\c \l Venous Thromboembolism Guidebook \l \c \c Eli V. Gelfand, MD Gregory Piazza, MD Samuel Z. Goldhaber, MD Harvard Medical School 2002 \c \p Copyright 2002, Samuel Z. Goldhaber Distribution in printed or electronic formats prohibited in absence of written permission from the authors. \p \bIntroduction to the PDA Version\b This document is best read with PalmReader, which can be found and downloaded free of charge at \uhttp://www.peanutpress.com.\u The pocket version of the Venous Thromboembolism Guidebook is organized slightly differently from the published article. For the PDA user's convenience, references for each section of the Guidebook are listed immediately following that section. To improve performance, the figures are omitted, however their detailed description remains in the text. \b\xHow to use this book\x\b >From the table of contents, select the topic that interests you. Tapping on the \bGoTo\b button on the bottom of the screen will take you directly to the text. If that book section is more detailed, you will be taken to a page with a list of text links. Tapping on these will take you directly to your sub-topic of interest. Tap the \b<--\b icon in PalmReader to return to the original list of text links, tap the \bC\b icon to return to the Table of Contents. General information on the Book is available by tapping the \bInfo\b icon. \b\xIntroduction\x\b This Venous Thromboembolism Guidebook incorporates evolving contemporary concepts in diagnosis and management of pulmonary embolism (PE) and deep venous thrombosis (DVT) into a user-friendly menu. The purpose of this document is to provide a literature-based review of the current clinical approach to venous thromboembolism as well as up-to-date references for further study in this important topic. \p \bDisclaimer\b The authors caution that the information contained herein is meant solely as a guideline. Each patient situation is unique and readers are strongly encouraged to use their best clinical judgement when particular questions arise. While we make every effort to keep this information updated, the field is rapidly changing. \b\xAbbreviations used\x\b APLAS - antiphospholipid antibody syndrome APC - activated Protein C DVT - deep venous thrombosis LMWH - low-molecular weight heparin PE - pulmonary embolism PIOPED - Prospective Investigation of Pulmonary Embolism Diagnosis RV - right ventricle (or right ventricular) UFH - unfractionated heparin VTE - venous thromboembolism \b\xRisk Factors for VTE\x\b \bA. Inherited Risks\b 1. Factor V Leiden and APC resistance: increased risk of first DVT/PE as well as recurrent pregnancy loss. It is unclear whether the Factor V Leiden mutation increases risk of recurrent DVT/PE. 2. Prothrombin gene mutation 20210: increases risk of DVT/PE two- to three-fold. It is also associated with cerebral vein thrombosis 3. Hyperhomocysteinemia (almost always acquired; rarely inherited) 4. Antithrombin III deficiency 5. Protein C deficiency 6. Protein S deficiency \p \w="100%" J. S. Miles, J. P. Miletich, S. Z. Goldhaber, C. H. Hennekens, P. M. Ridker. G20210A Mutation in the Prothrombin Gene and the Risk of Recurrent Venous Thromboembolism. \iJ Am Coll Card\i 2001:37(1):215-8 A. W. Lensing, P. Prandoni, M. H. Prins, and H. R. Buller. Deep-vein thrombosis [see comments]. \iLancet\i 1999:353 (9151):479-485 \w="100%" \p \bB. Acquired Risks\b 1. Lupus Anticoagulant / Antiphospholipid Antibody Syndrome (APLAS): the risk of recurrent thrombosis is high in this population. Therefore, whenever possible, patients with DVT or PE who also have the antiphospholipid-antibody syndrome should be maintained with a target INR of at least 3.0 usually with indefinite duration of anticoagulation. 2. Malignancy: incidence of newly diagnosed cancer after a first episode of venous thromboembolism is elevated for at least two years. Subsequently, the risk has been shown to be lower among patients treated with oral anticoagulants for six months than among those treated for six weeks. 3. Age 4. CHF 5. Chronic renal disease: especially nephrotic syndrome 6. Hypertension 7. Surgery / Trauma / Hospitalization with immobility 8. Pregnancy / Oral contraceptives / Hormone replacement therapy: third generation oral contraceptives are especially thrombogenic. Hormone replacement therapy including estrogen alone as well as estrogen/progesterone combinations increases venous thromboembolism risk 2- to 4-fold. Caution should also be exercised with selective estrogen receptor modulators (SERMS) such as tamoxifen and raloxifen as both have been shown to increase risk of venous thromboembolism. 9. Past medical or family history of PE/DVT 10. Environmental Risks \ta. Obesity: up to a three-fold increase in PE risk with BMI >29.\t \tb. Cigarette smoking: more than a doubling of risk among heavy smokers (>35 cigarettes/d)\t \tc. Immobility: including coach class air travel\t \p \w="100%" A. Piccioli, P. Prandoni. Venous thromboembolism as first manifestation of cancer. Acta Haematol 2001:106(1-2):13-7 H. Jick, J. A. Kaye, C. Vasilakis-Scaramozza, and S. S. Jick. Risk of venous thromboembolism among users of third generation oral contraceptives compared with users of oral contraceptives with levonorgestrel before and after 1995: cohort and case-control analysis. \iBMJ\i 2000:321 (7270):1190-1195 S. Schulman and P. Lindmarker. Incidence of cancer after prophylaxis with warfarin against recurrent venous thromboembolism. Duration of Anticoagulation Trial [see comments]. \iN.Engl.J.Med.\i 2000:342 (26):1953-1958 S. R. Cummings, S. Eckert, K. A. Krueger, D. Grady, T. J. Powles, J. A. Cauley, L. Norton, T. Nickelsen, N. H. Bjarnason, M. Morrow, M. E. Lippman, D. Black, J. E. Glusman, A. Costa, and V. C. Jordan. The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation [see comments] [published erratum appears in JAMA 1999 Dec 8;282(22):2124]. \iJAMA\i 1999:281(23):2189-2197 B. Fisher, J. P. Costantino, D. L. Wickerham, C. K. Redmond, M. Kavanah, W. M. Cronin, V. Vogel, A. Robidoux, N. Dimitrov, J. Atkins, M. Daly, S. Wieand, E. Tan-Chiu, L. Ford, and N. Wolmark. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study [see comments]. \iJ.Natl.Cancer Inst.\i 1998:90 (18):1371-1388 S. Z. Goldhaber, F. Grodstein, M. J. Stampfer, J. E. Manson, G. A. Colditz, F. E. Speizer, W. C. Willett, and C. H. Hennekens. A prospective study of risk factors for pulmonary embolism in women [see comments]. \iJAMA\i 1997:277 (8):642-645M. A. Khamashta, M. J. Cuadrado, F. Mujic, N. A. Taub, B. J. Hunt, and G. R. Hughes. The management of thrombosis in the antiphospholipid-antibody syndrome [see comments]. \iN.Engl.J.Med.\i 1995:332 (15):993-997 \w="100%" \p \bC. Hypercoagulable Work-Up\b 1. High Yield: "The Big Four" \ta. Activated Protein C Resistance (Factor V Leiden)\t \tb. Plasma homocysteine level\t \tc. Lupus anticoagulant / antiphospholipid antibody screen\t \td. Prothrombin gene mutation 20210\t 2. Low Yield: "The Little Four" \ta. Antithrombin III\t \tb. Protein C\t \tc. Protein S\t \td. High levels of factor VII\t \b\xDiagnosis: Principles, H&P\b\x \bDiagnostic Highlights\b: 1. D-dimer ELISA is an excellent screening test for PE. It is widely available, rapid and inexpensive 2. An integrated approach to PE diagnosis in essential 3. Spiral CT scan of the chest cannot reliably detect important but distal PE 4. A negative venous ultrasound of the legs does not exclude PE \p \bClinical Clues to PE\b \bHistory\b Dyspnea is the most frequent symptom, and tachypnea is the most frequent sign of PE. Whereas dyspnea, syncope, or cyanosis usually indicates a massive PE, pleuritic chest pain, cough, or hemoptysis often suggests a small embolism located distally near the pleura. In older patients who complain of vague chest discomfort, the diagnosis of PE may not be apparent unless signs of right heart failure are present. Unfortunately, because acute coronary ischemic syndromes are so common, one may overlook the possibility of life-threatening PE and may inadvertently discharge these patients from the hospital after the exclusion of myocardial infarction with serial cardiac enzymes and electrocardiography. \p \bPhysical Examination\b Young and previously healthy individuals may simply appear anxious but otherwise seem deceptively well, even with an anatomically large PE. They need not have "classic" signs such as tachycardia, low-grade fever, neck vein distension, or an accentuated pulmonic component of the second heart sound. High-grade fever may occur rarely and fever is not limited to patients with pulmonary hemorrhage or infarction. Sometimes, a paradoxical bradycardia occurs. \p \bDifferential Diagnosis of Pulmonary Embolism\b \tMyocardial infarction COPD exacerbation Aortic dissection Pneumonia or bronchitis Congestive heart failure ("left-sided") Cardiomyopathy with global ventricular dysfunction Primary pulmonary hypertension Asthma Pericarditis and pericardial tamponade Intrathoracic malignancy Rib fracture Pneumothorax Costochondritis "Musculoskeletal pain" Anxiety Cholecystitis or splenic pathology (transmitted pleuritic discomfort from subdiaphragmatic irritation)\t \p \w="100%" S. Z. Goldhaber, L. Visani, and M. De Rosa. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER) [see comments]. \iLancet\i 1999:353 (9162):1386-1389 \w="100%" \p \x\bDiagnosis: Blood Tests\x\b \bArterial Blood Gases\b Arterial blood gases play no useful role in diagnostic evaluation or triage of patients with suspected PE; in fact, arterial blood gas results are often misleading. The room air pO2 and the alveolar-arterial oxygen (A-a O2) gradient do not differ between those who have PE at angiography and those suspected of PE who have normal pulmonary angiograms. Furthermore, about one-fifth to one- quarter of patients with angiographically proven PE have normal pO2 on room air, as well as normal (A-a O2) gradients. Therefore, room air PO2 and the (A-a O2) gradient should \inot\i be used to screen for or "rule out" PE. \p \w="100%" P. D. Stein, S. Z. Goldhaber, J. W. Henry, and A. C. Miller. Arterial blood gas analysis in the assessment of suspected acute pulmonary embolism [see comments]. \iChest\i 1996:109 (1):78-81 P. D. Stein, S. Z. Goldhaber, and J. W. Henry. Alveolar-arterial oxygen gradient in the assessment of acute pulmonary embolism [see comments]. \iChest\i 1995:107 (1):139-143 \w="100%" \p \bCardiac Troponins\b While neither sensitive nor specific for the detection of pulmonary embolism, cardiac troponins may have a unique role in risk stratification of PE patients. In a study of 56 patients with documented PE, cardiac troponin T (cTnT) was measured within 12 hours of admission. cTnT was elevated (? 0.1 ?g/L) in 32% of patients with moderate to massive PE but not in patients with small PE. An elevated cTnT correlated with an increased prevalence of in-hospital death (odds ratio 29.6), prolonged hypotension and cardiogenic shock (odds ratio 11.4), need for resuscitation (odds ratio 18.0), and need for pressor support (odds ratio 37.6). cTnT remained an independent predictor of 30-day mortality (odds ratio 15.2). Troponins are probably elevated because of microinfarction of the RV without coronary atherosclerosis. Measuring troponin levels routinely may help improve risk stratification in patients with PE and identify a high-risk population in which more aggressive therapy may be warranted. \p \w="100%" E. Giannitsis, M. Muller-Bardorff, V. Kurowski, B. Weidtmann, U. Wiegand, M. Kampmann, and H. A. Katus. Independent prognostic value of cardiac troponin T in patients with confirmed pulmonary embolism. \iCirculation\i 2000:102 (2):211-217 \w="100%" \p \bPlasma D-dimer ELISA/Latex FDPs\b The D-dimer ELISA is an excellent screening test for PE. The plasma D-dimer ELISA has a high sensitivity and a high negative predictive value and therefore can be used to help exclude PE. In an overview of 9 trials, the ELISA had a sensitivity of 97%, specificity of 45%, PPV of 50%, and NPV of 94%. D-dimer alone can exclude PE in up to 30% of patients without the need for further costly imaging studies. The quantitative plasma D-dimer ELISA level is elevated (greater than 500 ng/ml) in more than 90 percent of patients with PE, reflecting plasmin's breakdown of fibrin into D-dimers and indicating endogenous (though clinically ineffective) thrombolysis. A qualitative latex agglutination D-dimer, which is more readily available and less expensive than an ELISA, can be obtained initially; if elevated, the ELISA will also be elevated. The latest available latex D-dimer assays have demonstrated an overall sensitivity of 96%, specificity of 45% and NPV of 98%, making this a useful test to exclude venous thromboembolism in patients with low or moderate pretest probability of disease.D-dimer levels are not specific and will be elevated in postoperative patients as well as in patients with myocardial infarction, sepsis, or almost any systemic illness. \p \w="100%" S.M. Bates, A. Grand'Maison, M. Johnston, I. Naguit, M.J. Kovacs, and J.S. Ginsberg. A latex D-dimer reliably excludes venous thromboembolism. \iArch Intern Med\i 2001;161:447-453 P. de Moerloose, J. J. Michiels, and H. Bounameaux. The place of D-dimer testing in an integrated approach of patients suspected of pulmonary embolism. \iSemin.Thromb.Hemost.\i 1998;24 (4):409-412 S. Z. Goldhaber, G. R. Simons, C. G. Elliott, W. D. Haire, R. Toltzis, S. C. Blacklow, M. H. Doolittle, and D. S. Weinberg. Quantitative plasma D-dimer levels among patients undergoing pulmonary angiography for suspected pulmonary embolism [see comments]. \iJAMA\i 1993:270 (23):2819-2822 \w="100%" \p \bElectrocardiogram\b Electrocardiographic Findings In PE: \tIncomplete or complete right bundle branch block. S in Lead I and aVL greater than 1.5 millimeter. Transition zone shift to V5. Q waves in leads III and aVF, but not in Lead II. QRS axis greater than 90 degrees or indeterminate axis. Low limb lead voltage. T wave inversion in leads III and aVF or in leads V1-V4. Concurrent deep S wave in lead I, Q wave and T wave inversion in lead III ("SIQIIITIII pattern")\t \p \w="100%" K.R. Daniel, D.M. Courtney, and J.A. Kline. Assessment of cardiac stress from massive pulmonary embolism with 12-lead ECG. \iChest\i 2001; 120:474-481 E. Ferrari, A. Imbert, T. Chevalier, A. Mihoubi, P. Morand, and M. Baudouy. The ECG in pulmonary embolism. Predictive value of negative T waves in precordial leads – 80 case reports [see comments]. \iChest\i 1997:111 (3):537-543 \w="100%" \p \b\xImaging Tests for diagnosis of PE\x\b \bChest X-Ray\b The chest X-ray serves as an integral part in the formulation of clinical suspicion for pulmonary embolism and may help suggest alternative pathology as the cause of the patient's presentation. A normal or near normal chest X-ray in a dyspneic patient may suggest PE. However, because many PE patients have comorbid conditions with abnormal chest X-ray findings, the diagnosis of PE should not be excluded on the basis of abnormalities typical of other cardiopulmonary conditions. Well-established abnormalities include focal oligemia (Westermark's Sign), a peripheral wedged-shaped density above the diaphragm (Hampton's Hump), or an enlarged right descending pulmonary artery (Palla's Sign). Based on a recent review of the International Cooperative Pulmonary Embolism Registry (ICOPER), the most common chest X-ray interpretations in patients with PE are as follows: \t1) Cardiac enlargement (27%) 2) Normal (24%) 3) Pleural effusion (23%) 4) Elevated hemidiaphragm (20%) 5) Pulmonary artery enlargement (19%) 6) Atelectasis (18%) 7) Pulmonary infiltrate (17%)\t \p \w="100%" C. G. Elliott, S. Z. Goldhaber, L. Visani, and M. DeRosa. Chest radiographs in acute pulmonary embolism. Results from the International Cooperative Pulmonary Embolism Registry. \iChest\i 2000:118 (1):33-38 \w="100%" \p \bVentilation-Perfusion Lung Scanning\b Until recently, ventilation-perfusion lung scan (V/Q scan) was the principal imaging modality in the initial work-up of pulmonary embolism. Interpreted as high-, intermediate-, and low-probability, V/Q scans have been problematic, only providing definitive information less than 50% of the time. While a normal or nearly normal V/Q scan practically excludes the possibility of PE, a high-probability scan in the setting of moderate to high clinical suspicion virtually guarantees the diagnosis. The clinical dilemma arises in the majority of patients who have intermediate-probability V/Q scans. Among these patients, many will ultimately be diagnosed with PE while a significant amount will be ruled out for venous thromboembolism. Therefore, these patients require further testing to evaluate for PE. The Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) indicated that high probability lung scans identify about only half of the patients with PE. Thus, if one relied upon the high probability scan to detect PE, the diagnosis would be missed in at least half of PE patients. \p \bSpiral CT of the Chest\b Recently, spiral chest CT scanning with contrast has been used with increasing frequency as the initial imaging study for evaluation of pulmonary embolism. Spiral CT scanning requires the peripheral injection of contrast. The sensitivity of spiral CT is highest in identifying PE in the proximal pulmonary arteries. Despite advances in this imaging technology, first-generation, "single-slice" CT still has the potential to miss small segmental or large subsegmental PE that may be clinically significant. Next-generation multislice CT is expected to have better ability than single-slice CT for detecting subsegmental PE because of its shorter image acquisition time, thinner sections and a more extensive coverage of the entire thorax. At this time, spiral chest CT is an excellent imaging modality when massive, central PE is suspected. Spiral CT is also commonly used in the setting of an abnormal chest X-ray where the specificity of V/Q scan interpretation may be limited. Abnormalities seen by spiral chest CT include intraluminal filling defects, enlarged pulmonary arteries, pulmonary hemorrhage and infarction, and pleural effusion. An additional benefit of spiral CT as an initial imaging modality is its ability to evaluate for other etiologies in the differential diagnosis of pulmonary embolism. In a recent study by Bounameaux that included 299 patients all with elevated D-dimers, spiral chest CT had a sensitivity of 70% and specificity of 91%. These results were consistent with two prior overviews. Prospective Investigation of Pulmonary Embolism Diagnosis II (PIOPED II) study will determine sensitivity, specificity, positive and negative predictive values of spiral CT for diagnosis of acute pulmonary embolism, using V/Q scan, lower extremity ultrasound and pulmonary angiography as a composite reference test. \p \w="100%" P. Costello, and K.B. Gupta. Pulmonary embolism: imaging modalities – V/Q scan, spiral (helical) CT, and MRI. \iSemin Vasc Med\i 2001;1(2):155-163 P.M.T. Pattynama, and J.-W. Kuiper. Second-generation, subsecond multislice computed-tomography: advancing the role of helical CT pulmonary angiography in suspected pulmonary embolism. \iSemin Vasc Med\i 2001;1(2):195-203 M. D. Mullins, D. M. Becker, K. D. Hagspiel, and J. T. Philbrick. The role of spiral volumetric computed tomography in the diagnosis of pulmonary embolism. \iArch.Intern.Med.\i 2000;160 (3):293-298 S. W. Rathbun, G. E. Raskob, and T. L. Whitsett. Sensitivity and specificity of helical computed tomography in the diagnosis of pulmonary embolism: a systematic review [see comments]. \iAnn.Intern.Med.\i 2000;132 (3):227-232. \w="100%" \p \bMagnetic Resonance Angiography\b Although currently investigational, magnetic resonance imaging has become an extremely promising imaging modality with recent advances in technique allowing high resolution angiography during a single suspended breath that could potentially provide excellent visualization of small vessels. Currently, MRI, like CT, does not have spatial resolution of contrast pulmonary angiography and thus has sensitivity limited to the main and segmental vessels. Small initial trials have revealed excellent sensitivity and specificity for the proximal pulmonary vessels. Potential benefits of MRI over spiral CT include the luxury of avoiding the risks of iodinated contrast medium and ionizing radiation, allowing imaging of patients with renal insufficiency and contrast dye allergy. In addition, functional and structural assessment of the right ventricle can be performed during the same study. \p \w="100%" S. Kruger, P. Haage, R. Hoffmann, C. Breuer, A. Bucker, P. Hanrath, R.W. Gunther. Diagnosis of pulmonary arterial hypertension and pulmonary embolism with magnetic resonance angiography. Chest 2001;120(5):1556-61 J. F. Meaney, J. G. Weg, T. L. Chenevert, D. Stafford-Johnson, B. H. Hamilton, and M. R. Prince. Diagnosis of pulmonary embolism with magnetic resonance angiography [see comments]. \iN.Engl.J.Med.\i 1997;336 (20):1422-1427 \w="100%" \p \bEchocardiography\b \bOverview\b Echocardiography is becoming an increasingly important tool in the evaluation and treatment of pulmonary embolism. Although it is a relatively insensitive study in screening for PE, echocardiography is a rapid, practical, and sensitive technique for the identification of right ventricular overload secondary to PE. As a screening modality, echocardiography is neither sensitive nor recommended in clinically stable patients. Approximately 60% of patients with proven PE will have normal echocardiograms. In hemodynamically unstable patients where the disease process is unknown, echocardiography may help suggest PE while evaluating for other causes such as tamponade or aortic dissection. When used as a risk stratification tool, echocardiography is an excellent modality for detecting patients with moderate to severe right ventricular dysfunction which correlates with a high risk of adverse outcomes. The frequency of \iechocardiographic signs of PE\i depends upon the population being studied. Important echocardiographic abnormalities observed in pulmonary embolism include: \t1) Right ventricular dilatation and hypokinesis, which correlates with greater than 30% involvement of pulmonary vascular cross-sectional area with pulmonary emboli on lung scanning. In particular, \iMcConnell Sign\i is highly specific for acute pulmonary embolism: it includes moderate to severe right ventricular free wall hypokinesis with sparing of the right ventricular apex. The border between the hypokinetic right ventricular free wall and normally-contracting apex is known as the "hinge point." A potential explanation for this pattern of regional abnormality is related to the tethering of the right ventricular apex to a hyperdynamic left ventricle. 2) Paradoxical motion of the interventricular septum (septal deviation toward the LV as opposed to the RV) 3) Tricuspid regurgitation (TR) 4) Loss of respiratory-phasic changes of the IVC (collapse of the IVC during inspiration) 5) Decrease in the difference between left ventricular area during diastole and systole (indicates low cardiac output secondary to right ventricular failure and represents cardiogenic shock) 6) Pulmonary hypertension (as calculated by the modified Bernoulli equation)\t Occasionally, right ventricular dysfunction will be observed in the absence of pulmonary hypertension. In these cases, the differential diagnosis should also include cardiomyopathy and right ventricular infarction in addition to acute pulmonary embolism. Right ventricular dilatation and hypokinesis may occur in chronic pulmonary hypertension of any cause. Long-term elevation of right ventricular afterload is usually accompanied by right ventricular hypertrophy. In patients with chronic pulmonary hypertension, the velocity of the tricuspid regurgitant jet may be elevated to a greater level than in patients with acute PE and no underlying cardiopulmonary disease. Disease processes such as primary pulmonary hypertension tend to exhibit more global right ventricular hypokinesis when compared to the regional abnormalities seen in acute pulmonary embolism. \p \bTransesophageal Echocardiography\b For those patients in whom transthoracic imaging is unsatisfactory, transesophageal echocardiography (TEE) can be carried out. Transesophageal echocardiography has the potential to diagnose pulmonary embolism by directly visualizing the thrombus rather than indirectly through signs of RV dysfunction. Of particular importance, TEE can provide an assessment of the extent and surgical accessibility of pulmonary thromboembolic disease needed in patients being considered for emergent pulmonary embolectomy. TEE can provide excellent visualization of the main pulmonary artery and right pulmonary artery until it divides into lobar branches. The left pulmonary artery is more difficult to evaluate because of interference from the left main bronchus. TEE may have a unique role in the evaluation of patients with sudden unexplained cardiac compromise and pulseless electrical activity. Occult acute pulmonary embolism should be considered in these patients as a recent series of 1,246 patients presenting with cardiac arrest in Vienna revealed PE in 5% of patients (of which 63% had pulseless electrical activity). If possible, TEE for evaluation of proximal hemodynamically significant PE should be undertaken as quickly as possible in appropriate patients during resuscitation. \p \w="100%" I. Kurkciyan, G. Meron, F. Sterz, K. Janata, H. Domanovits, M. Holzer, A. Berzlanovich, H. C. Bankl, and A. N. Laggner. Pulmonary embolism as a cause of cardiac arrest: presentation and outcome. \iArch.Intern.Med.\i 2000;160 (10):1529-1535 K. A. Comess, F. A. DeRook, M. L. Russell, T. A. Tognazzi-Evans, and K. W. Beach. The incidence of pulmonary embolism in unexplained sudden cardiac arrest with pulseless electrical activity* [In Process Citation]. \iAm.J.Med.\i 2000;109 (5):351-356 P. Pruszczyk, A. Torbicki, R. Pacho, M. Chlebus, A. Kuch-Wocial, B. Pruszynski, and H. Gurba. Noninvasive diagnosis of suspected severe pulmonary embolism: transesophageal echocardiography vs spiral CT [see comments]. \iChest\i 1997;112 (3):722-728 M. V. McConnell, S. D. Solomon, M. E. Rayan, P. C. Come, S. Z. Goldhaber, and R. T. Lee. Regional right ventricular dysfunction detected by echocardiography in acute pulmonary embolism. \iAm.J.Cardiol.\i 1996;78 (4):469-473 M. W. Wolfe, R. T. Lee, M. L. Feldstein, J. A. Parker, P. C. Come, and S. Z. Goldhaber. Prognostic significance of right ventricular hypokinesis and perfusion lung scan defects in pulmonary embolism. \iAm.Heart J.\i 1994;127 (5):1371-1375. \w="100%" \p \bContrast Pulmonary Angiography\b \bOverview\b Contrast pulmonary angiography remains the gold standard study for patients with suspected PE. Pulmonary angiography is best used to resolve the dilemma of nondiagnostic lung scanning, spiral CT, normal venous ultrasonography, and normal echocardiography in the setting of high clinical suspicion. It is an invasive test that carries a small but real risk of morbidity and mortality. Out of 1,111 PIOPED patients, five patient deaths were attributed to complications of pulmonary angiography. Nevertheless, contrast pulmonary angiography is considered to be safe when performed by experienced angiographers. \p \w="100%" P. D. Stein, C. Athanasoulis, A. Alavi, R. H. Greenspan, C. A. Hales, H. A. Saltzman, C. E. Vreim, M. L. Terrin, and J. G. Weg. Complications and validity of pulmonary angiography in acute pulmonary embolism. \iCirculation\i 1992;85 (2):462-468 \w="100%" \p \x\bPE Diagnosis: Integrated Approach\x\b An integrated diagnostic approach that includes judicious use of initial screening tests with further imaging studies is essential in making the diagnosis of pulmonary embolism. The following is a proposed protocol for the diagnosis of PE. As with all medical conditions, the work-up for pulmonary embolism should begin with a thorough history and physical examination. As clinical suspicion for PE develops, a chest X-ray and D-dimer ELISA should comprise the initial investigative tests (Fig. 1 in printed version). A negative chest X-ray and D-dimer allow the work-up for PE to stop. However, a positive D-dimer warrants an imaging study. In patients with significant abnormality on chest X-ray, significant history of pulmonary disease or suspicion of a massive PE, a spiral chest CT may be elected (Fig. 2 in printed version). A positive spiral CT requires treatment for PE, whereas in a setting of low clinical suspicion, a negative spiral CT should prompt investigation for an alternative diagnosis. A negative spiral CT in a patient whose presentation arouses intermediate or high clinical suspicion for PE, other diagnostic tests are needed, including leg vein ultrasound and, possibly, a pulmonary angiogram. In patients without significant abnormality on chest X-ray, a ventilation-perfusion lung scan should be sought (Fig. 3 in printed version). A normal or near normal study requires no further evaluation for PE. Likewise, a high-probability lung scan requires no further study and rather warrants prompt risk stratification and treatment. An intermediate-probability reading poses a diagnostic dilemma and therefore should be followed by further studies. A venous ultrasound to evaluate for DVT as a source of pulmonary emboli should be done and if positive allows for treatment of both the DVT as well as the suspected PE. A negative venous ultrasound in the setting of continued clinical suspicion calls for invasive evaluation for PE via contrast pulmonary angiography. \p \b\xDiagnosis of DVT\x\b \bClinical Clues to DVT\b \bHistory\b Usually described in the lower extremities, deep venous thrombosis may also be seen in the upper extremities in association with central venous lines and thoracic outlet obstructive syndromes. Lower extremity DVT is often first noticed as an increasingly annoying "pulling sensation" at the insertion of the lower calf muscle into the posterior portion of the lower leg. This insidious feeling can then become more pronounced and accompanied by warmth, swelling, and erythema. \p \bPhysical Examination\b Tenderness may be present along the course of the involved veins, and a cord may be palpable. Additional signs include increased tissue turgor, distension of superficial veins, and the appearance of prominent venous collaterals. Homan's sign, which is increased resistance or pain during dorsiflexion of the foot, is unreliable and nonspecific. \p \bDVT Symptoms and Signs\b \ta. Insidious, progressive, annoying "pulling sensation" where lower calf muscle inserts into posterior aspect of the leg. b. Warmth, swelling, tenderness due to increased tissue turgor/distension. c. Occasional palpable cord and prominent superficial collaterals.\t \p \bDifferential Diagnosis of DVT\b \tPhlebitis without thrombosis Superficial thrombophlebitis Venous insufficiency without acute thrombosis Ruptured Baker's cyst Muscle or soft tissue injury (hematoma) Cellulitis Lymphangitis Lymphedema Peripheral edema secondary to CHF, severe liver disease, renal failure, or nephrotic syndrome \t \p \w="100%" A. W. Lensing, P. Prandoni, M. H. Prins, and H. R. Buller. Deep-vein thrombosis [see comments]. \iLancet\i 1999;353 (9151):479-485 \w="100%" \p \bImaging Tests - DVT\b \bVenous Ultrasonography with Color Doppler\b When DVT is suspected, venous ultrasonography should ordinarily be the first test that is ordered. Venous ultrasound is usually excellent for diagnosing or excluding an initial episode of DVT in symptomatic patients. For reasons that are unclear, it is quite insensitive for detection of asymptomatic DVT, particularly following orthopedic surgery or neurosurgical procedures. Venous ultrasound should not be used to rule-in or rule-out PE. Venous ultrasonography routinely entails a combination (called "Duplex") of vein compression (B mode imaging) and pulsed Doppler spectrum analysis with or without color. Normally, manual pressure of the transducer applied to the surface of the skin will cause the vein walls to collapse. Failure to compress a vein is the cardinal sign of DVT on ultrasound examination. Isolated calf vein thrombosis may be accurately detected on ultrasound examination, but this will depend upon the skill of the examiner. Venous ultrasound is limited in the abdomen (e.g. pelvic veins) and thorax (e.g. subclavian vein) as these veins cannot be compressed due to anatomic constraints. The venous ultrasound examination is inadequate for diagnosis of pelvic vein thrombosis. When ovarian or other pelvic vein thrombosis is suspected, MRI or contrast CT are the preferred imaging tests. Ultrasonography may suffice for detection of an extensive upper extremity DVT. However, because the anatomy may hinder the identification of small- and medium-sized thromboses, MRI or contrast venography should be considered. If the clinical suspicion of DVT is high even though the ultrasound is normal, this discrepancy should be pursued by obtaining another imaging test rather than by relying upon the ultrasound examination as the final arbiter. The choice usually lies between contrast venography and magnetic resonance imaging (MRI). The biggest disadvantage of contrast venography is that with massive DVT, none of the deep veins of the leg can be filled with contrast agent and, therefore, the diagnosis of DVT must be inferred merely by failure to fill the deep venous system. The results from a properly obtained MRI are usually more definitive than contrast venography. MRI can also help determine whether a visualized thrombus is acute, subacute, or chronic. Unlike venography, MRI is noninvasive and, therefore, has greater patient and physician acceptability. No contrast agent is needed, so the risks of anaphylaxis and renal failure are averted. The diagnoses of recurrent DVT and acute venous insufficiency can mimic each other, yet their management differs drastically. Recurrent DVT requires immediate and intensive anticoagulation, whereas venous insufficiency can be managed by prescribing vascular compression stockings, without hospitalization. Duplex scanning may identify acute thrombus superimposed upon chronic thrombus. However, if ultrasound examination is inadequate, MRI or contrast venography are usually recommended when confronted with this diagnostic dilemma. \p \w="100%" L. Bressollette, M. Nonent, E. Oger, J.F. Garcia, P. Larroche, B. Guias, P.Y. Scarabin, D. Mottier. Diagnostic accuracy of compression ultrasonography for the detection of asymptomatic deep venous thrombosis in medical patients--the TADEUS project. \iThromb Haemost\i. 2001;86(2):529-33 M.R. Mac Cillavry, B.-J. Sanson, H.R. Buller, and D.P.M. Brandjes. Compression ultrasonography of the leg veins in patients with clinically suspected pulmonary embolism. \iThromb Haemost\i 2000;84:973-6 C. Kearon, J. S. Ginsberg, and J. Hirsh. The role of venous ultrasonography in the diagnosis of suspected deep venous thrombosis and pulmonary embolism. \iAnn.Intern.Med.\i 1998;129 (12):1044-1049 B. G. Birdwell, G. E. Raskob, T. L. Whitsett, S. S. Durica, P. C. Comp, J. N. George, T. L. Tytle, and P. A. McKee. The clinical validity of normal compression ultrasonography in outpatients suspected of having deep venous thrombosis. \iAnn.Intern.Med.\i 1998;128 (1):1-7 F. Turkstra, P.M.M. Kuijer, E.J.R. van Beek, D.P.M. Brandjes, J.W. ten Cate, and H.R. Buller. Diagnostic utility of ultrasonography of leg veins in patients suspected of having pulmonary embolism. \iAnn Intern Med\i 1997;126:775-781 A. Piccioli, P. Prandoni, and S. Z. Goldhaber. Epidemiologic characteristics, management, and outcome of deep venous thrombosis in a tertiary-care hospital: the Brigham and Women's Hospital DVT registry. \iAm.Heart J.\i 1996;132 (5):1010-1014. \w="100%" \p \bMR Venography\b Magnetic resonance venography can provide detailed imaging of the venous system while also estimating the age of thrombus. MRI is most helpful in the evaluation of suspected pelvic vein thrombosis as well as upper extremity DVT. MR venography is also an excellent 2nd test when the clinical suspicion of DVT is high but the venous ultrasound is negative. \bContrast Venography\b Contrast venography is useful if there is a discrepancy between the venous ultrasound and the clinical evaluation (e.g., low clinical suspicion and positive venous ultrasound or high clinical suspicion and negative venous ultrasound) and to help differentiate acute from chronic thrombosis and acute superimposed upon chronic thrombosis. It is important to note that contrast venography may not provide a definite diagnosis when there is complete obstruction of the deep vein that prevents passage of contrast. \p \bOther methods\b Platelet scintigraphy which utilizing 111-Indium oxine labeling has recently been shown to be a potentially useful adjunct in diagnosis of DVT and in evaluation of effects of anticoagulant therapy. Methods involving radiolabeled peptides such as glycoprotein IIb/IIIa receptor antagonists are currently under investigation. \p \w="100%" Y. Morimoto, T. Sugimoto, T. Mukai, Y. Okita, M. Okada. Diagnosis of deep vein thrombosis using platelet scintigraphy. Ann Thorac Cardiovasc Surg 2001;7(3):138-42 \w="100%" \p \b\xRisk Stratification of Patients with PE\x\b \bOverview\b Pulmonary embolism presents as a broad spectrum of clinical syndromes. These presentations may range from small emboli causing only minimal symptoms to marked hemodynamic instability culminating in cardiogenic shock. The majority of patients falls between these extremes upon presentation and yet some go on to suffer rapid deterioration and adverse outcomes. Traditionally, patients were risk stratified on the basis of hemodynamics and were classified as either "unstable" with a systolic blood pressure less than 90 mmHg or as "normal." It is now understood that while most patients present with "normal" hemodynamics, many of these have evidence of right ventricular dysfunction and the potential to experience adverse outcomes if treated as "stable" patients. Thus, risk stratification of the pulmonary embolism patient is an integral part of management because certain subsets of patients are at higher risk for poor outcomes and recurrent disease. These patients, if identified early enough, may benefit from aggressive management strategies such as thrombolysis or embolectomy. Echocardiography and elevated cardiac troponins should be used to risk stratify patients. \bThe History and Physical Examination\b A recent study evaluating clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER) revealed several variables derived from the histories and physical examinations of acute PE patients that proved to be significant independent predictors of increased mortality at three months. \bEchocardiographic Risk Stratification\b Echocardiography is an excellent tool for risk stratification and prognostication in patients with acute pulmonary embolism. Several echocardiographic findings including right ventricular dysfunction have been well-established as a predictors of adverse outcomes in PE. \bRight Ventricular Dysfunction\b RV dysfunction has proven to be one of the most powerful predictors of mortality and recurrent PE. Normotensive patients with no evidence of RV dysfunction enjoy excellent outcomes with anticoagulation. There is mounting evidence that normotensive patient with echocardiographic findings of RV dysfunction are not stable and benefit from aggressive interventions such as thrombolysis and embolectomy. The identification of these high-risk patients by echocardiography has brought into question the traditional conservative view of withholding aggressive therapies such as thrombolysis and embolectomy until patients show evidence of hemodynamic instability. \p \w="100%" S. Grifoni, I. Olivotto, P. Cecchini, F. Pieralli, A. Camaiti, G. Santoro, A. Conti, G. Agnelli, and G. Berni. Short-term clinical outcome of patients with acute pulmonary embolism, normal blood pressure, and echocardiographic right ventricular dysfunction. \iCirculation\i 2000;101 (24):2817-2822 S. Z. Goldhaber, L. Visani, and M. De Rosa. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER) [see comments]. \iLancet\i 1999;353 (9162):1386-1389 \w="100%" \p \bPersistent Pulmonary Hypertension\b Patients with pulmonary artery systolic pressures greater than or equal to 50 mmHg at admission have been found to be three times more likely to suffer persistent pulmonary hypertension and right ventricular dysfunction at 6 weeks. Patients with evidence of persistent pulmonary hypertension and RV dysfunction had diminished 5-year survival when compared to patients who had normalized their pulmonary artery pressures by 6 weeks. \p \w="100%" A. Ribeiro, P. Lindmarker, A. Juhlin-Dannfelt, H. Johnsson, and L. Jorfeldt. Echocardiography Doppler in pulmonary embolism: right ventricular dysfunction as a predictor of mortality rate. \iAm.Heart J.\i 1997;134 (3):479-487 \w="100%" \p \bPatent Foramen Ovale\b A patent foramen ovale in combination with PE increases the mortality rate. \w="100%" S. Konstantinides, A. geibel, W. Kasper, M. Olschewski, L. Blumel, and H. Just. Patent foramen ovale in an important predictor of adverse outcome in patients with major pulmonary embolism. \iCirculation\i 1998;97:1946-1951 \w="100%" \p \bFree-Floating Right Heart Thrombus\b Free-floating right heart thrombus is highly correlated with PE and a poor prognosis. \w="100%" L. Chartier, J. Bera, M. Delomez, P. Asseman, J. P. Beregi, J. J. Bauchart, H. Warembourg, and C. Thery. Free-floating thrombi in the right heart: diagnosis, management, and prognostic indexes in 38 consecutive patients. \iCirculation\i 1999;99(21):2779-2783 \w="100%" \p \bCardiac Troponin\b In a study of 56 patients with documented PE, cardiac Troponin T (cTnT) was measured within 12 hours of admission. cTnT was elevated (? 0.1 ?g/L) in 32% of patients with moderate to massive PE but not in patients with small PE. An elevated cTnT correlated with an increased prevalence of in-hospital death (odds ratio 29.6), prolonged hypotension and cardiogenic shock (odds ratio 11.4), need for resuscitation (odds ratio 18.0), and need for pressor support (odds ratio 37.6). cTnT remained an independent predictor of 30 day mortality (odds ratio 15.2). Troponins are probably elevated because of microinfarction of the RV without coronary atherosclerosis. Measuring troponin levels routinely may help improve risk stratification in patients with PE and identify a high-risk population in which more aggressive therapy may be warranted. \p \w="100%" E. Giannitsis, M. Muller-Bardorff, V. Kurowski, B. Weidtmann, U. Wiegand, M. Kampmann, and H. A. Katus. Independent prognostic value of cardiac troponin T in patients with confirmed pulmonary embolism. \iCirculation\i 2000;102 (2):211-217 \w="100%" \p \b\xManagement of PE\x\b \bMassive PE\b For patients presenting with massive pulmonary embolism and cardiogenic shock, thrombolysis is a life-saving intervention. In a small clinical trial, pulmonary embolism patients with hypotension and heart failure were randomized to thrombolysis with streptokinase plus standard anticoagulation versus anticoagulation alone. After enrolling eight patients, the trial was stopped early because all four patients randomized to anticoagulation alone died while all of those who received thrombolysis survived. Three of the four patients that died were found to have right ventricular infarction in the absence of significant coronary disease. This study supports the consensus belief that thrombolysis is effective in averting death from progressive heart failure in patients presenting with cardiogenic shock. \p \w="100%" C. Jerjes-Sanchez, A. Ramirez-Rivera, Garcia M. de Lourdes, R. Arriaga-Nava, S. Valencia, A. Rosado-Buzzo, J. A. Pierzo, and E. Rosas. Streptokinase and Heparin versus Heparin Alone in Massive Pulmonary Embolism: A Randomized Controlled Trial. \iJ.Thromb.Thrombolysis.\i 1995;2 (3):227-229. \w="100%" \p \bPE with Normal BP and RV Hypokinesis on Echocardiogram\b While less than 5% of patients with acute pulmonary embolism present in cardiogenic shock, many more present with normal blood pressures and evidence of RV dysfunction on echocardiogram. In a multicenter randomized controlled trial, 101 PE patients were randomized to receive rt-PA (100 mg/2 h) followed by heparin versus heparin alone. Among patients with baseline RV dysfunction, 39% of patients randomized to rt-PA improved RV wall motion while 2.4% worsened. Of those randomized to heparin alone, 17% demonstrated improvement in RV function while 17% worsened. Even more importantly, no clinical episodes of recurrent PE occurred among rt-PA patients while five clinically suspected recurrent PEs (two of which were fatal) were noted in the heparin only group. These findings suggest that primary therapy (thrombolysis) should be considered in patients with RV dysfunction and "impending hemodynamic instability" who are at high risk for adverse clinical outcomes including recurrent possible fatal events. However, thrombolysis under these circumstances is a debatable indication and a clinical trial is overdue. \p \w="100%" S.Z. Goldhaber. Thrombolysis in pulmonary embolism: a large-scale clinical trial is overdue. \iCirculation\i 2001: in press. S.Z. Goldhaber. Thrombolysis in pulmonary embolism: a debatable indication. \iThromb Haemost\i 2001;86:444-51 S. Z. Goldhaber, W. D. Haire, M. L. Feldstein, M. Miller, R. Toltzis, J. L. Smith, A. M. Taveira da Silva, P. C. Come, R. T. Lee, and J. A. Parker. Alteplase versus heparin in acute pulmonary embolism: randomised trial assessing right-ventricular function and pulmonary perfusion. \iLancet\i 1993;341 (8844):507-511 \w="100%" \p \bPE with Normal Blood Pressure and Normal RV Function on Echocardiogram\b Patients with normal blood pressures and normal RV function have a good prognosis when managed with anticoagulation. \w="100%" S. Z. Goldhaber. Optimizing anticoagulant therapy in the management of pulmonary embolism. \iSemin.Thromb.Hemost.\i 1999; 25 Suppl 3:129-133 \w="100%" \p \b\xDVT Location and Extent of Disease\x\b \bMassive DVT\b Pelvic vein thrombosis may occur in the setting of conditions such as pregnancy, ovarian cancer, total hip replacement, or trauma and is often found in combination with proximal DVT of the leg. Iliofemoral DVT often leads to chronic venous insufficiency, especially if the clot itself is not managed with primary therapy such as thrombolysis or embolectomy. \bSVC Syndrome\b Superior Vena Cava (SVC) Syndrome is usually caused by catheter-associated thrombosis (see below) or by DVT associated with extrinsic compression (often by tumor or thoracic outlet obstruction) of the subclavian or other major upper extremity veins. Emergency management may include radiation or chemotherapy to reduce the impingement of the tumor on the upper extremity vessels, as well as steroids to reduce associated edema and inflammation. The bulk of the thrombus may be reduced by employing site-directed thrombolytic therapy, administered through a catheter placed by an experienced interventional radiologist. \bProximal Leg DVT\b This is the most common type of DVT. Proximal DVT by definition involves one of the following veins: the common femoral, superficial femoral, the profunda femoris, or popliteal. \iBeware that the superficial femoral vein, despite its name, is actually a deep vein.\i \bUpper Extremity DVT\b The subclavian, internal jugular, and axillary veins are most often affected. Underlying causes may include indwelling central venous catheters, anatomic lesions such as a cervical rib, or hypercoagulable states either due to inherited conditions (e.g., Factor V Leiden) or acquired diseases such as adenocarcinoma. \bIsolated Calf DVT\b The previous practice of serial observation alone with two to four ultrasound tests over 7 to 14 days in such patients has shifted to routine treatment with anticoagulation. These patients, if untreated, are at risk of suffering proximal propagation of DVT (approximately 30% of patients), paradoxical embolism, and even fatal PE. It is the small calf DVT that can "fit" and "squeeze" through a patent foramen ovale or small atrial septal defect that usually cause paradoxical embolization. Calf vein thromboses may also be significant as a source of chronic pulmonary emboli. \p \w="100%" A. W. Lensing, P. Prandoni, M. H. Prins, and H. R. Buller. Deep-vein thrombosis [see comments]. \iLancet\i 1999;353 (9151):479-485 C. I. Lagerstedt, C. G. Olsson, B. O. Fagher, B. W. Oqvist, and U. Albrechtsson. Need for long-term anticoagulant treatment in symptomatic calf-vein thrombosis. \iLancet\i 1985;2 (8454):515-518 \w="100%" \p \bRecurrent DVT\b It may be difficult to distinguish recurrent DVT from acute venous insufficiency, especially with venous ultrasonography. Nevertheless, the distinction is crucial. Recurrent DVT patients usually require hospitalization for intensive and immediate heparinization, followed by prolonged, sometimes lifelong, outpatient anticoagulation. However, patients with flare-ups of venous insufficiency can almost always be managed at home, without anticoagulation. Such individuals usually obtain moderate improvement with vascular compression stockings that are carefully measured and fitted. If ultrasound examination is indeterminate, MRI or contrast venography can be especially useful in resolving the diagnostic dilemma of recurrent DVT versus venous insufficiency. \b\xTherapy of DVT and PE\x\b \bAnticoagulation Overview\b Patients with normal systemic arterial pressure and normal right ventricular function generally have a good prognosis following PE. For such individuals, secondary prevention is usually adequate with anticoagulation or, if major bleeding from anticoagulation is likely, with placement of an inferior vena caval filter. Anticoagulation is also the foundation for DVT management. Patients with active and major bleeding will need placement of an inferior vena caval filter if they have pelvic or proximal leg DVT. Although the filter will not prevent continued venous thrombosis, it is usually effective in preventing fatal PE arising from the pelvic or deep leg veins. \p \bContinuous Infusion of Unfractionated Heparin\b Dose-adjusted intravenous heparin is the foundation for immediate management of acute PE or DVT. Heparin acts by preventing new thrombus from forming and allowing endogenous fibrinolytic mechanisms to lyse thrombus. If venous thromboembolism is strongly suspected, continuous infusion of unfractionated heparin should be initiated immediately, before lung scanning or venous ultrasonography are undertaken.For patients with pulmonary embolism, treatment with unfractionated heparin is usually initiated with a bolus of 5000 to 10,000 units followed by a continuous intravenous infusion with a rate between 1000 to 1500 units per hour. The rate is titrated to an activated partial thromboplastin time (aPTT) between two to three times normal (approximately 60 to 80 seconds). Use of heparin nomograms that are weight-based may allow for more rapid attainment of a target aPTT. Standard anticoagulation requires continuation of intravenous unfractionated heparin for five to seven days with simultaneous initiation of oral anticoagulants. \p \w="100%" S. Z. Goldhaber. Optimizing anticoagulant therapy in the management of pulmonary embolism. \iSemin.Thromb.Hemost.\i 1999; 25 Suppl 3:129-133 \w="100%" \p \bHigh Dose, Adjusted Subcutaneous Unfractionated heparin\b This approach is useful for avoiding intravenous lines, but the absorption of unfractionated heparin is hindered by its suboptimal bioavailability. Typically, subcutaneous unfractionated heparin is poorly absorbed during the first few days of administration. Afterwards, the heparin is rather suddenly released from fat depots into plasma, resulting in a pattern of delayed therapeutic anticoagulation in many patients, with subsequent excessive anticoagulation. \p \w="100%" D. R. Hirsch, T. H. Lee, R. B. Morrison, W. Carlson, and S. Z. Goldhaber. Shortened hospitalization by means of adjusted-dose subcutaneous heparin for deep venous thrombosis. \iAm.Heart J.\i 1996;131 (2):276-280 \w="100%" \p \bLow Molecular Weight Heparin (LMWH)\b \bOverview\b Low molecular weight heparins (LMWH) such as enoxaparin inhibit activated coagulation Factor X (FXa) via conformational change of the antithrombin III molecule. The longer half-life, better bioavailability, and more predictable response of LMWH make it easy to administer subcutaneously without the need for routine laboratory monitoring. Of note, LMWH is renally-cleared, unlike unfractionated heparin, which is largely cleared by the liver. \p \bUse of LMWH in Venous Thromboembolism\b Multiple trials have shown that LMWH (dosed by body weight) is at least as effective and safe as unfractionated heparin in DVT. A meta-analysis of randomized of LMWH versus continuous IV heparin for DVT found that LMWH had a 30% decrease in mortality, 40% reduction in major bleeding events, and one-third lower rate of thrombocytopenia when compared to unfractionated heparin. LMWH also allows for shorter hospitalizations, improved physical and social functioning, and overall cost savings. Currently, the LMWHs, enoxaparin and recently tinzaparin, have been approved for use in the US. The US FDA has approved enoxaparin for outpatient treatment of DVT with or without pulmonary embolism, as a bridge to Coumadin. Two dosing regimens exist: 1 mg/kg subcutaneously every twelve hours for both outpatients and inpatients and 1.5 mg/kg subcutaneously once daily for inpatients. The PTT should NOT be used to monitor or adjust LMWH dosing, because the PTT will often be misleadingly low, despite a therapeutic concentration of LMWH. Instead, the plasma anti-Xa level should be used. This is often called a "heparin level." The target anti-Xa activity for therapeutic indications is 0.3 to 1.0 anti-Xa IU/ml. Anti-Xa levels should be checked 4-6 hours after the second or third dose of LMWH. Patient populations that may require anti-Xa levels include those with renal insufficiency and massive obesity. \p \w="100%" G. Merli, T.E. Spiro, C.G. Olsson, U. Abildgaard, B.L. Davidson, A. Eldor, D. Elias, A. Grigg, D. Musset, G.M. Rodgers, A.A. Trowbridge, R.D. Yusen, K. Zawilska. Subcutaneous enoxaparin once or twice daily compared with intravenous unfractionated heparin for treatment of venous thromboembolic disease. \iAnn Intern Med\i 2001;134(3):191-202 M. K. Gould, A. D. Dembitzer, G. D. Sanders, and A. M. Garber. Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis. A cost-effectiveness analysis [see comments]. \iAnn.Intern.Med.\i 1999;130 (10):789-799 M. K. Gould, A. D. Dembitzer, R. L. Doyle, T. J. Hastie, and A. M. Garber. Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis. A meta-analysis of randomized, controlled trials. \iAnn.Intern.Med.\i 1999;130 (10):800-809 R. M. Baron and S. Z. Goldhaber. Deep venous thrombosis: early discharge strategies and outpatient management. \iJ.Thromb.Thrombolysis.\i 1999;7 (2):113-122 \w="100%" \p \bHeparin-Induced Thrombocytopenia (HIT)\b Heparin-induced Thrombocytopenia is more common than is widely believed. HIT is caused by heparin-dependent IgG antibodies that are directed against an antigen complex of heparin and platelet factor 4. HIT IgG causes primarily venous procoagulant effects via platelet and endothelial activation and heparin neutralization. HIT must be distinguished from an early mild decrease in platelet count that generally recovers within three days despite continued use of heparin. \iHIT should be suspected in patients that experience a platelet count decrease of greater than 50% of baseline in association with even small amounts of heparin (such as heparin flush solutions) or in patients who experience new thromboembolic events while receiving heparin.\i HIT typically occurs 4-14 days after initial heparin exposure. Of note, thrombocytopenia from HIT rarely causes bleeding. Laboratory tests for heparin-induced platelet aggregation are insensitive. The "gold standard" test is an ELISA that measures heparin-platelet factor 4 complexes. There are several "do's" and "don'ts" in the management of HIT. Coumadin should be avoided as its use in the presence of a procoagulant state can precipitate limb gangrene. Platelet infusions simply add "more fuel to the fire." IVC filters can result in devastating caval, pelvic, and leg thrombosis. Finally, low molecular weight heparin, while less likely to initiate HIT, will often cross-react with the IgG antibodies once HIT has occurred. Treatment options for HIT include recombinant hirudin, and the recently-approved argatroban. Argatroban has a shorter half-life than hirudin and, unlike hirudin, does not require downward dose adjustments for renal insufficiency. Although HIT is not a standard indication, plasmapheresis may also be used. \p \w="100%" B. E. Lewis, D. E. Wallis, and W. Matthai for the ARG-911 Study Investigators. Argatroban provides effective and safe anticoagulation in patients with heparin-induced thrombocytopenia: A prospective, historical controlled study. \iJ.Am.Coll.Cardiol\i. 2000; 35: 266A T. E. Warkentin and A. Greinacher. Laboratory testing for heparin-induced thrombocytopenia. In: \iHeparin-Induced Thrombocytopenia\i. T. E. Warkentin and A. Greinacher (eds). New York: Marcel Dekker, Inc. 211-214, 2000. A. Greinacher, U. Janssens, G. Berg, M. Bock, H. Kwasny, B. Kemkes-Matthes, P. Eichler, H. Volpel, B. Potzsch, and M. Luz. Lepirudin (recombinant hirudin) for parenteral anticoagulation in patients with heparin-induced thrombocytopenia. Heparin-Associated Thrombocytopenia Study (HAT) investigators. \iCirculation\i 1999;100 (6):587-593 \w="100%" \p \bWarfarin (Coumadin\a174)\b After initial therapy with heparin, venous thromboembolism patients require long-term anticoagulation to prevent recurrent events. Warfarin is extremely effective in preventing recurrence of venous thromboembolism but carries a significant risk of hemorrhage. In general, "loading" patients with initial doses greater than 5 mg daily has been associated with an increased risk of bleeding events and is not recommended. For most patients with venous thromboembolism, a therapeutic INR range of 2.0 to 3.0 can be achieved within 5-7 days. Dose adjustments of greater than 20% of the previous dose should be avoided if possible. Changes in the INR are most reflective of the warfarin dose given 3-5 days previously. Special attention should be paid to drug interactions with warfarin. Acetaminophen, antibiotics such as trimetoprim/sulfamethoxazole and the cephalosporins, as well as COX-2 inhibitors such as celecoxib can potentiate the effects of warfarin. 1% to 2% of patients have a genetic mutation of cytochrome P450 that causes slow metabolism of warfarin. These patients require less then 2 mg daily of warfarin. Currently, the standard duration of anticoagulation for upper-extremity or isolated calf DVT is 3 months. For proximal leg DVT or PE, 6 months of anticoagulation is recommended. However, the recent DOTAVK trial showed equivalence of shorter-term anticoagulation (6 weeks for isolated calf DVT and 3 months for proximal leg DVT or PE) to the currently recommended course. Patients who suffer from idiopathic DVT or PE as well as recurrent venous thromboembolism may benefit from longer treatment. The ongoing PREVENT trial is addressing this point. Please contact Dr. Samuel Z. Goldhaber (\usgoldhaber@partners.org\u) to discuss enrolling patients with idiopathic PE or DVT in the NIH-sponsored PREVENT Trial. \p \bTips for Outpatient Anticoagulation\b 1) Insist upon detailed and explicit communication among physicians and nurses from different disciplines. Make no assumptions about who will regulate anticoagulation. 2) Explain to the patient and family the rationale for anticoagulation and the major risks from too intensive therapy (i.e., hemorrhage) and too little therapy (i.e., thromboembolism). The patient and family should understand the relationship between the prothrombin time, International Normalized Ratio, and dosing adjustments of anticoagulant. 3) Consider fingerstick testing of prothrombin time/INR/partial thromboplastin time. Self-management using point-of-care fingerstick INR machines has been shown to reduce the incidence of out-of-range INRs and improve quality of life and patient satisfaction. 4) Whenever possible, use a software supported electronic surveillance system rather than a paper notebook based system. This system should flag patients in whom an expected laboratory value has not yet been reported. 5) Arrange for laboratory values to be reported as the International Normalized Ratio rather than as the prothrombin time in seconds or as the prothrombin time ratio. 6) Consider use of centralized "anticoagulation clinics." \p \w="100%" L. Pinede, J. Ninet, P. Duhaut, S. Chabaud, S. Demolombe-Rague, I. Durieu, P. Nony, C. Sanson, J.P. Boissel Comparison of 3 and 6 months of oral anticoagulant therapy after a first episode of proximal deep vein thrombosis or pulmonary embolism and comparison of 6 and 12 weeks of therapy after isolated calf deep vein thrombosis. \iCirculation\i 2001;103(20):2453-60 M. E. Cromheecke, M. Levi, L. P. Colly, B. J. de Mol, M. H. Prins, B. A. Hutten, R. Mak, K. C. Keyzers, and H. R. Buller. Oral anticoagulation self-management and management by a specialist anticoagulation clinic: a randomised cross-over comparison. \iLancet\i 2000;356 (9224):97-102 G. P. Aithal, C. P. Day, P. J. Kesteven, and A. K. Daly. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications [see comments]. \iLancet\i 1999;353 (9154):717-719 M. A. Crowther, J. B. Ginsberg, C. Kearon, L. Harrison, J. Johnson, M. P. Massicotte, and J. Hirsh. A randomized trial comparing 5-mg and 10-mg warfarin loading doses [see comments]. \iArch.Intern.Med.\i 1999; 159 (1):46-48 S. Z. Goldhaber. Optimizing anticoagulant therapy in the management of pulmonary embolism. \iSemin.Thromb.Hemost.\i 1999; 25 Suppl 3:129-133 \w="100%" \p \bParadoxical Thrombosis with Warfarin Alone\b Dutch investigators tested the strategy of managing uncomplicated DVT by just utilizing oral anticoagulation, without concomitant heparin. They compared this approach with standard anticoagulation that combines heparin with oral anticoagulation until the oral anticoagulation is fully effective. The recurrence rate of symptomatic thrombosis was three times higher in the group that received oral anticoagulation alone. Initiation of warfarin in the presence of active venous thrombosis is believed to cause paradoxical thrombosis due to early depletion of protein C and S while clotting factors that are inactivated more slowly remain unopposed. Therefore, patients with acute venous thrombosis should receive heparin until oral anticoagulants have become fully effective, a process that usually takes about five days. \p \w="100%" D. P. Brandjes, H. Heijboer, H. R. Buller, M. de Rijk, H. Jagt, and J. W. ten Cate. Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximal-vein thrombosis. \iN.Engl.J.Med.\i 1992; 327 (21):1485-1489 \w="100%" \p \bCorrection of Excessive Oral Anticoagulation\b In the event of excessive oral anticoagulation, low dose oral vitamin K is recommended over high dose oral or subcutaneous vitamin K. In general, high doses of vitamin K do not decrease the INR faster than lower doses and instead make the patient temporarily refractory to future anticoagulation. Withholding one to two doses of warfarin, and giving 2.5 mg of oral vitamin K has been shown to be effective in reversing excessive anticoagulation. \p \w="100%" M. A. Crowther, D. Donovan, L. Harrison, J. McGinnis, and J. Ginsberg. Low-dose oral vitamin K reliably reverses over-anticoagulation due to warfarin. \iThromb.Haemost.\i 1998; 79 (6):1116-1118 R. T. Weibert, D. T. Le, S. R. Kayser, and S. I. Rapaport. Correction of excessive anticoagulation with low-dose oral vitamin K1. \iAnn.Intern.Med.\i 1997; 26 (12):959-962 \w="100%" \p \bInferior Vena Caval Filters\b \bIndications for IVC Filter Placement\b 1) PE or recurrent PE despite adequate anticoagulation 2) Contraindications to anticoagulation 3) Open surgical pulmonary embolectomy \p \bLimitations\b 1) IVC filter placement does not address the thrombotic process. (Therefore, whenever possible, patients should be anticoagulated, even if this is not feasible at the time of IVC filter insertion.) 2) Peripheral leg edema can ensue. 3) Large venous collaterals can develop and permit PE. 4) Filters may fail because of technical problems such as filter tilt or improper deployment of filter legs with the Greenfield filter. 5) Increased incidence of DVT 6) Lack of mortality benefit While effective for the prevention of PE, IVC filters appear to increase the DVT rate in the absence of concomitant anticoagulation. In a randomized study of 400 patients, IVC filters initially reduced the incidence of PE but at 2 years increased the incidence of DVT to 21% compared to 12% in those without filters (P=0.02). The mortality rate at 2 years was no different between the two groups. Another study revealed that patients with filters were more likely to be rehospitalized for DVT. \bNOTE:\b 1. MR imaging may be performed 10-14 days after IVC filter placement. 2. For suprarenal placement, a Greenfield filter should be used because it is the only IVC filter with data confirming its efficacy and safety in this position. \p \w="100%" R. H. White, H. Zhou, J. Kim, and P. S. Romano. A population-based study of the effectiveness of inferior vena cava filter use among patients with venous thromboembolism. \iArch.Intern.Med.\i 2000; 160 (13):2033-2041 C. A. Athanasoulis, J. A. Kaufman, E. F. Halpern, A. C. Waltman, S. C. Geller, and C. M. Fan. Inferior vena caval filters: review of a 26-year single-center clinical experience. \iRadiology\i 2000; 216 (1):54-66 H. Decousus, A. Leizorovicz, F. Parent, Y. Page, B. Tardy, P. Girard, S. Laporte, R. Faivre, B. Charbonnier, F. G. Barral, Y. Huet, and G. Simonneau. A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. Prevention du Risque d'Embolie Pulmonaire par Interruption Cave Study Group [see comments]. \iN.Engl.J.Med.\i 1998; 338 (7):409-415 \w="100%" \p \bPrimary Therapy - PE and DVT\b \bThrombolysis\b \bPE\b Thrombolysis is lifesaving in patients with massive PE and cardiogenic shock. While hemodynamic collapse is an ominous sign, few patients with PE present in cardiogenic shock. Much more commonly, PE patients demonstrate normal systemic arterial pressure combined with occult right ventricular dysfunction that is detectable only on echocardiographic evaluation. The presence of moderate or severe right ventricular hypokinesis, even in the absence of systemic arterial hypotension, implies "impending hemodynamic instability" and suggests that primary therapy of PE with thrombolysis or embolectomy be strongly considered. Thrombolysis has been shown to improve clinical outcomes in patients with preserved blood pressure but worsening right ventricular dysfunction. The efficacy of PE thrombolysis appears to be inversely proportional to duration of symptoms and delay seems to attenuate resolution of the obstruction on angiography especially outside of a two week "window period." \p \w="100%" S. Z. Goldhaber. Echocardiography in the diagnosis and management of pulmonary embolism: a report card. \iAnn.Intern.Med.\i 2002: in press S. Z. Goldhaber. The current role of thrombolytic therapy for pulmonary embolism \iSemin.Vasc.Surg.\i 2000;13 (3):217-220 S. Z. Goldhaber. A contemporary approach to thrombolytic therapy for pulmonary embolism [In Process Citation]. \iVasc.Med.\i 2000; 5 (2):115-123 L. B. Daniels, J. A. Parker, S. R. Patel, F. Grodstein, and S. Z. Goldhaber. Relation of duration of symptoms with response to thrombolytic therapy in pulmonary embolism. \iAm.J.Cardiol.\i 1997;80 (2):184-188 \w="100%" \p \bDVT\b Thrombolysis in DVT should theoretically restore venous valve patency and function although this has not been proven. DVT thrombolysis is most helpful in patients with upper-extremity thrombosis secondary to a long-term indwelling central venous catheter that must remain in place. Thrombolytics may also be used in young otherwise healthy patients with iliofemoral DVT with marked swelling and pain-limiting walking. Unlike thrombolysis in PE which may be administered peripherally, thrombolytics should be catheter-directed into the DVT. Peripherally administered thrombolytics cannot gain access to the totally obstructed deep venous system. \p \w="100%" J. Schweizer, W. Kirch, R. Koch, H. Elix, G. Hellner, L. Forkmann, and A. Graf. Short- and long-term results after thrombolytic treatment of deep venous thrombosis [In Process Citation]. \iJ.Am.Coll.Cardiol.\i 2000; 36 (4):1336-1343 M. W. Mewissen, G. R. Seabrook, M. H. Meissner, J. Cynamon, N. Labropoulos, and S. H. Haughton. Catheter-directed thrombolysis for lower extremity deep venous thrombosis: report of a national multicenter registry [published erratum appears in Radiology 1999 Dec;213(3):930]. \iRadiology\i 1999; 211 (1):39-49 \w="100%" \p \bAdministration of Thrombolytics\b All patients being considered for thrombolysis should be meticulously screened for contraindications including: \t1) Intracranial disease 2) Recent surgery 3) Recent trauma 4) Severe or uncontrolled hypertension 5) Recent prolonged CPR\t NOTE: None of the FDA-approved regimens for PE thrombolysis employs \bconcomitant heparin\b. This is an important distinction from thrombolysis in myocardial infarction. At the end of thrombolytic infusion in PE patients, the PTT should be obtained. If the PTT is less than twice the upper limit of normal, heparin may be initiated or resumed without the need of a loading dose. If the PTT is greater than twice the upper limit of normal, the test should be repeated every 4 hours until it falls in the range in which heparin may be administered. \p \bComplications\b The complications of thrombolysis largely pertain to bleeding especially intracranial hemorrhage. ICOPER, a registry (not a controlled clinical trial), reported a 3.0% risk of intracranial hemorrhage. \p \w="100%" S. Z. Goldhaber, L. Visani, and M. De Rosa. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER) [see comments]. \iLancet\i 1999; 353 (9162):1386-1389 \w="100%" \p \bOpen Surgical Embolectomy\b Open surgical embolectomy should be considered as soon as a decision has been made that PE is causing moderate or severe right heart dysfunction and that thrombolysis is contraindicated or has failed. Other indications for surgical embolectomy include persistent right heart thrombi and acute profound hemodynamic or respiratory compromise requiring cardiopulmonary resuscitation. In general, surgical embolectomy is most effective in saddle or main pulmonary artery embolism. Of note, an inferior vena cava filter is often placed post-operatively as the patient cannot be fully anticoagulated acutely after surgery secondary to risks of hemorrhage. \p \w="100%" M. Ullmann, W. Hemmer, and A. Hannekum. The urgent pulmonary embolectomy: mechanical resuscitation in the operating theatre determines the outcome. \iThorac.Cardiovasc.Surg.\i 1999; 47 (1):5-8 \w="100%" \p \bCatheter-Assisted Embolectomy\b In patients with massive pulmonary embolism evidenced by signs of right heart failure or right ventricular dysfunction on echocardiogram as well as obstruction of a main artery or two or more lobar arteries, catheter-assisted embolectomy may be considered. This intervention is often elected when thrombolysis is contraindicated and as an alternative to open surgical embolectomy. Catheter-based techniques work best on fresh thrombi and are therefore most effective within the first 5 days of evolution of PE or DVT. Some of the most recent experience with catheter-based techniques involves a suction-catheter that acts by fragmenting thrombus and evacuating the debris. \p \w="100%" M. Fava, S. Loyola, and I. Huete. Massive pulmonary embolism: treatment with the hydrolyser thrombectomy catheter \iJ.Vasc.Interv.Radiol.\i 2000;11 (9):1159-1164 \w="100%" \p \b\xPrevention of VTE\x\b \bOverview\b Venous thromboembolism prophylaxis should be virtually universal among hospitalized patients. Prophylaxis should be considered even after discharge for immobile or postoperative patients. The various prophylaxis modalities include graduated compression stockings, intermittent pneumatic compression boots, and IVC filters as well as heparin, warfarin, and aspirin. \p \w="100%" S. Z. Goldhaber, K. Dunn, and R. C. MacDougall. New onset venous thromboembolism among hospitalized patients at Brigham and Women's Hospital is caused more often by prophylaxis failure than by withholding treatment. \iChest\i 2000; 118:1680-1684 \w="100%" \p \bIVC Filters\b While effective for the prevention of PE, IVC filters appear to increase the DVT rate in the absence of concomitant anticoagulation. In a randomized study of 400 patients, IVC filters initially reduced the incidence of PE but at 2 years increased the incidence of DVT to 21% compared to 12% in those without filters (P=0.02). The mortality rate at 2 years was no different between the two groups. Another study revealed that patients with filters were more likely to be rehospitalized for DVT. \p \w="100%" R. H. White, H. Zhou, J. Kim, and P. S. Romano. A population-based study of the effectiveness of inferior vena cava filter use among patients with venous thromboembolism. \iArch.Intern.Med.\i 2000;160 (13):2033-2041 C. A. Athanasoulis, J. A. Kaufman, E. F. Halpern, A. C. Waltman, S. C. Geller, and C. M. Fan. Inferior vena caval filters: review of a 26-year single-center clinical experience. \iRadiology\i 2000; 216 (1):54-66 H. Decousus, A. Leizorovicz, F. Parent, Y. Page, B. Tardy, P. Girard, S. Laporte, R. Faivre, B. Charbonnier, F. G. Barral, Y. Huet, and G. Simonneau. A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. Prevention du Risque d'Embolie Pulmonaire par Interruption Cave Study Group [see comments]. \iN.Engl.J.Med.\i 1998; 338 (7):409-415 \w="100%" \p \bProphylactic Anticoagulation\b Prophylactic anticoagulation may be accomplished safely and effectively in most hospitalized individuals including both medical and surgical patients. \p \bMedical Patients\b The Medenox study examined the efficacy of the low molecular weight heparin enoxaparin in preventing all venous thromboembolic events as well as proximal DVT. The study revealed that enoxaparin at 40 mg subcutaneously daily reduced the incidence of all venous thromboembolic events to 5.5% versus 14.9% for placebo and decreased the risk of proximal DVT to 1.7% versus 4.9% in the placebo arm. Enoxaparin 20 mg subcutaneously daily did not appear to reduce the incidence of venous thromboembolic events. The incidence of adverse events did not differ significantly between the groups. A meta-analysis among medical patients revealed a 52% decrease in risk of major hemorrhage among patients treated with low molecular weight heparin compared to unfractionated "mini-heparin" (doses of 10,000 to 15,000 IU daily given in BID or TID injections). \p \w="100%" P. Mismetti, S. Laporte-Simitsidis, B. Tardy, M. Cucherat, A. Buchmuller, D. Juillard-Delsart, and H. Decousus. Prevention of venous thromboembolism in internal medicine with unfractionated or low-molecular-weight heparins: a meta-analysis of randomised clinical trials. \iThromb.Haemost.\i 2000; 83 (1):14-19 M. M. Samama, A. T. Cohen, J. Y. Darmon, L. Desjardins, A. Eldor, C. Janbon, A. Leizorovicz, H. Nguyen, C. G. Olsson, A. G. Turpie, and N. Weisslinger. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group [see comments]. \iN.Engl.J.Med.\i 1999; 341 (11):793-800 \w="100%" \p \bSurgical Patients\b Among virtually all surgical patients, prophylaxis is of integral importance as many patients are hypercoagulable after surgery and immobile due to pain or activity restriction. In a study of orthopedic patients, 76% of thromboembolic events after total hip arthroplasty and 47% of the events after total knee arthroplasty were diagnosed after discharge from the hospital. In fact, the risk of DVT and PE remained elevated up to 10 weeks after hip arthroplasty and up to 4 weeks after knee arthroplasty. These findings support the belief that posthospitalization DVT and PE are important problems and that prophylactic anticoagulation should continue after discharge. \p \w="100%" R. H. White, P. S. Romano, H. Zhou, J. Rodrigo, and W. Bargar. Incidence and time course of thromboembolic outcomes following total hip or knee arthroplasty. \iArch.Intern.Med.\i 1998; 158 (14):1525-1531 \w="100%" \p \bHip Fracture Patients\b In the PEP trial of hip fracture patients, aspirin was shown to reduce incidence of DVT and PE in patients undergoing surgery for hip fracture as well as elective arthroplasty when compared to placebo. Similarly proportional reductions in risk were seen in patients also receiving other prophylaxis such as subcutaneous heparin. We do not endorse using aspirin alone for hip fracture venous thromboembolism prophylaxis despite the results of the PEP trial. \p \w="100%" Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial [see comments]. \iLancet\i 2000; 355 (9212):1295-1302 \w="100%" \p A table of recommended prophylaxis strategies is included below. \b\xRecommended prophylaxis strategies\x\b \w="100%" \bGeneral Surgery:\b \tUnfractionated Heparin 5,000 U BID/TID or Enoxaparin 40 mg SC q 24h or Dalteparin 2,500 or 5,000 U SC q 24ht \w="100%" \p \bTotal Hip Replacement\b \tWarfarin (target INR 2.5) or Enoxaparin 30 mg SC BID or 40 mg SC QD\t \w="100%" \p \bTotal Knee Replacement\b \tEnoxaparin 30 mg SC BID or 40 mg SC QD \w="100%" \p \bNeurosurgery\b Graduated compression stockings and intermittent pneumatic compression +/- unfractionated heparin 5,000 U SC \w="100%" \p \bTrauma (non-brain)\b Enoxaparin 30 mg SC BID \w="100%" \p \bThoracic Surgery\b Graduated compression stockings, intermittent pneumatic compression, and unfractionated heparin 5,000 U SC TID \w="100%" \p \bRadical Prostatectomy\b Warfarin (target INR 1.5) and intermittent pneumatic compression \w="100%" \p \bMedical Patients\b Graduated compression stockings or Intermittent pneumatic compression or Unfractionated heparin 5,000 U SC BID/TID or Enoxaparin 40 mg SC QD \w="100%"