pulmonary disorders
Pulmonary Embolism (PE)
Anticoagulation in Pulmonary Embolism
Initial anticoagulation followed by maintenance anticoagulation is indicated for patients with acute pulmonary embolism to prevent further embolization as well as new clot formation. Anticoagulant therapy for acute PE should be started whenever PE is strongly suspected, as long as the risk of bleeding is deemed low. Otherwise, anticoagulation should be started as soon as the diagnosis is made. The likelihood of benefit versus harm in treating emboli in smaller, subsegmental vessels (particularly asymptomatic and incidentally discovered emboli) is currently unknown, and it is possible that for certain patients harm may outweigh benefit. Still, treatment is recommended for the vast majority of patients. The primary complication of anticoagulation therapy is bleeding, and patients should be closely observed for bleeding during hospitalization. Initial anticoagulationchoices for acute PE include Intravenous unfractionatedheparin Subcutaneous low molecular weightheparin Factor Xainhibitors (oralapixaban,edoxaban, orrivaroxaban, or subcutaneousfondaparinux) Directthrombininhibitors (argatroban,dabigatran) for patients withheparin-induced thrombocytopenia Intravenous unfractionatedheparinhas a short half-life (useful when the potential for bleeding is deemed higher than usual) and is reversible withprotamine. An initial bolus of unfractionatedheparinis given, followed by an infusion ofheparindosed by protocol to achieve an activated partial thromboplastin time (PTT) 1.5 to 2.5 times that of normal control. Therefore, unfractionatedheparinrequires ongoing hospitalization to administer. Further, the pharmacokinetics of unfractionatedheparinare relatively unpredictable, resulting in frequent periods of over-anticoagulation and under-anticoagulation and necessitating frequent dose adjustments. Some clinicians prefer this IV unfractionatedheparinregimen when thrombolytic therapy is given or contemplated or when patients are at risk of bleeding because if bleeding occurs, the short half-life means that anticoagulation is quickly reversed after the infusion is stopped. Subcutaneous low molecular weightheparinhas several advantages over unfractionatedheparinincluding Superior bioavailability Weight-based dosing results in a more predictable anticoagulation effect than does weight-based dosing of unfractionatedheparin, which allows for quicker time to therapeutic coverage Ease of administration (can be given subcutaneously once or twice a day) Decreased incidence of bleeding Potentially better outcomes The potential for patients to self-inject (thereby allowing earlier discharge from the hospital) Lower risk ofheparin-induced thrombocytopenia compared with standard, unfractionatedheparin Low molecular weight heparins that can be used includedalteparin,enoxaparin, and tinzaparin. In patients with renal insufficiency, dose reductions are needed, and subsequent verification of appropriate dosing should be done by checking serumfactor Xalevels (target: 0.5 to 1.2 IU/mL measured at 3 to 4 hours after the 4th dose). Low molecular weight heparins are generally contraindicated in patients with severe renal insufficiency (creatinine clearance < 30 mL/minute). Low molecular weight heparins are partially reversible withprotamine. Adverse effects of all heparins include Bleeding Thrombocytopenia (including Heparin-induced thrombocytopenia with the potential for thromboembolism) Urticaria Anaphylaxis (rare) Bleeding caused by over-heparinization with unfractionatedheparincan be treated with aprotamineinfusion. Over-heparinization with a low molecular weightheparincan also be treated withprotamine. Fondaparinuxis afactor Xaantagonist given subcutaneously. It can be used in acute DVT and acute PE instead ofheparinor low molecular weightheparin. Outcomes appear to be similar to those of unfractionatedheparin. Advantages include once or twice a day fixed-dose administration, no need for monitoring of the degree of anticoagulation, and lower risk of thrombocytopenia. The drug is contraindicated if creatinine clearance is < 30 mL/minute. , have the advantages of oral fixed dosing and the ability to be used as Maintenance anticoagulation with no need for laboratory monitoring of the anticoagulant effect. They also cause few adverse interactions with other drugs, although azole antifungal therapy and older HIV therapies (protease inhibitors) will increase oral Dose reductions are indicated for patients with renal insufficiency.Apixabancan be used in patients with renal insufficiency, and use is safe in patients undergoing hemodialysis. may be possible using recombinant activated factor VII ( Anticoagulation references ). The half-lives of the The safety and efficacy of these medications in patients with PE complicated by severe cardiopulmonary decompensation have not yet been studied, and parenteral drugs should be used for anticoagulation in these patients until there is significant improvement in cardiopulmonary function. Thedirectthrombininhibitordabigatranis also effective for treatment of acute DVT and PE.Dabigatranrequires overlap with a parenteral anticoagulant when used as initial therapy,Idarucizumabis effective at reversingdabigatran. Finally, in patients with suspected or proven Heparin-induced thrombocytopenia , intravenous Maintenance anticoagulationis indicated to reduce the risk of clot extension or embolization and to reduce the risk of new clot formation. Medication choices for maintenance anticoagulation include Oralvitamin Kantagonist (VKA) (warfarinin the United States) Oralfactor Xainhibitors (apixaban,rivaroxaban,edoxaban) Oral directthrombininhibitor (dabigatran) Rarely subcutaneous low molecular weightheparinor subcutaneousfondaparinux Warfarinis an effective long-term oral anticoagulant option that has been used for decades, but it is inconvenient for a number of reasons. In most patients,warfarinis started on the same day asheparin(orfondaparinux) therapy used for initial anticoagulation.Heparin(orfondaparinux) therapy should be overlapped withwarfarintherapy for a minimum of 5 daysanduntil the international normalized ratio (INR) has been within the therapeutic range (2.0 to 3.0) for at least 24 hours. The major disadvantages ofwarfarinare the need for periodic INR monitoring, with frequent dose adjustments, and drug, supplement, and food interactions. Physicians prescribingwarfarinshould be wary of such interactions; in a patient takingwarfarin, virtually any newly ingested drug or substance should be checked. Bleeding is the most common complication ofwarfarintreatment; patients>65 years and those with comorbidities (especially diabetes, recent myocardial infarction, hematocrit<30%, or creatinine>1.5 mg/dL [>133 micromol/L]) and a history of stroke or gastrointestinal bleeding seem to be at greatest risk. Bleeding can be reversed with vitamin K and, in an emergency, with fresh frozen plasma or a new concentrate formulation (prothrombin complex concentrates) containing factor II (prothrombin), factor VII,factor IX,factor X, protein C, and protein S. Vitamin K may cause flushing, local pain, and, rarely, anaphylaxis. Warfarin-induced necrosis, a devastating complication ofwarfarintherapy, is a paradoxical hypercoagulable state that can arise upon the initiation ofwarfarin.Warfarininactivates vitamin K-dependent clotting factors II, VII, IX, and X. At the same time, vitamin K-dependent proteins C and S are inactivated. This may cause a paradoxical hypercoagulable state in which microthrombi form in cutaneous and subcutaneous venules, resulting in skin necrosis. Based on these considerations and the development of more convenient oral anticoagulants,warfarinuse has been declining substantially. However, cost considerations continue to makewarfarina reasonable treatment option for some patients. In a patient takingwarfarin, virtually any new drug or supplement should be checked for potential interactions. ( Anticoagulation references , One important caveat is thatedoxabanrequires that a preceding 5 to 10 days of initialheparinor low molecular weightheparinbe given. The directthrombininhibitordabigatrancan also be used for maintenance anticoagulation therapy. As withedoxaban, 5 to 10 days of treatment with unfractionatedheparinor low molecular weightheparinis needed beforedabigatrancan be initiated. Clinically relevant bleeding is lower withdabigatranthan withwarfarin. The use ofdabigatranas maintenance therapy has the same advantages and disadvantages as the use of thefactor Xainhibitors. The need for initialheparintreatment beforeedoxabanordabigatranis given is a reflection of the way the clinical trials were conducted. ( Anticoagulation references ). in patients already treated with anticoagulation for 6 to 12 months ( Anticoagulation references ). Duration of maintenance anticoagulationfor PE is dependent on a variety of factors (eg, risk factors for PE, bleeding risk) and can range from 3 months to lifelong therapy. Clearly transient risk factors (eg, immobilization, recent surgery, trauma) require only 3 months of treatment. Patients with unprovoked PE, those with more durable risk factors for PE (eg, cancer, thrombophilic disorder), and those with recurrent PE might benefit from lifelong anticoagulation provided the bleeding risk is low or moderate. In patients with unprovoked venous thromboembolism, annual assessment of bleeding risk versus clotting risk should be done and an informed joint decision regarding continuing anticoagulation reached. Risk factors for bleedinginclude Age > 65 years Previous bleeding Thrombocytopenia Antiplatelet therapy Poor anticoagulant control Frequent falls Liver failure Alcohol overuse Recent surgery Reduced functional capacity Previous stroke Diabetes Anemia Cancer Renal failure Low risk for bleeding is defined as no risk factors for bleeding, moderate risk for bleeding is defined as one risk factor, and high risk for bleeding is defined as two or more risk factors. 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