Course Authors

Victor F. Tapson, M.D.

Dr. Tapson is Professor of Medicine, Duke University School of Medicine. Within the past 12 months, Dr. Tapson has received research grant support from Actelion, Cotherix, Encysive, Pfizer, Sanofi Aventis and United Therapeutics, and has been a consultant for Actelion, Sanofi Aventis and United Therapeutics.

This activity is made possible by an unrestricted educational grant from .

Estimated course time: 1 hour(s).

Albert Einstein College of Medicine – Montefiore Medical Center designates this enduring material activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

In support of improving patient care, this activity has been planned and implemented by Albert Einstein College of Medicine-Montefiore Medical Center and InterMDnet. Albert Einstein College of Medicine – Montefiore Medical Center is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

 

Learning Objectives

Upon completion of this Cyberounds^®, you should be able to:

• Describe underlying risk factors for venous thromboembolism

• Describe appropriate diagnostic approaches to suspected acute DVT and PE

• Discuss the mechanism of action of various anticoagulants

• Discuss the side-effect profiles of warfarin, UFH and LMWH

• Discuss results of clinical trials in VTE prevention and treatment.

 

Venous thromboembolism constitutes a clinical spectrum encompassing deep venous thrombosis (DVT) and pulmonary embolism (PE). This disorder occurs very commonly in hospitalized medically ill and surgical patients especially.(1) While DVT often arises in the calf veins, PE most commonly results from DVT occurring in the veins of the proximal lower extremities, that is, including and proximal to the popliteal veins. The majority of deaths occur within hours of acute PE, often as the consequence of previously unrecognized and untreated DVT or acute PE.(2)

Both DVT and PE are frequently clinically unsuspected, leading to significant diagnostic and therapeutic delays and accounting for substantial morbidity and mortality.(3) In the International Cooperative Pulmonary Embolism Registry, the 3-month mortality rate was 17.5% and PE was the principal cause of death among 2,454 consecutive patients with PE.(4) In the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED), the mortality rate was approximately 15% but only 10% of deaths during the first year of follow-up were attributed to PE.(5) The frequency of unsuspected PE in patients at autopsy has not diminished over the past three decades.(6) Among patients who die from PE, the disease is most commonly unsuspected(6) until autopsy.

Although most cases of acute PE resolve with therapy, occasionally a substantial residual thromboembolic burden persists or develops over time.(7) If the obstruction becomes extensive, pulmonary hypertension develops. A potential long-term sequela from acute DVT is chronic leg pain and swelling (postphlebitic syndrome) which may result in significant morbidity.(8)

One or more components of Virchow's triad (stasis, hypercoagulability and intimal injury) are present in the majority of patients with VTE. These risk factors help guide prophylaxis and, together with compatible symptoms and signs, also help the clinician suspect the diagnosis of DVT or PE.

Clinical Manifestations

The history and physical examination are neither sensitive nor specific for DVT or PE. Patients with lower extremity venous thrombosis often do not exhibit erythema, warmth, pain, swelling or tenderness. When these signs are present, they are nonspecific but still may merit further evaluation.(9) Homans' sign (pain in the calf with dorsiflexion of the foot) may be present in the setting of DVT but is neither sensitive nor specific enough to be relied upon.

The most common symptom of acute PE is dyspnea, which is often sudden in onset. Pleuritic chest pain, hemoptysis, palpitations, anxiety and lightheadedness may all be associated with acute PE. Syncope and/or sudden death may occur with massive PE. Tachypnea and tachycardia are the most common signs of PE but are also nonspecific.

Diagnosis

The differential diagnosis for acute PE is broad and includes a number of cardiopulmonary diseases and, occasionally, intra-abdominal processes may be mimicked by PE.

Hypoxemia is extremely common but not always present in acute PE.(9) The diagnostic utility of plasma measurements of circulating D-dimer (a specific derivative of cross-linked fibrin) has been extensively evaluated in patients with PE. A number of D-dimer assays are available, and the sensitivity and specificity of these assays vary. A positive D-dimer test means that DVT or PE is possible but it is by no means proof. Similarly, although a negative D-dimer, particularly by ELISA assay, may strongly suggest that VTE is absent, a high clinical suspicion should not be ignored.(10) In general, in the setting of a high clinical suspicion for acute VTE, D-dimer testing should not be ordered and one should proceed straight to imaging.

Troponin levels may be elevated in acute PE. Troponin elevation is specific for cardiac myocyte damage and the right ventricle appears to be the source of the enzyme elevation in acute PE.(11) Troponin levels cannot, however, be used like D-dimer testing -- that is, they are not sensitive enough to exclude PE, even when the clinical suspicion is relatively low, without additional diagnostic testing.

Only one-third of patients with massive or submassive emboli have electrocardiographic manifestations of acute cor pulmonale such as the S1-Q3-T3 pattern, right bundle branch block, P-wave pulmonale or right axis deviation. All of these findings are also nonspecific but may offer clues.(9)

Common chest radiographic findings include pleural effusion, atelectasis, pulmonary infiltrates and mild elevation of a hemidiaphragm.(9) Classic findings of pulmonary infarction such as Hamptons hump (on chest x-ray, a wedge-shaped costophrenic zone of consolidation) or decreased vascularity (Westermark's sign) are suggestive of the diagnosis but they are infrequent.

Under most circumstances, however, the chest radiograph cannot be used for conclusive diagnosis or exclusion. Although the radiograph may exclude other processes, such as pneumonia, pneumothorax or rib fracture, which may cause similar symptoms, acute PE may frequently coexist with other underlying heart or lung diseases. Symptoms, signs, radiographic findings, electrocardiography and the plasma D-dimer measurement cannot be considered diagnostic of PE or DVT. When these entities are suspected, further evaluation with noninvasive or invasive testing is necessary.

Specific Imaging Studies

A normal perfusion scan excludes the diagnosis of PE with a high enough degree of certainty that further diagnostic evaluation is almost never necessary. However, low or intermediate probability (nondiagnostic) VQ scans are commonly found with PE and, in such situations, further evaluation with pulmonary arteriography or leg studies is often appropriate.

In the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED), the specificity of high probability scans was 97% but the sensitivity was only 41%. Of note, 33% of patients with intermediate probability VQ scans and 12% of patients with low probability scans were diagnosed definitively with PE by pulmonary arteriography. Stable patients with suspected acute PE, nondiagnostic lung scans and adequate cardiopulmonary reserve (absence of hypotension or severe hypoxemia) may undergo leg ultrasound in an attempt to diagnose DVT. A negative D-dimer also provides reassurance when the VQ scan is nondiagnostic unless the clinical suspicion is high.(10)

Increased experience and advances in CT technology with multidetector scanning have made scanning more rapid as well as potentially enhancing sensitivity to the 80% to 90% range and specificity to consistently above 90%. Spiral CT is most sensitive for detecting emboli in the main, lobar, or segmental pulmonary arteries; its specificity for clot in these vessels is also excellent. For subsegmental emboli, spiral CT appears to be less accurate, but recent clinical trial and meta-analytic data suggest that the outcome after a negative spiral CT scan is excellent with the risk of recurrent VTE being exceedingly low. Results from a large North American multicenter trial comparing CT scanning with ventilation-perfusion scanning (PIOPED II) indicate that by including images of the legs in the setting of suspected PE (without additional contrast), the sensitivity for VTE is increased from 83% to 90%.(13)

Clinical prediction rules have been used together with D-dimer testing and multidetector chest CT scanning. A recent prospective clinical trial used a dichotomized version of the Wells score so that instead of high, moderate and low probability, only two categories of probability were included.(14) Patients with suspected PE that were classified as "PE likely," underwent CT imaging directly, while the "PE unlikely" patients underwent D-dimer testing and CT was done if the D-dimer was abnormal, while PE was excluded if it was normal. The outcomes in the patients with low suspicion and a normal D-dimer, or with a negative CT were excellent; the algorithm was completed and allowed a management decision in 97.9% of patients.(14) Pooling of studies involving chest CT scanning supports its utility.(15)

Pulmonary arteriography has remained the accepted "gold standard" technique for the diagnosis of acute PE.(16) However, with the advent of CT, it is infrequently used. Echocardiography, which can often be obtained more rapidly than either lung scanning or pulmonary arteriography, may reveal abnormalities of right ventricular size or function that strongly support the diagnosis of hemodynamically significant PE.(16)

Treatment

Parenteral anticoagulation with low-molecular-weight heparin (LMWH) or with standard, unfractionated heparin is initiated for DVT or PE unless contraindicated.(17) The unstable patient requires a rapid evaluation and integration of data to optimize therapeutic decisions and outcome. Extensive experience with outpatient therapy with LMWH further supports the lack of need for bed rest, unless a patient has extensive DVT with substantial pain and or swelling.(17)

Anticoagulant Therapy

The primary anticoagulants used to treat acute DVT or PE include unfractionated heparin and LMWH. Although heparins do not directly dissolve thrombi or emboli, they allow the fibrinolytic system to proceed unopposed and more readily reduce the size of the thromboembolic burden. Whereas the growth of thrombus can be prevented, early recurrence can sometimes develop, even in the setting of therapeutic anticoagulation.

Anticoagulation reduces mortality in acute PE. When DVT or PE is diagnosed, anticoagulation should be instituted immediately unless contraindications are present. It is appropriate to initiate therapy in patients in whom there is a high index of suspicion for acute PE, even while diagnostic testing is underway, when the bleeding risk is low. Warfarin can be initiated as soon as parenteral therapy is started. At least 5 days of subcutaneous LMWH or intravenous unfractionated heparin are generally recommended.(17) Ideally, the parenteral anticoagulant should be maintained until the international normalized ratio (INR) is stable at 2.0 to 3.0.

The LMWH preparations have significant advantages over unfractionated heparin and have dramatically changed the approach to prophylaxis and treatment of thromboembolic disease.(17) Among the advantages of LMWH are greater bioavailability, subcutaneous delivery for therapy, no need for monitoring in most cases and a lower risk of heparin-induced thrombocytopenia. Both argatroban and lepirudin have been FDA-approved for use in the setting of VTE with HIT.

A number of clinical trials have strongly suggested the efficacy and safety of LMWH for treatment of established acute proximal DVT using recurrent symptomatic VTE as the primary outcome measure,(18) and efficacy has been demonstrated for acute PE as well, with meta-analytic data supporting the use of LMWH in VTE.(19) Outpatient therapy with LMWH has become standard for patients who do not have extensive DVT or otherwise require admission, as long as teaching can be accomplished and compliance is adequate.(20)

In the United States, three LMWH preparations are currently approved by the Food and Drug Administration (FDA) for treatment of patients with proven DVT with or without acute PE. Enoxaparin is approved for both inpatients and outpatients at a dose of 1 mg/kg subcutaneously every 12 hours or as 1.5 mg/kg once daily for inpatient use. The second preparation, tinzaparin, is administered as 175 units once daily, with the FDA-approval based on therapy of inpatients with DVT. The third drug, fondaparinux, is approved for treatment of DVT or PE. When continuous intravenous unfractionated heparin is used, a weight-based protocol should be followed.(17)

Patients with acute VTE require long-term anticoagulation to prevent a high frequency (as high as 50%) of symptomatic extension of thrombosis or recurrent VTE. Documented VTE in the setting of transient risk factors should be treated for three to six months. Treatment over a more extended interval is appropriate when significant risk factors persist, when thromboembolism is idiopathic or when previous episodes of VTE have been documented.(17)

Vena Caval Interruption

In the setting of proven DVT or PE, the primary indications for filter placement include contraindications to anticoagulation, significant bleeding complications during anticoagulation and recurrent embolism while on adequate therapy.(17) More recently, retrievable filters have been used in patients in whom the risk of bleeding appears to be short-term; such devices can be removed up to two weeks later.(21) Several available devices can be removed as late as 90 days after placement. Far less data are available regarding filters for prophylactic use in the absence of thrombosis.

Thrombolytic Therapy

Thrombolytic agents activate plasminogen to form plasmin, which then results in fibrinolysis and fibrinogenolysis. The clearest indication for thrombolytic therapy is when PE causes hemodynamic instability (hypotension).(17) Other settings in which thrombolytic therapy might be considered include echocardiographic right ventricular dysfunction without hypotension,(22) severely compromised oxygenation, a massive radiographic embolic burden and when extensive DVT accompanies nonmassive embolism. However, much less evidence supports the use of thrombolytic agents when extensive DVT accompanies nonmassive embolism. Low-dose direct thrombolytic infusions or mechanical fragmentation techniques appear reasonable when the treating physician has experience with them.

Hemorrhage is the primary concern with thrombolytic therapy and this therapy is contraindicated in patients at high risk for bleeding. The most devastating complication associated with thrombolytics is intracranial hemorrhage, which occurs in less than 1% of patients in clinical trials. The rate appears to be slightly higher outside of controlled clinical trials.(4) Retroperitoneal hemorrhage may result from a vascular puncture above the inguinal ligament and may be life-threatening. The risk-benefit of thrombolytics must always be assessed as best as possible.

Hemodynamic Management of Massive PE

Massive PE should always be considered in the setting of the sudden onset of hypotension, extreme hypoxemia, electromechanical dissociation or cardiac arrest. When hypotension is present, intravenous saline should be infused rapidly, but cautiously, because right ventricular function is often markedly compromised.(23) Dopamine or norepinephrine appear appropriate in massive PE and should be administered if the blood pressure is not rapidly restored.(23) Because death from PE results from right ventricular failure, dobutamine can be considered to augment right ventricular output; however, this drug may also worsen hypotension.

Prevention

The risk of DVT and, thus, PE is significant in hospitalized patients.(1),(3),(6) A substantial reduction in the incidence of DVT can be achieved when patients at risk receive appropriate prophylaxis.(24) Such preventive measures appear to be grossly underused. Anticoagulant prophylaxis appears more effective than mechanical prophylaxis but the risk of both thrombosis and bleeding must be considered.(24) Both heparin and LMWH have been studied as prophylaxis for various indications.

After total hip or knee replacement, the risk of DVT is 50% or greater without prophylaxis. The superiority of LMWH over standard, unfractionated heparin has been clearly demonstrated in these settings, as well as in trauma and spinal cord injury.(24) In general medical patients, the risk of DVT without prophylaxis may be as high as 15% based upon studies, some of which utilize bilateral venography as an endpoint.(25)

In the medical population, three prospective, randomized, double-blind trials have demonstrated that LMWH (either enoxaparin, dalteparin or fondaparinux) is superior to placebo in preventing acute DVT.(25),(26),(27) LMWH (enoxaparin 40 mg subcutaneously once daily) has been compared to subcutaneous heparin (5000 units every 8 hours) in general medical patients and both have proven effective in preventing DVT.(28) The advantages of LMWH, however, support its use. Although 5,000 units of heparin every 12 hours has been commonly used, there are less data to support this regimen. Intermittent pneumatic compression devices should be used when prophylactic doses of anticoagulants are contraindicated.(24) Both methods combined would be reasonable in patients deemed at exceptionally high risk, but combination regimens have not been studied in large populations of such individuals.

Every hospitalized patient should be assessed for the need for prophylactic measures, and all hospitals should formulate their own written guidelines for each particular clinical setting based on the available medical literature.(24)

Summary

Acute venous thromboembolism is responsible for substantial morbidity and mortality. The clinician must be aware of risk factors for this disease and understand appropriate diagnostic approaches to suspected acute DVT and PE. The diagnosis must be documented as quickly as possible but treatment should be considered even prior to establishing the diagnosis in the setting of a high clinical suspicion, unless the bleeding risk is deemed high.

LMWH or standard, unfractionated heparin should be initiated acutely, with warfarin for long-term therapy. LMWH preparations have certain advantages over standard heparin. More aggressive therapy, such as thrombolytic agents, can be considered in individualized situations.