
 Pharmacotherapy
 Additional Therapeutic Options
References
 
Thrombolytic Therapy
Thrombolytic agents dissolve thrombus by converting plasminogen to plasmin. In the U.S., streptokinase, urokinase, and alteplase (recombinant tissue plasminogen activator, rtPA) are approved for use in the treatment of VTE.

Early administration of a thrombolytic agent to patients with DVT may result in more rapid resolution of acute symptoms than conventional treatment with heparin and warfarin, and some studies have reported a reduction in postphlebitic syndrome (51–54). However, significant improvements in other clinical outcomes (pulmonary embolization, mortality) have not been demonstrated, and these agents are associated with a 1%–2% incidence of intracranial hemorrhage, with older adults being at greater risk for this complication. As a result, the use of thrombolytic agents in patients with DVT is rarely warranted.

Several clinical trials have evaluated the use of thrombolytic agents for the treatment of PE (55–57). These studies indicate that, compared with heparin, thrombolytic therapy results in more rapid resolution of thromboembolus, greater reduction in pulmonary vascular resistance within the first 24 hours of treatment, and greater improvement in perfusion lung scans at 1–3 days. However, none of these studies have shown a reduction in mortality following thrombolytic treatment, in part because the 3-month mortality rate in patients receiving heparin and warfarin is less than 10%, and any direct beneficial effect of thrombolytic therapy is partially or completely offset by the increased risk of bleeding complications. Based on these considerations, the use of thrombolytic therapy should be reserved for patients with acute massive PE who are hemodynamically unstable (hypotensive) or who have echocardiographic evidence for significant right ventricular dysfunction, and who have a relatively low risk for major hemorrhage (58,59). Since few older adults with PE fulfill these criteria, thrombolytic therapy is used infrequently.

Current dosing recommendations for thrombolytic agents in patients with PE are listed in Table 5. Heparin should not be administered concomitantly with streptokinase or urokinase; concurrent use of heparin with alteplase is optional. In patients receiving streptokinase or urokinase, a thrombin time or aPTT should be obtained 2–4 hours into treatment, with prolongation of either test by >=10 seconds indicating activation of fibrinolysis. Routine monitoring of alteplase is not recommended. Once the infusion of thrombolytic agent has been completed, heparin should be initiated as soon as the aPTT falls below two times the control value.


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  		Table 5. Dosing of Thrombolytic Agents for the Treatment of Pulmonary Embolism.

 
Inferior Vena Caval Procedures
The primary indication for insertion of an inferior vena caval (IVC) filter is the presence of a major contraindication to anticoagulation in an individual at high risk for developing PE due to lower extremity DVT (grade 1C+). Additional indications for IVC filters include recurrent VTE despite adequate anticoagulation, chronic recurrent PE with pulmonary hypertension, acute massive PE, and concurrent performance of pulmonary embolectomy or endarterectomy (grade 1C). Placement of an IVC filter as primary prophylaxis in high-risk patients without documented VTE has not been shown to improve outcomes and is not currently recommended (60).

The most commonly used IVC filter was developed by Greenfield and Rutherford (61). The device can be inserted into the IVC from either the jugular vein or femoral vein under fluoroscopic or ultrasonic guidance. Complication rates are low, and the long-term patency rate is about 98% (61). When feasible, anticoagulation should be administered after placement of an IVC filter, since the filter alone is not an effective treatment for VTE. In patients with upper extremity DVT who have an indication for insertion of a filter, placement of a device in the superior vena cava may be performed (62).

Pulmonary Embolectomy
Emergency pulmonary embolectomy by an experienced cardiac surgical team may be considered in patients with documented massive PE and persistent hemodynamic instability (shock) despite conventional therapy, including the use of a thrombolytic agent (unless contraindicated) (63–65). Perioperative mortality is high, and major complications, including neurocognitive dysfunction, renal failure, and adult respiratory distress syndrome are common. Patients with preexisting cardiopulmonary disease and those who suffer cardiac arrest prior to surgery are at increased risk for adverse outcomes (65).

Catheter-Based Procedures
Catheter-based systems for transvenous extraction of pulmonary emboli have been developed, and preliminary studies indicate that periprocedural mortality in high-risk patients is similar to pulmonary embolectomy, but with less morbidity (66). At the present time, there is insufficient experience with this technique to recommend it for general use. In patients with paradoxical systemic embolization due to patent foramen ovale or ostium secundum atrial septal defect, percutaneous closure of the defect by an experienced interventionalist is an effective therapy (67).

Pulmonary Thromboendarterectomy
A small percentage of patients with PE develop progressive pulmonary hypertension that may be difficult to distinguish clinically from primary pulmonary hypertension (68). In patients with proximal pulmonary artery obstruction, pulmonary thromboendarterectomy may substantially reduce the pulmonary artery pressure and improve functional status and quality of life (69,70).


   Acknowledgments
 
Abstracted from the American College of Chest Physicians Sixth Consensus Conference on Antithrombotic Therapy, Chest. 2001;119:176S–193S.

Address correspondence to Michael W. Rich, MD, Cardiovascular Division, Washington University, 660 S. Euclid Avenue, Box 8086, St. Louis, MO 63110. E-mail: mrich{at}im.wustl.edu

Received June 5, 2003

Accepted June 6, 2003


   References
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 Abstract
 Clinical Features
 Pharmacotherapy
 Additional Therapeutic Options
 References
 

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