Chapter 29. Pulmonary Embolic Disease

• Otherwise unexplained dyspnea, tachypnea, or chest pain.
• Clinical, electrocardiogram, or echocardiographic evidence of acute cor pulmonale.
• Positive chest computed tomography angiography scan with contrast.
• High-probability ventilation-perfusion lung scan or high-probability perfusion lung scan with a normal chest radiograph.
• Positive venous ultrasound of the legs with a convincing clinical history and suggestive lung scan.
• Diagnostic contrast pulmonary angiogram.

The term “venous thromboembolism” (VTE) encompasses both pulmonary embolism (PE) and deep venous thrombosis (DVT) and accounts for more than 250,000 hospitalizations per year in the United States. VTE constitutes one of the most common causes of cardiovascular and cardiopulmonary illnesses in Western civilization. PE causes or contributes to at least 50,000 deaths per year in the United States, a rate that has probably remained constant for the past three decades. However, a significant proportion of cases of PE remain undiagnosed, partly due to the variable nature of its clinical presentation and partly due to the lack of access of appropriate diagnostic testing modalities at the point of initial care. With the increasing use of computed tomographic pulmonary angiography (CT-PA) in mainstream clinical practice, a larger proportion of PE cases are now being diagnosed. In fact, the estimated incidence of PE has approximately doubled after the introduction of CT-PA in routine clinical practice, from 62.1 to 112.3 cases per 100,000 individuals. For those who survive PE, further disability includes the potential development of chronic pulmonary hypertension or chronic venous insufficiency. After a VTE event, patients and their physicians are concerned about the presence of an occult carcinoma, the risk of a recurrent PE after anticoagulation therapy has been discontinued, and whether the patients' family members are at risk for VTE.

“Primary” PE occurs in the absence of surgery or trauma. Patients with this condition often have an underlying hypercoagulable state, although a specific thrombophilic condition may not be identified. A common scenario is a clinically silent tendency toward thrombosis, which is precipitated by a stressor such as prolonged immobilization, oral contraceptives, pregnancy, or hormone replacement therapy. Recently, there has been an increased appreciation of the risks of VTE among patients with medical illnesses, including cancer (which itself may be associated with a hypercoagulable state), congestive heart failure, and chronic obstructive pulmonary disease.

The prevalence of “secondary” PE is high among patients undergoing certain types of surgery, especially orthopedic surgery of the hip and knee, gynecologic cancer surgery, major trauma, and craniotomy for brain tumor. PE in these patients may occur as late as a month after discharge from the hospital.

Thrombophilia

A thorough history should be obtained, including history of prior VTE, family history of VTE, history of frequent miscarriages, past history of cancer, recent history of heparin use (suggestive of heparin-induced thrombocytopenia), and history of prothrombotic conditions (myeloproliferative disease, nephrotic syndrome, collagen-vascular disease, and congestive heart failure). An acquired or inheritable risk factor is found in 50% of patients who present with an initial VTE. Principal thrombophilic risk factors for VTE are listed in Table 29–1. The two most common genetic mutations that predispose to VTE are the factor V Leiden and the prothrombin gene. Both are autosomal dominant. Whether factor V Leiden predisposes to recurrent VTE after anticoagulation is discontinued remains controversial. The prothrombin gene mutation is associated with an increased risk of recurrent VTE after discontinuation of anticoagulation, especially in patients who have coinherited the factor V Leiden mutation.

Laboratory screening for inherited thrombophilia does not always impact the treatment plan and therefore is not always indicated. Regardless of whether a risk factor is identified, just the history of having had a VTE event is the most significant risk factor for predicting future recurrence. Screening for deficiencies of antithrombin III, protein C, and protein S is a low-yield strategy that produces positive findings in less than 5% of patients. Heparin decreases the antithrombin III level, whereas warfarin, pregnancy, and oral contraceptives decrease the protein C and S levels, thereby resulting in potentially spurious diagnoses of these hypercoagulable states. There are no data that support screening for or treating hyperhomocysteinemia in the setting of VTE. A positive finding of inherited thrombophilia does not necessarily imply that the patient is at higher risk for recurrent VTE or would benefit from extended duration of anticoagulation. Therefore, the 2012 American College of Chest Physicians (ACCP) guidelines do not find that testing for inherited thrombophilic disorders should be a major determinant of VTE treatment. However, in patients with a strong family history of VTE, or based on strong patient preferences, screening can be considered for the patient and first-degree relatives, particularly if it may impact decisions about oral contraceptive use.

In contrast to screening for inheritable disorders, because malignancy is a hypercoagulable state and because VTE may be the first presenting symptom of malignancy, age-appropriate cancer screening after VTE is prudent.

Women's Health

PE poses a special threat for women because VTE is associated with the use of oral contraceptives, pregnancy, and hormone replacement therapy.

One-third of pregnancy-related VTE occurs postpartum. The risk of DVT is present throughout pregnancy and is highest during the third trimester. After delivery, two of the most important risk factors for VTE are increased maternal age and cesarean section. Emergency cesarean section increases the VTE risk by about 50% compared with elective cesarean section.

Among women with a history of VTE during pregnancy or puerperium in one study, the prevalence of factor V Leiden was 44% and the prevalence of the prothrombin gene mutation was 17%. Compared with controls, the Leiden mutation increased the risk of VTE ninefold, and the prothrombin gene mutation increased the risk by a factor of 15. The combination of the Leiden and prothrombin gene mutations increased the VTE risk to more than 100 times that seen in the controls. Irrespective of factor V Leiden, pregnancy itself causes hypercoagulability because it induces a relative state of activated protein C resistance.

Hormone replacement therapy also predisposes to VTE. In 1996, three separate large data sets implicated hormone replacement therapy as doubling, tripling, or even quadrupling the risk of VTE. As with oral contraceptives, the risk of VTE peaks during the first year of hormone replacement therapy.

PE is often difficult to diagnose due to the variable nature of its clinical presentation. Acute PE can manifest clinically as massive, submassive, or nonmassive based on the severity of the clinical presentation, although this distinction is somewhat vague and does not necessarily correlate with clinical outcomes. Acute massive PE is a life-threatening condition characterized by sudden onset of chest pain, hypotension, hypoxemia, and distended neck veins, and it needs to be differentiated quickly from other potentially lethal conditions including acute myocardial infarction, tension pneumothorax, or pericardial tamponade. Despite the availability of radionuclide lung scanning, chest computed tomography (CT) scanning, and pulmonary angiography, many pulmonary emboli are not discovered until postmortem examination. Appreciation of the clinical settings that make patients susceptible to PE and maintenance of a high degree of clinical suspicion are, therefore, of paramount importance.

Symptoms & Signs

The most common symptoms or signs of PE are nonspecific: dyspnea, tachypnea, chest pain, or tachycardia. Patients with life-threatening or massive PE are apt to have dyspnea, syncope, or cyanosis rather than chest pain. Less than one-third of patients with PE have symptoms of a DVT. Massive PE should be suspected in hypotensive patients who have evidence of, or predisposing factors for, venous thrombosis and clinical findings of acute cor pulmonale (acute right ventricular failure), such as distended neck veins, an S3 gallop, a right ventricular heave, tachycardia, or tachypnea. The definition of massive PE proposed by the American Heart Association is: an acute PE with sustained hypotension (systolic blood pressure < 90 mm Hg for at least 15 minutes or requiring inotropic support, not due to a cause other than PE, such as arrhythmia, hypovolemia, sepsis, or left ventricular dysfunction), pulselessness, or persistent profound bradycardia (heart rate < 40 bpm with signs or symptoms of shock). Submassive PE has been defined as an acute PE without systemic hypotension (systolic blood pressure > 90 mm Hg) but with either evidence of right ventricular dysfunction or myocardial necrosis. Low-risk or nonmassive PE is defined as an acute PE without the presence of hemodynamic instability, right ventricular dysfunction, or myocardial necrosis.

Patients with severe chest pain or hemoptysis usually have anatomically small PE near the periphery of the lung. This is where innervation is greatest and where pulmonary infarction is most likely to occur from a dearth of collateral bronchial circulation.

Decision algorithms have been developed to help determine the probability of PE based on clinical symptoms and signs and to guide the selection of diagnostic tests in order to make a rapid and accurate diagnosis and thus initiate treatment without delay. To this end, an integrated diagnostic approach for cases of suspected PE, as shown in Figure 29–1, has been shown to be useful. The diagnostic workup should begin by quantifying the clinical suspicion with a precise clinical scoring algorithm.

Traditionally, the clinical likelihood of PE has been estimated subjectively by “gestalt” as low, moderate, or high. However, to better define the clinical probability of PE in a given patient, quantitative clinical scoring systems have been devised in order to provide the clinician with a standardized and objective approach.

One of the most widely used clinical scoring systems is the Ottawa Scoring System (also known as the modified Wells index), which has a maximum of 12.5 points (Table 29–2). The greatest emphasis is placed on the presence of signs or symptoms of DVT (3 points) and whether an alternative diagnosis is unlikely (3 points). If the score exceeds 4 points, the overall likelihood of PE being confirmed with imaging tests is 41%. However, if the score is 4 points or less, the likelihood of PE is only 8%. Although this scoring system has the advantage of simplicity and rapidity, it offers a somewhat subjective approach with regard to the important, heavily weighted category of “alternative diagnosis unlikely.”

In clinical settings such as outpatient clinics or emergency departments where the overall prevalence of PE is low but many patients have symptoms such as chest pain or shortness of breath, the Pulmonary Embolism Rule-out Criteria (PERC) may be used to exclude a PE without additional diagnostic testing. The eight factors that constitute the PERC are age < 50 years, heart rate < 100 bpm, oxygen saturation ≥ 95%, no hemoptysis, no estrogen use, no prior history of PE or DVT, no unilateral leg swelling, and no surgery or trauma needing hospitalization within the past 4 weeks. If a patient does not have any of the PERC criteria and has a low clinical suspicion of PE using clinical gestalt or the modified Wells index, then the diagnosis of PE can likely be excluded without additional diagnostic testing. This approach has been validated in a multicenter cohort study of > 8000 emergency department patients, but it should only be used in a setting where the prevalence of acute PE is low.

Diagnostic Studies

Nonimaging Studies

Electrocardiography

Electrocardiograms (ECG) may show evidence of acute cor pulmonale, manifested by a new S1 Q3 T3 pattern, new incomplete right bundle branch block, right axis deviation, or right ventricular ischemia or strain with ST segment depressions in the right precordial leads. However, these changes are usually only seen in patients with acute massive PE, and therefore, absence of these ECG changes in a patient with suspected PE should not preclude additional diagnostic testing. Some ECG findings that have been associated with an adverse prognosis in patients with acute PE include atrial arrhythmias, right bundle branch block, Q waves in the inferior leads III and aVF, and ST segment changes and T-wave inversions in the precordial leads.

Arterial Blood Gases

Neither measurement of room air arterial blood gases nor calculation of the alveolar-arterial oxygen gradient is useful in excluding the diagnosis of PE. Among patients in whom PE is suspected, neither test helped differentiate patients with a confirmed PE at angiography from those with a normal pulmonary angiogram. Therefore, arterial blood gases should not be obtained as a screening test for suspected PE.

Plasma d-Dimer Enzyme-Linked Immunosorbent Assay

Endogenous fibrinolysis, although ineffective in preventing PE, almost always causes the release of d-dimers from fibrin clot in the presence of established PE. However, an elevated d-dimer test is not specific and may occur in a variety of other conditions including acute comorbid illnesses, such as acute myocardial infarction, metastatic cancer, sepsis, or recent surgery. A normal (< 500 ng/mL) result virtually excludes the diagnosis of PE: among patients with a normal d-dimer level, the likelihood of PE is < 5%. Despite its sensitivity, in patients with a very high clinical suspicion of PE, the d-dimer should not be used in isolation to exclude PE. The combination of low clinical suspicion, ideally quantified with a validated scoring system, and a normal d-dimer enzyme-linked immunosorbent assay makes PE exceedingly unlikely.

Troponin Levels

Screening for troponins is now the standard blood test for cardiac injury, and it is obtained routinely when acute myocardial infarction or unstable angina is suspected. Circulating troponin indicates irreversible myocardial cell damage and is much more sensitive than creatine kinase or its myocardial muscle isoenzyme. Cardiac markers of injury should not be used, however, as a primary diagnostic test for acute PE. Nevertheless, elevation of cardiac troponin is an adverse prognostic factor in patients with acute PE and is associated with a markedly increased mortality rate and requirement for inotropic support and mechanical ventilation. Troponin elevation also correlates with ECG evidence of right ventricular strain. This suggests that release of troponin from the myocardium during PE may result from acute right ventricular microinfarction due to pressure overload, impaired coronary artery blood flow, or hypoxemia caused by the PE. A meta-analysis of 20 observational studies showed that patients with acute PE with elevated troponin T or troponin I levels had a fivefold higher risk of short-term mortality and a ninefold increased risk of death due to PE.

Brain Natriuretic Peptide (BNP) Levels

As with cardiac troponins, measurement of BNP levels or N-terminal proBNP (NT-proBNP) levels should not be used to diagnose an acute PE. However, elevation of BNP or NT-proBNP levels may be a reflection of right ventricular dysfunction in the setting of an acute PE and therefore may have prognostic value. In a meta-analysis of 16 studies of patients with acute PE, in-hospital or short-term mortality was increased sixfold in those with a BNP level > 100 pg/mL and 16-fold among those with an NT-proBNP level > 600 ng/L.

Imaging Studies

Chest Radiography

Chest radiography can help exclude diseases such as lobar pneumonia, pneumothorax, or cardiogenic pulmonary edema, which can have clinical presentations that mimic acute PE. However, patients with these disorders can also have concomitant PE.

Radionuclide Lung Scanning

This study has served as the principal diagnostic imaging test for PE but is now with increasing frequency being superseded by chest CT scanning. Lung scanning is most useful when unequivocally normal or when highly suggestive of PE (Figure 29–2). Neither intermediate nor low-probability scans (in the presence of high clinical suspicion) exclude PE. For example, with the combination of a low-probability scan and high clinical suspicion for PE, the likelihood of PE is 40%. When lung scanning is performed, the ventilation scan is being used less frequently than previously because its contribution to the diagnostic decision is only marginally better than the combination of a perfusion scan and chest radiograph.

Chest CT Scanning

The chest CT is diagnostic of PE when an intraluminal pulmonary arterial filling defect is surrounded by contrast material. CT scanning has two major advantages over lung scanning: (1) directly visualizing thrombus and (2) establishing alternative diagnoses on CT images of the lung parenchyma that are not evident on a chest film.

Conventional chest CT scanning relies on imaging a series of consecutive sections of the chest. With the introduction of spiral chest CT scanning, patients can be scanned continually. As patients are advanced through the spiral CT scanner, the x-ray source and single-row detector array rotate around them. These scans are performed during a single breath-hold, thereby eliminating respiratory motion artifact that previously limited thoracic imaging. Overlap data from adjacent slices are acquired, thus reducing the possibility of missed pathology. Scans are performed in less than 30 seconds, and excellent vascular opacification with the contrast agent can usually be achieved (Figure 29–3). However, the major limitation has been failure to detect PEs beyond the third-order pulmonary arterial branches.

Further innovations occurred with the introduction of multidetector CT scanners, which acquire four slices simultaneously during each rotation of the x-ray source. Multidetector CT improves resolution from 5 mm to 1.25 mm and allows for better visualization of subsegmental vessels. Compared with conventional spiral CT, the sensitivity of multirow detector scanners for the diagnosis of acute PE increased from about 70% to 80–90%. In the PIOPED II study, which used multidetector CT angiography, the sensitivity and specificity were 83% and 96%, respectively. The positive predictive value was 96% with a concordant clinical assessment. The addition of CT venography to image DVTs improves the sensitivity from 83% to 90% with no change in specificity. In order to answer concerns that CT angiography could miss clinically important PEs in the branch pulmonary arteries, another randomized trial directly compared CT angiography with V̇/Q̇ scanning. In this study, CT was found to be noninferior. PE was diagnosed in more patients in the CT group than in the V̇/Q̇ scanning group. The risk of VTE during 3-month follow-up after having a negative imaging study was 0.4% for CT and 1% for V̇/Q̇ scan.

Occasionally, determining whether a pulmonary embolus represents the residua of prior PE or a new event may be challenging. A systematic review of the literature has shown that over half of patients with PE will still have a defect on either CT scan or radionuclide imaging 6 months after diagnosis.

Venous Ultrasonography

In combination with color Doppler imaging, venous ultrasonography is known as duplex sonography and is the principal diagnostic imaging test for suspected acute DVT. Sonographic evaluation uses compression ultrasound along the full length of the femoral, popliteal, and calf veins. The transducer is held transverse to the vein and, normally, the vein collapses with gentle manual compression. The compressed vein appears as if it is winking. The main criterion for diagnosing DVT is lack of compression of a deep vein. This diagnosis can be confirmed by direct visualization of thrombus on ultrasound or by abnormal venous flow on Doppler examination (eg, loss of physiologic respiratory variation or loss of the expected augmentation of blood flow during calf compression).

Among symptomatic patients, duplex sonography is very accurate, with high sensitivity and specificity. Its sensitivity decreases when assessing asymptomatic patients. Major limitations include an inability to image pelvic vein thrombosis directly, lower sensitivity for diagnosing isolated calf DVT, and difficulty diagnosing an acute DVT superimposed upon a chronic one. Magnetic resonance imaging may be useful under these circumstances.

Importantly, many patients with PE do not have evidence of leg DVT, probably because the thrombus has already embolized to the pulmonary arteries. Therefore, PE is not necessarily ruled out if the clinical suspicion is high and imaging evidence of DVT is lacking.

Echocardiography

Echocardiography should not be used routinely to diagnose suspected PE because most patients with PE have normal echocardiograms. However, the echocardiogram, like the troponin level, is an excellent tool for risk stratification and prognostication. Echocardiography is useful diagnostically when the differential diagnosis includes pericardial tamponade, right ventricular infarction, and dissection of the aorta as well as PE.

Imaging a normal left ventricle in the presence of a dilated, hypokinetic right ventricle strongly suggests the diagnosis of PE (Figure 29–4). The presence of right ventricular mid-free wall akinesis with sparing of the apex (the McConnell sign) has been found to be highly specific for acute PE. Echocardiographic findings in PE patients are summarized in Table 29–3.

The pulmonary arterial systolic pressure can be estimated by measuring the peak velocity of the tricuspid regurgitant jet obtained with Doppler echocardiography. The gradient across the tricuspid valve can be estimated by using the modified Bernoulli equation, P = 4V2, where V is the peak velocity of the regurgitant jet, and P represents the peak pressure difference between the right atrium and right ventricle. The estimated right atrial pressure is added to the gradient to obtain an estimate of pulmonary arterial systolic pressure. The pulmonary artery systolic pressure may be low, normal, or mildly elevated in the setting of acute PE. Significant pulmonary hypertension suggests a subacute or chronic process. The incidence of chronic thromboembolic pulmonary hypertension following a first episode of PE is low overall (~1%), but in patients with unexplained persistent dyspnea after PE, the incidence may be as high as 4% after 2 years. Echocardiography to measure pulmonary artery pressure and exclude chronic thromboembolic pulmonary hypertension should be obtained for patients with persistent unexplained dyspnea following treatment of PE.

Transesophageal echocardiography for suspected PE is best reserved for critically ill patients. Transesophageal echocardiography diagnoses PE by direct visualization of thrombus, assesses its extent, and provides guidance regarding its surgical accessibility. Transesophageal echocardiography may also have a valuable role in detecting unexplained sudden cardiac arrest and pulseless electrical activity due to acute PE. In a series of 1246 patients who suffered cardiac arrest, 5% of cases were caused by PE; of those with PE, 63% of cardiac arrest cases were caused by pulseless electrical activity. Therefore, when pulseless electrical activity is present, the possibility of an acute PE should be considered.

Pulmonary Angiography

Pulmonary angiography is considered to be the “gold standard” diagnostic modality for the diagnosis of acute PE. This imaging method is rapidly becoming a lost art and is being undertaken primarily for therapeutic interventions (such as suction catheter embolectomy) rather than to solve diagnostic dilemmas. Most diagnostic questions can be resolved with the new-generation chest CT scanners, which provide resolution to subsegmental branches. A constant intraluminal filling defect seen in more than one projection is the most reliable angiographic diagnostic feature for PE.

Pulmonary angiography can almost always be accomplished safely, although the risk may be increased in patients with severe pulmonary hypertension. Selective angiography should be performed, with the equivocal portion of the perfusion lung scan or chest CT scan serving as a road map. To avoid damaging the intima of the pulmonary artery, soft, flexible catheters with side holes should be used, rather than stiff catheters with end holes. Low-osmolar contrast agents minimize the transient hypotension, heat, and coughing that often occur with conventional radioactive contrast agents.

PE is easier and less expensive to prevent than to diagnose or treat; therefore, virtually all hospitalized patients should receive prophylaxis against VTE. Unfortunately, such prophylaxis is underutilized, even for high-risk patients. Furthermore, prophylaxis, even when instituted, may not be effective. Nonetheless, prevention programs should be established at all hospitals to ensure that adequate measures are implemented. Nurses and physicians must collaborate to achieve this goal by instituting protocols that are both streamlined and standardized. In addition, quality assurance personnel should adopt a proactive stance to encourage the development of such programs.

The preventive measures should be based on an assessment of the patient's level of risk for PE and whether the optimal strategy will be nonpharmacologic, pharmacologic, or combined modalities. Because the risk of PE continues after discharge from the hospital, prophylaxis should be continued at home among those patients at moderate or high risk for VTE.

Nonpharmacologic Prevention

The most commonly used nonpharmacologic measures are graduated compression stockings (GCS) and intermittent pneumatic compression devices (IPC or “SCD boots”). Vascular compression with either GCS or IPC is effective among surgical patients, because it counters the otherwise-unopposed perioperative venodilation that appears causally related to postoperative venous thrombosis. Even among low-risk general surgery patients, graduated compression stockings can substantially reduce the frequency of venous thrombosis and should therefore be considered first-line prophylaxis against PE in all hospitalized patients, except those with peripheral arterial occlusive disease whose condition may be worsened by vascular compression.

IPC boots, which provide intermittent inflation of air-filled cuffs, prevent venous stasis in the legs; they also appear to stimulate the endogenous fibrinolytic system. Because it appears that GCS and IPC boots work through somewhat different—although complementary—mechanisms, these modalities can be used in combination in patients at moderate or high risk for venous thrombosis.

Pharmacologic Prevention

Anticoagulant drugs can be used instead of—or in addition to—nonpharmacologic prophylaxis. A number of agents are used for prophylaxis against VTE in patients at high risk for thrombosis. These include unfractionated heparin (usually administered at a dose of 5000 units subcutaneously twice or thrice daily), low-molecular-weight heparins (LMWHs) such as enoxaparin or dalteparin, and antithrombin-binding pentasaccharides such as fondaparinux. Other agents have recently been recommended for use for VTE prophylaxis in selected patient populations, such as vitamin K antagonists such as warfarin, and newer antithrombotic agents such as dabigatran, rivaroxaban, and apixaban.

The ACCP recently published clinical guidelines for the use of thromboprophylaxis in hospitalized patients. All critically ill patients should receive thromboprophylaxis with either LMWH (such as enoxaparin or dalteparin) or low-dose unfractionated heparin, unless they are actively bleeding or are at high risk of major bleeding, in which case they should receive nonpharmacologic prophylaxis with GCS or IPC devices until the bleeding risk is reduced. For acutely ill, nonsurgical hospitalized patients who are at high risk for thrombosis, pharmacologic prophylaxis is recommended with LMWH, low-dose unfractionated heparin (at a dose of 5000 units two to three times per day), or fondaparinux. For nonsurgical hospitalized patients with high risk for thrombosis who are bleeding or are at risk for major bleeding, nonpharmacologic prophylaxis should be used. Hospitalized patients at low risk for thrombosis should not receive any thromboprophylaxis, and early and frequent ambulation is desirable in these patients.

The recent ACCP clinical guidelines also provide detailed recommendations for the use of thromboprophylaxis for patients undergoing orthopedic and nonorthopedic surgery. Table 29–4 lists the various pharmacologic agents that are recommended for use in patients undergoing orthopedic and general surgery. In patients undergoing total hip or total knee arthroplasty, the ACCP recommends the use of one of the following agents for thromboprophylaxis for a minimum of 10–14 days: LMWH (enoxaparin or dalteparin), fondaparinux, apixaban, dabigatran, rivaroxaban, low-dose unfractionated heparin, adjusted-dose vitamin K antagonist (warfarin), aspirin, or an IPC device. In patients undergoing major orthopedic surgery who have an increased risk of bleeding, they recommend the use of an IPC or no prophylaxis rather than pharmacologic treatment. Patients undergoing general and abdominal-pelvic surgery at very low or low risk for VTE should receive nonpharmacologic prophylaxis using IPC devices and early ambulation, whereas those at moderate to high risk for VTE but not at high risk for major bleeding should receive pharmacologic prophylaxis with LMWH or low-dose unfractionated heparin, along with use of nonpharmacologic agents such as IPC devices in high-risk patients.

Future Directions

Many hospitals routinely use protocol-driven prophylaxis for all hospitalized patients, especially for medical patients hospitalized in intensive care units. The current guidelines from the ACCP, as well as guidelines published by the American College of Physicians (ACP), form the basis of most of these protocols. The emphasis on preventive strategies includes the time of hospital discharge or transfer to a skilled nursing facility or rehabilitation hospital. Orders to prescribe these prophylactic measures often are prompted by a computerized order entry system that reminds physicians about the need for prophylaxis. As studies with the use of newer antithrombotic agents are completed and reported, the safety and efficacy of these agents will be better defined, and clinical guidelines for their use in thromboprophylaxis will need to be updated accordingly.

Not all PEs are created equal. The most important concept in PE management is that acute PE spans a wide range of risk, from small asymptomatic emboli to massive thromboembolism with catastrophic cardiovascular collapse and death due to right ventricular failure. Therapy must be geared to patient risk. Low-risk patients will do well with anticoagulation alone, whereas high-risk patients may require thrombolysis or embolectomy in addition to anticoagulation.

The Pulmonary Embolism Severity Index (PESI) is a clinical scoring system that uses a total of 11 parameters, including demographic characteristics (age and male sex), comorbid illnesses (cancer, heart failure, and chronic lung disease), and clinical findings (heart rate, systolic blood pressure, respiratory rate, body temperature, alteration of mental status, and arterial oxygen saturation), and has been shown to independently predict mortality at 30 days in patients with acute PE. A simplified version of the PESI has also been developed and is similar in prognostic utility but easier to use in the clinical setting. The original and simplified PESI scoring systems are summarized in Table 29–5.

The most important imaging test for risk stratification is echocardiographic assessment of right ventricular function. Even if the initial systemic blood pressure is normal, patients with echocardiographic evidence of right ventricular dysfunction may develop cardiogenic shock within 24 hours; these patients may have a high mortality rate. In contrast, the mortality rate is low in normotensive patients with normal right ventricular function on echocardiography. Pulmonary hypertension, as estimated by Doppler echocardiography, that persists for more than 5 weeks after the diagnosis of PE is associated with an adverse long-term prognosis.

Biomarkers that reflect right ventricular strain or ischemia may also be useful tools to assess risk. The combination of either an elevated BNP or an elevated troponin level in conjunction with echocardiographic evidence of right ventricular dysfunction increases the odds of an in-hospital complication by 10-fold. Elevated levels of these biomarkers should prompt an echocardiogram to look for right ventricular dysfunction.

The treatment of PE must be initiated as soon as possible, and the timing of initiation of therapy depends on the clinical suspicion of PE and the expected delay between ordering a diagnostic test and making a definitive diagnosis of acute PE. The clinical suspicion of acute PE should be informed by the use of a validated clinical scoring system such as the Ottawa scoring system described earlier. If there is strong clinical suspicion of acute PE, empiric treatment with a parenteral anticoagulation agent should be started while waiting for the test results to arrive. In patients with intermediate clinical suspicion for acute PE in whom the test results are expected to be delayed for 4 hours or more, empiric anticoagulation should be initiated. In patients with a low clinical suspicion for acute PE, empiric anticoagulation should not be given until the test results are obtained, provided the results are available within 24 hours. However, in patients in whom the risk of major bleeding is moderate or high, the decision to initiate anticoagulation should be made on a case-by-case basis considering the overall clinical picture, as well as the patient's preferences and values. If anticoagulation is contraindicated and an acute PE is confirmed, the patient should be considered for placement of an inferior vena cava (IVC) filter, as detailed later.

Unfractionated heparin has traditionally been the first choice for anticoagulation for acute PE. However, in recent times, the use of LMWH is recommended as preferred anticoagulation agents for most patients with acute PE, as studies have shown that these agents are either equivalent or superior in efficacy, have lower rates of adverse reactions including thrombocytopenia, have more predictable pharmacokinetics, and do not require frequent monitoring of the activated partial thromboplastin time (aPTT). Newer anticoagulant agents have also been developed over the past few years and are used as acceptable alternatives to LMWH in certain clinical situations.

Heparin

Although unfractionated heparin has served as the standard foundation of PE treatment for more than 40 years, this anticoagulant has important limitations. Its variable protein binding leads to an often unpredictable dose response and makes it a drug that is difficult to administer properly in everyday clinical practice. Subtherapeutic levels of heparin increase the risk of recurrent PE, while excessive levels of heparin increase the risk of major bleeding.

Unfractionated heparin for PE treatment is usually ordered as an intravenous bolus followed by a continuous intravenous infusion. The required dose is unpredictable and must be adjusted according to the aPTT. Heparin is usually administered as a bolus of 5000–10,000 units (80 units/kg) followed by a weight-based hourly infusion (18 units/kg/h), which is titrated based on the aPTT, which is measured every 4–6 hours (Table 29–6). In general, the target partial thromboplastin time is 60–80 seconds.

With the increasing use of LMWHs, the use of unfractionated heparin is now restricted to the following clinical situations: patients with acute PE and persistent hypotension (since the LMWHs have not been well studied in this subgroup); patients with increased risk of bleeding (due to its shorter half-life); patients with morbid obesity or severe anasarca (due to concern about adequate subcutaneous absorption); patients with severe renal insufficiency (since most LMWHs are renally excreted); and patients in whom thrombolytic therapy is being considered.

Patients being treated with heparin who have a subsequent drop in platelet count should be evaluated for heparin-induced thrombocytopenia. The platelet count may decline within hours or, more commonly, 5–10 days after exposure to heparin. Patients with known or suspected heparin-induced thrombocytopenia should be treated with either direct thrombin inhibitors (such as lepirudin, argatroban, or bivalirudin) or heparinoids (such as danaparoid). Heparin, LMWH, and warfarin monotherapy should be avoided in the setting of known or suspected heparin-induced thrombocytopenia.

Low-Molecular-Weight Heparin

LMWHs have revolutionized the initial management of VTE (Table 29–7) and are now considered first-line agents for the initial treatment of acute PE in the majority of patients. In addition, LMWHs are the preferred agents for long-term anticoagulation for PE patients who are pregnant or have underlying cancer. The use of LMWHs to treat DVT has dramatically converted the therapy of this illness from a 5- to 6-day hospitalization to primarily outpatient or overnight in-hospital management. In the United States, two LMWHs are commonly used for the treatment of patients with symptomatic DVT, with or without PE: enoxaparin and dalteparin (Table 29–8). The U.S. Food and Drug Administration–approved outpatient therapy for DVT with the LMWH enoxaparin is 1 mg/kg actual body weight given subcutaneously twice daily, or a once-daily subcutaneous dose of 1.5 mg/kg actual body weight. Dalteparin is administered subcutaneously at a dose of 100 IU/kg actual body weight twice daily or 200 IU/kg actual body weight once daily, up to a maximum daily dose of 18,000 IU per day. Tinzaparin is administered once daily at a dose of 175 IU/kg actual body weight, but is contraindicated in patients > 70 years of age with renal insufficiency. Patients with cancer, extensive clot burden, or obesity (actual body weight > 100 kg or a body mass index of 30–40) preferably should be treated with enoxaparin at the 1 mg/kg twice-daily dose.

LMWHs appear to be safer than unfractionated heparin because osteopenia and heparin-induced thrombocytopenia occur far less often. They have a much more predictable dose response than unfractionated heparin and can usually be administered on the basis of weight alone, without any blood testing to modify the dose. They have a minimal effect on the partial thromboplastin time. Renal insufficiency (particularly a creatinine clearance [CrCl] < 30 mL/min), low body weight, massive obesity, elderly age, and pregnancy increase the risk of incorrect dosing, resulting in either over- or under-anticoagulation. Avoidance of LMWH, dose-adjustment, or monitoring of anti-factor Xa activity may be necessary in these patients (Table 29–9). Even though dose adjustment is not recommended for patients with mild to moderate renal insufficiency (CrCl ≥ 30 mL/min), spontaneous bleeding from standard weight-based dosing of LMWHs may develop in such patients.

In a meta-analysis of randomized DVT treatment trials comparing LMWHs with unfractionated heparin, LMWHs were found to be more effective and safer. Their use resulted in fewer recurrent thromboemboli, less bleeding, less thrombocytopenia, and an improved quality of life and patient satisfaction. The strategy of using LMWHs was also more cost-effective. The 2007 ACP guidelines thus recommend the initial use of LMWH in lieu of unfractionated heparin for the inpatient or outpatient treatment of DVT. The more recently published clinical guidelines by the ACCP also recommend the preferential use of subcutaneous LMWH or fondaparinux over intravenous or subcutaneous unfractionated heparin for patients diagnosed with acute PE.

Fondaparinux

Fondaparinux is a subcutaneously administered synthetic pentasaccharide that contains the antithrombin binding domain found in heparin and LMWH, which binds to antithrombin and inactivates factor Xa, leading to a formation of a covalent antithrombin–Xa complex. Subcutaneous fondaparinux has been shown to be noninferior to intravenous unfractionated heparin for treatment of acute PE and has the advantages of not requiring dose adjustment and a lower risk of thrombocytopenia.

Fondaparinux has almost complete bioavailability after subcutaneous administration, a predictable anticoagulant response, and a long half-life, making it amenable to once-daily, fixed-dose administration. Fondaparinux is given at a dose of 7.5 mg subcutaneously once daily for patients with a body weight of 50–100 kg, 5 mg once daily for those with body weight < 50 kg, and 10 mg once daily for those with body weight > 100 kg.

However, fondaparinux is cleared almost exclusively by the kidneys and is thus contraindicated in patients with renal insufficiency (CrCl < 30 mL/min). The dose should be reduced by 50% in patients with mild to moderate renal insufficiency (CrCl 30–50 mL/min). Most patients do not need monitoring of factor Xa levels while on fondaparinux, but in those who do, fondaparinux-specific factor Xa assays are needed. If uncontrollable bleeding occurs with the use of fondaparinux, recombinant factor VIIIa may be used since protamine sulfate is ineffective.

Thrombolysis

PE thrombolysis remains a controversial treatment option because large clinical trials using survival as an end point have not been conducted. Nevertheless, successful thrombolysis usually reverses right heart failure rapidly and safely, thereby preventing a downhill spiral of cardiogenic shock. Thrombolysis may also prevent chronic pulmonary hypertension over the long term and thus improve exercise tolerance and quality of life. It is certain that thrombolysis should be considered only for those patients at high risk for an adverse clinical outcome with anticoagulation alone. Although no precise indications currently exist in the absence of massive PE with cardiogenic shock, the clinician should be wary of conservative management in the presence of risk factors for a poor prognosis (Table 29–10). The ACCP guidelines, as well as American Heart Association (AHA) guidelines (AHA Class IIa indication), recommend consideration of thrombolysis in the setting of massive acute PE with acceptable bleeding risk.

However, thrombolysis for submassive PE remains controversial. Thrombolysis for submassive PE with adverse prognostic features (hemodynamic instability, respiratory insufficiency, severe right ventricular dysfunction, or major myocardial necrosis) is an AHA Class IIb indication. The ACCP guidelines also state that in selected patients with acute PE who do not have hypotension but have a high risk of developing hypotension and carry a low bleeding risk, thrombolytic therapy should be considered. However, clinical evaluation of a patient who is at risk of developing hypotension can be very challenging. Echocardiography helps identify a subgroup of PE patients with impending right ventricular failure who appear to be at high risk for adverse clinical outcomes if treated with heparin alone. Right ventricular dysfunction can also be inferred when right ventricular dilatation is seen on CT scan. In addition, ECG evidence of right ventricular dilation and dysfunction (pseudoinfarct pattern or T-wave inversion in the anterior precordial leads); ultrasonographic evidence of residual DVT burden in the lower limbs; persistent hypoxia; elevated levels of serum biomarkers such as BNP, NT-proBNP, and cardiac troponins T and I; and the presence of comorbid illnesses that lead to a lower cardiopulmonary reserve suggest an adverse clinical outcome in patients with acute PE, and thrombolytic therapy can be considered in these patients if bleeding risk is low. The combination of elevated cardiac biomarkers (which likely indicate right ventricular infarction or strain) along with echocardiographic evidence of right ventricular dysfunction predicts a poor outcome in acute submassive PE.

A careful assessment of the risks of bleeding must be made before the decision to use thrombolytic therapy is made. Contraindications to the use of systemic thrombolytic therapy in patients with acute PE include the presence of an intracranial neoplasm, recent intracranial surgery or head trauma within the past 2 months, history of internal bleeding within the past 6 months, history of a hemorrhagic stroke, history of nonhemorrhagic stroke within the past 2 months, any surgery within the past 10 days, history of a bleeding diathesis, thrombocytopenia (< 100,000/mm3), or uncontrolled hypertension (systolic blood pressure > 200 mm Hg or diastolic blood pressure > 110 mm Hg).

If a decision to use thrombolytic therapy is made, the ACCP recommends the use of shorter infusion time (2 hours) and use of a peripheral vein rather than a central venous catheter for administration of the thrombolytic agent. The preferred agent is alteplase (t-PA), but streptokinase or urokinase may also be used.

There are a number of invasive catheter-based approaches for delivery of thrombolytic agents directly into the pulmonary embolus rather than systemically, including intraembolic thrombolytic delivery, catheter suction, rheolytic and rotational devices, and ultrasound-enhanced thrombolysis. These are sophisticated techniques that may necessitate transport of the patient to a facility with an experienced interventional radiology department. Studies of these approaches are very limited, and the success rates are heavily dependent upon the expertise and familiarity with a certain approach of the treating interventional radiologist. Patients undergoing these procedures usually need to be monitored in an intensive care unit setting for several days and are vulnerable to complications related to vascular access, injury to the great vessels, arrhythmias, exposure to iodinated contrast, and of course, major bleeding. The ACCP guidelines suggest the use of catheter-directed thrombus removal in patients with acute PE associated with hypotension in whom systemic thrombolysis is contraindicated or has failed or in patients who are in shock that is likely to cause death before systemic thrombolysis can take effect and that it should only be performed in centers with adequate resources and expertise in these techniques.

Embolectomy

Patients at high risk for an adverse outcome with anticoagulation alone should be considered for embolectomy if they have contraindications to thrombolytic therapy. Embolectomy can be performed as a catheter-based procedure in the interventional laboratory or in the operating room. Clinical success has been reported, but randomized trials are lacking. Catheter embolectomy has a very limited application because it cannot successfully remove large amounts of thrombus, due to limitations in available catheter devices.

Surgical embolectomy for acute PE should be considered for patients who would otherwise receive thrombolytic therapy but who have contraindications to this treatment modality. The operation is best performed by median sternotomy with continuous transesophageal echocardiogram monitoring. The embolus should be removed under direct visualization, never “blindly.” With experience, all lobar and most segmental pulmonary artery branches can be visualized. It is crucial to refer high-risk PE patients as soon as their prognosis with anticoagulation has been established. Taking a “watch and wait” approach and delaying referring until the onset of cardiogenic shock requiring pressors yields poor results.

To manage severe chronic thromboembolic pulmonary hypertension (CTEPH) due to a prior PE, a separate and more technically challenging operation can be performed—a pulmonary thromboendarterectomy. This operation is recommended by the ACCP guidelines by an experienced thromboendarterectomy team for selected patients with CTEPH who have central disease. If successful, this operation can reduce and possibly cure pulmonary hypertension. This surgery requires careful dissection of the old thrombus, which has turned whitish and hardened, from the walls of the pulmonary arteries. Complications include pulmonary arterial perforation and hemorrhage; pulmonary steal syndrome, in which blood rushes from previously well-perfused lung tissue to newly perfused tissue; and reperfusion pulmonary edema. For patients who are not candidates for pulmonary thromboendarterectomy, balloon pulmonary angioplasty can be considered.

Inferior Vena Cava Filters

There are two unequivocal indications for placing an IVC filter for patients with acute PE associated with acute proximal DVT: (1) concomitant major bleeding requiring transfusion, intracranial hemorrhage, or any absolute contraindication to the use of anticoagulant therapy; and (2) recurrent PE despite prolonged intensive anticoagulation. Other situations in which an IVC filter may be considered are patients with massive PE or CTEPH in whom another embolic event would be devastating; a proximal DVT in a patient with poor cardiopulmonary reserve; or DVT in a patient with a high bleeding risk. Although IVC filters reduce the frequency of PE, they do not halt the thrombotic process and are associated with a doubling of the rate of DVT. If the contraindication to anticoagulation is expected to be short-term, a retrievable IVC filter can be placed, and removal can be assessed periodically after 3–12 months. If the patient becomes a candidate for anticoagulation after an IVC filter has been placed, the patient should be preferentially anticoagulated and filter removal should be considered.

Warfarin

Warfarin is the standard oral anticoagulant used in the United States. For most patients with acute PE, treatment is initiated with a heparin (either LMWH or unfractionated heparin) or fondaparinux, and then transitioned to warfarin for long-term treatment. Warfarin dosing is adjusted according to a standardized prothrombin time by using the international normalized ratio (INR). For PE and DVT, the target INR is ordinarily between 2.0 and 3.0. The current ACCP guidelines recommend the use of vitamin K antagonists such as warfarin as the preferred choice for long-term therapy for patients with acute PE who do not have cancer. Warfarin can be started on the same day or after the initiation of heparin or fondaparinux, and patients should have an overlap of at least 5 days or until the INR has been within the therapeutic range for at least 24 hours. Warfarin should not be initiated before the administration of heparin or fondaparinux, because it can cause a transient hypercoagulable state and has been associated with a threefold increased risk of recurrent PE or DVT when used alone without “bridging.”

Unfortunately, warfarin treatment is limited by a narrow therapeutic window. Too little anticoagulant effect leads to thromboembolism, and excessive anticoagulation leads to bleeding. The drug is plagued by a long list of interactions with other drugs that either decrease or increase warfarin's anticoagulant effect. The consumption of vitamin K–containing foods such as green leafy vegetables decreases the anticoagulant effect, whereas the ingestion of alcohol increases the likelihood of hemorrhage.

Optimal warfarin dosing can be facilitated by understanding the following factors. First, use of acetaminophen in high doses may lead to an unintended increase in the INR. Second, warfarin should be initiated in a dose of about 5 mg once daily for an average-sized adult, rather than initiating much higher loading doses. Third, since 2–3% of patients have a genetic mutation that results in slow metabolism of warfarin, the INR should be tested after several doses of warfarin, rather than waiting for 5 days after initiation of therapy. Pharmacogenetic testing to help guide initial warfarin dosing is being studied and may become common practice in the future. Finally, for patients who require long-term anticoagulation, point-of-care fingerstick INR testing machines can be prescribed for home use for patients who are able to be trained to self-adjust their warfarin doses based on the results of the INR.

Although warfarin is the most commonly used drug for long-term outpatient anticoagulation, for select patient populations, such as those with cancer, difficult to control INR values, or recurrent embolism despite therapeutic INR, long-term LMWH may be preferable to warfarin.

When the INR exceeds 5.0 in the absence of clinical bleeding, warfarin should be withheld and oral vitamin K administered, usually in a dose of 2.5 mg. Although oral vitamin K is preferable, it may be given subcutaneously when gastrointestinal absorption is uncertain. Occasionally, patients will require immediate reversal of excessive anticoagulation. This can be accomplished by the emergency administration of fresh frozen plasma, usually 2 units. However, to ensure continued reversal, vitamin K should be administered concomitantly.

Newer Anticoagulants

Rivaroxaban is an oral factor Xa inhibitor and has been shown to be noninferior to a standard treatment approach (enoxaparin followed by warfarin or acenocoumarol titrated to an INR of 2.0–3.0) in one clinical trial of patients with acute PE. Although the risk of major bleeding was lower with rivaroxaban in this trial, the absolute benefit was small, and the open-label design of the trial led to the potential for bias. Dabigatran etexilate is a direct thrombin inhibitor that has been approved for use for stroke prophylaxis in patients with nonvalvular atrial fibrillation but has not yet been adequately studied as a treatment for acute PE. Current guidelines do not yet recommend the use of these drugs as first-line agents for the treatment of acute PE.

Adjunctive Measures

Occasionally, PE patients will require ventilatory assistance for respiratory failure or will rarely require pulmonary artery catheterization to determine optimal fluid management. Most patients with acute PE, however, can be cared for in an intermediate-care or step-down unit. Most will benefit from supplemental oxygen. Opioids usually do not relieve the chest discomfort. Nonsteroidal anti-inflammatory agents are often effective, and combining them with anticoagulation usually does not pose an undue risk of bleeding complications.

Patients with PE and concomitant DVT of the leg should wear below-knee GCS (ideally 30–40 mm Hg or, if not tolerated, 20–30 mm Hg), to provide leg support while ambulating, for a minimum of 1 year after DVT diagnosis. The stockings help prevent distention of the vein wall and may mitigate the syndrome of chronic venous insufficiency—most often characterized by leg swelling and discomfort—that most DVT patients experience.

Duration of Treatment of Acute Pulmonary Embolism

The optimal duration of anticoagulation for patients with acute PE remains extremely controversial. The ACP guidelines recommend that anticoagulation be continued for 3–6 months for VTE due to transient risk factors (such as postoperative state) and for > 12 months or indefinitely for recurrent VTE. For first-time idiopathic VTE (ie, PE that occurs without relation to cancer, surgery, or trauma), the optimal duration of anticoagulation is not known, but a minimum of 3 months is suggested for most patients. Although several trials have shown that extended duration (beyond 3–12 months) of anticoagulant therapy for idiopathic VTE does reduce the rate of VTE recurrence, the follow-up has only been for 4 years, and therefore, the risk-benefit ratio needs to be determined on a case-by-case basis.

The recent ACCP guidelines have provided detailed recommendations with regard to the treatment approach as well as the optimal duration of anticoagulant therapy in patients with acute PE. Once the decision to initiate treatment for acute PE has been made, the ACCP recommends the use of parenteral anticoagulation with LMWH, subcutaneous fondaparinux, or unfractionated heparin administered either intravenously or subcutaneously. Subcutaneous LMWH or fondaparinux is the preferred first-line agent for initial treatment, and if LMWH is being used, once-daily dosing is preferred (enoxaparin 1.5 mg/kg actual body weight or dalteparin 200 IU/kg ideal body weight, up to a maximum of 18,000 IU/day).

For patients with acute PE provoked by surgery, the recommended duration of anticoagulation is 3 months. In patients with acute PE provoked by a nonsurgical transient risk factor such as prolonged immobilization, the duration of therapy should be 3 months. In patients with an unprovoked acute PE, anticoagulation should be given for at least 3 months, and extended therapy beyond 3 months should be considered for those with low to moderate bleeding risk. In patients with a second unprovoked VTE (PE or DVT), extended anticoagulation therapy for > 3 months should be given for those with low to moderate bleeding risk, and those with high bleeding risk should be treated for 3 months. Patients with active cancer who develop PE and have a low to moderate bleeding risk should receive extended anticoagulation therapy for > 3 months. The risks and benefits of extended anticoagulation should be assessed at periodic intervals, and the patient's preferences and values should be incorporated in the decision-making process. Further research is required to identify those patients prospectively who are at highest risk for recurrence after discontinuation of anticoagulation.

A special group of patients are those with the antiphospholipid antibody syndrome as they may benefit from extended duration or more intense anticoagulation.

Venous Thromboembolism in Pregnancy

The risk of VTE is increased fivefold during pregnancy. There is insufficient evidence to definitively guide the management of VTE during pregnancy, as most of the evidence comes from retrospective studies. Warfarin should be avoided in early pregnancy because it may lead to embryopathy between 6 and 12 weeks of gestation. On the other hand, unfractionated heparin and LMWH are not associated with embryopathy because they do not cross the placenta. However, prolonged unfractionated heparin use may lead to osteoporosis, may lead to heparin-induced thrombocytopenia, and is inconvenient to use due to the need for frequent aPTT testing to titrate the dose. LMWHs are more convenient to use, are associated with a lower risk of thrombocytopenia, and may also carry a lower risk of osteoporosis when compared to unfractionated heparin. However, the correct dosing of LMWH may also be difficult to determine by weight during pregnancy; thus, anti-factor Xa levels may need to be monitored periodically to ensure adequacy of dosing. Single-dose, prefilled vials of LMWH that are preservative-free should be preferably used in pregnant patients, as some preservatives used in multidose vials may have adverse fetal effects.

The ACCP guidelines recommend the use of LMWH over unfractionated heparin for both prevention and treatment of VTE during pregnancy. LMWH should be stopped at least 24 hours before induction of labor or induction of epidural anesthesia or cesarean section. Heparin can be started 6 hours after vaginal delivery or 12 hours after a cesarean section if there is no significant bleeding risk. Patients may then be transitioned to warfarin with discontinuation of heparin once the INR is within the therapeutic range.

Although PE can be as devastating emotionally and physically as myocardial infarction, the burden on individual patients may be even greater because the general public does not have as good an understanding of PE, particularly in terms of the potential incomplete recovery from it and long-term disability it engenders. Young patients with PE repeatedly voice a common theme. Although they appear healthy, they have actually suffered a life-threatening illness. Because of their youth and healthy appearance, others may not empathize with their fears and feelings about the illness. Virtually all patients with PE will wonder why they were stricken with the illness and whether they harbor an underlying coagulopathy (or “bad” gene) that predisposed them. When anticoagulation is discontinued after an adequate course of therapy, patients are often fearful of recurrent PE. It is therefore essential to have an open discussion about the various treatment options available, the adverse effect profile of the drugs used, and the recommended duration of treatment using evidence-based clinical guidelines, and also to understand the patient's values and expectations for treatment, in order to make balanced, collaborative treatment choices that both the patient and the treating clinician can agree on. A close collaboration with an experienced clinical pharmacist is also of benefit to assist with long-term management of patients on anticoagulant therapy. Regular assessments and ongoing discussions with the patient about the risks and benefits of ongoing treatment are essential, especially in those on long-term anticoagulation.