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Pulmonary
embolism is the occlusion of one or more pulmonary arteries by thrombi
that originate elsewhere, typically in the large veins of the lower
extremities or pelvis. Risk factors are conditions that impair venous
return, conditions that cause endothelial injury or dysfunction,
and underlying hypercoagulable states. Symptoms are nonspecific
and include dyspnea, pleuritic chest pain, cough, and, in severe cases,
syncope or cardiorespiratory arrest. Signs are also nonspecific
and may include tachypnea, tachycardia, hypotension, and a loud pulmonic
component of the 2nd heart sound. Diagnosis is based on a CT angiogram,
ventilation/perfusion scan, or a pulmonary arteriogram. Treatment
is with anticoagulants and sometimes clot dissolution with thrombolytics or
surgical removal. Preventive measures include anticoagulants and
sometimes insertion of an inferior vena caval filter.
Pulmonary embolism (PE) affects an estimated 117 people per 100,000 person years, resulting in about 350,000 cases yearly, and causes up to 85,000 deaths/yr. PE affects mainly adults.
Etiology
and Pathophysiology
Nearly all PEs arise from thrombi in the lower extremity or pelvic veins (deep venous thrombosis [DVT]—see Peripheral Venous and Lymphatic Disorders: Deep Venous Thrombosis (DVT)). Thrombi in either the lower extremity or pelvic veins may be occult. Risk of embolization is higher with thrombi proximal to the calf veins. Thromboemboli can also originate in upper extremity veins or in right-sided cardiac chambers. Risk factors for DVT and PE are similar in children and adults and include conditions that impair venous return, conditions that cause endothelial injury or dysfunction, and underlying hypercoagulability disorders (see Table 1: Pulmonary Embolism (PE): Risk Factors for Deep Venous Thrombosis and Pulmonary Embolism ). Bed rest and confinement without walking, even for a few hours, are common precipitators.
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Table 1
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Risk Factors for Deep Venous
Thrombosis and Pulmonary Embolism
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Age > 60 yr
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Atrial fibrillation
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Cigarette smoking (including passive smoke)
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Estrogen receptor modulators ( raloxifene , tamoxifen )
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Exogenous estrogens and progestins, including oral contraceptives and estrogen therapy
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Extremity or pelvic trauma
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Heart failure*
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Hypercoagulability disorders*
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Antiphospholipid antibody syndrome
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Antithrombin III deficiency
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Factor V Leiden mutation (activated protein C resistance)
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Heparin -induced thrombocytopenia and thrombosis
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Hereditary fibrinolytic defects
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Increase in von Willebrand's factor
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Paroxysmal nocturnal hemoglobinuria
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Prothrombin G-A gene variant
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Tissue factor pathway inhibitor
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Immobilization*
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Indwelling venous catheters
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Malignancy*
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Myeloproliferative disease (hyperviscosity)
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Nephrotic syndrome
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Obesity
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Pregnancy and postpartum*
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Prior venous thromboembolism
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Sickle cell anemia
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Surgery within past 3 mo*
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*Among the most common risk factors.
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Once DVT develops, clots may dislodge and travel through the venous system and right side of the heart to lodge in the pulmonary arteries, where they partially or completely occlude one or more vessels. The consequences depend on the size and number of emboli, the pulmonary reaction, the underlying condition of the lungs, and the ability of the body's intrinsic thrombolytic system to dissolve the clots.
Small emboli may have no acute physiologic effects; many begin to lyse immediately and resolve within hours or days. Larger emboli can cause a reflex increase in ventilation (tachypnea), hypoxemia from ventilation/perfusion (V/Q) mismatch and shunting, atelectasis from alveolar hypocapnia and abnormalities in surfactant, and an increase in pulmonary vascular resistance caused by mechanical obstruction and vasoconstriction. Endogenous lysis reduces most emboli, even those of moderate size, without treatment, and physiologic alterations decrease over hours or days. Some emboli resist lysis and may organize and persist. Occasionally, chronic residual obstruction leads to pulmonary hypertension (chronic thromboembolic pulmonary hypertension) that may develop over years and result in chronic right heart failure. When large emboli occlude major arteries, or when many small emboli occlude > 50% of the distal arterial system, right ventricular pressure increases, causing acute right ventricular failure, failure with shock (massive PE), or sudden death in severe cases. Risk factors for death include age > 70 yr, cancer, and COPD. The risk of death depends on the degree and rate of rise of right-sided pressures and on the patient's underlying cardiopulmonary status; higher pressures more commonly occur in patients with preexisting cardiopulmonary disease. Otherwise healthy patients may survive a PE that occludes > 50% of the pulmonary vascular bed.
Pulmonary infarction occurs in < 10% of patients diagnosed with PE. This low rate has been attributed to the dual blood supply to the lung (ie, bronchial and pulmonary).
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Sidebar 1
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Symptoms and Signs
Most PEs are small, physiologically insignificant, and asymptomatic. Even when present, symptoms are nonspecific and vary in frequency and intensity, depending on the extent of pulmonary vascular occlusion and preexisting cardiopulmonary function.
Larger emboli cause acute dyspnea, pleuritic chest pain, or both. Dyspnea may be intermittent. Less common symptoms include cough and hemoptysis. The first symptom in an older patient may be altered mental status. Massive PE presents with hypotension, tachycardia, syncope, or cardiac arrest.
The most common signs of PE are tachycardia and tachypnea. Less commonly, patients have hypotension, a loud 2nd heart sound (S2) due to a loud pulmonic component (P2), and crackles or wheezing. In the presence of right ventricular failure, distended internal jugular veins and a right ventricular heave may be evident, and right ventricular gallop (3rd and 4th heart sounds [S3 and S4]), with or without tricuspid regurgitation, may be audible. Fever can occur; DVT and PE are often overlooked causes of fever.
Pulmonary infarction is typically characterized by chest pain (mainly pleuritic), fever, and, occasionally, hemoptysis. Chronic thromboembolic pulmonary hypertension causes symptoms and signs of right heart failure, including exertional dyspnea, easy fatigue, and peripheral edema that develops over months to years.
Diagnosis
Diagnosis is challenging, because symptoms and signs are nonspecific and diagnostic tests are either imperfect or invasive. Diagnosis starts by including PE in the differential diagnosis of a large number of nonspecific symptoms, such as dyspnea, pleuritic chest pain, fever, hemoptysis, and cough. Thus, PE should be considered in the differential diagnosis of patients suspected of having such conditions as cardiac ischemia, heart failure, COPD exacerbation, pneumothorax, pneumonia, sepsis, acute chest syndrome (in sickle cell patients), and acute anxiety with hyperventilation. PE also should be considered in any older patient with tachypnea and altered mental status.
Initial evaluation should include pulse oximetry and chest x‑ray. Some experts also recommend ECG, ABG, or both, sometimes to exclude other diagnoses (eg, acute MI). The chest x‑ray usually is nonspecific but may show atelectasis, focal infiltrates, an elevated hemidiaphragm, or a pleural effusion. The classic findings of focal loss of vascular markings (Westermark's sign), a peripheral wedge-shaped density (Hampton's hump), or enlargement of the right descending pulmonary artery (Palla's sign) are suggestive but uncommon (ie, insensitive) and have an unknown specificity. Chest x-ray can also help exclude pneumonia.
Pulse oximetry provides a quick way to assess oxygenation; hypoxemia is one sign of PE, and it requires further evaluation. ABG measurement may show an increased alveolar to arterial oxygen (A-a) gradient (see Tests of Pulmonary Function (PFT): Arterial Blood Gas Sampling) or hypocapnia; one or both of these is moderately sensitive for PE but is not specific. ABG testing should be considered particularly for patients with dyspnea or tachypnea who are not hypoxemic by pulse oximetry.
ECG most often shows tachycardia and various ST-T wave abnormalities, which are not specific for PE (see Fig. 1: Pulmonary Embolism (PE): An ECG in pulmonary embolism. ). An S1Q3T3 or a new right bundle branch block may indicate the effect of abrupt rise in right ventricular pressure on right ventricular conduction; these are moderately specific but insensitive, occurring in only about 5% of patients. Right axis deviation (R > S in V1) and P-pulmonale may be present. T-wave inversion in leads V1 to V4 also occurs.
Clinical probability:
Clinical probability of PE can be assessed by combining ECG and chest x-ray findings with those from the history and physical examination (see Table 2: Pulmonary Embolism (PE): Clinical Prediction Rule for Diagnosing Pulmonary Embolism). Judgment of whether PE is more likely than an alternate diagnosis is somewhat subjective. PE should probably be considered more likely if one or more of its symptoms and signs, particularly dyspnea, hemoptysis, tachycardia, or hypoxemia, cannot be explained clinically or by chest x-ray results. Patients with a low clinical probability of PE may need only minimal additional testing. Patients with an intermediate clinical probability are likely to need more additional testing. Patients with a high probability may be candidates for immediate treatment pending confirmation with additional testing. Patients do not need any testing for PE if the clinical probability is very low and there are no objective cardiopulmonary abnormalities.
Noninvasive testing:
Noninvasive testing typically can be obtained more quickly and carries less morbidity than invasive testing. Tests most useful for diagnosing or excluding PE are d-dimer testing, V/Q scanning, duplex ultrasonography, CT angiography (helical CT scanning with IV contrast), and echocardiography.
There is no universally accepted algorithm for the best choice and sequence of tests, but one common approach is to screen with the D-dimer, obtain lower extremity ultrasonography (which exposes the patient to no ionizing radiation) when the D-dimer is positive, and progress to CT angiography (or V/Q scanning) if duplex ultrasonography is negative. Patients with moderate to high probability of disease based on clinical criteria who have low or intermediate probability V/Q scans usually require pulmonary arteriography or CT angiography to make or exclude the diagnosis. A lower extremity ultrasound is not diagnostic for PE, but a study that reveals thrombus formation establishes the need for anticoagulation and obviates the need for further diagnostic testing. A negative ultrasound study does not negate the need for additional studies. Positive D-dimers, ECG, ABG measurements, chest x-ray, and echocardiograms are adjunctive tests that lack sufficient specificity to be diagnostic alone.
D-Dimer is a by-product of intrinsic fibrinolysis; thus elevated levels occur in the presence of a recent thrombus. However, a positive result is not specific for venous thrombus because many patients without DVT or PE also have elevated levels. More importantly, absence of elevated levels suggests the absence of recent thrombus because the test is sensitive; > 95% of patients with DVT or PE have elevated levels. Thus, a low D-dimer level has a negative predictive value of > 95%, making such a result sufficiently reliable for excluding the diagnosis of PE in routine practice among patients with a low or moderate pretest probability.
V/Q scans detect areas of lung that are ventilated but not perfused, as occurs in PE; results are reported as low, intermediate, or high probability of PE based on patterns of V/Q mismatch. A completely normal scan excludes PE with nearly 100% accuracy, but a low-probability scan still carries a 15% likelihood of PE. Perfusion deficits may occur in many other lung conditions, including pleural effusion, chest mass, pulmonary hypertension, pneumonia, and COPD. With an intermediate probability scan, there is a 30 to 40% probability of PE; with a high probability scan, there is an 80 to 90% probability of PE.
Duplex ultrasonography is a safe, noninvasive, portable technique for detecting lower extremity (primarily femoral vein) thrombi. A clot can be detected by visualizing the lining of the vein, by demonstrating incompressibility of the vein, or by demonstrating reduced flow by Doppler. The test has a sensitivity of > 90% and a specificity of > 95% for thrombus. It cannot reliably detect a clot in calf or iliac veins. Absence of thrombi in the femoral veins does not exclude the possibility of thrombus from other sources, but patients with negative duplex test results have > 95% event-free survival, because thrombi from other sources are so much less common.
CT angiography is an alternative to V/Q scanning and pulmonary arteriography in many settings because it is fast, available, and noninvasive and gives more information about other lung pathology. However, patients must be able to hold their breath for several seconds. The sensitivity of CT angiography is highest for PE in lobar and segmental vessels and lowest for emboli in smaller subsegmental vessels (about 30% of all PEs) and thus is less sensitive than perfusion scans. Overall sensitivities range from 53 to 100%, with values at the lower end of this range for subsegmental vessels. Specificities range from 81 to 100%. A positive scan may be diagnostic of PE, but a negative scan does not necessarily exclude subsegmental disease, though the clinical significance of emboli in smaller subsegmental vessels remains to be determined. Newer multidetector scans are more sensitive (about 83%) and are specific (about 96%) overall. Magnetic resonance angiography (MRA) is an alternative to CT angiography for patients who cannot tolerate contrast and for pregnant patients.
Echocardiography as a diagnostic test for PE is controversial. Its sensitivity is > 80% for detecting right ventricular dysfunction (eg, dilation and hypokinesis, which occur when pulmonary artery pressure exceeds 40 mm Hg). This is a useful measure of hemodynamic severity in acute PE, but right ventricular dysfunction is present in multiple conditions, including COPD, heart failure, and sleep apnea, and is therefore a nonspecific finding. Estimation of pulmonary artery systolic pressure using Doppler flow signals gives additional useful information about the severity of acute PE. Absence of right ventricular dysfunction or pulmonary hypertension makes the diagnosis of a large PE unlikely but does not exclude the diagnosis of a smaller one.
Cardiac marker testing is evolving as a useful means of stratifying mortality risk in patients with acute PE. Elevated troponin levels can signify right ventricular strain. Elevated brain natriuretic peptide (BNP) and pro-BNP levels are not helpful, but low levels appear to signify good prognosis. The clinical role of these tests remains to be determined, because they are not specific either for right ventricular strain or for PE.
Patients with PE and no known risk factors should be considered for hypercoagulability testing (see Thrombotic Disorders), especially if they are < 35 yr, have recurrent PE, or have a positive family history.
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Table 2
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Clinical Prediction Rule
for Diagnosing
Pulmonary Embolism
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I. Establish clinical probability—add points to determine total score and thus probability
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Clinical Risk
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Points
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Clinical signs and symptoms of DVT (objective leg swelling, pain with palpation)
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3
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PE as or more likely than alternative diagnosis
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3
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Heart rate > 100 beats/min
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1.5
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Immobilization ≥ 3 days
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1.5
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Surgery in previous 4 wk
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1.5
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Previous DVT or PE
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1.5
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Hemoptysis
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1
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Malignancy (including those stopping cancer treatment within 6 mo)
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1
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Total Score
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Probability
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High
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Moderate
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< 2
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Low
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II. Use pretest probability to determine testing
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Heparin options include unfractionated and low molecular weight heparins. DVT = Deep venous thrombosis; PE = pulmonary embolism; V/Q = ventilation/perfusion.
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Invasive
tests:
Pulmonary arteriography is indicated
Pulmonary arteriography is still the most accurate test for diagnosing PE, but it is needed much less often because of the sensitivity of ultrasonography and CT angiography. A pulmonary arteriogram that reveals intraluminal filling defects or abrupt cutoff of flow is positive. Findings suggestive but not diagnostic of PE include partial occlusion of pulmonary arterial branches with increased proximal and decreased distal caliber, oligemic zones, and persistence of dye in the proximal artery during the late (venous) phase of the pulmonary arteriogram. In lung segments with obstructed arteries, venous filling with contrast medium is delayed or absent.
Prognosis
An estimated 10% of patients with PE die within 1 h. Of those who survive the first hour, only about 30% are diagnosed and receive treatment; > 95% of these patients survive. Thus, most patients with PE are never diagnosed; it is in such patients that most mortality from PE occurs. The best prospects for reducing mortality lie in improving diagnosis, not in improving treatment. Patients with chronic thromboembolic disease represent a tiny fraction of patients with PE who survive. Anticoagulant therapy reduces the rate of recurrence of PE to about 5% in all patients.
Treatment
Initial treatment of PE is O2 for hypoxemia and IV 0.9% saline and vasopressors for hypotension and anticoagulation. All patients with strongly suspected or confirmed PE should be hospitalized and, ideally, should also be continually monitored for life-threatening cardiovascular complications in the first 24 to 48 h. Clot elimination should be considered in massive pulmonary embolism at the time of diagnosis.
Clot elimination:
Clot elimination by means of embolectomy or dissolution by IV thrombolytic therapy should be considered for hypotensive patients. It may also be indicated for patients with clinical, ECG, or echocardiographic evidence of right ventricular overload or failure, but data supporting use in these patients are scarce and not definitive, and controlled prospective studies are unlikely to be done.
Embolectomy is reserved for patients with PE who are hypotensive despite supportive measures (persistent systolic BP ≤ 90 mm Hg after fluid therapy and O2 or if pressor therapy is required) or on the verge of cardiac or respiratory arrest. Surgical embolectomy appears to improve survival in patients with massive PE but is not widely available. Catheter-based embolectomy can be performed by some interventional radiologists. The decision to proceed with embolectomy and the choice of technique depends on local resources and expertise.
Thrombolytic therapy with tissue plasminogen activator (tPA), streptokinase , or urokinase offers a noninvasive way to rapidly restore pulmonary blood flow but is controversial, because long-term benefits do not clearly outweigh the risk of hemorrhage. In patients with submassive PE (ie, who are normotensive but have right ventricular dysfunction), thrombolytics speed the resolution of radiographic abnormalities and the return of hemodynamic function (heart rate and right ventricular function) and prevent cardiopulmonary deterioration but have not been shown to improve survival. Thrombolytics are recommended by some for patients with submassive PE suspected on the basis of echocardiographic evidence of proximal pulmonary artery (large) embolism or of right ventricular dysfunction due to either PE or preexisting disease. Others reserve thrombolytic therapy for patients with massive PE. Absolute contraindications to thrombolytics include prior hemorrhagic stroke, ischemic stroke within 1 yr, active external or internal bleeding from any source, intracranial injury or surgery within 2 mo, intracranial tumor, recent femoral or large arterial catheterization, GI bleeding within 6 mo, and CPR. Relative contraindications include recent surgery (≤ 10 days), hemorrhagic diathesis (as in hepatic insufficiency), pregnancy, current use of anticoagulants with INR > 2, punctures of large noncompressible veins (eg, subclavian or internal jugular veins), peptic ulcer disease or other conditions that increase the risk of bleeding, and severe hypertension (systolic BP > 180 or diastolic BP > 110 mm Hg).
Options for thrombolysis include streptokinase , urokinase, and alteplase (recombinant tPA). No agent is proven superior to the others. Standard IV regimens are streptokinase 250,000 units over 30 min followed by continuous infusion of 100,000 units/h for 24 h; urokinase 4400 units/kg over 10 min followed by 4400 units/kg/h for 12 h; or alteplase 100 mg continuous infusion over 2 h followed by an additional 40 mg over another 4 h (10 mg/h) if clinical presentation and repeat pulmonary angiogram suggest failure of clot lysis and initial dosing does not cause bleeding. Streptokinase is now rarely used because of the risk of allergic and pyrogenic reactions and because administration requires constant infusion for > 24 h.
An initial loading dose of heparin should be given concurrently, but the activated PTT should be allowed to fall to 1.5 to 2.5 times the baseline value before beginning continuous heparin infusion. Direct delivery of thrombolytics to the clot via a pulmonary artery catheter is occasionally used for patients with massive PE or for those with relative contraindications to systemic thrombolytics, but this approach does not prevent systemic thrombolysis. Bleeding, if it occurs, can be reversed with cryoprecipitate or fresh frozen plasma. Accessible vascular access sites can be compressed.
Anticoagulation:
Because embolization rarely involves an entire venous thrombus, anticoagulation is required acutely to prevent residual clot from extending and embolizing. Patients in whom anticoagulants are contraindicated or those who have thromboemboli despite therapeutic anticoagulation should have placement of a removable percutaneous inferior vena cava filter.
Heparin , either unfractionated or low molecular weight, is the mainstay of treatment of acute DVT and PE and should be given immediately on diagnosis or sooner if clinical suspicion is high and if the patient has cardiorespiratory compromise. Inadequate anticoagulation in the first 24 h is linked to increased risk of recurrent PE for up to 3 mo. Heparin accelerates the action of antithrombin III, an inhibitor of coagulation factors; unfractionated heparin also has antithrombin III–mediated anti-inflammatory properties, which may facilitate clot organization and reduce thrombophlebitis. Unfractionated heparin should be given as a bolus and infusion by protocol (see Fig. 2: Pulmonary Embolism (PE): Weight-based heparin dosing.) to achieve an activated PTT 1.5 to 2.5 times that of normal control. Subcutaneous low mol wt heparin (LMWH) is as effective as unfractionated heparin and may cause less thrombocytopenia (see Table 3: Pulmonary Embolism (PE): Some Low Molecular Weight Heparin Options in Thromboembolic Disease). Because of its long half-life, it is useful in outpatient treatment (usually restricted to patients with DVT without PE) and to facilitate earlier discharge of patients who have not achieved therapeutic anticoagulation with warfarin .
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Table 3
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Some Low Molecular Weight
Heparin
Options in Thromboembolic Disease
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Heparin
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Treatment Dose
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Prophylactic Dose
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Dalteparin
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100 units/kg sc q 12 h or 200 units/kg once/day
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2500–5000 units once/day
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Enoxaparin
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1 mg/kg sc q 12 h or 1.5 mg/kg sc once/day
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After abdominal surgery: 40 mg sc once/day
After hip or knee replacement surgery: 30 mg sc q 12 h
Unstable angina or non-Q wave MI: 1 mg/kg sc q 12 h
Other patients not undergoing surgery: 40 mg sc once/day
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Tinzaparin
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175 units/kg sc once/day (with or without PE)
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3500 units once/day
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PE = pulmonary embolism; HIT = heparin -induced thrombocytopenia.
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Dosing for unfractionated heparin is given elsewhere (see Fig. 2: Pulmonary Embolism (PE): Weight-based heparin dosing.).
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Note: Although the LMWHs can be given by continuous IV infusion, the LMWHs generally are given by sc injection in the abdominal area while the patient is supine.
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All heparins can cause bleeding, thrombocytopenia, urticaria, and, rarely, thrombosis or anaphylaxis. Long-term heparin administration may cause hypokalemia, liver enzyme elevations, and osteoporosis. Before use, patients should be screened for GI bleeding by testing for occult blood in stool. During treatment, they should be monitored for bleeding with serial CBCs and tests for occult blood in stool. Bleeding caused by overheparinization can be stopped with a maximum of 50 mg of protamine per 5000 units unfractionated heparin infused over 15 to 30 min (or 1 mg in 20 mL normal saline infused over 10 to 20 min for LMWH, though the precise dose is undefined because protamine only partially neutralizes LMWH inactivation of factor Xa). Treatment with heparin or LMWH is continued until full anticoagulation has been achieved with oral warfarin . The use of LMWH in long-term anticoagulation after acute PE has not been studied but will likely be limited by cost and ease of administration compared with oral warfarin .
Fondaparinux , a selective factor Xa inhibitor, may be used as an alternative to unfractionated heparin or LMWH for the initial treatment of DVT or PE. It is given in a fixed dose of 7.5 mg sc once/day (10 mg for patients > 100 kg, 5 mg for patients < 50 kg). It has the advantage of fixed dosing and is less likely to produce thrombocytopenia.
Warfarin is the oral drug of choice for long-term anticoagulation in all patients except pregnant women and patients with new or worsening venous thromboembolism during warfarin treatment. Five to 10 mg po once/day should be started when the PTT has been consistently ≥ 1.5 to 2.0 times control values. The therapeutic goal with warfarin is usually an INR of 2 to 3.
Physicians prescribing warfarin should be wary of drug interactions (see Table 4: Pulmonary Embolism (PE): Drug, Herbal Preparation, and Food Interactions With Warfarin), including interactions with nonprescription drugs and medicinal herbs. Patients with temporary risk factors for DVT or PE (eg, fracture or surgery) can stop the drug after 3 to 6 mo. Patients with permanent risk factors (eg, hypercoagulability), no known risk factors, or recurrent DVT or PE should take warfarin for at least 6 mo and possibly for life unless complications of therapy intervene. In low-risk patients, low-intensity warfarin (to maintain INR at 1.5 to 2.0) may be safe and effective for at least 2 to 4 yr, but this regimen requires further proof of safety before it can be routinely recommended.
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Table 4
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Drug, Herbal Preparation,
and Food Interactions With Warfarin
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Drug
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Level of Causation
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Type of Effect
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Degree of Interaction*
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Analgesics, Anti-Inflammatory Drugs, and Immunologic Drugs
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Acetaminophen
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Highly probable
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Potentiation
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Moderate
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Azathioprine
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Probable
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Inhibition
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Moderate
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Celecoxib
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Possible
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Potentiation
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Moderate
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Indomethacin
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Possible
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Potentiation
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Major
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Interferon
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Probable
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Potentiation
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Moderate
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Mesalamine
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Highly probable
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Inhibition
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Major
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Sulfasalazine
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Possible
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Inhibition
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Major
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Tramadol
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Probable
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Potentiation
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Moderate
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Anti-infective Drugs
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Amoxicillin
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Possible
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Potentiation
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Major
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Amoxicillin/clavulanate
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Probable
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Potentiation
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Major
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Amoxicillin /tranexamic rinse
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Possible
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Potentiation
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Major
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Azithromycin
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Probable
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Potentiation
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Major
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Chloramphenicol
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Possible
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Potentiation
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Moderate
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Clarithromycin
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Probable
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Potentiation
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Moderate
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Dicloxacillin
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Probable
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Inhibition
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Moderate
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Gatifloxacin
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Possible
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Potentiation
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Moderate
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Levofloxacin
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Probable
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Potentiation
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Moderate
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Miconazole topical gel
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Possible
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Potentiation
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Major
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Miconazole vaginal suppositories
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Highly probable
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Potentiation
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Moderate
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Ofloxacin
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Possible
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Potentiation
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Major
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Ribavirin
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Highly probable
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Inhibition
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Moderate
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Ritonavir
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Probable
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Potentiation or Inhibition
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Moderate
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Saquinavir
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Possible
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Potentiation
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Moderate
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Terbinafine
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Possible
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Potentiation or Inhibition
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Moderate
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Voriconazole
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Highly probable
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Potentiation
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Minor
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Cardiovascular Drugs
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Bosentan
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Probable
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Inhibition
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Moderate
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Fenofibrate
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Highly probable
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Potentiation
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Moderate
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Fluvastatin
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Probable
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Potentiation
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Moderate
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Gemfibrozil
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Possible
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Potentiation
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Moderate
|
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Ropinirole
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Probable
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Potentiation
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Moderate
|
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Simvastatin
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Probable
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Potentiation
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Minor
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Telmisartan
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Possible
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Inhibition
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Minor
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CNS Drugs
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Citalopram
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Highly probable
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Potentiation
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Mild
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Entacapone
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Highly probable
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Potentiation
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Mild
|
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Felbamate
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Possible
|
Potentiation
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Moderate
|
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Fluvoxamine
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Probable
|
Potentiation
|
Moderate
|
|
Sertraline
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Highly probable
|
Potentiation
|
Mild
|
|
Trazodone
|
Highly probable
|
Inhibition
|
Major
|
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Food
|
|
Fish oil
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Highly probable
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Potentiation
|
Moderate
|
|
Grapefruit juice
|
Probable
|
Potentiation
|
Moderate
|
|
Mango
|
Highly probable
|
Potentiation
|
Moderate
|
|
Soy milk
|
Probable
|
Inhibition
|
Minor
|
|
Sushi containing seaweed
|
Possible
|
Inhibition
|
Moderate
|
|
GI Drugs
|
|
Orlistat
|
Possible
|
Potentiation
|
Moderate
|
|
Herbal Supplements
|
|
Boldo-fenugreek
|
Highly probable
|
Potentiation
|
Moderate
|
|
Danshen
|
Probable
|
Potentiation
|
Major
|
|
Danshen/methyl salicylate
|
Possible
|
Potentiation
|
Major
|
|
Dong quai
|
Probable
|
Potentiation
|
Moderate
|
|
Ginseng
|
Probable
|
Inhibition
|
Major
|
|
Lycium barbarum L
|
Probable
|
Potentiation
|
Moderate
|
|
Quilinggao
|
Highly probable
|
Potentiation
|
Moderate
|
|
Other Drugs
|
|
Acarbose
|
Possible
|
Potentiation
|
Moderate
|
|
Chelation therapy
|
Probable
|
Inhibition
|
Moderate
|
|
Curbicin
|
Possible
|
Potentiation
|
Minor
|
|
Cyclophosphamide / methotrexate / fluorouracil (CMF)
|
Possible
|
Potentiation
|
Moderate
|
|
Danazol
|
Possible
|
Potentiation
|
Major
|
|
Fluorouracil
|
Probable
|
Potentiation
|
Major
|
|
Gemcitabine
|
Probable
|
Potentiation
|
Moderate
|
|
Influenza vaccine
|
Probable
|
Inhibition
|
Minor
|
|
Levamisole/ fluorouracil
|
Probable
|
Potentiation
|
Moderate
|
|
Mercaptopurine
|
Highly probable
|
Inhibition
|
Moderate
|
|
Paclitaxel
|
Probable
|
Potentiation
|
Moderate
|
|
Raloxifene hydrochloride
|
Probable
|
Inhibition
|
Minor
|
|
Tolterodine
|
Probable
|
Potentiation
|
Moderate
|
|
Trastuzumab
|
Possible
|
Potentiation
|
Major
|
|
Ubidecarenone
|
Possible
|
Inhibition
|
Moderate
|
|
Zileuton
|
Highly probable
|
Potentiation
|
Minor
|
|
*Potentiation was considered major if death or major bleeding occurred or if warfarin therapy had to cease. It was considered moderate if there was a change in INR that required a change in warfarin dose, if the INR increased to > 5, or there was an INR increase of > 1.5. It was considered mild if an INR increase occurred but no change in warfarin dose was needed, the INR was < 5, or the INR increase was < 1.5.
|
|
Inhibition was considered major if thrombosis occurred. Inhibition was considered moderate if there was a change in INR that required a change in warfarin dose or an INR decrease to < 1.5 or a decrease by > 1.5 units. Inhibition was considered mild if an INR decrease occurred that did not require a change in warfarin dose and INR decreased to a ratio that remained > 1.5 and the decrease in INR was < 1.5.
|
|
Data from Holbrook AM, Periera J, Labiris R, et al: Systematic overview of warfarin and its drug and food interactions. Archives of Internal Medicine 165 (10): 1095-1106, 2005.
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Bleeding is the most common complication of warfarin treatment; patients > 65 and those with comorbidities (especially diabetes, recent MI, Hct < 30%, creatinine > 1.5 mg/dL) and a history of stroke or GI bleeding appear to be at greatest risk. Bleeding can be reversed with 2.5 to 10 mg of vitamin K sc or po and, in an emergency, with fresh frozen plasma. Vitamin K may cause flushing, local pain, and, rarely, anaphylaxis.
Prevention
Prevention of PE means prevention of DVT; the need depends on the patient's risks. Bed-bound patients and those undergoing surgical, especially orthopedic, procedures especially benefit, and most of these patients can be identified before a thrombus forms (see Table 3: Peripheral Venous and Lymphatic Disorders: Risk of Deep Venous Thrombosis and Pulmonary Embolism in Surgical Patients). Preventive drugs include low-dose unfractionated heparin (LDUH), LMWH, warfarin , newer anticoagulants, compression devices, and elastic stockings. Choice of drug or device depends on duration of treatment, contraindications, relative costs, and ease of use.
LDUH is given in doses of 5000 units sc 2 h preoperatively and q 8 to 12 h thereafter for 7 to 10 days or until the patient is fully ambulatory. Immobilized patients not undergoing surgery should receive 5000 units sc q 12 h until they are ambulatory.
LMWH dosing depends on the drug and on whether the drug is being used for prevention or treatment; enoxaparin , dalteparin , and tinzaparin are equally effective as LDUH for preventing DVT and PE.
Fondaparinux , 2.5 mg once/day is equal to or more effective than LMWH depending on the surgical setting (eg, orthopedic surgery). Fondaparinux can usually be substituted for heparin or LMWH for prevention.
Warfarin is usually effective and safe at a dose of 2 to 5 mg once/day or at a dose adjusted to maintain an INR of 2 to 3.
Newer anticoagulants, including hirudin, a subcutaneous direct thrombin inhibitor, and danaparoid , have demonstrated efficacy in DVT and PE prevention but warrant further study to determine their cost-effectiveness and safety relative to heparins and warfarin (also see Table 3: Pulmonary Embolism (PE): Some Low Molecular Weight Heparin Options in Thromboembolic Disease and Table 5: Pulmonary Embolism (PE): Some Anticoagulation Options Other Than Heparin in Thromboembolic Disease). Aspirin is better than placebo but worse than all other available drugs for preventing DVT and PE.
An inferior vena cava filter (IVCF) may help prevent PE in patients with lower extremity DVT, although, despite widespread use, efficacy is unstudied and unproved. A filter is most commonly placed in patients with contraindications to anticoagulation, with recurrent DVT (or emboli) despite adequate anticoagulation, following embolectomy, and, occasionally, in those whose marginal cardiopulmonary function raises concern for their ability to tolerate additional small emboli. Because venous collaterals can develop, providing a pathway for emboli to circumvent the IVCF, patients with recurrent DVT or nonmodifiable risk factors for DVT may still require anticoagulation. An IVCF is placed in the inferior vena cava just below the renal veins via catheterization of an internal jugular or femoral vein. Some IVCFs are removable. Occasionally, a filter dislodges, may migrate up the venous bed, even to the heart, and need removal or replacement. A filter can also become clotted, causing bilateral lower extremity venous congestion (including acute phlegmasia cerulea dolens), lower body ischemia, and acute renal failure. Filter clotting requires careful evaluation for complications and risks of intervention.
Intermittent pneumatic compression (IPC) provides rhythmic external compression to the legs or to the legs and thighs. It is more effective for preventing calf than proximal DVT and thus is considered inadequate after hip or knee surgery. IPC is contraindicated in obese patients and can theoretically trigger PE in immobilized patients who have developed occult DVT while not undergoing preventive treatment.
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Table 5
|
| | |
|
Some Anticoagulation Options
Other Than
Heparin in Thromboembolic Disease
|
|
Anticoagulant
|
Treatment Dose
|
Prophylactic Dose
|
|
Vitamin K inhibitor
|
|
Warfarin *
|
2–5 mg po once/day initially, then adjust to desired INR (2 to 3)
|
Same as treatment dose
|
|
Thrombin Inhibitors
|
|
Argatroban
|
Not indicated for treatment of PE or DVT
|
For prevention of PE or DVT due to HIT: 2 µg/kg/min
|
|
Hirudin
|
0.75 mg/kg sc q 12 h
|
15 mg sc bid for 9–12 days, beginning 5–15 min before surgery, after induction of regional block anesthesia, if used
Injection site: abdominal; injections should be rotated among at least 4 different sites
|
|
Lepirudin
|
1.25 mg/kg sc q 12 h
|
0.4 mg/kg (up to 44 mg) IV bolus followed by 0.15 mg/kg/h (up to 16.5 mg/h) for 2–10 days
Adjust infusion rate according to activated PTT ratio
|
|
Factor Xa inhibitor
|
|
Fondaparinux †
|
Weight < 50 kg: 5 mg sc once/day
50–100 kg: 7.5 mg sc once/day
> 100 kg: 10 mg sc once/day
|
Treatment begins ≥ 6 h after surgery
After hip fracture surgery: 2.5 mg sc once/day for 29–33 days
After total hip replacement or laparotomy: 2.5 mg sc once/day for 5–11 days (usually 5–9 days)
|
|
PE = pulmonary embolism; DVT = deep venous thrombosis; HIT = heparin -induced thrombocytopenia.
* Warfarin dose (treatment and prophylactic) should be adjusted to maintain INR between 2 and 3.
† Fondaparinux should be avoided in patients with renal failure (an estimated creatinine clearance of < 30 mL/min).
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|
Graded elastic stockings have largely been abandoned for external pneumatic leg compression. For surgical procedures with a high incidence of venous thromboembolism, such as hip and lower extremity orthopedic surgery, LDUH q 8 h, LMWH, or adjusted-dose warfarin is recommended. For total knee replacement, risk reductions provided by LMWH and IPC are comparable but not optimal, so both should be used. The regimens for orthopedic surgery may be initiated preoperatively and should be continued for at least 7 days postoperatively. In selected patients at very high risk of both venous thromboembolism and bleeding, placement of an IVCF is an option for prophylaxis.
A high risk of venous thromboembolism also occurs with elective neurosurgery, acute spinal cord injury, and multiple trauma. Although physical methods (IPC, elastic stockings) have been used in neurosurgical patients because of concern about intracranial bleeding, LMWH appears to be an acceptable alternative. The combination of IPC and LMWH may be more effective than either alone in high-risk patients. Limited data support the combination of IPC, elastic stockings, and LMWH in spinal cord injury or in multiple trauma. For very high risk patients, an IVCF may be considered.
The most common nonsurgical conditions in which DVT prophylaxis is indicated are acute MI and ischemic stroke. For MI patients, LDUH is effective; IPC, elastic stockings, or both may be used when anticoagulants are contraindicated. For stroke patients, LDUH or LMWH can be used; IPC, elastic stockings, or both may be beneficial.
Recommendations for some other nonsurgical conditions include LDUH for patients with heart failure; adjusted-dose warfarin (INR 1.3 to 1.9) for patients with metastatic breast cancer; and warfarin 1 mg/day for cancer patients with an indwelling central venous catheter.
Last full review/revision July 2007 by John H. Newman, MD
Content last modified May 2008
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