Pulmonary Embolism Medication
- Author: Daniel R Ouellette, MD, FCCP; Chief Editor: Zab Mosenifar, MD, FACP, FCCP more...
Immediate therapeutic anticoagulation is initiated for patients with suspected deep venous thrombosis (DVT) or pulmonary embolism (PE). Anticoagulation therapy with heparin reduces mortality rates from 30% to less than 10%. Anticoagulation is essential, but anticoagulation alone does not guarantee a successful outcome. DVT and PE may recur or extend despite full and effective heparin anticoagulation.
Chronic anticoagulation is critical to prevent relapse of DVT or PE following initial heparinization. Heparin works by activating antithrombin III to slow or prevent the progression of DVT and to reduce the size and frequency of PE. Heparin does not dissolve existing clot.
Heparin augments the activity of antithrombin III and prevents the conversion of fibrinogen to fibrin. Full-dose LMWH or full-dose unfractionated IV heparin should be initiated at the first suspicion of DVT or PE.
With proper dosing, several LMWH products have been found safer and more effective than unfractionated heparin both for prophylaxis and for treatment of DVT and PE. Monitoring the aPTT is neither necessary nor useful when giving LMWH, because the drug is most active in a tissue phase and does not exert most of its effects on coagulation factor IIa.
Many different LMWH products are available around the world. Because of pharmacokinetic differences, dosing is highly product specific. Several LMWH products are approved for use in the United States: enoxaparin (Lovenox), dalteparin (Fragmin), and tinzaparin (Innohep). Enoxaparin and tinzaparin are currently approved by the FDA for treatment of DVT. Dalteparin is FDA approved for prophylaxis and has approval for cancer patients. Each of the other agents has been approved by the FDA at a lower dose for prophylaxis, but all appear to be safe and effective at some therapeutic dose in patients with active DVT or PE.
Fractionated LMWH administered subcutaneously is now the preferred choice for initial anticoagulation therapy. Unfractionated IV heparin can be nearly as effective but is more difficult to titrate for therapeutic effect. Warfarin maintenance therapy may be initiated after 1-3 days of effective heparinization.
The weight-adjusted heparin dosing regimens that are appropriate for prophylaxis and treatment of coronary artery thrombosis are too low to be used unmodified in the treatment of active DVT and PE. Coronary artery thrombosis does not result from hypercoagulability but rather from platelet adhesion to ruptured plaque. In contrast, patients with DVT and PE are in the midst of a hypercoagulable crisis, and aggressive countermeasures are essential to reduce mortality and morbidity rates.
Exonaparin was the first low-molecular-weight heparin (LMWH) released in the United States. It was approved by the FDA for both treatment and prophylaxis of DVT and PE. Enoxaparin enhances the inhibition of factor Xa and thrombin by increasing antithrombin III activity. In addition, it preferentially increases the inhibition of factor Xa. LMWH has been used widely in pregnancy, although clinical trials are not yet available to demonstrate that it is as safe as unfractionated heparin. Except in overdoses, checking PT or aPTT has no utility, as aPTT does not correlate with anticoagulant effect of fractionated LMWH. Factor Xa levels can be monitored if concern arises about whether the dose is adequate.
Dalteparin is an LMWH with many similarities to enoxaparin but with a different dosing schedule. It is approved for DVT prophylaxis in patients undergoing abdominal surgery. Except in overdoses, checking PT or aPTT has no utility, as aPTT does not correlate with anticoagulant effect of fractionated LMWH. LMWH. Factor Xa levels can be monitored if concern arises about whether the dose is adequate.
Tinzaparin is approved for treatment of DVT in hospitalized patients. Enhances inhibition of factor Xa and thrombin by increasing antithrombin III activity. In addition, preferentially increases inhibition of factor Xa.
Heparin augments the activity of antithrombin III and prevents conversion of fibrinogen to fibrin. It does not actively lyse but is able to inhibit further thrombogenesis. Heparin prevents the reaccumulation of a clot after spontaneous fibrinolysis. When UFH is used, the aPTT should not be checked until 6 hours after the initial heparin bolus, because an extremely high or low value during this time should not provoke any action
Warfarin (Coumadin) interferes with the hepatic synthesis of vitamin K–dependent coagulation factors. It is used for the prophylaxis and treatment of venous thrombosis, pulmonary embolism, and thromboembolic disorders. Never administer warfarin to patients with thrombosis until after they have been fully anticoagulated with heparin (the first few days of warfarin therapy produce a hypercoagulable state). Failing to anticoagulate with heparin before starting warfarin causes clot extension and recurrent thromboembolism in approximately 40% of patients, compared with 8% of those who receive full-dose heparin before starting warfarin. Heparin should be continued for the first 5-7 days of oral warfarin therapy, regardless of the PT time, to allow time for depletion of procoagulant vitamin K–dependent proteins.
Tailor the warfarin dose to maintain an INR in the range of 2.5-3.5. The risk of serious bleeding (including hemorrhagic stroke) is approximately constant when the INR is 2.5-4.5 but rises dramatically when the INR is over 5. In the United Kingdom, a higher INR target of 3-4 often is recommended.
Evidence suggests that 6 months of anticoagulation reduces the rate of recurrence to half of the recurrence rate observed when only 6 weeks of anticoagulation is given. Long-term anticoagulation is indicated for patients with an irreversible underlying risk factor and recurrent DVT or recurrent pulmonary embolism.
Procoagulant vitamin K–dependent proteins are responsible for a transient hypercoagulable state when warfarin is first started and stopped. This is the phenomenon that occasionally causes warfarin-induced necrosis of large areas of skin or of distal appendages. Heparin is always used to protect against this hypercoagulability when warfarin is started; when warfarin is stopped, however, the problem resurfaces, causing an abrupt, temporary rise in the rate of recurrent venous thromboembolism.
At least 186 different foods and drugs reportedly interact with warfarin. Clinically significant interactions have been verified for a total of 26 common drugs and foods, including 6 antibiotics and 5 cardiac drugs. Every effort should be made to keep the patient adequately anticoagulated at all times, because procoagulant factors recover first when warfarin therapy is inadequate.
Patients who have difficulty maintaining adequate anticoagulation while taking warfarin may be asked to limit their intake of foods that contain vitamin K.
Foods that have moderate to high amounts of vitamin K include Brussels sprouts, kale, green tea, asparagus, avocado, broccoli, cabbage, cauliflower, collard greens, liver, soybean oil, soybeans, certain beans, mustard greens, peas (black-eyed peas, split peas, chick peas), turnip greens, parsley, green onions, spinach, and lettuce.
Fondaparinux sodium is a synthetic anticoagulant that works by inhibiting factor Xa, a key component involved in blood clotting. It provides a highly predictable response and has a bioavailability of 100%. The drug has a rapid onset of action and a half-life of 14-16 hours, allowing for sustained antithrombotic activity over a 24-hour period. Fondaparinux sodium does not affect prothrombin time or activated partial thromboplastin time, nor does it affect platelet function or aggregation.
Thrombolysis is indicated for hemodynamically unstable patients with pulmonary embolism. Thrombolysis dramatically improves acute cor pulmonale. Thrombolytic therapy has replaced surgical embolectomy as the treatment for hemodynamically unstable patients with massive pulmonary embolism.
Fibrinolytic regimens currently in common use for pulmonary embolism include 2 forms of recombinant tPA, alteplase and reteplase, along with urokinase and streptokinase. Alteplase usually is given as a front-loaded infusion over 90 or 120 minutes. Urokinase and streptokinase usually are given as infusions over 24 hours or more. Reteplase is a new-generation thrombolytic with a longer half-life; it is given as a single bolus or as 2 boluses administered 30 minutes apart.
Of the 4 drugs, the faster-acting agents reteplase and alteplase are preferred for patients with pulmonary embolism, because the condition of patients with pulmonary embolism can deteriorate extremely rapidly.
Many comparative clinical studies have shown that administration of a 2-hour infusion of alteplase is more effective (and more rapidly effective) than urokinase or streptokinase over a 12-hour period. One prospective, randomized study comparing reteplase and alteplase found that total pulmonary resistance (along with pulmonary artery pressure and cardiac index) improved significantly after just one half hour in the reteplase group as compared with 2 hours in the alteplase group. Fibrinolytic agents do not seem to differ significantly with respect to safety or overall efficacy.
Streptokinase is least desirable of all the fibrinolytic agents because antigenic problems and other adverse reactions force the cessation of therapy in a large number of cases.
Empiric thrombolysis may be indicated in selected hemodynamically unstable patients, particularly when the clinical likelihood of pulmonary embolism is overwhelming and the patient's condition is deteriorating. The overall risk of severe complications from thrombolysis is low and the potential benefit in a deteriorating patient with pulmonary embolism is high. Empiric therapy especially is indicated when a patient is compromised so severely that he or she will not survive long enough to obtain a confirmatory study. Empiric thrombolysis should be reserved, however, for cases that truly meet these definitions, as many other clinical entities (including aortic dissection) may masquerade as pulmonary embolism, yet may not benefit from thrombolysis in any way.
Newborns may be relatively resistant to thrombolytics because of their lack of fibrinogen activity.
Reteplase is a second-generation recombinant tissue plasminogen activator (recombinant tPA) that forms plasmin after facilitating cleavage of endogenous plasminogen. In clinical trials, reteplase has been shown to be comparable to the recombinant tPA alteplase in achieving TIMI, 2 or 3 patency, at 90 minutes. Reteplase is given as a single bolus or as 2 boluses administered 30 minutes apart.
As a fibrinolytic agent, reteplase seems to work faster than its forerunner, alteplase, and may be more effective in patients with larger clot burdens. It has also been reported to be more effective than other agents in lysis of older clots. Two major differences help to explain these improvements. Because reteplase does not bind fibrin as tightly as does alteplase, this allows reteplase drug to diffuse more freely through the clot. Another advantage seems to be that reteplase does not compete with plasminogen for fibrin-binding sites, allowing plasminogen at the site of the clot to be transformed into clot-dissolving plasmin.
The FDA has not approved reteplase for administration to patients with pulmonary embolism. Studies of the drug's use for pulmonary embolism have employed the same dose approved by the FDA for coronary artery fibrinolysis.
Alteplase, a recombinant tPA, is used in the management of acute myocardial infarction (AMI), acute ischemic stroke, and pulmonary embolism. Alteplase is most often used to treat patients with pulmonary embolism in the ED. It is usually given as a front-loaded infusion over 90-120 minutes. It is FDA approved for this indication. Most ED personnel are familiar with alteplase's use, because it is widely employed in the treatment of patients with AMI. An accelerated 90-minute regimen is widely used, and most believe it is safer and more effective than the approved 2-hour infusion. An accelerated-regimen dose is based on patient weight.
Heparin therapy should be instituted or reinstituted near the end of or immediately following infusion, when the aPTT or thrombin time returns to twice normal or less.
Urokinase (Abbokinase, Kinlytic)
Urokinase is a direct plasminogen activator produced by human fetal kidney cells grown in culture. It acts on the endogenous fibrinolytic system and converts plasminogen to the enzyme plasmin, which, in turn, degrades fibrin clots, fibrinogen, and other plasma proteins. An advantage of urokinase is that it is nonantigenic; however, it is more expensive than streptokinase, which limits its use. When urokinase is used for localized fibrinolysis, it is given as a local, catheter-directed, continuous infusion directly into area of the thrombus with no loading dose. When it is used for pulmonary embolism, a loading dose is necessary.
Streptokinase acts with plasminogen to convert plasminogen to plasmin. Plasmin degrades fibrin clots, fibrinogen, and other plasma proteins. An increase in fibrinolytic activity that degrades fibrinogen levels for 24-36 hours takes place with IV infusion of streptokinase. The agent is highly antigenic, and it is highly likely that treatment will be interrupted due to allergic drug reactions.
Chills, fever, nausea, and skin rashes are frequent (up to 20%). Blood pressure and heart rate drop in approximately 10% of cases during or shortly after treatment.
Late complications may include purpura, respiratory distress syndrome, serum sickness, Guillain-Barré syndrome, vasculitis, and renal or hepatic dysfunction.
Direct Thrombin Inhibitors and Factor Xa Inhibitors
Factor Xa inhibitors inhibit platelet activation by selectively blocking the active site of factor Xa without requiring a cofactor (eg, antithrombin III) for activity. Direct thrombin inhibitors prevents thrombus development through direct, competitive inhibition of thrombin, thus blocking the conversion of fibrinogen to fibrin during the coagulation cascade.
Indicated for treatment of PE and for prevention of recurrence (following initial 6 months of treatment).
Indicated for treatment of PE and for prevention of recurrence (following initial 6 months of treatment).
Dabigatran is indicated for treatment of DVT and PE in patients who have been treated with a parenteral anticoagulant for 5-10 days. It is also indicated to reduce the risk of recurrence of DVT and PE in patients who have been previously treated.
Edoxaban is a factor Xa inhibitor indicated for treatment of DVT and PE in patients who have been initially treated with a parenteral anticoagulant for 5-10 days.
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