Firas Al Solaiman and John R. Bartholomew
Venous thromboembolism (VTE) is a common disease that includes both pulmonary embolism (PE) and deep vein thrombosis (DVT). It is the third most frequently occurring cardiovascular condition after ischemic heart disease and cerebrovascular accidents in the United States. Approximately 1 million people develop DVT and 600,000 develop PE each year, and death from VTE has been estimated to occur in as many as 60,000 to 200,000 Americans annually.1
ESSENTIAL FACTS ABOUT VTE
It is important to recognize the natural history of VTE to more fully appreciate its short-term mortality and long-term morbidity.
VTE is a recurrent disease with a risk of recurrence up to 30% at 10 years for unprovoked events.2
PE is the third most common cause of hospital-related death and is the most common preventable cause of hospital death.3,4
The mortality rate for PE without treatment is approximately 30%.5
Patients with an acute PE who have right ventricular (RV) dysfunction documented by a transthoracic echocardiogram (TTE) have a higher in-hospital mortality (14%) and short-term mortality (20%) rate at 3 months.6
Chronic thromboembolic pulmonary hypertension (CTPH) develops in as many as 3.8% of all PE patients by 2 years after their initial event.7
Approximately 40% to 50% of all patients with an acute symptomatic DVT (proximal to the popliteal vein), who are asymptomatic for PE, will have a high-probability ventilation/perfusion scan.
The most common long-term complication of DVT is the postthrombotic syndrome (PTS), characterized by chronic leg swelling, pain, and nonhealing venous stasis ulcers, which occurs in as many as 30% of all patients within 10 years after a documented DVT.8,9
RISK FACTORS FOR VENOUS THROMBOEMBOLISM
Venous thrombosis results from the combination of acquired and hereditary causes. The most common acquired and hereditary risk factors (referred to as hypercoagulable states or thrombophilia) are shown in Tables 49.1 and 49.2.
TABLE
49.1 Acquired Risk Factors For VTE
TABLE
49.2 Hereditary Risk Factors for VTE
As many as 20% of white patients presenting with an idiopathic or unprovoked DVT are heterozygous for the factor V Leiden mutation, while 6% are heterozygous for the prothrombin G20210A mutation10Both of these disorders are rare in the African and Asian populations.11,12 Other, less common hereditary hypercoagulable states include protein C and S and antithrombin deficiencies, hyperhomocystinemia, elevated levels of factor VIII, and dysfibrinogenemia.
DEEP VEIN THROMBOSIS: CLINICAL PRESENTATION AND DIAGNOSIS
Although VTE is considered to be one disease entity, the clinical presentation and diagnosis for DVT and PE are different. The characteristic symptoms for an acute DVT include leg or arm pain, swelling, increased skin temperature, and discoloration (erythrocyanosis), although these findings may be absent. Unfortunately, the clinical examination is often unreliable and the diagnosis is only confirmed in 20% to 40% of patients presenting with typical signs and symptoms.13 This is due in part to the varied differential diagnosis for DVT, which includes:
Cellulitis
Arthritis, synovitis, myositis
Lymphedema
Arterial insufficiency
Muscle ache or tear
Baker cyst
Chronic venous insufficiency
Systemic causes of edema (congestive heart failure [CHF], nephrotic syndrome, liver dysfunction, hypoalbuminemia)
Clinical models have been developed to help diagnose an acute DVT. Wells et al. stratified outpatients presenting with a suspected DVT into low, intermediate, or high pretest probability categories based on a number of clinical “points.”14 According to their model, 3% of low, 17% of moderate, and 75% of high pretest probability patients were diagnosed with a DVT. Although it is not widely used, this model may be a helpful objective assessment tool for clinicians (Table 49.3).
TABLE
49.3 Clinical Feature Score According to Wells et al. Criteria
Risk score: low, <0 points; moderate, 1–2 points; high, >3 points. Adapted from Wells PS, Anderson DR, Bormanis J, et al. Value of assessment of pretest probability of deep-vein thrombosis in clinical management. Lancet. 1997; 350:1795–1878.
OBJECTIVE TESTING FOR DEEP VEIN THROMBOSIS
DVT can be confirmed using invasive and noninvasive studies as well as laboratory tests. These tests include:
D-Dimer assay
Duplex ultrasonography
Venography
Computed tomography venography (CTV)
Magnetic resonance venography (MRV)
Impedance plethysmography (IPG)
The more commonly used diagnostic tests include a D-dimer assay and duplex ultrasonography.
D-Dimer
D-Dimer is a specific fragment of a fibrin clot whose presence indicates degradation of fibrin and serves as an indirect indicator for thrombotic activity. D-Dimer assay has been utilized to a great extent in the outpatient setting and emergency departments to rule out VTE, because of its high sensitivity and negative predictive value. An elevated D-dimer level, however, is not specific for VTE and can be seen in a variety of conditions, including pregnancy, infection, disseminated intravascular coagulation (DIC), hemorrhage, malignancy, liver disease, surgery, trauma, cardiac or renal failure, acute coronary syndrome (ACS), and acute nonlacunar stroke. It is important to remember that not all D-dimer assays are alike and that it can be measured using a number of different methods. A recent analysis found that the Enzyme-linked immunosorbent assay (ELISA) and quantitative rapid ELISA tests were superior to other methods.15
Most physicians feel that anticoagulation can be withheld from patients suspected of acute VTE in the outpatient setting if the D-dimer assay is negative. It is extremely important, however, for clinicians to know the sensitivity and specificity of their hospital’s D-dimer assay before making such a decision. If the clinician’s suspicion of VTE remains high despite a negative D-dimer assay, further imaging studies are recommended.
Duplex Ultrasonography
Duplex ultrasonography is a readily available, noninvasive modality that can be performed routinely in the hospital or outpatient setting or at bedside for a critically ill patient. It has replaced venography as the diagnostic method of choice for acute DVT and is the most accurate noninvasive test currently available. Duplex ultrasonography allows for direct visualization of the venous system. An inability to compress the vein with the ultrasound transducer is considered diagnostic for DVT. The other ultrasound findings that may help in the diagnosis of acute DVT are listed in Table 49.4.
TABLE
49.4 Ultrasound Characteristics of Acute DVT
Physicians must recognize that duplex ultrasonography is very operator dependent. Its sensitivity is approximately 95% and its specificity 96% in symptomatic patients with a proximal DVT, but it is less reliable in asymptomaticpatients, those with thrombus above the inguinal ligament, or those with calf vein thrombosis. The sensitivity and specificity for isolated calf vein thrombosis approaches 60% to 70%.16
In a study involving 375 patients, the validity of withholding anticoagulation in patients with a negative ultrasound and a low clinical suspicion for DVT was examined.17 Only three patients who had anticoagulation withheld developed a new VTE event. Two patients developed an isolated calf vein DVT and one patient a proximal DVT (total of 0.8%). No patient developed a PE at the 3-month follow-up.
Duplex ultrasonography may also be useful in patients suspected of an acute PE. If the arms or legs are positive for an acute DVT, further confirmatory studies may be unnecessary in most patients, assuming that would not change the management of the patient.
Venography
The venogram is an invasive procedure now replaced for the diagnosis of DVT by duplex ultrasonography. An intraluminal-filling defect must be seen in at least two different projections for confirmation. A venogram should be considered in the appropriate clinical setting or when other tests are nondiagnostic. Despite its clinical utility, complications such as contrast allergy and postprocedural acute DVT should not be overlooked. The latter complication has been reported to occur in approximately 1% to 2% of all patients.
Other Diagnostic Testing Options
CTV of the legs can be performed in conjunction with a computed tomographic pulmonary angiogram (CTPA) of the chest used to rule out PE. Although more radiation is required, no additional contrast is needed and imaging of the more proximal leg veins (iliacs), pelvic veins, and the inferior vena cava (IVC) is possible. However, recent studies showed that routine CTV of the pelvis during CTPA does not significantly improve the detection of VTE and therefore should not be performed routinely in all patients being evaluated for PE.18,19
MRV imaging can also be utilized to diagnose DVT. Its sensitivity and specificity has been reported to be >95% when compared to standard venography for the diagnosis of a proximal DVT, although outcome data are lacking. It has several advantages, including (a) detecting pelvic, iliac, and IVC thrombosis and (b) no need for ionizing radiation. Potential drawbacks include lack of availability, high cost, reader expertise, difficulty with morbidly obese patients, and the presence of metallic objects (stents or other hardware) in the area of interest. The MRV modality may be beneficial in pregnancy when there is a high clinical suspicion for an IVC, pelvic, or iliac vein DVT that is not detectable with duplex ultrasonography, or for patients with an allergy to contrast dye. However, this imaging technique should not be used in patients with acute or chronic renal insufficiency to prevent the adverse effect of nephrogenic systemic fibrosis (NSF).20
IPG has largely been replaced by duplex ultrasonography at hospitals in the United States.
PULMONARY EMBOLISM: CLINICAL PRESENTATION AND DIAGNOSIS
Autopsy studies continue to demonstrate that most fatal cases of PE are unrecognized or not diagnosed.21 Patients presenting with PE often have nonspecific signs and symptoms, making the diagnosis more difficult and frequently overlooked. In a review of the most common signs and symptoms of patients presenting with an acute PE without underlying cardiopulmonary disease, dyspnea was most common, followed by pleuritic chest pain. These manifestations are valuable clues to the diagnosis in this patient population. However, in the individual with heart or lung disease, they may be mistaken for symptoms of the underlying disease process. Other signs and symptoms of an acute PE include cough, leg swelling, thrombophlebitis, hemoptysis, palpitations, wheezing, angina-like pain, apprehension, and fever.22.
Patients may present with a massive or submassive PE, or they may be entirely asymptomatic. Patients who have a massive PE (systolic arterial pressure <90 mm Hg) present with circulatory collapse and shock or syncope. Fortunately, this is not a common manifestation, representing only in about 8% of all patients.23 Acute shortness of breath, with tachycardia, chest pain, tachypnea, and cyanosis, may be the result of a submassive PE (pulmonary hypertension or RV dysfunction without arterial hypotension or shock). Patients with acute PE may also be entirely asymptomatic, especially in the postoperative period. Because of the wide variety of clinical presentations, both noninvasive and invasive diagnostic methods may be necessary to confirm the diagnosis. The differential diagnosis of PE includes:
Unstable angina, myocardial infarction (MI)
Pneumonia
Chronic obstructive pulmonary disease (COPD), bronchitis
CHF
Pericarditis
Pneumothorax
Costochondritis
The diagnosis of PE should start with establishing the clinical probability. Wells et al. stratified the clinical features of PE into “points” (similar to their DVT criteria), and their model is useful as an objective tool to assess the pretest probability of an acute PE (Table 49.5).24 In their model, the probability of an acute PE with >6 points (high risk) was 78.4%, while that for 2 to 6 points (moderate risk) was 27.8% and for <2 points (low risk), it was 3.4%. The combination of a negative D-dimer and low to moderate pretest probability has a very high negative predictive value (~99%). In validation study using Wells criteria in combination with negative D-dimer, only 0.5% of patients with low to moderate pretest probability for PE later developed nonfatal VTE.25 D-Dimer has limited value in patients with a high clinical suspicion for PE,26 and the clinician should proceed directly with multidetector CTPA scan.
TABLE
49.5 Wells et al. Clinical Prediction for PE
Risk score: low probability < 2, moderate probability 2–6, high probability > 6. Adapted from Wells PS, Anderson DR, Rodger M, et al. Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D-dimer. Thromb Haemost. 2000;83:416–420
OBJECTIVE TESTING FOR PULMONARY EMBOLISM
Traditional tests used to assist a physician faced with the presumptive diagnosis of an acute PE include a chest x-ray, electrocardiogram (ECG), and an arterial blood gas.
The chest x-ray may be more helpful to rule out pneumonia, a pneumothorax, or a malignancy. The most common x-ray features of acute PE are consolidation, a pleural effusion, atelectasis, Hampton hump (wedge-shaped opacity along the pleural surface), Westermark sign (oligemia), and Palla sign (an enlarged right descending pulmonary artery).27 These latter three classic radiographic findings are rarely seen, however.
An ECG may exclude cardiac causes that mimic PE, such as an MI or a pericarditis. ECG findings suggestive of a PE include sinus tachycardia, new-onset atrial fibrillation or flutter, right bundle branch block, right-axis deviation, and nonspecific ST–T-wave changes. The classic finding of S1Q3T3 indicates acute cor pulmonale but is seen in <10% of all patients.27 Evidence of acute RV myocardial injury may also be seen, manifest as ST-segment elevation isolated to lead V1 and, at times, extending to lead V2.
PE must not be excluded based on either a normal arterial blood gas or a normal alveolar–arterial gradient (A-a gradient). In several studies, up to 20% of patients had normal oxygen levels and A-a gradients despite angiographically proven PE.28
Computed Tomography Pulmonary Angiography
CTPA not only allows direct visualization of the thrombus but also has great value in excluding other diseases, including an aortic dissection, pneumonia, or malignancy.
Over the last decade, multidetector spiral computed tomography (CT) has become the standard imaging technique for diagnosis of PE. Earlier reports suggested that a single row detector CTPA is both highly sensitive and specific for the diagnosis of a central PE (main, lobar, or segmental pulmonary arteries) but insensitive to the diagnosis of a subsegmental event, with a potential to miss smaller emboli. However, the use of multidetector CTPA has greatly increased its sensitivity and specificity for diagnosis of small peripheral or subsegmental PEs. A recent study suggested that CTPA is more sensitive than a ventilation/perfusion (V/Q) scan for the diagnosis of PE.29 In a meta-analysis of 23 studies involving 4,657 patients with a negative multidetector CT who did not receive anticoagulation therapy, the incidence of VTE was only 1.4%.30
CTPA can also assist in risk-stratifying patients with acute PE by identifying patients with an enlarged RV. RV enlargement on multidetector CT (defined by RV/left ventricular [LV] diameter ratio > 0.9) has been shown to predict doubling of mortality in the 30 days following diagnosis.31The major disadvantage of CTPA is the risk of contrast-induced nephropathy and radiation exposure.
Ventilation/Perfusion Scan
The V/Q scan was long considered one of the most useful aids to diagnose acute PE. The PIOPED trial (prospective investigation of pulmonary embolism diagnosis) combined low, intermediate, or high preclinical suspicion with a normal-, low-, intermediate-, or high-probability V/Q scan.32A normal V/Q scan effectively excluded the diagnosis of an acute PE, whereas if the clinical suspicion and the perfusion scan showed high probabilities, the diagnosis was very likely. Ventilation/perfusion scans interpreted as low or intermediate probability were considered nondiagnostic and required further testing to confirm or exclude an acute PE.
In the PIOPED trial, 88% of patients with a high clinical suspicion and high-probability V/Q scan had acute PE confirmed by pulmonary angiography. Among patients with a low-probability V/Q scan, angiographically proven PE was identified in 40% and 4% of patients with a high and low preclinical suspicion, respectively.
Unfortunately, in as many as 75% to 80% of all PIOPED patients, no definitive diagnosis could be made because studies were interpreted either as low or intermediate probability.
Ventilation/perfusion scanning has been replaced by multidetector CTPA and currently is considered a second-line modality in the diagnosis of PE. However, V/Q scan remains a valuable tool in the diagnosis of acute PE in patients with a normal chest x-ray or patients who cannot undergo CTPA (contrast allergy, renal insufficiency, or pregnancy)
Pulmonary Angiography
Pulmonary angiography remains the reference standard for which most studies are compared in the diagnosis of PE, despite the fact that it is not universally available, is invasive, and is costly. The definitive diagnosis of acute PE requires the presence of an intraluminal-filling defect in at least two views or demonstration of an occluded pulmonary artery. It is not without complications, and morbidity of 5% and mortality of 0.5% were reported in the PIOPED trial.32
Echocardiography (Transthoracic and Transesophageal)
Abnormal TTE findings in acute PE include RV dilatation, RV hypokinesis, interventricular septal flattening or paradoxical motion, decreased inspiratory collapse of IVC, pulmonary artery hypertension and pulmonary artery dilatation, tricuspid regurgitation, patent foramen ovale (PFO) and rarely direct visualization of thrombus. The finding of akinesia of the mid-free RV wall with relative sparing of apex is referred to as McConnell sign. This sign was found in one study to have 94% specificity and 71% positive predictive value for the diagnosis of acute PE.33
Hemodynamically unstable patients generally suffer severe RV dysfunction; however, RV hypokinesis presents in only 40% of patients with normal systemic pressure. A TTE alone cannot be used to diagnose PE but is a useful tool for risk stratification and identifying patients with acute PE who may have a poor prognosis. RV dysfunction on TTE has been associated with increased mortality among patients with acute PE. In a retrospective study, patients with an RV/LV ratio ≥0.9 were 2.6 times more likely to die during hospitalization independently of other risk factors.34
Transesophageal echocardiogram (TEE) can be used as a rapid bedside test to allow direct visualization of the main pulmonary arteries and should be considered in the hemodynamically unstable patients who cannot be moved to undergo a CTPA scan or pulmonary angiogram.35
In PIOPED III, magnetic resonance angiography (MRA) had insufficient sensitivity and a high rate of technically inadequate images. Addition of MRV to MRA improves sensitivity; however, 52% of patients in the study had a technically inadequate study. At the current time, an MRA/MRV should be considered only at those centers with experience with this modality and only for patients for whom standard tests are contraindicated.36
Cardiospecific Biomarkers in Pulmonary Embolism
Cardiospecific biomarkers, including cardiac troponin and brain natriuretic peptide (BNP), have become useful in the risk stratification strategy of patients with an acute PE. Elevation in troponin levels and BNP correlate with the presence of RV dysfunction and appear to be independent risk factors for poor or fatal outcome. In a meta-analysis of 1985 acute PE patients, any elevation in troponin was found to confer a fivefold increase in short-term mortality.37A troponin level is considered the single most useful blood test for the risk stratification of patients with acute PE, while a normal BNP has a negative predictive value of 97% to 100%.38,39
KEY POINTS IN DIAGNOSIS OF VTE
Clinical prediction rules should be used to estimate the pretest probability for DVT and PE.
In patients with a low to moderate pretest probability for DVT or PE, a negative high sensitivity D-dimer has a very high negative predictive value (indicating a very low likelihood of VTE).
Patients with a high pretest probability of VTE require additional diagnostic imaging studies.
Duplex ultrasonography is accepted as the first-line diagnostic imaging study for DVT.
Begin anticoagulation once suspect DVT (unless there is a contraindication for its use).
Patients with a high pretest probability of PE require additional diagnostic imaging studies such CTPA.
Multidetector CTPA is accepted as the first-line diagnostic imaging study for acute PE.
A V/Q scan is helpful if the chest x-ray is normal and a CTPA scan not possible or if the patient has renal insufficiency.
Two D-echo or TEE is useful for the critically ill patient as a bedside test to help diagnose PE.
The presence of DVT on duplex ultrasonography is generally adequate for treatment of a PE.
Pulmonary angiogram remains the gold standard diagnostic imaging for PE if diagnosis uncertain.
Troponins, BNP, and RV enlargement on echo or CT help predict outcome and are useful for risk stratification.
Begin anticoagulation once suspect PE (unless there is a contraindication for its use) using risk stratification tools including echocardiography and troponins or BNP.
TREATMENT OF VENOUS THROMBOEMBOLISM
The goals of treatment for VTE are to prevent extension, propagation, or embolization and recurrence of thrombosis. Treatment is also aimed at preserving valve function and preventing the PTS in patients with DVT and to prevent CTPH and RV dysfunction in individuals with PE. Initial inpatient management should begin with weight-adjusted unfractionated heparin (UFH), a weight-based low-molecular-weight heparin (LMWH) preparation, or the anti-Xa inhibitor fondaparinux. A vitamin K antagonist (VKA) should be started as soon as possible, overlapping for a minimum of 5 days with one of the above-listed anticoagulants until the international normalized ratio (INR) is stable and ≥2.0 for at least 24 hours.
Unfractionated Heparin
UFH is generally administered intravenously, although it can also be effective when given subcutaneously. Dosing is generally determined from a weight-based nomogram, and a bolus of 80 U/kg followed by 18 U/kg/h is commonly recommended for most adult patients. Subsequent dose adjustments are made based on the results of either an activated partial thromboplastin time (aPTT) or an anti-Xa assay using an amidolytic assay.
Heparin has a number of drawbacks. It has a variable anticoagulant response among patients, a relatively short half-life, and adverse effects of bleeding, osteoporosis, and heparin-induced thrombocytopenia (HIT). HIT (an immune-mediated disorder that typically occurs 4 to 11 days after exposure to heparin products) is reported to occur in as many as 3% to 5% of all patients receiving UFH but occurs much less frequently in patients receiving any of the LMWH preparations. It can result in significant morbidity and mortality, with life- and limb-threatening thrombotic complications including the loss of a limb, stroke, MI, DVT, or PE. Treatment revolves around immediate cessation of UFH or LMWH and replacement with an alternative antithrombotic agent (direct thrombin inhibitor [DTI]). Currently, two DTIs are approved by the U.S. Food and Drug Administration (FDA) for the treatment of HIT: argatroban, a small synthetic molecule, and a hirudin derivative (lepirudin).
Low-Molecular-Weight Heparin
Depolymerization of UFH by chemical or enzymatic cleavage of its polysaccharide chains yields a mixture of heparin fragments known as LMWH that have a mean molecular weight of approximately 5,000 Da. This reduction in molecular weight leads to more predictable pharmacokinetics and a greater bioavailability than with UFH. A subcutaneous administered LMWH is the preferred anticoagulant for most hemodynamically stable patients. Advantages of the LMWHs include:
Once or twice-daily subcutaneous injections
Easy administration
Dose by a weight-base adjusted regimen
No monitoring necessary for most patients (see below)
Outpatient administration
Lower incidence of HIT
Less osteoclast activation and lower incidence of osteoporosis
Although laboratory monitoring is generally not necessary, it is recommended in patients who are morbidly obese or who have significant renal disease, and in pediatric or pregnant patients. In these individuals, a 4-hour postinjection anti-Xa level using LMWH as the standard is recommended. Therapeutic levels are 0.6 to 1.0 IU/mL for twice-daily injections and 1.0 to 2.0 IU/mL for once-a-day administration.40 LMWH preparations require dose adjustment for patients with a creatinine clearance ≤30 mL/min and are contraindicated in patients on hemodialysis.
The introduction of LMWH has dramatically altered the management of DVT in the United States. Two landmark clinical trials and a meta-analysis have demonstrated that subcutaneous injection of LMWH is as safe and effective in the outpatient treatment of acute DVT as UFH given in a hospital setting.41 Meta-analyses comparing LMWH to UFH found similar rates of major bleeding and recurrent VTE.42
Although the LMWHs are not approved in the United States for outpatient treatment of acute PE, several clinical trials have demonstrated their safety. A meta-analysis comparing UFH with LMWH in the inpatient treatment of hemodynamically stable PE patients demonstrated similar incidences of recurrent VTE, bleeding, and death.43 Heparin should still be first line of therapy in the following cases:
Persistent hypotension due to PE (massive PE)
Increased risk of bleeding
Concern about subcutaneous absorption (morbid obesity, anasarca)
When thrombolysis is being considered
Patients with end-stage renal disease
Fondaparinux
Fondaparinux (Arixtra) is the only synthetic pentasaccharide that has been approved by the FDA for the treatment of acute DVT and PE. It is administered subcutaneously once daily and is almost 100% bioavailable. Dosing is weight based; 5 mg is recommended for individuals weighing <50 kg, 7.5 mg for those who weigh 50 to 100 kg, and 10 mg for individuals who weigh >100 kg. Fondaparinux does not require dose adjustment or monitoring, but caution should be exercised while using this drug because of its long half-life and the lack of an antidote. Warfarin should be started concurrently and continued for at least 5 days, until a therapeutic INR is attained. Fondaparinux is contraindicated in patients with renal insufficiency defined as a creatinine clearance <30 mL/min and in patients on hemodialysis.
Vitamin K Antagonists
Warfarin is the only VKA available for long-term management of VTE in the United States and currently remains the mainstay therapy for long-term treatment of VTE. Despite its use for many decades, two areas often remain confusing and controversial to physicians. One is the optimal dose for initiating therapy; the other revolves around duration of anticoagulation. Two trials compared different initiating doses of warfarin (5 vs. 10 mg). Both studies reported that 5 mg reduced the likelihood of excessive early anticoagulation, avoided rapid drops in the level of protein C, and did not appear to prolong the time required to achieve a therapeutic INR.44,45 In contrast, a more recent study performed in the outpatient setting demonstrated that higher initial doses (10 mg) of warfarin were superior to lower doses (5 mg).46In this study, patients reached a target INR on average 1.4 days earlier, without an increase in recurrent events or major bleeding. In general, the dose should be tailored to each individual patient. Lower doses are often recommended for elderly patients and for those who have comorbid conditions such as recent surgery, hypertension, stroke, CHF, renal or liver disease, anemia, diabetes, cancer, or a history of bleeding. Genotype-based dosing is a tool that has gained much attention in managing warfarin. The FDA has approved labeling changes for warfarin recommending lower initiation doses for patients with genetic variations in VKORC1 and CYP2C9 enzymes. However, clinical evidence for the clinical utility and cost-effectiveness of this approach is lacking.47
There is controversy about the optimal length of treatment. Most patients require 3 months of therapy if an underlying precipitating event (surgery, trauma, medical condition) has been identified and resolved, whereas longer therapy is recommended if no underlying cause can be found (idiopathic or unprovoked) or if the precipitating factor cannot be rectified.
Two studies have demonstrated the benefits of longterm anticoagulation in patients with an idiopathic DVT. The prevention of recurrent venous thromboembolism (PREVENT) trial compared patients treated with low-intensity warfarin (INR of 1.5 to 2.0) to placebo following 6 months of standard VKA therapy. This trial showed a 64% reduction in recurrent VTE in the low-intensity warfarin group when compared to those on the placebo group. Patients were followed on average for 4.3 years, and there was no significant difference in bleeding between the two groups.48
The second trial, Extended Low-Intensity Anticoagulation for Thromboembolism (ELATE) trial, compared long-term low-intensity warfarin (INR 1.5 to 1.9) to the conventional dose maintaining an INR between 2.0 to 3.0. These authors found conventional-dose warfarin better than low-intensity warfarin in preventing recurrences of VTE, without a significant increase in the risk of bleeding.49
The latest American College of Chest Physicians (ACCP) guidelines recommend at least 3 months of therapy for patients with an idiopathic or unprovoked VTE and suggest that indefinite therapy is considered if the patient is at low risk for bleeding.50
Patients with the antiphospholipid antibody syndrome, individuals who are homozygous for factor V Leiden, deficient in antithrombin or individuals with two or more hereditary thrombophilia conditions should also be considered for long-term anticoagulation although no specific recommendations were addressed for these conditions in the latest ACCP guidelines.50 For patients with VTE and cancer, LMWH is recommended for the first 3 to 6 months of treatment. This patient population should receive indefinite anticoagulation or until the cancer is deemed cured.50
New Oral Anticoagulants
Until recently, warfarin was the only available oral anticoagulant for the treatment of VTE. Multiple new oral agents, with different mechanisms of action, have been evaluated in phase III clinical trials and have become available in the markets outside the United States. These new anticoagulants are poised to replace warfarin and potentially change completely the way patients with VTE are being managed. The agents that are most advanced in their development are the oral DTI (dabigatran etexilate) and oral direct factor Xa inhibitors (such apixaban and rivaroxaban). In contrast to warfarin, these new oral anticoagulants in general have a more rapid onset of action that may obviate the need for parenteral anticoagulation in the initial treatment of VTE. Also because these agents have stable pharmacodynamics, unlike warfarin, routine monitoring is not required, which make them more ideal agents for long-term anticoagulation. Currently there are no antidotes for these agents.
Oral Direct Thrombin Inhibitors
Ximelagatran was the first oral DTI to complete phase III clinical trials; however, because of the high incidence of hepatotoxicity, the sponsoring company withdrew it from the market.
Dabigatran etexilate—a prodrug—has been shown to be not inferior to subcutaneous enoxaparin in the prevention of VTE after total knee or total hip arthroplasty with similar bleeding risks.51–53 In a randomized, double-blind, noninferiority trial involving 2,539 patients with acute VTE (RE-COVER), a fixed dose of dabigatran without requiring laboratory monitoring was shown to be as effective as warfarin for the treatment of acute VTE, with a similar safety profile.54 Dabigatran is not approved yet by the FDA for prevention and treatment of VTE. However, it has been approved recently for theprevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation based on the data from the RE-LY trial.55 It requires dose adjustments for patients with a creatinine clearance of 15 to 30 mL/min and is not recommended if the creatinine clearance is ≤15 mL/min.
Oral Direct Factor Xa Inhibitors
Rivaroxaban is an oral direct factor Xa inhibitor with a relatively short half-life of 5 to 9 hours and rapid onset of action of 2.5 to 4 hours. In the EINSTEIN trial,56 oral rivaroxaban given alone (twice daily for 3 weeks followed by once daily thereafter) was not inferior to subcutaneous enoxaparin followed by a VKA antagonist for treatment of acute symptomatic DVT with a similar safety profile.
In the RECORD trials57–60—four phase III doubleblinded randomized trials—rivaroxaban has been shown to be superior to enoxaparin for the prevention of VTE following knee and hip arthroplasty with a similar safety profile. Rivaroxaban was recently approved in USA for the prevention of VTE in adults following hip and knee arthroplasty.
Rivaroxaban should not be used in patients with severe renal insufficiency or significant hepatic impairment.
Apixaban is another oral direct factor Xa inhibitor with promising data. Apixiban was found to be comparable to warfarin in a small phase II trial for the treatment of DVT.61 In two phase III trials,62,63apixaban was superior to enoxaparin when given using the European regimen (40 mg daily starting on the evening before surgery) in preventing VTE after knee and hip arthroplasty. However, in another study,64 apixaban failed to meet the noninferiority standards for the prevention of VTE after knee arthroplasty when compared to enoxaparin (given in the North American regimen of 30 mg every 12 hours starting 12 to 24 hours after surgery). Other direct factor Xa inhibitors in development include betrixaban, razaxaban, and otamixaban.
Thrombolytic Therapy for Venous Thromboembolism
Thrombolytic therapy for the initial treatment of VTE has been used for well over a quarter of a century. It has been promoted for the treatment of both DVT and PE. Currently, there are three agents available in the United States: rt-PA, reteplase, and tenecteplase.
The goal of thrombolytic therapy for an acute DVT is to produce rapid clot lysis, with the intent of preserving valvular function and preventing the PTS. Earlier data pooled from six randomized DVT trials comparing streptokinase to heparin demonstrated that thrombus resolution was achieved 3.7 times more often among individuals treated with streptokinase. These studies also showed that major bleeding was approximately three times more frequent in the streptokinase groups.65 More recent reports utilizing urokinase and recombinant tissue-type plasminogen activator (t-PA) have reported similar findings.66
Thrombolytic therapy for DVT is best performed using a catheter-directed infusion. It should be initiated within the first 2 weeks of an acute event and should be reserved for individuals at low risk for bleeding and good functional status with an acute extensive proximal DVT or in patients with a limb-threatening circulatory compromise as in phlegmasia cerulea dolens, or individuals with effort vein thrombosis of the upper extremity (Paget–von Schroetter syndrome). It may also be beneficial in patients with an occluded central venous catheter, in hopes of preserving the function of the catheter and avoiding its removal.
One of the more controversial areas is the use of thrombolytic therapy for acute PE. Most clinicians favor the use of these agents over pulmonary embolectomy for patients with a massive PE defined as a systolic blood pressure (BP) under 90 mm Hg. Thrombolysis accelerates resolution of emboli, improving RV function, pulmonary perfusion, and the hemodynamic status of the patient.
In a meta-analysis of nine trials using thrombolytic therapy for acute PE, Anderson et al. found more rapid resolution of the radiographic appearance and hemodynamic abnormalities when compared to heparin. There was no difference, in the clinically relevant outcomes of death or the rate of resolution of symptoms in the two groups, but there was a 1% to 2% increased risk of intracranial hemorrhage in the thrombolysis group.50
Thrombolytic therapy has also been recommended for a carefully selected subgroup of patients who are hemodynamically stable but have high risk features (echocardiographic evidence for RV dysfunction and positive biomarkers) and judged to have a low risk of bleeding. In this setting, the goal of therapy is rapid reversal of right-sided heart dysfunction, to reduce the potential for CTPH, death, and recurrent pulmonary emboli.50
Thrombolytic therapy should be reserved for those individuals with a massive PE and hemodynamic instability. Although the risk for major bleeding has improved with physician experience, and the intracranial bleeding rate is small, the current ACCP guidelines do not recommend thrombolytic therapy for patients with smaller emboli or routine use in the majority of individuals with PE-associated RV dysfunction.50
To date, most studies demonstrate a favorable outcome for patients who are hemodynamically stable and who are promptly diagnosed and treated for acute PE with UFH, LMWH, or fondaparinux.
MECHANICAL AND SURGICAL APPROACHES TO TREATING VTE
Other therapeutic options for the management of acute VTE have been tried, including mechanical and surgical approaches. Open surgical thrombectomy had previously fallen out of favor; however, with newer surgical techniques, it has regained a role in the management of DVT. Percutaneous mechanical thrombectomy using rotational or hydrodynamic (rheolytic) devices may provide another option for patients with DVT. These devices may be beneficial in individuals who are not candidates for thrombolytic therapy or in patients who may not tolerate traditional doses of thrombolytic therapy but who have considerable clot burden. Angioplasty and stenting have also been used and may be of help in treating individuals with a left common iliac vein stenosis, known as the May–Thurner syndrome. For most of these devices, only small case studies have been reported; therefore, the experience has been insufficient to recommend their routine use.
Percutaneous embolectomy and pulmonary embolectomy are other available options for a patient with PE who is not a candidate for thrombolytic therapy. The percutaneous devices remove, fragment, or aspirate emboli, offering rapid relief of central thrombus. Pulmonary embolectomy, generally considered for select patients who are not candidates for thrombolysis, may be lifesaving for a patient presenting with hemodynamic instability. Pulmonary thromboendarterectomy is considered the treatment of choice for patients with CTPH when their disease is accessible surgically.
Inferior Vena Cava Interruption (IVC Filters)
Absolute indications for IVC filter placement are (a) a contradiction to anticoagulation, (b) recurrent thromboembolic disease despite adequate anticoagulation therapy, (c) complication of anticoagulation therapy, and (d) for patients who require pulmonary embolectomy or a thromboendarterectomy.
There are a number of relative indications for IVC filter placement, including free-floating thrombus, PE in the setting of cor pulmonale, ataxia, or patients with a recent VTE who require urgent surgery.
Recurrent clinically symptomatic PE after IVC filter placement has been reported in approximately 2% to 5% of cases.67 The source of PE could be de novo thrombus forming within the filter, or propagation of a preexisting thrombus through the filter, or thrombus that originates from the arm or neck veins. Current recommendations advise that patients with IVC filters receive full-dose anticoagulation once it becomes safe to do so. In one study of 400 patients who received either an IVC filter or standard anticoagulation for treatment of VTE, a statistically higher DVT recurrence rate was identified in the filter population.68
In addition to the increased risk for recurrent VTE, IVC filters can lead to thrombosis at the venous access site, filter migration, or penetration and obstruction of the vena cava. Therefore, it is prudent to adhere strictly to the appropriate criteria when evaluating patients for IVC filter placement.
Although they are not yet FDA approved as “optional devices,” retrievable IVC filters are approved as permanent filters. Indications for their use should follow the same guidelines as used for the placement of permanent filters.69
THROMBOPROPHYLAXIS
Although thromboprophylaxis should be provided to all hospitalized patients, unfortunately all physicians do not universally practice this policy, largely because it is either overlooked or not even considered. Individuals who are considered at greatest risk for VTE are those over 40 years of age, patients who are immobilized, or patients who have an underlying medical condition (MI, stroke, CHF, pneumonia), have a trauma, or underwent a recent surgical procedure (especially hip fracture, total knee or hip replacement, or neurosurgical procedures).
There are two major forms of prophylaxis, mechanical and pharmacologic. Those who cannot receive prophylactic anticoagulation should be prescribed mechanical modalities such as graduated compression stockings or intermittent pneumatic compression devices. Pharmacologic prophylaxis can be achieved by a number of agents, including UFH, LMWH, fondaparinux, the DTI desirudin (only approved for hip replacement surgery), or a VKA. In high-risk populations such as those with hip fracture, or hip or knee replacement, a combination of mechanical and pharmacologic therapies should be considered. A new oral anticoagulant, Rivaroxaban, was recently approved in USA for the prevention of VTE in adults following hip and knee arthroplasty. Other oral anticoagulant agents (dabigatran and apixaban) are available outside the United States for prophylaxis and will likely be available sometime in the near future in the United States.
More specific indications for certain high-risk clinical situations are listed below. These recommendations are based on the most recent ACCP guidelines.70
Hip fracture surgery—Fondaparinux
Total hip/knee arthroplasty—LMWH, Fondaparinux, Rivaroxaban or warfarin with an INR target of 2.0 to 3.0
Neurosurgery—Intermittent pneumatic compression devices with or without graduated compression stockings, postoperative use of UFH, or LMWH when acceptable bleeding risk
Medical conditions—LMWH or UFH
High-risk general surgery/gynecologic surgery—LMWH, fondaparinux, or UFH and intermittent pneumatic compression ± graduated compression stockings
Prophylaxis should continue until the patient starts ambulating and/or the physician is comfortable that the individual is no longer at risk to develop a VTE. In select surgical procedures, extended prophylaxis is recommended. For example, extended prophylaxis for up to 28 to 35 days is recommended for patients who have had a hip fracture or who undergo total hip replacement surgery.70 Patients undergoing high-risk general surgery or gynecologic surgery (especially cancer surgery) should also receive extended prophylaxis (up to 28 days is recommended).70
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QUESTIONS AND ANSWERS
Questions
1. A 57-year-old male is brought to the emergency room by emergency medical services (EMS) after suffering from a syncopal episode. He has noticed dyspnea on exertion for the last 2 days and suddenly lost consciousness while sitting on his couch. His wife witnessed the event. He did not have jerky movements, and he regained consciousness spontaneously after 2 minutes. EMS found him hypoxic with O2 saturation of 84% on room air.He denied chest pain or dizziness preceding the syncopal event and denied fever or chills. In the ED, his blood pressure (BP) was 110/70, heart rate 110, and sat 94% on 2 L of O2. On exam, he had no jugular venous distension (JVD), normal heart sounds with no murmurs, and clear lungs without crackles or rales. There was 1+ LE edema. EKG showed sinus tachycardia and nonspecific T-wave changes in the inferior leads. Bedside troponin is positive. CK and full metabolic profile are negative. He smokes one pack of cigarettes a day. He denies HTN or hyperlipidemia. His father had coronary artery bypass graft (CABG) at age 75. He just returned 2 weeks ago from a short business trip to China where he was treated for traveler diarrhea. In managing this patient, what is your first diagnostic test?
a. Transthoracic echo (TTE)
b. Left heart catheterization
c. Spiral computed tomography (CT) of the chest
d. Transesophageal echocardiogram (TEE)
e. Pharmacologic nuclear stress test
2. A 50-year-old male is brought to the emergency room by EMS after suffering from a syncopal episode. He has noticed dyspnea on exertion for the last 2 days and suddenly lost consciousness while sitting on his couch. His wife witnessed the event. He did not have jerky movements, and he regained consciousness spontaneously after 2 minutes. EMS found him hypoxic with O2 saturation of 84% on room air. He denied chest pain or dizziness preceding the syncopal event and denied fever or chills. In the ED, his BP was 110/70, heart rate 101, and sat 94% on 2 L of O2. On exam, he had no JVD, normal heart sounds with no murmurs, and clear lungs without crackles or rales. There was 1 + LE edema. EKG showed sinus tachycardia and nonspecific T-wave changes in the inferior leads. Bedside troponin is negative. CK and full metabolic profile are negative. He smokes one pack of cigarettes a day. He denies HTN or hyperlipidemia. His father had CABG at age 75. He just returned 2 weeks ago from a short business trip to China where he was treated for traveler diarrhea.
CT scan of the chest is done and showed saddle pulmonary embolism (PE). What is the most appropriate treatment?
a. TPA + IV heparin
b. IV heparin bolus followed by continuous drip
c. Inferior vena cava (IVC) filter placement
d. Surgical embolectomy
3. A 68-year-old woman who is currently undergoing chemotherapy for a recent diagnosis of breast cancer presents to the emergency room with 2 days of right leg swelling. She denies chest pain, shortness of breath, dizziness, or syncope. She has a history of HTN and hyperlipidemia. She has no previous cardiac history. She is active and walks 1 to 2 miles daily. On physical exam, she has 2+ pitting edema of her right leg with mild calf tenderness. Pedal pulses are normal. Skin is warm with normal capillary refill. Lower extremity ultrasound showed right common femoral and distal iliac arteries to be dilated and not compressible.
Her platelet count is 110K and hemoglobin 10.7. Blood count and metabolic profile otherwise are normal. What is the most appropriate treatment?
a. IVC filter insertion
b. Enoxaparin with bridge to coumadin until INR is therapeutic
c. Low-molecular-weight heparin (LMWH) as monotherapy
d. LMWH and placement of IVC filter
e. Catheter-directed thrombolysis
4. A 45-year-old obese female with a history of hypertension, hyperlipidemia, and rheumatoid arthritis is hospitalized for elective cholecystectomy. On postoperative day 1 after uncomplicated surgery, she develops sudden onset of chest pain and shortness of breath. On exam, she has a heart rate of 124 bpm, her BP is 78/50, and O2 sat 86% on room air and 95% on 4 L of O2. Heart sounds are normal with no murmur. Lungs are clear to auscultation. Lower extremities show bilateral mild pitting edema. Her metabolic panel and blood count are normal. Troponin T is 0.12 (slightly elevated). Bedside stat echo shows moderate right ventricular (RV) dysfunction. Spiral CT of the chest shows large thrombus in the main pulmonary artery extending into left and right pulmonary arteries. The best treatment is:
a. IV heparin bolus followed by heparin drip
b. TPA followed by IV heparin
c. Insertion of IVC filter
d. Call cardiothoracic surgery for emergent surgical pulmonary artery thrombectomy
5. A 28-year-old female para 0 gravida 1, who is 12 weeks pregnant, presented to the emergency room with right leg swelling, redness, and pain. The pain started 2 days ago and has gotten worse since. She denies leg trauma, recent surgery, or immobilization. She has no chest pain, shortness of breath, dizziness, or syncope. Her heart rate is 89, BP 125/80, and sat 97% on RA. D-Dimer test was positive. Ultrasound of her lower extremities showed dilated and noncompressible right femoral and popliteal veins. She is healthy and has no previous medical history. Her mother had PE after delivery of her second child. She smoked for 5 years and quit recently when she learned that she was pregnant. The best treatment option is:
a. IV heparin with bridge to coumadin
b. Therapeutic dose subcutaneous enoxaparin with bridge to coumadin
c. Therapeutic dose subcutaneous enoxaparin as monotherapy
d. Coumadin alone; no need for bridging
e. IVC filter
6. Duration of anticoagulation for the patient in Question 5 should be:
a. 3 months
b. 6 months
c. Throughout her pregnancy
d. Throughout her pregnancy, hold around delivery and resume for 6 more weeks postpartum
e. Lifelong
7. A 69-year-old obese female was recently diagnosed with nonresectable lung cancer is in the process of initiating chemo therapy and radiation therapy. She presented to the emergency room with sudden onset of shortness of breath. She has hypertension and hyperlipidemia. She has no known cardiac disease. She denies chest pain, cough, fever, or chills. Physical exam reveals heart rate of 95 bpm, BP 120/78, and sat 91% on RA. She has normal heart sounds and decreased breath sounds over the right lower lobe. She has right leg swelling. EKG shows sinus tachycardia with nonspecific T-wave changes. Chest x-ray shows a right lower lobe nodule and moderate left pleural effusion. Her metabolic panel is normal, D-dimer is 750 ng/ml {500 upper normal limit), and troponin is negative. Lower extremity venous ultrasound is negative for DVT. Spiral CT of the chest is not diagnostic due to tachycardia and motion artifact. The best next step in confirming your diagnosis is:
a. Repeat spiral CT of the chest
b. Ventilation/perfusion {V/Q) scan
c. Magnetic resonance imaging (MRI) of the chest
d. Pulmonary artery angiogram
e. Transthoracic Echocardiogram
f. Transesophageal echocardiogram (TEE)
8. Pulmonary angiogram was done and showed left and right lower lobe segmental and subsegmental filling defect consistent with acute PE. Best treatment option and duration of therapy is:
a. LMWH bridge to coumadin for 6 months.
b. Heparin bridge to coumadin for 6 months
c. LMWH as monotherapy for 6 months
d. LMWH as monotherapy for 6 months, followed by transition to coumadin indefinitely
e. Fondaparinux as monotherapy for 6 months
f. Dabigatran indefinitely
Answers
1. Answer C: The patient is at risk for PE with a recent long-distance trip. Syncope is not an uncommon presentation for acute PE and should not be overlooked. Positive troponin here reflects RV strain and not acute coronary syndrome (ACS).
2. Answer A: The patient is hemodynamically stable. Treatment of choice is full-dose anticoagulation with unfractionated intravenous heparin or subcutaneous therapeutic dose LMWH. There is no indication for thrombolysis or surgical embolectomy in the absence of hemodynamic instability. IVC filter is not indicated unless the patient has contraindication for full-dose anticoagulation.
3. Answer C: The patient has an unprovoked thromboembolic event in the setting of an active malignancy. The current guidelines recommend use of LMWH as monotherapy for 3 to 6 months before considering transition to coumadin. Catheter-directed thrombolysis would be indicated if the limb was threatened due to extensive thrombosis. IVC filter is not indicated unless the patient has contraindication for full-dose anticoagulation.
4. Answer D: The patient is hemodynamically unstable, and treatment with heparin only carries a mortality as high as 50%. T-PA is contraindicated few hours after surgery. Emergent thrombectomy should be considered in cases of hemodynamic instability when thrombolytic therapy is contraindicated.
5. Answer C: Coumadin is teratogenic and should not be used during pregnancy. Therapeutic dose of enoxaparin would be the best option for this patient. Treatment options for this patient include LMWH or full dose subcutaneous unfractionated heparin that is associated with a high risk of osteoporosis when taken for a long time.
6. Answer D: During the postpartum period, this patient continues to be hypercoagulable and should be kept anticoagulated for at least 6 weeks. The patient can be transitioned to coumadin after delivery.
7. Answer D: Pulmonary artery angiogram is still considered the gold standard for diagnosing PE and should be considered when a high clinical suspicion cannot be confirmed by other modalities. Because of her abnormal chest x-ray, a V/Q scan is unlikely to be helpful in confirming the diagnosis. Transthoracic Echocardiogram is used to risk stratify patients with confirmed acute PE; however, it cannot be used to establish the diagnosis. Even though a central PE can be visualized by TEE, segmental or subsegmental PE would be missed.
8. Answer D: Patients with unprovoked venous thromboembolism (VTE) in the setting of an active malignancy should be treated indefinitely in the absence of contraindications, as long as their malignancy is active. LMWH is the treatment of choice in the first 3 to 6 months in patients with active malignancy. Dabigatran is not approved for treatment of venous thrombosis at this time.