Chapter 138. Anticoagulants, Antiplatelet Agents, and Fibrinolytics

Antithrombotic therapy is used to treat ST elevation MI, non-ST elevation MI, unstable angina, deep venous thrombosis, pulmonary embolism, transient ischemic attack, and ischemic stroke. These agents are also used to prevent occlusive vascular events in patients at risk. Detailed management strategies and dosing regimens are provided in Chapter 18 "Acute Coronary Syndromes: Management of Acute Myocardial Infarction and Unstable Angina," Chapter 25 "Thromboembolism," and Chapter 141 "Stroke and Transient Ischemic Attack." This chapter provides an overview of antithrombotic agents.

The goals of anticoagulant therapy include (1) stop further acute thrombosis, (2) reduce the risk of embolism from a thrombus, and (3) prevent the formation of de novo thrombus in patients at risk.

Oral Agents

Warfarin is the most commonly used oral anticoagulant in the United States. It works by preferentially inhibiting vitamin K dependent cofactors in the extrinsic coagulation cascade. Dosing is guided by measuring the international normalized ratio (INR), and most patients are therapeutic in a range of 2 to 3. Patients with mechanical heart valves or antiphospholipid antibody syndrome require an INR of 2.5 to 3.5. It takes about 3 to 4 days to reach full anticoagulation upon initiating treatment. A parenteral anticoagulant should be used until the INR is maintained in the desired range for 2 days as warfarin therapy causes a transient state of thrombogenesis at the start of therapy. A number of medications, foods, or disease states interfere with warfarin absorption or metabolism and cause clinically significant consequences. Warfarin use is contraindicated during pregnancy due to teratogenicity. Complications of warfarin use include bleeding from over-anticoagulation, increased bleeding risk in patients with hypertension, anemia, prior cerebrovascular disease, GI lesions, and renal disease. Skin necrosis is associated with protein C deficiency. Figure 138-1 describes the management of warfarin-induced coagulopathy.

Dabigatran is currently the only available oral direct thrombin inhibitor in the United States. It requires no laboratory monitoring. No reversal agent is available and long-term safety has not been established. Rivaroxaban, a direct Factor Xa inhibitor, is available in Europe and Canada.

Parenteral Agents

Parenteral agents include unfractionated heparin (UFH), low molecular weight heparin (LMWH) (eg, enoxaparin, dalteparin), Xa inhibitors (fondaparinux), and direct thrombin inhibitors (eg, bivalirudin, lepirudin, argatroban). UFH and LMWH are used to treat and prevent deep vein thrombosis, as well as pulmonary embolism (PE), unstable angina, and acute myocardial infarction. Enoxaparin 1 milligram/kilogram SC every 12 hours may be used in outpatient management of DVT. Dosing regimens for UFH and LMWH are weight based. UFH requires monitoring of the activated partial thromboplastin time (aPTT). Therapeutic range is 1.5 to 2.5 "normal" value. Heparin and LMWH may be used during pregnancy. Bivalirudin and argatroban are alternatives to UFH and LMWH during percutaneous intervention (PCI) for acute coronary syndrome (ACS). The 2 major complications of heparin are bleeding and heparin induced thrombocytopenia (HIT). Use hirudin, lepirudin, or argatroban for anticoagulation in patients with HIT. LMWH carries a lower bleeding risk than UFH, but a higher bleeding risk in patients with renal disease. LMWH may also cause pruritis, local skin reaction, or rarely, skin necrosis.

Oral agents include aspirin, clopidogrel, ticlopidine, and dipyridamole. Aspirin is an irreversible cyclooxygenase inhibitor; its effects last for the life of the platelet. Nonenteric-coated aspirin (162 to 325 milligrams) should be administered in the setting of ACS, and although it is contraindicated during active GI hemorrhage, it is generally considered safe to give to closely monitored patients with guaiac positive stool. Clopidogrel and ticlopidine inhibit platelet activation by rendering the fibrinogen receptor ineffective. A loading dose of clopidrogrel 600 milligram PO results in full antiplatelet effect by 2 hours, and sustained effects for up to 48 hours. Ticlopidine is infrequently used due to risk of neutropenia and TTP. Side effects of aspirin are mainly GI and dose related. Complications of clopidogrel include dyspepsia, rash, or diarrhea. Omeprazole reduces efficacy.

Parenteral Agents

GPIIb/IIIa agents alter the common final pathway receptor in platelet aggregation. Agents used in conjunction with PCI include abciximab 0.25 milligram/kilogram IV bolus followed by 0.125 microgram/killogram/min (up to 10 micrograms) IV, eptifibatide 180 micrograms/kilogram IV bolus over 1 to 2 min followed by 2 micrograms/kilogram/min IV, or tirofiban 0.4 microgram/kilogram/min IV for 30 min followed by 0.1 microgram/kilogram/min IV. These agents should be used in consultation with the interventional cardiologist. Patients receiving GPIIb/IIIa agents are at increased risk of bleeding complications.

Fibrinolytic agents include streptokinase, anistreplase, alteplase/tPA, reteplase, and tenecteplase. Although mechanisms of action vary, each agent eventually converts plasminogen to plasmin, which breaks down the fibrin in a thrombus. Alteplase/tPA theoretically causes less systemic fibrinolysis, without the antigenic side effects of streptokinase and anistreplase that limit retreatment within 6 months and treatment within 12 months of a streptococcal infection. Strict adherence to established guidelines and informed consent is essential. Hemorrhagic complications, including intracranial hemorrhage, may occur. Streptokinase and anistreplase may cause hypotension or anaphylaxis. Contraindications to fibrinolytic therapy are listed in Table 138-1.

Emergency treatment of bleeding complications of antithrombotic therapy are listed in Table 138-2.