Chapter 133: Venous Thrombosis

Gary E. Raskob; Russell D. Hull; Harry R. Buller

INTRODUCTION

SUMMARY

Venous thromboembolism, consisting of deep vein thrombosis and/or pulmonary embolism, is a common disorder with an estimated 900,000 patients each year in the United States and more than 1 million each year in the European Union. Approximately one-third of these cases are fatal pulmonary emboli, and the remaining two-thirds are nonfatal episodes of symptomatic deep vein thrombosis or pulmonary embolism. The majority of fatal events occur as sudden death, underscoring the importance of prevention as the critical strategy for reducing death from pulmonary embolism. Of the nonfatal cases, approximately 60 percent present clinically as deep vein thrombosis and 40 percent present as pulmonary embolism. Most clinically important pulmonary emboli arise from proximal deep vein thrombosis of the leg (popliteal, femoral, or iliac vein thrombosis). Upper-extremity deep vein thrombosis also may lead to clinically important pulmonary embolism. The clinical features of deep vein thrombosis and pulmonary embolism are nonspecific. Objective diagnostic testing is required to confirm or exclude the presence of venous thromboembolism. A validated assay for plasma D-dimer, if available, provides a simple, rapid, and cost-effective first-line exclusion test in patients with low, unlikely, or intermediate clinical probability. Compression ultrasonography is highly sensitive and specific for clinically important deep vein thrombosis and is the primary imaging test for symptomatic patients. Compression ultrasonography of the proximal veins performed at presentation, and if normal, repeated once 5 to 7 days later, can safely exclude clinically important deep vein thrombosis. In centers with the expertise, a single comprehensive evaluation of the proximal and calf veins with duplex ultrasonography is sufficient. In patients with suspected pulmonary embolism, computed tomographic angiography, with or without additional testing using computed tomographic venography or compression ultrasonography of the legs, provides a definitive basis to give or withhold antithrombotic therapy in 90 percent of patients. Anticoagulant therapy is the preferred treatment for most patients with acute venous thromboembolism. Initial treatment with heparin or low-molecular-weight heparin, followed by long-term treatment with an oral vitamin K antagonist such as warfarin, is highly effective for preventing recurrent venous thromboembolism, and has been the traditional standard care. More recently, the direct oral anticoagulants including the thrombin inhibitor dabigatran, and the factor Xa inhibitors rivaroxaban, apixaban, and edoxaban, have been established to be as effective and safer than traditional standard anticoagulant therapy. Rivaroxaban and apixaban can be used as a single drug approach. Dabigatran and edoxaban are preceded by at least 5 days of heparin or low-molecular-weight heparin treatment. The direct oral anticoagulants are preferred over the vitamin K antagonists in most new patients commencing anticoagulant therapy. In cancer patients with venous thromboembolism, treatment with low-molecular-weight heparin for at least 6 months is the recommended approach. Thrombolytic therapy is indicated for patients with pulmonary embolism who present with hypotension or shock, and in selected patients who have impaired right ventricular function who are at high risk of hemodynamic collapse. Insertion of a vena cava filter is indicated for patients who have an absolute contraindication to anticoagulant therapy or who have recurrent venous thromboembolism despite adequate anticoagulant treatment. Anticoagulant treatment should be continued for at least 3 months in all patients, and 3 months is a sufficient duration for patients with first episode of venous thromboembolism secondary to a reversible risk factor. Indefinite anticoagulant therapy should be considered for patients with unprovoked (idiopathic) venous thromboembolism, and those with recurrent venous thromboembolism.

Acronyms and Abbreviations

aPTT, activated partial thromboplastin time; CDT, catheter-directed thrombolysis; CT, computed tomography; CTA, computed tomographic angiography; CTV, computed tomographic venography; DOAC, direct-acting oral anticoagulant; DVT, deep vein thrombosis; ELISA, enzyme-linked immunosorbent assay; INR, international normalized ratio; LMW, low molecular weight; PE, pulmonary embolism; PIOPED, Prospective Investigation of Pulmonary Embolism Diagnosis; VTE, venous thromboembolism.

DEFINITION AND EPIDEMIOLOGY

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Venous thrombosis commonly develops in the deep veins of the leg or the arm or in the superficial veins of these extremities. Venous thrombosis of superficial veins is a relatively benign disorder unless extension into the deep venous system occurs. Confusingly, one of the major deep veins in the leg is called the superficial femoral vein. Thrombosis involving the deep veins of the leg is divided into two prognostic categories: (1) calf vein thrombosis, in which thrombi remain confined to the deep calf veins, and (2) proximal vein thrombosis, in which thrombosis involves the popliteal, femoral, or iliac veins.¹

Pulmonary emboli originate from thrombi in the deep veins of the leg in 90 percent or more of patients. Other less common sources of pulmonary embolism (PE) include the deep pelvic veins, renal veins, inferior vena cava, right side of the heart, and axillary veins. Most clinically important pulmonary emboli arise from proximal deep vein thrombosis (DVT) of the leg. Upper-extremity DVT also may lead to important PE.² DVT and/or PE are referred to collectively as venous thromboembolism (VTE).

VTE is a common disorder.³ The estimated annual incidence of clinically evident VTE ranges between 0.75 and 2.7 per 1000 population based on studies done in North America, Western Europe, Australia, and Argentina.³ The literature indicates a strong and consistent association of increasing incidence of VTE with increasing age. The annual incidence increased to between 2 and 7 per 1000 population among those 70 years of age, and to between 3 and 12 per 1000 population among those 80 years of age or older.³ Although the incidence is lower in individuals of Chinese and Korean ethnicity,³ their disease burden is not low because of population aging. The high incidence of VTE in the elderly likely reflects the high prevalence of comorbid acquired risk factors in these patients, especially malignancy, heart failure, and surgery or hospitalization for medical illness, which account for the majority of the population-attributable risk of VTE in older individuals.

VTE causes a major burden of disease across low-, middle-, and high-income countries. VTE associated with hospitalization was the leading cause of premature death and years lived with disability in low- and middle-income countries, and second in high-income countries, and responsible for more premature death and disability than nosocomial pneumonia, catheter-related bloodstream infections, and adverse drug events.³

The direct ascertainment of deaths from VTE is difficult because of the low rate of autopsy in most countries, and because autopsy studies have consistently demonstrated that PE is often not diagnosed antemortem. The strongest evidence comes from the study by Cohen and colleagues, who used an incidence-based model in six European countries to estimate that there were 534,454 deaths related to VTE across the European Union in 2004.⁴ A similar approach applied to the data from the United States suggested approximately 300,000 deaths from VTE each year.⁵ The majority of deaths from VTE occur as sudden death, underscoring the critical role of prevention for reducing death from VTE.

Effective prophylaxis against VTE is available for most high-risk patients. Use of prophylaxis is more effective for preventing death and morbidity from VTE than is treatment of the established disease. Evidence-based recommendations for prevention are available.^6,7,8,9 Multifaceted interventions with alerts, such as computerized reminders or stickers on patient charts, are effective for increasing the prescription of appropriate thromboprophylaxis in hospitalized adult medical or surgical patients.¹⁰ There is also evidence that inclusion of VTE risk assessment at the time of hospital admission and the provision of appropriate prophylaxis is effective for reducing VTE-related death and readmission with nonfatal VTE.^11,12

Historically, the majority of the disease burden from VTE occurred in hospitalized patients. The burden of illness from VTE has shifted to the community setting such that most patients now present as outpatients to their primary care physician or to the emergency department. The main reason for this shift is the greatly reduced length of hospital stay for most surgical procedures or medical conditions, such that patients are discharged from the hospital either before the period of risk of VTE has ended or who have subclinical venous thrombi that subsequently evolve to symptomatic DVT or PE. The shift in burden of illness from the hospital to the community setting has led to an emphasis on effective and safe methods for outpatient prophylaxis, diagnosis and treatment.

ETIOLOGY AND PATHOGENESIS

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Venous thrombi are composed mainly of fibrin and red blood cells, with variable numbers of platelets and leukocytes. The formation, growth, and breakdown of venous thromboemboli reflect a balance between thrombogenic stimuli and protective mechanisms. The thrombogenic stimuli first identified by Virchow in the 19th century are (1) venous stasis, (2) activation of blood coagulation, and (3) vascular damage. The protective mechanisms are (1) inactivation of activated coagulation factors by circulating inhibitors (e.g., antithrombin and activated protein C), (2) clearance of activated coagulation factors and soluble fibrin polymer complexes by mononuclear phagocytes and the liver, and (3) lysis of fibrin by fibrinolytic enzymes derived from plasma and endothelial cells.

PE occurs in at least 50 percent of patients with documented proximal vein thrombosis.¹ Many of these emboli are asymptomatic. The clinical importance of PE depends on the size of the embolus and the patient’s cardiorespiratory reserve. Usually only part of the thrombus embolizes, and 30 to 70 percent of patients with PE detected by angiography also have identifiable DVT of the legs.^13,14 DVT and PE are not separate disorders but a continuous syndrome of VTE in which the initial clinical presentation may be symptoms of either DVT or PE. Therefore, strategies for diagnosis of VTE include both tests for detection of PE (e.g., computed tomography [CT] or lung scanning)^13,14,15,16 and tests for DVT of the legs (e.g., ultrasonography)^17,18,19 (see “Objective Testing for Pulmonary Embolism” and “Objective Testing for Deep Vein Thrombosis” below).

Acquired and inherited risk factors for VTE have been identified^20,21,22,23 and are shown in Table 133–1 (Chap. 130). Aging is the dominant risk factor for VTE (population attributable risk >90 percent).²³ Comorbidities, such as malignancy and heart failure, contribute to a higher population-attributable risk in older patients (≥65 years).²³ The risk of VTE increases when more than one risk factor is present.²⁴

Table 133–1.Risk Factors for Thromboembolism^*

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Table 133–1. Risk Factors for Thromboembolism^*

Acquired

Hereditary Thrombophilias^*

Advancing age (age >40 years)

Activated protein C resistance

History of prior thromboembolic event

Prothrombin G20210A

Recent surgery

Antithrombin deficiency

Recent trauma

Protein C deficiency

Prolonged immobilization

Protein S deficiency

Certain forms of cancer

Dysfibrinogenemia

Congestive heart failure

Recent myocardial infarction

Paralysis of legs

Use of female hormones

Pregnancy or postpartum period

Varicose veins

Obesity

Antiphospholipid antibody syndrome^**

Hyperhomocysteinemia

^*See also Chap. 130

^**See also Chap. 131

Activated protein C resistance is the most common hereditary abnormality predisposing to VTE. The defect results from substitution of glutamine for arginine at residue 506 in the factor V molecule, making factor Va resistant to proteolysis by activated protein C. The gene mutation is commonly designated factor V Leiden and follows autosomal dominant inheritance. Patients who are homozygous for the factor V Leiden mutation have a markedly increased risk of VTE and present with clinical thromboembolism at a younger age (median age: 31 years) than those who are heterozygous (median age: 46 years).^20,22 Factor V Leiden is present in approximately 5 percent of the normal population of European descent, 16 percent of patients with a first episode of DVT, and up to 35 percent of patients with unprovoked (idiopathic) DVT.^20,22,25 Prothrombin G20210A is another common gene mutation that predisposes to VTE. It is present in approximately 2 to 3 percent of apparently healthy individuals and in 7 percent of those with DVT.²² An inherited abnormality cannot be detected in up to 40 to 50 percent of patients with unprovoked DVT, suggesting that as yet undefined gene mutations are present that have an etiologic role (Chap. 130).

CLINICAL FEATURES

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VENOUS THROMBOSIS

The clinical features of DVT include leg pain, tenderness, and swelling, a palpable cord representing a thrombosed vessel, discoloration, venous distention, prominence of the superficial veins, and cyanosis. The clinical diagnosis of DVT is highly nonspecific because each of the symptoms or signs can be caused by nonthrombotic disorders. The rare exception is the patient with phlegmasia cerulea dolens (occlusion of the whole venous circulation, extreme swelling of the leg, and compromised arterial flow), in whom the diagnosis of massive iliofemoral thrombosis is obvious. This syndrome occurs in less than 1 percent of patients with symptomatic venous thrombosis. In most patients, the symptoms and signs are nonspecific. In 50 to 85 percent of patients, the clinical suspicion of DVT is not confirmed by objective testing.^17,18,19 Patients with minor symptoms and signs may have extensive deep venous thrombi. Conversely, patients with florid leg pain and swelling, suggesting extensive DVT, may have negative results by objective testing.

Although the clinical diagnosis is nonspecific, prospective studies have established that patients can be categorized as low, moderate, or high probability for DVT using a clinical prediction rule that incorporates signs, symptoms, and risk factors. A systematic review²⁶ of the studies found that the prevalence of DVT in the low, moderate, and high probability categories, respectively, was 5 percent (95 percent confidence interval [95% CI]: 4 to 8 percent), 17 percent (95% CI: 13 to 23 percent), and 53 percent (95% CI: 44 to 61 percent). The prevalence in the pretest category of “low probability” is not sufficiently low to withhold further diagnostic testing and treatment, and the prevalence in the “high probability” category is not sufficiently high to give anticoagulant therapy without performing further diagnostic testing. Consequently, the key role for clinical pretest categorization is for use within integrated diagnostic strategies employing measurement of D-dimer and venous imaging.

PULMONARY EMBOLISM

The clinical features of acute PE include the following symptoms and signs that may overlap: (1) transient dyspnea and tachypnea in the absence of other clinical features; (2) pleuritic chest pain, cough, hemoptysis, pleural effusion, and pulmonary infiltrates noted on chest radiogram caused by pulmonary infarction or congestive atelectasis (also known as ischemic pneumonitis or incomplete infarction); (3) severe dyspnea and tachypnea and right-side heart failure; (4) cardiovascular collapse with hypotension, syncope, and coma (usually associated with massive PE); and (5) several less common and nonspecific clinical presentations, including unexplained tachycardia or arrhythmia, resistant cardiac failure, wheezing, cough, fever, anxiety/apprehension, and confusion. All of these clinical features are nonspecific and can be caused by a variety of cardiorespiratory disorders. Patients can be assigned to categories of pretest probability using implicit clinical judgement, or clinical decision rules such as the Geneva score or approach of Wells.^27,28,29,30 However, the prevalences of PE in these categories are not sufficiently low or high to withhold further investigation altogether, and the measurement of D-dimer and/or diagnostic imaging is mandatory to exclude or confirm the presence of PE. The assessment of clinical pretest probability is an important first step in integrated diagnostic strategies that employ, for example, D-dimer, computed tomographic angiography (CTA), and objective testing for DVT.^27,28,29,30

LABORATORY FEATURES

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VTE is associated with nonspecific laboratory changes that constitute the acute-phase response to tissue injury. This response includes elevated levels of fibrinogen and factor VIII, increases in leukocyte and platelet counts, and systemic activation of blood coagulation, fibrin formation, and fibrin breakdown, with increases in plasma concentrations of prothrombin fragment 1.2, fibrinopeptide A, complexes of thrombin–antithrombin, and fibrin degradation products. All of these changes are nonspecific and may occur as a result of surgery, trauma, infection, inflammation, or infarction. None of the above reported laboratory changes can be used to establish the diagnosis of VTE or predict its development with high probability. The fibrin breakdown fragment D-dimer can be measured by an enzyme-linked immunosorbent assay (ELISA) or by a latex agglutination assay. Some of these assays have a rapid turnaround time and some are quantitative. A negative D-dimer result is useful for excluding the diagnosis in many patients with suspected DVT or suspected PE (see “Objective Testing for Deep Vein Thrombosis” and “Objective Testing for Pulmonary Embolism” below).^16,27,28,31 A positive result is highly nonspecific.

DIFFERENTIAL DIAGNOSIS OF DEEP VEIN THROMBOSIS

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The differential diagnosis in patients with clinically suspected DVT includes muscle strain or tear, direct twisting injury to the leg, lymphangitis or lymphatic obstruction, venous reflux, popliteal cyst, cellulitis, leg swelling in a paralyzed limb, and abnormality of the knee joint. An alternate diagnosis frequently is not evident at presentation, so excluding DVT is not possible without objective testing. The cause of symptoms often can be determined by careful followup once DVT has been excluded by objective testing. In approximately 25 percent of patients, however, the cause of pain, tenderness, and swelling remains uncertain even after careful followup.¹⁹

OBJECTIVE TESTING FOR DEEP VEIN THROMBOSIS

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D-DIMER ASSAY

Measurement of plasma D-dimer has been extensively evaluated as an exclusion test in patients with clinically suspected DVT.³¹ The different D-dimer assays (ELISA, quantitative rapid ELISA, latex agglutination, and whole-blood agglutination) have different sensitivities, specificities, and likelihood ratios for DVT. ELISA and quantitative rapid ELISA have high sensitivity (96 percent) and negative likelihood ratios of approximately 0.10 for DVT in symptomatic patients. Thus, for excluding DVT in symptomatic patients with a low or intermediate clinical pretest probability, a negative D-dimer result by a quantitative rapid ELISA technique is as diagnostically useful as a negative result by duplex ultrasonography.³¹ Measurement of D-dimer using an appropriate assay method can also be combined with ultrasonography imaging. If the two tests are negative at presentation, repeat ultrasonography imaging is unecessary.³² Use of the D-dimer test for patient care decisions depends on the local availability of an appropriate assay that has high sensitivity and has been validated by clinical outcome studies. The use of age-adjusted D-dimer cut-off levels for a negative result enhance the clinical utility of the test. Figure 133–1 shows a practical approach for the diagnosis of suspected DVT.

Figure 133–1.

Diagnosis of patients with suspected first episode of deep vein thrombosis (DVT). ^*Negative D-dimer can be used to exclude acute DVT, without the need for further diagnostic testing with compression ultrasonography (CUS), if the patient has low, unlikely, moderate, or intermediate clinical probability.^26,31 Ultrasonography should be performed in patients with a high clinical probability. A negative D-dimer can also be used with a negative CUS at presentation to exclude acute DVT without the need for a repeat CUS.^32,34 ^**CUS is performed with imaging of the common femoral vein in the groin and of the popliteal vein in the popliteal fossa extending distally 10 cm from midpatella. A repeat CUS is required in 5 to 7 days to detect extending calf vein thrombi.¹⁷ In centers with the expertise, a single negative result of full-leg duplex ultrasonography (CUS plus flow evaluation) is sufficient to exclude acute DVT.^18,34 ^‡CUS that indicates noncompressibility of deep vein segments is highly predictive of DVT (>95%) and provides an indication for antithrombotic therapy in most patients. If CUS is positive at a single site isolated in the groin, additional testing with venography, computed tomography, or magnetic resonance imaging should be performed because of the potential for false-positive CUS results from disorders producing vein compression in the groin (e.g., tumor mass).

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IMAGING TESTS

The objective diagnostic imaging tests that have a role in patients with clinically suspected DVT are ultrasonography and venography. Both of these tests have been validated by properly designed clinical trials, including prospective studies with long-term followup that have established the safety of withholding anticoagulant treatment in patients with negative test results.^17,18,19,33 Ultrasonography is the preferred imaging test for most patients. The role of venography is for selected patients, such as those in whom ultrasonography is unavailable or inconclusive. Ultrasonography using vein compression is effective for identifying patients with proximal vein thrombosis. Compression ultrasonography of the proximal veins performed at presentation (and, if normal, repeated once 5 to 7 days later) is a safe approach in symptomatic patients.¹⁷ In centers with experienced ultrasonography staff, a single comprehensive evaluation of the proximal and calf veins with duplex ultrasonography is sufficient and, if negative, a repeat test is not required.¹⁸ A randomized trial supports the equivalence of a comprehensive whole-leg color-coded Doppler ultrasonography approach to that of an approach using combined D-dimer testing and repeated ultrasonography for the management of suspected DVT.³⁴

The positive predictive value of a positive ultrasonography result isolated to the calf veins may vary among centers based on expertise and thrombosis prevalence. Therefore, the number of repeat ultrasonography evaluations avoided by evaluating the calf veins may be partially offset by an increased number of patients with positive ultrasonography results confined to the calf, for whom additional diagnostic testing and/or anticoagulant treatment is required. Most patients with a negative ultrasonographic result at presentation require a followup visit to establish the alternate diagnosis and to guide further care, so the return visit for repeat ultrasonography at 5 to 7 days may have added practical value.¹⁷

Diagnosis of acute recurrent DVT is particularly challenging because recurrent symptoms such as pain and swelling are common in patients with DVT despite adequate anticoagulant therapy, and because both ultrasonography and venography have limitations for excluding the presence of acute recurrent DVT.³⁵ Compression ultrasonography may remain abnormal for 1 year in 50 percent of patients, and for even longer in some patients,³⁶ because of persistent noncompressibility of the vein caused by fibrous organization of the original thrombus. Venography is of limited value for excluding the diagnosis of recurrent DVT because of obliteration or recanalization of the previously affected venous segments or nonfilled venous segments. Thus, measurement of plasma D-dimer may be particularly useful as an exclusion test in patients with suspected acute recurrent DVT. However, use of D-dimer must be evaluated separately in this patient group because many patients with a past history of VTE are receiving long-term oral anticoagulant therapy, which has the potential to cause a false-negative D-dimer result. Promising initial results were obtained in one study,³⁷ but further studies in larger numbers of patients are needed before using a negative D-dimer alone to exclude acute recurrent DVT can be routinely recommended.

DIFFERENTIAL DIAGNOSIS OF PULMONARY EMBOLISM

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The differential diagnosis in patients with suspected PE includes cardiopulmonary disorders for each of the modes of presentation (see “Pulmonary Embolism” above). For the presentation of dyspnea and tachypnea, they include atelectasis, pneumonia, pleuritis, pneumothorax, acute pulmonary edema, bronchitis, bronchiolitis, and acute bronchial obstruction. For pulmonary infarction exhibited by pleuritic chest pain or hemoptysis, they include pneumonia, pneumothorax, pericarditis, pulmonary or bronchial neoplasm, bronchiectasis, acute bronchitis, tuberculosis, diaphragmatic inflammation, myositis, muscle strain, and rib fracture. For the clinical presentation of right-side heart failure, they include myocardial infarction, myocarditis, and cardiac tamponade. For cardiovascular collapse, they include myocardial infarction, acute massive hemorrhage, Gram-negative septicemia, cardiac tamponade, and spontaneous pneumothorax.

OBJECTIVE TESTING FOR PULMONARY EMBOLISM

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The objective diagnostic imaging tests include CT, CTA, radionuclide lung scanning, selective pulmonary arteriography, and objective testing for DVT. Measurement of plasma D-dimer is useful as an exclusion test in patients with an unlikely or intermediate clinical probability.

D-DIMER ASSAY

The assay for plasma D-dimer is useful as an exclusion test, provided an appropriately validated test is available. A negative result by the rapid quantitative ELISA for D-dimer has a negative likelihood ratio similar to that of a normal perfusion scan.³¹ A positive D-dimer result is not useful diagnostically. Several management studies have found that PE can be excluded without performing imaging studies in patients with a low, intermediate, or unlikely clinical probability.³⁸ When combined with pretest clinical probability assessment, the use of an age-adjusted D-dimer cutoff value instead of a fixed D-dimer cutoff of 500 mcg/mL, improves the utility of the test, and enables more patients to have the diagnosis of PE safely excluded.³⁹

COMPUTED TOMOGRAPHY IMAGING AND ANGIOGRAPHY

CT imaging is the primary imaging test for the diagnosis of PE in most centers. Single-detector spiral CT is highly sensitive for large emboli (segmental or larger arteries), but is much less sensitive for emboli in subsegmental pulmonary arteries^16,40; such emboli may be clinically important in patients with severely impaired cardiorespiratory reserve. Therefore, a negative result by single-detector spiral CT should not be used alone to exclude the diagnosis of PE. A filling defect of a segmental or larger artery on single-detector spiral CT is associated with a high probability (>90 percent) of PE.⁴⁰

The development of multidetector row CT, together with the use of contrast enhancement, has established CT as the preferred diagnostic imaging test in most patients.^41,42,43 Contrast-enhanced CTA has the advantage of providing clear results (positive or negative), with a low rate of nondiagnostic test results, good characterization of nonvascular structures for alternate or associated diagnoses, and the ability to simultaneously evaluate the deep venous system of the legs (computed tomographic venography [CTV]).

The accuracy and clinical utility of multidetector CTA and combined CTA-CTV were evaluated in the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) II study.⁴³ Among 824 patients with a reference diagnosis and a completed CT study, CTA was inconclusive in 51 (6 percent) because of poor image quality. The sensitivity of CTA was 83 percent and the specificity was 96 percent. CTA-CTV was inconclusive in 87 (11 percent) of 824 patients because the image quality of either CTA or CTV was poor. Multidetector CTA-CTV had a higher sensitivity (90 percent) than CTA alone (83 percent), with similar specificity (~95 percent for both testing techniques). Positive results on CTA in combination with a high probability or intermediate probability of PE by the clinical assessment, or normal findings on CTA with a low clinical probability had a predictive value (positive or negative) of 92 to 96 percent.⁴³ Such values are consistent with those generally considered adequate to confirm or rule out the diagnosis of PE. Additional testing is necessary when the clinical probability is discordant with CTA or CTA-CTV imaging results.⁴³

Figure 133–2 summarizes the approach to diagnosis of suspected PE using CTA or CTA-CTV as the primary imaging test. A high-quality image by CTA is sufficient to establish or exclude the diagnosis of PE with high predictive value in most patients, and withholding anticoagulant therapy based on a negative CTA alone is associated with a low rate of subsequent VTE on followup.⁴⁴ Objective testing for DVT is useful in patients in whom the CTA image is of poor quality or inconclusive, and in patients who also have symptoms suggesting DVT. CTV has the advantage of being easily performed at the time of CTA, but incurs the risk of added radiation exposure for the patient. Compression ultrasonography can also be used, and avoids added radiation exposure and can be performed serially if needed.

Figure 133–2.

Integrated strategy for diagnosis of patients with suspected pulmonary embolism (PE) using computed tomographic angiography (CTA) as the primary imaging test. ^*Negative D-dimer alone can be used as an exclusion test with high negative predictive value (>96%) in patients with low or moderate probability by the clinical assessment.^27,30,31 Patients with a high clinical probability should undergo imaging with CTA or combined CTA-computed tomographic venography (CTV). ^**Positive results on CTA or combined CTA-CTV, in patients with a high or moderate probability of pulmonary embolism by the clinical assessment, have positive predictive value of 90% or more for venous thromboembolism. Similarly, abnormal results by compression ultrasonography (CUS) of the proximal deep veins of the legs have high positive predictive value for proximal vein thrombosis and provide an indication to give antithrombotic therapy. If the patient has a low probability by the clinical assessment, positive results by CTA or CTA-CTV in the main or lobar pulmonary arteries are still highly predictive (97%) for the presence of pulmonary embolism⁴³; further testing is recommended for patients with low clinical probability and positive CTA results only of segmental or subsegmental arteries, and the options include pulmonary arteriography or serial CUS. ^‡Negative results by CTA or by combined CTA-CTV have high negative predictive value (96%) in patients with low probability by the clinical assessment.⁴³ For patients with moderate clinical probability, the negative predictive value for combined CTA-CTV is also high (92%), but slightly lower for CTA alone (89%)⁴³; in CTA-alone group, and in patients with a high probability by the clinical assessment, serial CUS or pulmonary arteriography are recommended options.

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RADIONUCLIDE LUNG SCANNING

Radionuclide lung scanning continues to have a role in the diagnosis of suspected PE A normal perfusion lung scan excludes the diagnosis of clinically important PE.^15,45 A normal perfusion lung scan is found in approximately 10 percent of all patients with suspected PE seen at academic health centers or tertiary referral centers. A high-probability lung scan result (i.e., large perfusion defects with ventilation mismatch) has a positive predictive value for PE of 85 percent and provides a diagnostic end point to give antithrombotic treatment in most patients.^15,46,47 A high-probability lung scan is found in approximately 10 to 15 percent of symptomatic patients. For patients with a history of PE, careful comparison of the lung scan results to the most recent lung scan is required to ensure the perfusion defects are new. Further diagnostic testing is indicated for patients with a high-probability lung scan who have a “low” pretest clinical suspicion, and in those who are at high risk for major bleeding, to reduce the likelihood of a false-positive diagnosis.

The major limitation of lung scanning is that the results are inconclusive in most patients, even when considered together with the pretest clinical probability.¹⁵ The nondiagnostic lung scan patterns are found in approximately 70 percent of all patients with suspected PE.^13,15,47 These lung scan results have historically been called “low probability” (matching ventilation–perfusion abnormalities or small perfusion defects), “intermediate probability,” or “indeterminate” (because the perfusion defects correspond to an area of abnormality on chest radiograph). Further diagnostic testing is required in most of these patients because, regardless of the pretest clinical suspicion, the posttest probabilities of PE associated with these lung scan results are neither sufficiently high to give antithrombotic treatment nor sufficiently low to withhold therapy. The uncommon exception is the patient with a low clinical suspicion and a so-called low-probability lung scan result. However, even in these patients, objective testing for DVT with ultrasonography and/or measurement of plasma D-dimer is without risk for the patient and may provide added diagnostic value (see “Objective Testing for Deep Vein Thrombosis” below). A randomized trial has established that CTA is not inferior to using ventilation–perfusion lung scanning for excluding the diagnosis of PE when either test is used in an algorithm together with venous ultrasonography of the legs.⁴⁸

In centers where CTA is available, the major role for lung scanning is in select patients; for example, in younger women to reduce radiation exposure to the breast. Lung scanning can be useful in such patients who are less likely to have comorbid cardiorespiratory disorders and therefore a higher proportion of diagnostic scan results (normal or high probability).

MAGNETIC RESONANCE ANGIOGRAPHY

The accuracy of magnetic resonance angiography for diagnosing PE, with or without the addition of magnetic resonance venography, was evaluated in the PIOPED III study.⁴⁹ This was a prospective study of 371 adults with suspected PE recruited from seven hospitals and their emergency services. Magnetic resonance angiography was technically inadequate in 25 percent of patients (92 of 371); this rate ranged from 11 percent to 52 percent among the centers. If a technically adequate image was obtained, magnetic resonance angiography had a sensitivity of 78 percent and a specificity of 99 percent, and combined magnetic resonance angiography and venography had a sensitivity of 92 percent and a specificity of 96 percent. However, 52 percent of patients (194 of 370) had technically inadequate results with the combined approach.⁴⁹ Based on these findings, magnetic resonance angiography has a very limited role in the diagnosis of PE. In centers that routinely perform it well with a high rate of technically adequate images, magnetic resonance angiography and venography may be useful for patients in whom CTA or lung scanning are contraindicated.

PULMONARY ANGIOGRAPHY

Pulmonary angiography using selective catheterization of the pulmonary arteries is a relatively safe technique for patients who do not have pulmonary hypertension or cardiac failure.^13,15 If the expertise is available, pulmonary angiography should be used when other approaches are inconclusive and when definitive knowledge about the presence or absence of PE is required, because the risk of angiography in properly selected patients is less than the risk of unnecessary anticoagulant therapy.

OBJECTIVE TESTING FOR DEEP VEIN THROMBOSIS

Objective testing for DVT is useful in patients with suspected PE, particularly those with nondiagnostic lung scan results^33,47 or inconclusive CT results.⁵⁰ Detection of proximal vein thrombosis by objective testing provides an indication for anticoagulant treatment, regardless of the presence or absence of PE, and prevents the need for further testing. However, a negative result by objective testing for DVT does not exclude the presence of PE.^13,14 If the patient has adequate cardiorespiratory reserve, then serial ultrasonography testing for proximal vein thrombosis can be used as an alternative to pulmonary angiography in patients with nondiagnostic lung scan or inconclusive CT results, and withholding anticoagulant therapy is safe if repeated ultrasonography testing of the legs is negative.^33,47,50 The rationale is that the clinical objective in such patients is to prevent recurrent PE, which is unlikely in the absence of proximal vein thrombosis. Selective pulmonary angiography should be done among patients with features suggesting a possible alternate source of embolism to proximal DVT of the leg (e.g., upper-extremity thrombosis, renal vein thrombosis, pelvic vein thrombosis, or right-heart thrombus).

THERAPY, COURSE, AND PROGNOSIS

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CLINICAL COURSE OF VENOUS THROMBOEMBOLISM

Proximal Vein Thrombosis

Proximal vein thrombosis is a serious and potentially lethal condition. Untreated proximal vein thrombosis is associated with a 10 percent rate of fatal PE. Inadequately treated proximal vein thrombosis results in a 20 to 50 percent risk of recurrent VTE events.⁵¹ Prospective studies of patients with clinically suspected DVT or PE indicate that new VTE events on followup are uncommon (≤2 percent) among patients in whom proximal vein thrombosis is absent by objective testing.^{17,32,33,47,50} The aggregate data from diagnostic and treatment studies indicate that the presence of proximal vein thrombosis is the key prognostic marker for recurrent VTE.

Calf Vein Thrombosis

Thrombosis that remains confined to the calf veins is associated with low risk (≤1 percent) of clinically important PE. Extension of thrombosis into the popliteal vein or more proximally occurs in 15 to 25 percent of patients with untreated calf vein thrombosis.¹ Patients with documented calf vein thrombosis should either receive anticoagulant treatment to prevent extension or undergo monitoring for proximal extension using serial ultrasonography.

Postthrombotic Syndrome

The postthrombotic syndrome is a frequent complication of DVT.⁵² Patients with the postthrombotic syndrome complain of pain, heaviness, swelling, cramps, and itching or tingling of the affected leg. Ulceration may occur. The symptoms usually are aggravated by standing or walking and improve with rest and elevation of the leg. A prospective study documented a 25 percent incidence of moderate-to-severe postthrombotic symptoms 2 years after the initial diagnosis of proximal vein thrombosis in patients who were treated with initial heparin and oral anticoagulants for 3 months.⁵³ The study also demonstrated that ipsilateral recurrent venous thrombosis is strongly associated with subsequent development of moderate or severe postthrombotic symptoms. Thus, prevention of ipsilateral recurrent DVT likely reduces the incidence of the postthrombotic syndrome. Application of a properly fitted graded compression stocking, as soon after diagnosis as the patient’s symptoms will allow, can improve edema and pain in the acute stage of DVT and may also help control or relieve symptoms in patients who develop the postthrombotic syndrome. Conflicting findings have been found in randomized trials of graded compression stockings for preventing the development of the postthrombotic syndrome.^54,55

Chronic Thromboembolic Pulmonary Hypertension

Chronic thromboembolic pulmonary hypertension is a serious complication of PE. Historically, thromboembolic pulmonary hypertension was believed to be relatively rare and to occur only several years after the diagnosis of PE. A prospective cohort study provides important information on the incidence and timing of thromboembolic pulmonary hypertension.⁵⁶ The results indicate that thromboembolic pulmonary hypertension is more common and occurs earlier than previously thought. On prospective followup of 223 patients with documented PE, the cumulative incidence of chronic thromboembolic pulmonary hypertension was 3.8 percent at 2 years after diagnosis, despite state-of-the-art treatment for PE. The strongest independent risk factors were a history of PE (odds ratio: 19) and idiopathic PE at presentation (odds ratio: 5.7).⁵⁶

OBJECTIVES AND PRINCIPLES OF ANTITHROMBOTIC TREATMENT

The objectives of treatment in patients with established VTE are to (1) prevent death from PE, and (2) prevent morbidity from recurrent DVT or PE, especially the postthrombotic syndrome and chronic pulmonary hypertension.

For most patients, these objectives are achieved by providing adequate anticoagulant treatment. Thrombolytic therapy is indicated in selected patients (see “Thrombolytic Therapy” below). Use of an inferior vena cava filter is indicated to prevent death from PE in patients in whom anticoagulant treatment is absolutely contraindicated and in other selected patients (see “Anticoagulant Therapy” below). These recommendations and those below are linked to the strength of the evidence from clinical trials and evidence-based guidelines.^9,30,57,58

ANTICOAGULANT THERAPY

Anticoagulant therapy is the treatment of choice for most patients with proximal vein thrombosis or PE.^9,57,58 Patients with proximal DVT require both adequate initial anticoagulant treatment with heparin or low-molecular-weight (LMW) heparin and adequate long-term anticoagulant therapy to prevent recurrent VTE.^51,59,60 Anticoagulant therapy for at least 3 months is required to prevent a high frequency (15 to 25 percent) of symptomatic extension of thrombosis and/or recurrent venous thromboembolic events.^51,60,61 Adequate anticoagulant treatment reduces the incidence of recurrence during the first 3 months after diagnosis to 5 percent or less.^51,59,60,61

The absolute contraindications to anticoagulant treatment include intracranial bleeding, severe active bleeding, recent brain, eye, or spinal cord surgery, and malignant hypertension. Relative contraindications include recent major surgery, recent cerebrovascular accident, active gastrointestinal tract bleeding, severe hypertension, severe renal or hepatic failure, and severe thrombocytopenia (platelets <50 × 10⁹/L).

Parenteral Anticoagulants

Heparin and Low-Molecular-Weight Heparin Initial therapy with continuous intravenous heparin was the standard approach to treatment of VTE during the 1970s and 1980s. During the 1990s, LMW heparin given by subcutaneous injection once or twice daily was evaluated by clinical trials and shown to be as effective and safe as continuous intravenous heparin for the initial treatment of patients with proximal DVT and submassive PE.^57,58,62 The advantage of LMW heparin is that it does not require anticoagulant monitoring. LMW heparin given subcutaneously once or twice daily is preferred over intravenous unfractionated heparin for the initial treatment of most patients with either DVT or PE.^57,58 LMW heparin enables outpatient therapy for many patients with uncomplicated DVT and selected patients with PE. Intravenous unfractionated heparin remains a useful approach for initial anticoagulant therapy in patients with severe renal failure. Initial treatment with LMW heparin or unfractionated heparin should be continued for at least 5 days. Table 133–2 lists the specific LMW heparin regimens for the treatment of VTE.

Table 133–2.Anticoagulant Drug Regimens for Treatment of Venous Thromboembolism

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Table 133–2. Anticoagulant Drug Regimens for Treatment of Venous Thromboembolism

Drug

Regimen

LOW-MOLECULAR-WEIGHT HEPARINS

Enoxaparin

1.0 mg/kg BID^*

Dalteparin

200 IU/kg once daily^†

Tinzaparin

175 IU/kg once daily^‡

Nadroparin

6150 IU BID for 50–70 kg

4100 IU BID if patient weighs <50 kg

9200 IU BID if patient weighs >70 kg

Reviparin

4200 IU BID for 46–60 kg

3500 IU BID if patient weighs 35–45 kg

6300 IU BID if patient weighs >60 kg

INDIRECT FACTOR Xa INHIBITOR

Fondaparinux

7.5 mg once daily if patient weight 50–100 kg

5.0 mg once daily if patient weight <50 kg

10.0 mg once daily if patient weight >100 kg

DIRECT ORAL ANTICOAGULANTS

Dabigatran

150 mg BID after 5 days of parenteral low-molecular-weight heparin or heparin

Rivaroxaban

15 mg BID for 21 days, then 20 mg once daily

Taken with food

Apixaban

10 mg BID for 7 days, then 5 mg BID

After 6 months, 2.5 mg BID for extended therapy

Edoxaban

60 mg once daily after 5 days of parenteral low-molecular-weight heparin or heparin^§

^*A once-daily regimen of 1.5 mg/kg can be used but probably is less effective in patients with cancer.

^†After 1 month, can be followed by 150 IU/kg once daily as an alternative to an oral vitamin K antagonist for long-term treatment.

^‡This regimen can also be used for long-term treatment as an alternative to an oral vitamin K antagonist.

^§30 mg once daily if patient’s creatinine clearance is 30–50 mL/min or weight is ≤60 kg or if patient is taking strong P-glycoprotein inhibitor drugs.

If unfractionated heparin is used for initial therapy, it is important to achieve an adequate anticoagulant effect, defined as an activated partial thromboplastin time (aPTT) above the lower limit of therapeutic range within the first 24 hours.^63,64 Failure to achieve an adequate aPTT effect early during therapy is associated with a high incidence (25 percent) of recurrent VTE.⁶³ Two-thirds of the recurrent events occur between 2 and 12 weeks after the initial diagnosis despite treatment with oral anticoagulants, and the initial management with either unfractionated heparin or LMW heparin is critical to the patient’s long-term outcome.^63,64

Fondaparinux The synthetic pentasaccharide fondaparinux, which is an indirect inhibitor of factor Xa, has been evaluated by large randomized clinical trials.^65,66 These studies indicate fondaparinux is as effective and safe as LMW heparin for treatment of established DVT and as effective and safe as intravenous heparin for treatment of symptomatic PE. Fondaparinux is given subcutaneously once daily at a dose of 7.5 mg for patients weighing between 50 and 100 kg (85 percent of all patients evaluated in the clinical trials), 5 mg for patients weighing less than 50 kg, and 10 mg for patients weighing more than 100 kg.^65,66

Oral Anticoagulants

Vitamin K Antagonists Oral anticoagulant treatment using a vitamin K antagonist (e.g., sodium warfarin) has been the standard approach for long-term treatment in most patients for more than 60 years. Treatment with a vitamin K antagonist is started with initial heparin or LMW heparin therapy and overlapped for 4 to 5 days.

The preferred intensity of the anticoagulant effect of treatment with a vitamin K antagonist has been established by clinical trials.^69,70,71,72 The dose of vitamin K antagonist should be adjusted to maintain the international normalized ratio (INR) between 2.0 and 3.0. High-intensity vitamin K antagonist treatment (INR 3.0 to 4.0) should not be used because it has not improved effectiveness in patients with the antiphospholipid syndrome and recurrent thrombosis⁷¹ and has caused more bleeding.⁷² Low-intensity therapy (INR 1.5 to 1.9) is not recommended because it is less effective than standard-intensity treatment (INR 2.0 to 3.0) and does not reduce bleeding complications.⁷⁰

Long-term treatment with LMW heparin is indicated for select patients in whom vitamin K antagonists are contraindicated (e.g., pregnant women), and in patients with concurrent cancer for whom LMW heparin regimens are more effective.^67,68

Direct Oral Anticoagulants Oral anticoagulants that bind directly to the target coagulation enzyme of either thrombin or factor Xa have been evaluated in phase III clinical trials for the treatment of patients with VTE (Chap. 25).^{73,74,75,76,77,78} The advantages of these drugs are: (1) they can be administered orally once or twice daily without the need for anticoagulant monitoring and dose titration; (2) they have fewer clinically relevant drug interactions; (3) because of a fast onset of anticoagulant action, similar to that of LMW heparin, they can simplify treatment for many patients by replacing the standard approach of a parenteral drug (heparin, LMW heparin or fondaparinux) followed by an oral vitamin K antagonist with a single drug given for both initial and long-term therapy; and (4) they result in less clinically important bleeding. Table 133-2 lists the direct-acting oral anticoagulant (DOAC) regimens that have been evaluated by clinical trials for the treatment of established VTE.

Six phase III clinical trials evaluating the DOACs for the treatment of acute VTE have been completed and published.^{73,74,75,76,77,78} Table 133–3 outlines the design features of these trials and the efficacy and bleeding results. Each of these trials met the prespecified criteria for noninferiority of the efficacy of the DOAC for preventing recurrent VTE.

Table 133–3.Clinical trials of direct oral anticoagulants for treatment of venous thromboembolism

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Table 133–3. Clinical trials of direct oral anticoagulants for treatment of venous thromboembolism

Hokusai-VTE⁷⁸

AMPLIFY⁷⁷

EINSTEIN-DVT⁷⁵

EINSTEIN-PE⁷⁶

RE-COVER II⁷⁴

RE-COVER I⁷³

Drug

Edoxaban

Apixaban

Rivaroxaban

Dabigatran

Study design

Double-blind

Open label

Double-blind

Double blind

Heparin lead-in

At least 5 days

None

At least 5 days

Regimen

60 mg QD

30 mg QD if CrCl 30–50 mL/min, bw ≤60 kg or P-gp inhibitors

10 mg BID × 7 days then 5 mg BID

15 mg BID × 21 days then 20 mg QD

150 mg BID

Sample size

8292

5400

3449

4832

2568

2564

Treatment duration

Flexible: 3–12 months

6 months

Prespecified: 3, 6, or 12 months

6 months

Recurrent VTE

Edoxaban 3.2%^*

LMW(Hep)/warfarin 3.5%^*

P <0.001 noninferiority

Apixaban 2.3%

Enoxaparin/warfarin 2.7%

P <0.001 noninferiority

Rivaroxaban 2.1%

Enoxaparin/VKA 3.0%^**

P <0.001 noninferiority

Rivaroxaban 2.1%

Enoxaparin/VKA 1.8%

P = 0.003 noninferiority

Dabigatran 2.4%

Warfarin 2.1%

P <0.001 noninferiority

Dabigatran 2.3%

Warfarin 2.2%

P <0.001 noninferiority

Major bleeding

Edoxaban 1.4%

LMW(Hep)/warfarin 1.6%

Apixaban 0.6%

Enoxaparin/warfarin 1.8%

P <0.001 superiority

Rivaroxaban 0.8%

Enoxaparin/VKA 1.2%

Rivaroxaban 1.1%

Enoxaparin/VKA 2.2%

P = 0.003 superiority

Dabigatran 1.6%

Warfarin 1.9%

Dabigatran 1.2%

Warfarin 1.7%

CRNM bleeding

Edoxaban 7.2%

LMW(Hep)/warfarin 8.9%

P = 0.004 superiority

Apixaban 3.8%

Enoxaparin/warfarin 8.0%

P <0.001 superiority

Rivaroxaban 7.3%

Enoxaparin/VKA 7.0%

Rivaroxaban 9.5%

Enoxaparin/VKA 9.8%

Dabigatran 5.6%^§

Warfarin 8.8%^§

P = 0.002 superiority

Dabigatran 5.0%^§

Warfarin 7.9%^§

P <0.05 superiority

bw, Body weight; CrCl, creatinine clearance; CRNM, clinically relevant non-major bleeding; Hep, heparin; LMW, low molecular weight; P-gp, P glycoprotein; VKA, vitamin K antagonist; VTE, venous thromboembolism.

^*During overall study period. On-treatment rates were 1.6% for edoxaban and 1.9% for heparin/warfarin. The analysis for all the other studies used rates on treatment.

^**Either warfarin or acenocoumarol was used for the vitamin K antagonist therapy.

^§Rates are for the composite of major and clinically relevant nonmajor bleeding.

Adapted with permission from Raskob G, Büller H, Prins M, et al: Edoxaban for the long-term treatment of venous thromboembolism: Rationale and design of the Hokusai-venous thromboembolism study—Methodological implications for clinical trials. J Thromb Haemost 11(7):1287–1294, 2013.

The six trials included more than 27,000 patients with acute VTE, and meta-analyses of these studies has been done.⁷⁹ The meta-analyses provide added clinically useful information regarding specific major bleeding outcomes (intracranial bleeding and fatal bleeding), and regarding the risk-to-benefit profile in key patient subgroups commonly encountered by the clinician. These subgroups are patients presenting with symptomatic PE or symptomatic DVT, the elderly (age ≥75 years), the obese, patients with moderate renal impairment (creatinine clearance 30 to 49 mL/min), and patients with cancer. The DOACs were associated with clinically important reductions in major bleeding (relative risk [RR] 0.61), intracranial bleeding (RR 0.37), and fatal bleeding (RR 0.36).⁷⁹ For each of these outcomes, the results are consistent among the trials; none of the trials have a point estimate for these outcomes in favor of the vitamin K antagonists (supplementary data online⁷⁹). The number of patients who would need to be treated with a DOAC rather than a vitamin K antagonist to avoid one event of intracranial bleeding is 588, and for fatal bleeding is 1250. In view of the large number of VTE patients each year, and the devastating nature of these bleeding events, these are important impacts on population health. The results of cost-effectiveness studies have shown the DOACs to be cost-effective.

Regarding the key patient subgroups evaluated, the noninferior efficacy of the DOACs was consistent across all subgroups, with possibly superior efficacy in the elderly and in cancer patients.⁷⁹ The safety advantage of reduced major bleeding was also consistent across the subgroups, except possibly in cancer patients, in whom the pooled estimate of a 33 percent risk reduction did not achieve statistical significance.

The DOACs are preferred over vitamin K antagonists in most new patients commencing anticoagulant treatment for VTE. The exceptions are patients with severe renal impairment (creatinine clearance <30 mL/min), because they were not included in the clinical trials, and cancer patients, because only relatively small numbers of selected cancer patients were included, and because clinical trials comparing DOACs to the currently recommended standard therapy with LMW heparin have not been performed. For patients already taking long-term vitamin K antagonist therapy who are well controlled with a high proportion of time in therapeutic range, and for whom regular anticoagulant monitoring is not a burden, switching treatment to a DOAC is not indicated unless a clinical reason develops.

Some practical issues remain incompletely resolved. Rivaroxaban and apixaban can be used as a single-drug approach, whereas dabigatran and edoxaban are preceded by at least 5 days of heparin or LMW heparin treatment. Whether DOAC monotherapy is sufficient for the full spectrum of VTE severity, or whether “lead-in” heparin treatment is preferred in some patients, such as those with PE who have right ventricular dysfunction,⁷⁸ remains uncertain. The DOACs currently lack a specific reversal agent. In general, this should not be a reason to withhold from most patients the benefit of significantly reduced risks of major bleeding, intracranial bleeding and fatal bleeding with the DOACs. For the near term, vitamin K antagonists may be preferred in patients in whom prompt and measurable reversal of the anticoagulant effect will be required because of planned surgery or invasive procedures. Multiple rapid reversal agents for the DOACs are currently in development. Because the DOACs do not require laboratory monitoring, patients receiving DOACs may have less-frequent contact with their physician or anticoagulation clinic, and nonadherence to the prescribed therapy may not be detected as readily. Physicians and health systems should employ evidence-based strategies to enhance adherence and should evaluate patients at intervals to assess if ongoing anticoagulant therapy is appropriate and adhered to. The effectiveness and safety of the DOACs compared with LMW heparin treatment in cancer patients with VTE has not been evaluated, and LMW heparin remains indicated for these patients.

Duration of Anticoagulant Therapy

Anticoagulant treatment should be continued for at least 3 months in all patients with VTE.^9,57,58,80 Stopping treatment at 4 to 6 weeks resulted in an increased incidence of recurrent VTE during the following 6 months (absolute risk increase: 8 percent).^57,80,81,82 In contrast, treatment for 3 to 6 months resulted in a low rate of recurrence during the following 1 to 2 years (annual incidence 3 percent).^80,81,82

The decision to stop anticoagulant therapy, or continue treatment after 3 months is influenced mainly by the patient’s clinical presentation of thromboembolism as either “provoked,” which refers to VTE occurring in association with known risk factors, or “unprovoked,” in which identifiable risk factors for VTE are absent. Approximately 20 to 40 percent of all symptomatic patients present as unprovoked VTE.

In patients with a first episode of DVT or PE provoked by a reversible risk factor (e.g., surgery), treatment for 3 months is usually sufficient if the risk factor(s) is no longer present. If the risk factor(s) persist, for example prolonged immobility or cancer, treatment should be continued until the risk factor is reversed. It has been a customary practice to treat patients with PE for 6 months rather than 3 months, but the clinical trials indicate there is little to no added benefit of doing so, with a small but additional risk of bleeding.⁸⁰ Thus, for patients with DVT or PE provoked by a risk factor that has reversed, 3 months is sufficient and recommended over longer therapy.⁵⁷

Patients with a first episode of unprovoked VTE should be considered for indefinite anticoagulant therapy.^57,58 The term “indefinite” refers to continued treatment without a scheduled stopping date; treatment may be stopped in the future if the patient’s risk-to-benefit profile or preference for continued treatment changes. The decision to stop or continue anticoagulation after 3 months in patients with a first episode of unprovoked VTE should take into consideration the risk of recurrent VTE, the risk of bleeding, and patient preference. If indefinite anticoagulant treatment is chosen, the risks and benefits of continuing such treatment should be reassessed at periodic intervals.⁵⁷

There has been significant research to develop strategies to aid the clinician in assessing the risk of recurrent VTE in patients with unprovoked VTE. The presence of residual DVT assessed by compression ultrasonography,⁸³ elevated levels of plasma D-dimer after discontinuing anticoagulant treatment,⁸⁴ and male gender⁸⁵ are associated with an increased incidence of recurrent thromboembolism. The challenge, however, has been to identify the subgroup of patients with a sufficiently low annual risk of recurrence to warrant stopping anticoagulant therapy. Palaretti and colleagues evaluated an approach for patients with a first episode of unprovoked VTE or VTE associated with a minor risk factor (e.g., estrogens, pregnancy, or travel related thrombosis) which combined evaluation of the presence or absence of residual thrombosis by ultrasonography with serial D-dimer measurement to guide the decision to stop or continue anticoagulant therapy.⁸⁶ Patients in whom residual vein thrombosis was absent after 3 months of treatment, or in those with residual vein thrombosis who had been treated for at least 1 year, and who had serially negative D-dimer measurements for 3 months after stopping vitamin K antagonist treatment, had an annual rate of recurrent VTE of 3 percent during followup off anticoagulant therapy; this compared to 0.7 percent per year in 373 patients who resumed anticoagulation because of an elevated D-dimer measurement, and 8.8 percent per year among the 109 patients with elevated D-dimer who did not continue anticoagulant therapy.⁸⁶ An annual risk of recurrent VTE of 3 percent may be low enough to discontinue therapy in patients in whom the annual risk of bleeding, especially major bleeding, is similar or higher. However, if the risk of major bleeding is low, for example 1 percent per year or lower, then the annual risk of recurrent VTE of 3 percent may not be sufficiently low to stop anticoagulation, especially if the patient’s preference is on avoiding further recurrent VTE events.

A variety of thrombophilic conditions have been identified and can be evaluated in the laboratory. These include deficiencies of the naturally occurring inhibitors of coagulation such as antithrombin, protein C, and protein S; specific gene mutations including factor V Leiden and prothrombin 20210A; elevated levels of coagulation factor VIII; and the presence of antiphospholipid antibodies (Chap. 131). The role of the presence or absence of thrombophilia in guiding decisions about duration of therapy has been controversial and is incompletely resolved. Indefinite anticoagulant treatment should be considered in patients with a first episode of VTE and antiphospholipid antibodies or the presence of one or a combination of the more potent thrombophilias (deficiency of antithrombin, protein C or protein S, homozygous factor V Leiden, or prothrombin 20210A gene mutation, or one of these with a family history of VTE). Again, patient preference is important to the decision.

The DOACs have been evaluated by randomized trials for the extended treatment of patients with VTE who have completed an initial course of 6 months of anticoagulant therapy.^75,87,88,89 Most of the patients in these trials had unprovoked VTE at their initial presentation and all had clinical equipoise about the benefit to risk tradeoff of receiving extended anticoagulant therapy. The results of the trials are consistent. The DOACs produced 80 percent or greater reductions in the annual incidence of recurrent VTE of 7 to 9 percent per year in patients receiving placebo to approximately 2 percent per year in those given DOACs.^75,87,88,89 The rates of major bleeding were 0.1 to 0.7 percent. Clinically relevant nonmajor bleeding occurred in 3 to 4 percent of patients.^75,87,88,89 In the AMPLIFY Extension trial,⁸⁹ the rate of major bleeding for the 2.5 mg apixaban regimen was 0.2 percent per year, compared with 0.5 percent for placebo. The low rates of major bleeding, coupled with the advantage of not requiring laboratory monitoring of the anticoagulant effect, will likely tip the balance in favor of extended treatment for more patients with unprovoked VTE.

Aspirin has also been evaluated for the extended treatment of patients with a first episode of unprovoked VTE who have received a course of 6 months or more of anticoagulant therapy.^90.91 Aspirin produced a statistically significant 42 percent RR reduction in recurrent VTE in one study (from 11.2 percent to 6.6 percent per year),⁹⁰ and a nonsignificant (p = 0.09) 26 percent RR reduction in the second study (from 6.5 percent to 4.8 percent per year).⁹¹ The rates of major bleeding for aspirin (0.5 to 0.6 percent per year) were similar to placebo. Although intuitive to the clinician, there is no data to indicate that aspirin causes less major bleeding than the DOACs, although it is likely that the efficacy for preventing recurrent VTE is significantly less (only about half as effective as the DOACs).

Oral anticoagulant treatment should be given indefinitely for most patients with a second episode of unprovoked VTE,^57,58,92 because stopping treatment at 3 to 6 months in these patients results in a high incidence (21 percent) of recurrent VTE during the following 4 years.⁹² The risk of recurrent thromboembolism during 4-year followup was reduced by 87 percent (from 21 percent to 3 percent) by continuing anticoagulant treatment⁹²; this benefit is partially offset by the risk of bleeding.

Anticoagulant Therapy of Venous Thromboembolism in Cancer Patients

Use of LMW heparin for long-term treatment of VTE has been evaluated in clinical trials.^67,68 The studies indicate that long-term treatment with subcutaneous LMW heparin for 3 to 6 months is at least as effective as, and in cancer patients is more effective than, an oral vitamin K antagonist adjusted to maintain the INR between 2.0 and 3.0. Therefore, patients with VTE associated with concurrent cancer should be treated with LMW heparin for the first 3 to 6 months of long-term treatment.^9,57,58 The patients then should receive anticoagulation indefinitely or until the cancer resolves. The regimens of LMW heparin that are established as effective for long-term treatment are dalteparin 200 U/kg once daily for 1 month, followed by 150 U/kg daily thereafter, or tinzaparin 175 U/kg once daily.

Anticoagulant Therapy During Pregnancy

LMW heparin or adjusted-dose subcutaneous heparin are the options for anticoagulant therapy of pregnant patients with VTE.^94,95,96 LMW heparin is preferred because it has the safety advantages of causing less thrombocytopenia and probably less osteoporosis than unfractionated heparin An additional advantage is that LMW heparin is effective when given once daily, whereas unfractionated heparin requires twice-daily injection. A study indicates no major change in the peak anti–factor Xa levels over the course of pregnancy in most patients treated with a once-daily therapeutic LMW heparin regimen (tinzaparin 175 U/kg).⁹⁶ Measurement of the anti–factor Xa level may provide reassurance that major drug accumulation is not occurring. However, the appropriate dose adjustments in response to a decreased anti–factor Xa level are uncertain. The DOACs have not been evaluated in pregnant patients. Evidence-based guidelines for antithrombotic therapy during pregnancy are available.⁹⁴

Side Effects of Anticoagulant Therapy

Bleeding Bleeding is the most common side effect of anticoagulant therapy. Bleeding can be classified as major or clinically relevant nonmajor according to standardized international criteria. Major bleeding is defined as clinically overt bleeding resulting in a decline of hemoglobin of at least 2 g/dL, transfusion of at least 2 U of packed red cells, or bleeding that is retroperitoneal or intracranial, or occurs into other critical spaces. The rates of major bleeding in contemporary clinical trials of initial therapy with intravenous heparin, LMW heparin, or fondaparinux are 1 to 2 percent.^{65,66,73,74,75,76,77,78} Patients at increased risk of major bleeding are those who have undergone surgery or experienced trauma within the previous 14 days; those with a history of gastrointestinal or intracranial bleeding, peptic ulcer disease, or genitourinary bleeding; and those with miscellaneous conditions predisposing to bleeding, such as thrombocytopenia, liver disease, and multiple invasive lines.

Major bleeding occurs in approximately 1 to 2 percent of patients during the first 3 months of oral anticoagulant treatment using a vitamin K antagonist and in 1 to 3 percent per year of treatment thereafter.⁹⁷ A meta-analysis suggests the clinical impact of major bleeding during long-term oral vitamin K antagonist treatment is greater than widely appreciated.⁹⁷ The estimated case fatality rate for this major bleeding is 13 percent, and the rate of intracranial bleeding was 1.15 per 100 patient-years. These risks are important considerations in the decision about extended or indefinite anticoagulant therapy in patients with VTE. As noted above, clinical trials of the DOACs and meta-analysis indicate clinically important lower rates of bleeding, including major, intracranial, and fatal bleeding than the vitamin K antagonists.^{73,74,75,76,77,78,79}

Heparin-Induced Thrombocytopenia (See also Chap. 118.) Heparin or LMW heparin may cause thrombocytopenia. In large clinical studies of acute VTE treatment, thrombocytopenia occurred in less than 1 percent of more than 2000 patients treated with unfractionated heparin or LMW heparin.⁶⁶ Nevertheless, heparin-induced thrombocytopenia can be a serious complication when accompanied by extension or recurrence of VTE or the development of arterial thrombosis. Such complications may precede or coincide with the fall in platelet count and are associated with a high rate of limb loss and a high mortality. Heparin in all forms should be discontinued when the diagnosis of heparin-induced thrombocytopenia is made on clinical grounds, and treatment with an alternative anticoagulant, such as danaparoid, bivalirudin, or argatroban, should be initiated. The DOACs have potential to be useful for anticoagulant therapy in patients with heparin-induced thrombocytopenia, but their use has not been evaluated by clinical trials in this patient group.

Heparin-Induced Osteoporosis Osteoporosis may occur as a result of long-term treatment with heparin or LMW heparin (usually after more than 3 months). The earliest clinical manifestation of heparin-associated osteoporosis usually is nonspecific low back pain primarily involving the vertebrae or the ribs. Patients also may present with spontaneous fractures. Up to one-third of patients treated with long-term heparin may have subclinical reduction in bone density. Whether these patients are predisposed to future fractures is not known. The incidence of symptomatic osteoporosis in clinical trials of LMW heparin treatment for 3 to 6 months was very low and are not increased compared to warfarin treatment. Patients with osteoporosis or fractures often had other risk factors such as bone metastases.

Other Side Effects of Heparin Heparin or LMW heparin may cause elevated liver transaminase levels. These elevations are of unknown clinical significance and usually return to normal after the heparin or LMW heparin is discontinued. Awareness of this biochemical effect is important so as to avoid unnecessary interruption of heparin therapy and unnecessary liver biopsies in patients who may develop elevated transaminase levels during heparin or LMW heparin therapy. Additional rare side effects of heparin include hypersensitivity and skin reactions, such as skin necrosis, alopecia, and hyperkalemia occurring as a result of hypoaldosteronism.

THROMBOLYTIC THERAPY

Thrombolytic therapy is indicated for patients with PE who present with hypotension or shock, and for select patients with PE who have evidence of right ventricular dysfunction and are at high risk of hemodynamic collapse.³⁰ Thrombolytic therapy provides more rapid lysis of pulmonary emboli and more rapid restoration of right ventricular function and pulmonary perfusion than does anticoagulant treatment.^30,98,99 Effective regimens are 100 mg of recombinant tissue plasminogen activator by intravenous infusion over 2 hours (50 mg/h), or 30 to 50 mg (depending on body weight) of tenecteplase given as a single bolus injection.^98,99 Heparin then is given by continuous infusion once the thrombin time or aPTT is less than twice the control value.^98,99 The starting infusion dose is 1000 U/h. Chapters 25 and 135 provide further details of thrombolytic therapy.

The recently reported PEITHO trial⁹⁹ evaluated the effectiveness and safety of thrombolysis with tenecteplase followed by anticoagulant therapy compared with anticoagulant therapy alone in 1006 patients with PE and evidence of both right ventricular dysfunction by echocardiography or CT scan, and evidence of myocardial injury by the results of troponin I or troponin T measurement. The primary outcome of death or hemodynamic compensation (or collapse) within 7 days occurred in 13 of 506 patients (2.6 percent) given thrombolysis, compared with 28 of 499 (5.6 percent) receiving anticoagulant therapy alone (p = 0.02).⁹⁹ Stroke occurred in 12 patients (2.4 percent) in the thrombolysis group, compared with one (0.2 percent) in the anticoagulant alone group (p = 0.003). Extracranial bleeding occurred in 32 patients (6.3 percent) given thrombolysis, and in six patients (1.2 percent) receiving anticoagulant therapy alone (p <0.001). At day 7, death had occurred in six patients (1.2 percent) given thrombolysis and in nine patients (1.8 percent) given anticoagulant therapy alone; the corresponding rates at day 30 were 2.4 percent and 3.2 percent, respectively.⁹⁹ The findings indicate thrombolytic therapy prevented hemodynamic decompensation, but increased the risk of major bleeding and stroke. The study was not large enough to resolve the key question of whether thrombolysis will improve survival. At present, the risk of thrombolysis outweighs the benefit for most patients with PE who do not have hypotension but who do have evidence of right ventricular dysfunction. Further trials are needed in this group of patients.

The role of thrombolytic therapy in patients with DVT is limited. Thrombolytic therapy may be indicated in patients with acute massive proximal vein thrombosis (phlegmasia cerulea dolens with impending venous gangrene) or in occasional patients with extensive iliofemoral vein thrombosis who have severe symptoms because of venous outflow obstruction. Thrombolytic therapy can be given by systemic infusion or catheter-directed infusion. Catheter-directed thrombolysis (CDT) is probably effective for reducing the incidence of the postphlebitic syndrome.¹⁰⁰ Although it was hoped that the catheter-directed approach might be associated with a lower risk of major bleeding, particularly intracranial bleeding, than systemic injection, comparative effectiveness research data suggest the risks of bleeding still outweigh the benefits of this approach.¹⁰¹ From a national database of more than 90,000 patients with a principal diagnosis of proximal DVT or thrombosis involving the vena cava, the outcomes of the 3600 patients who received CDT with a similar number of propensity-matched patients treated with anticoagulation alone were compared. The CDT patients were more likely to have intracranial bleeding (0.9 percent vs. 0.3 percent), and transfusion (11.1 percent vs. 6.5 percent), and more likely to have filter placement (34.8 percent vs. 15.6 percent) and to experience PE (17.9 percent vs. 11.4 percent).¹⁰¹ The important message from this analysis of CDT use in practice is that the rate of intracranial bleeding is appreciable (0.9 percent) and not sufficiently low to recommend the use of CDT for DVT, other than exceptional circumstances such as threatened limb viability.

INFERIOR VENA CAVA FILTER

Insertion of an inferior vena cava filter is indicated for patients with acute VTE and an absolute contraindication to anticoagulant therapy and also indicated for the rare patients who have objectively documented recurrent VTE during adequate anticoagulant therapy.

Insertion of a vena cava filter is effective for preventing PE. However, use of a permanent filter results in an increased incidence of recurrent DVT 1 to 2 years after insertion (increase in cumulative incidence at 2 years increases from 12 percent to 21 percent).¹⁰² Therefore, if the indication for filter placement is transient, such as a contraindication to anticoagulation as the result of a temporary high risk of bleeding, a retrievable vena cava filter should be used. A retrievable filter can then be removed in the several weeks to months later, once the filter is no longer required. If a permanent filter is placed, long-term anticoagulant treatment should be given as soon as safely possible to prevent morbidity from recurrent DVT.

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VENOUS THROMBOSIS

PULMONARY EMBOLISM

D-DIMER ASSAY

Figure 133–1.

IMAGING TESTS

D-DIMER ASSAY

COMPUTED TOMOGRAPHY IMAGING AND ANGIOGRAPHY

Figure 133–2.

RADIONUCLIDE LUNG SCANNING

MAGNETIC RESONANCE ANGIOGRAPHY

PULMONARY ANGIOGRAPHY

OBJECTIVE TESTING FOR DEEP VEIN THROMBOSIS

CLINICAL COURSE OF VENOUS THROMBOEMBOLISM

Proximal Vein Thrombosis

Calf Vein Thrombosis

Postthrombotic Syndrome

Chronic Thromboembolic Pulmonary Hypertension

OBJECTIVES AND PRINCIPLES OF ANTITHROMBOTIC TREATMENT

ANTICOAGULANT THERAPY

Parenteral Anticoagulants

Oral Anticoagulants

Duration of Anticoagulant Therapy

Anticoagulant Therapy of Venous Thromboembolism in Cancer Patients

Anticoagulant Therapy During Pregnancy

Side Effects of Anticoagulant Therapy

THROMBOLYTIC THERAPY

INFERIOR VENA CAVA FILTER

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