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What to Do When Antithrombotic Therapies Go Wrong
Emerg Med 39(5):9, 2007
Anticoagulation and antiplatelet drugs have been used for more than 100 years, but they still pose a challenge to emergency physicians. Here is a guide to the pitfalls of aspirin (alone or with dipyridamole), clopidogrel, ticlopidine, glycoprotein IIb/IIIa inhibitors, warfarin, enoxaparin, dalteparin, heparin, and bivalirudin.
By Joseph Lang, MD, and Chad Dunn, MD
Dr. Lang is an assistant professor and Dr. Dunn is a resident in the department of emergency medicine at the Eastern Virginia Medical School in Norfolk. |
Using anticoagulation and antiplatelet therapy to prevent and treat thrombosis is standard practice in modern medicine. From long-established agents such as aspirin to newer medications such as enoxaparin, these medications can be lifesavers. But they can also cause life-threatening complications if not used properly (see table below). Clinicians must be able to recognize the signs and symptoms of these complications and manage any problems that arise from them.
This article discusses the mechanisms of action, contraindications, complications, and treatments for complications of drugs commonly used for anticoagulation and antiplatelet therapy. Because they constitute an article in themselves, thrombolytics will not be included in this discussion.
ASPIRIN: STILL A FIRST-LINE AGENT
Aspirin was developed in the 1890s by Felix Hoffman, and since then it has been used for a variety of ailments. Today it remains one of the first-line anticoagulation agents used in both coronary artery disease (CAD) and cerebrovascular disease. Besides its effectiveness, aspirin’s other benefits are once-daily dosing and low cost.
Aspirin irreversibly blocks the platelet enzyme cyclooxygenase, which in turn prevents the formation of thromboxane A2, the mediator that promotes platelet activation. By blocking this step, aspirin prevents platelet plug formation.
Patients for whom aspirin therapy is contraindicated are those with previous hypersensitivity reactions, severe hepatic disease, previous bleeding disorders, and major active gastrointestinal (GI) bleeding. However, most clinicians prescribe aspirin for patients with acute coronary syndrome and occult bleeding because the benefits outweigh the risks.
Complications associated with aspirin use are GI bleeding, hypersensitivity reactions, and excessive bleeding after trauma or spontaneous hemorrhaging. Like most allergic reactions, aspirin hypersensitivity reactions are managed with histamine blockers and possibly steroids or beta-adrenergic agents for bronchospasm. Aspirin can also trigger reactive airway disease in some patients.
Gastrointestinal bleeding—either minor or massive—is the major complication of aspirin therapy. The overall rate of upper GI bleeding in patients taking aspirin is 2% to 2.5%. Factors that increase the rate of upper GI bleeding are a history of upper GI bleeding and aspirin doses greater than 100 mg daily. A factor that decreases the occurrence of bleeding is the concurrent use of antisecretory agents, such as histamine-2 blockers and proton pump inhibitors (PPIs).
Patients with significant upper GI bleeding usually require hospital admission and may also need fluid or blood resuscitation, a PPI, and consultation with a gastroenterologist. If severe hemorrhage is present or the patient is experiencing an ongoing life-threatening hemorrhage such as an intracranial bleed, transfusion of 5 to 10 units of platelets may be necessary. Because the patient’s native platelets have been deactivated by the aspirin, transfusing platelets to bring the levels up by 50,000 can promote active clotting and prevent further hemorrhage (see table below).
TICLOPIDINE AND CLOPIDOGREL: OFTEN USED WITH ASPIRIN
Ticlopidine and clopidogrel are a newer class of antiplatelet drugs that are often used in conjunction with aspirin. They are in the class known as thienopyridines and work by inhibiting adenosine diphosphate (ADP)-induced platelet function. Like aspirin, the effects of both drugs are irreversible in the platelet and are constant for the life of the platelet. Because of its many complications, ticlopidine is not the first choice of most clinicians.
Both ticlopidine and clopidogrel are contraindicated in patients who have active severe bleeding and a history of hypersensitivity to these agents. Patients with renal failure and hepatic insufficiency should be monitored closely, as well as patients who are also taking warfarin.
Side effects of both drugs include pruritus, purpura, rash, and diarrhea. The incidence of major bleeding, such as intracranial hemorrhage, is equal to that of aspirin for both agents. One study showed that clopidogrel increased the risk of major bleeding to 3.7% when it was used along with aspirin, as opposed to 2.7% when aspirin was used with a placebo. In patients with severe bleeding or those who develop severe bleeding while on either medication, platelets should be transfused to raise counts by 50,000, just as with patients on aspirin. Clopidogrel should not be substituted for aspirin in patients with a history of upper GI bleeding because it raises the risk of another bleeding episode from 2% to 2.5% up to 8%.
A serious consequence of using ticlopidine—which is not seen in aspirin therapy alone—is thrombotic thrombocytopenic purpura (TTP). The manufacturer’s drug information for ticlopidine includes a black box warning about the risk of TTP with a statement that the incidence is as high as 1 in 2000 to 4000 patients. Clopidogrel’s prescribing information gives the incidence of TTP as 4 in 1,000,000 patients exposed to the drug. All patients with TTP require hospitalization and consultation with a hematologist because they may benefit from prompt plasmapheresis. A platelet transfusion may worsen TTP and is contraindicated in these patients.
Another possible reaction to ticlopidine and clopidogrel is severe neutropenia. Ticlopidine’s manufacturer notes that 0.8% of patients taking the drug develop this problem, and in one trial 4 out of 9599 patients taking clopidogrel developed severe neutropenia. Treatment recommendations include stopping the drug, consulting a hematologist, and possibly admitting the patient to the hospital, especially for concurrent infections.
Patients taking ticlopidine should have hematologic monitoring every two weeks during the first three months of therapy and then within two weeks after stopping therapy. Hematologic monitoring checks for a decrease in neutrophils below 70% of baseline, a drop in hemoglobin and platelets, and the appearance of schistocytes, which are evidence of TTP. No routine monitoring is needed for clopidogrel effects; the patient should be monitored only as clinically indicated.
ASPIRIN/DIPYRIDAMOLE: A COMBINATION DRUG
Aspirin/dipyridamole combines 25 mg of aspirin and 200 mg of extended-release dipyridamole in one tablet. Used for its antiplatelet activity, this drug relies on the additive effects of both medications. Dipyridamole inhibits adeno-sine uptake into platelets, endothelial cells, and erythrocytes, increasing cyclic 3’, 5’-adenosine monophosphate (cAMP) in the platelet and making it less responsive to platelet-activating factor, collagen, and ADP. This decreases the platelet’s activation and aggregation abilities.
Aspirin/dipyridamole is contraindicated in patients with a history of an allergic reaction to the drug or to aspirin alone and in those with renal or hepatic failure. The drug should be used cautiously in patients with CAD because dipyridamole may aggravate chest pain. The drug is a pregnancy category D medication.
Aspirin/dipyridamole’s side effects and complications are similar to aspirin’s and include GI problems and GI bleeding. In one large study, the risk of GI bleeding was 4.1% in the aspirin/dipyridamole group and 3.2% in the aspirin group, and the risk of intracranial hemorrhage was 0.6% in the aspirin/dipyridamole group and 0.4% in the aspirin group. Headache is also a frequent complaint of patients when they start taking aspirin/dipyridamole, with 39% of patients complaining of headache in one study.
If severe bleeding occurs, treatment is the same as for a patient on aspirin alone. A platelet transfusion to bring the platelet count up 50,000 is recommended because aspirin affects the native platelets in the body. Because the effects of dipyridamole last only about 15 hours, no specific reversal or treatment is necessary.
GLYCOPROTEIN IIb/IIIa INHIBITORS: RELATIVE NEWCOMERS
Glycoprotein IIb/IIIa inhibitors are relative newcomers in the antiplatelet medication group. Drugs in this class prevent the binding of fibrinogen on the IIb/IIIa receptor, which in turn inhibits platelet activation and prevents aggregation of the platelet matrix. This class contains many different drugs but only three are in regular use: abciximab, tirofiban, and eptifibatide.
These medications are contraindicated in patients with a previous hypersensitivity or bleeding disorder, severe hypertension (systolic blood pressure greater than 200 mm Hg), or severe renal insufficiency. The drugs are also contraindicated in patients on hemodialysis, patients who have had major surgery in the preceding six weeks, and those with a history of hemorrhagic cerebrovascular accident (CVA) or those with ischemic CVA in the past 30 days. Extreme caution should be used when administering these drugs to patients with a history of a platelet count below 100,000.
A major side effect of glycoprotein IIb/IIIa inhibitors is bleeding, especially at the femoral sheath site from catheterization for percutaneous coronary intervention (PCI). In general, abciximab has a major bleeding rate of 1.9% when used with standard-dose heparin compared to 1% with a placebo, and a minor bleeding rate of 7.6% when used with standard-dose heparin compared to 2.6% with a placebo. Abciximab and heparin can also cause thrombocytopenia in 2.5% to 3% of patients.
Patients given tirofiban along with heparin have a major bleeding rate of 1.4% to 2.2% compared to a rate of 0.8% to 1.6% for those on heparin alone. Thrombocytopenia occurs in patients on tirofiban and heparin at a rate of 1.5% compared to a rate of 0.6% with heparin alone. With eptifibatide, major bleeding occurred in 1.3% to 4.7% of patients compared to 0.4% to 4.5% on a placebo, and thrombocytopenia occurred in 1.2% of patients versus 0.6% on a placebo. Bleeding can also occur at GI, cerebrovascular, and peripheral sites.
Hypersensitivity to these drugs can be a problem.This is best managed with antihistamines, steroids, and epinephrine in the case of anaphylaxis. Abciximab is a monoclonal antibody and is not reversible in vivo, so if a bleeding complication occurs, the medication and any heparin that is being given should be discontinued and platelets transfused. Due to the medication that remains in the body, multiple units of platelets may be needed to correct the bleeding. Tirofiban and eptifibatide are peptides and are reversible in the platelet itself, so the only measure needed is to discontinue the medication.
WARFARIN: AN ORAL ANTICOAGULANT
Warfarin was discovered in the early 20th century after livestock ate a mold on fresh clover and died of hemorrhagic disease. It was later learned that the clover contained coumarin, an anticoagulant. First developed as a rat poison, warfarin is now the most popular oral anticoagulant on the market. It inhibits vitamin K, preventing it from reducing to its active form. Vitamin K is a cofactor in hepatic manufacturing of clotting factors II, VII, IX, and X and anticoagulant proteins C and S. This coagulation pathway is commonly referred to as the extrinsic pathway.
Warfarin does not affect clotting factors that have already been produced, so achieving an anticoagulated state may take 48 hours or more. Because the half-life of anticoagulant protein C is approximately eight hours, the body loses the effects of one of its natural anticoagulants after eight hours of warfarin administration. Protein S loses its anticoagulant effect in approximately 30 hours due to warfarin administration. The half-lives of the clotting factors last from 6 to 72 hours, so the patient is actually hypercoagulable up to 72 hours after initiation of warfarin therapy. During this time period, patients need to be covered with either heparin or a low-molecular-weight heparin (LMWH) if warfarin therapy is started.
Contraindications to the use of warfarin include previous hypersensitivity to the drug, active bleeding, pregnancy, and a history of bleeding disorders and liver failure. Warfarin is not affected by renal dysfunction and is safe to use in patients with this problem. The clinician must weigh the risks of this medication against its benefits, especially in elderly patients who may not be steady on their feet and are at high risk for falling.
Like many other medications, warfarin is metabolized by the cytochrome P450 system. Many foods and medications interact with warfarin metabolism and prolong or decrease the prothrombin time/international normalized ratio (PT/INR) (see box below).
The major risk with warfarin, of course, is bleeding. Up to 15% of patients taking warfarin will suffer a bleeding complication each year and 0.8% of these bleeding episodes will be fatal. The higher the PT/INR, the higher the risk of bleeding, especially with an INR greater than 4. Trauma patients on warfarin have an especially high risk of bleeding and need close observation as well as imaging studies such as computed tomography scans. The emergency physician should also be alert for drug interactions. Patients may be taking other medications that interact with warfarin and increase the risk of bleeding.
Skin necrosis is another complication of warfarin. This typically occurs after the first few days of therapy and is caused by capillary thrombosis in the subcutaneous (SC) fat layer of the skin. If the patient develops a skin lesion, the drug should be stopped. Heparin may be started in its place, but because heparin is given intravenously, this can present a problem if the patient requires long-term anticoagulation.
In managing warfarin’s complications, immediate coagulation must be provided and vitamin K replaced to allow the body to respond with the vitamin K-dependent pathways. The degree of reversal is determined by both the INR and the level of bleeding. If the INR is less than 5 or between 5 and 9 and no bleeding has occurred, the next dose of warfarin can be held and the INR rechecked in 24 hours. In patients at risk for bleeding, 1 to 5 mg of oral vitamin K can be administered. If the INR is greater than 9 and no active bleeding is present, the warfarin should be held, 5 to 10 mg of oral vitamin K administered, and the INR rechecked in 24 hours.
In a patient with a markedly elevated INR and a critical need for anticoagulation, such as someone with a prosthetic heart valve, administration of heparin while the INR is being corrected should be considered. Due to the timing of the replacement of the vitamin K-dependent pathways, the INR will start to fall within eight hours.
Patients with an elevated INR and active bleeding need both vitamin K and fresh frozen plasma (FFP). Vitamin K may be given orally, subcutaneously, intramuscularly, or intravenously. Giving the drug orally is as effective as the other routes and is safer. A hematoma may develop with SC and IM dosages, and IV formulations may cause anaphylaxis. However, IV formulations may work best in critically ill patients, and vitamin K can be given by slow IV infusion. For rapid reversal of INR, three to six units of FFP may be given intravenously.
Prothrombin concentrate complex (PCC) may be used in place of FFP for a more rapid reversal. If bleeding is life-threatening and the INR is under 4, 25 U/kg of PCC can be given intravenously; if the INR is 4 to 6, 35 U/kg should be administered; if the INR is over 6, 50 U/kg is the appropriate dose. It should be noted that PCC can cause thrombosis and that the drug is not available at all facilities.
ENOXAPARIN AND DALTEPARIN: AMONG THE NEWEST DRUGS
Enoxaparin and dalteparin are antithrombotic medications in the class of LMWHs. These are among the newest drugs for the prophylaxis and treatment of thrombosis and are administered subcutaneously only. Based on recent studies, enoxaparin appears about as effective as unfractionated heparin but with fewer associated complications.
Like heparin, enoxaparin and dalteparin bind to antithrombin, and the complex results in inactivation of coagulation enzymes. But while the heparin-antithrombin complex preferentially inhibits thrombin (factor IIa), the LMWH complex has its most significant inhibitory effect on factor Xa. Consequently, partial thromboplastin time is not a reliable measure of anticoagulation effects. Instead, anti-Xa levels can be measured.
Enoxaparin and dalteparin are absolutely contraindicated in patients with active major bleeding and allergies to these medications, heparin, or pork products. Also, an LMWH should not be given to patients with thrombocytopenia who have a positive in vitro test for antiplatelet antibody in the presence of such a medication. The two drugs are relatively contraindicated in pregnant women with mechanical prosthetic heart valves because not enough studies have been done. People with a history of heparin-induced thrombocytopenia may be given an LMWH with extreme caution. Although dalteparin has been shown in animal studies to cause no harm to the fetus, no well-controlled studies have been done on humans.
A rare side effect of enoxaparin and dalteparin is major hemorrhage. If this occurs, protamine should be administered, although the beneficial effects might not be as pronounced as with heparin reversal. Anaphylaxis may occur with protamine usage. Because there is no reliable reversal agent, major hemorrhage is one of the main concerns when using enoxaparin and dalteparin.
Thrombocytopenia may also occur with LMWH. If the patient’s platelet count falls below 100,000, the medication should be stopped. Although heparin-induced thrombocytopenia syndrome (HITS) with thrombosis occurs less commonly with LMWH than with heparin therapy, if it does occur, the LMWH should be stopped and the patient treated with non-heparin anticoagulants, such as argatroban, danaparoid, lepirudin, or hirudin.
As with all medications, the potential for a systemic allergic reaction exists, including pruritus, urticaria, and anaphylaxis. These reactions should be treated with histamine blockers. Steroids, beta-agonists, and epinephrine may be useful as well, depending on the clinical picture.
Other, less serious reactions include pain, erythema, hematoma, and ecchymosis at the injection site and reversible elevations of serum aminotransferases. Supportive therapy is all that is required.
The manufacturer’s drug information includes a black box warning that epidural or spinal puncture in patients receiving an LMWH increases the risk of epidural or spinal hematoma, which may result in long-term or permanent paralysis. Finally, multidose vials of LMWH should not be used in pregnant patients because the vials contain benzyl alcohol as a preservative. Benzyl alcohol crosses the placenta and is associated with “gasping syndrome” in neonates, which causes gasping respirations, hypotension, bradycardia, and cardiovascular collapse and is frequently fatal.
HEPARIN: AN OLD ANTICOAGULANT
Discovered in 1916, heparin is one of the oldest anticoagulants available. It inhibits thrombin and other factors in the intrinsic system of the clotting cascade. Although heparin also has an antiplatelet effect, it does not have an antithrombotic effect; it only prevents clot formation and expansion of an existing clot. Its half-life is 30 to 150 minutes.
Contraindications for using heparin are previous hypersensitivity, active GI tract bleeding, intracranial hemorrhage, current bacterial endocarditis, and a history of HITS. The drug should be used cautiously in patients with liver disease, those taking warfarin, and those with platelet counts below 100,000.
Bleeding is the major potential complication with heparin usage. If the bleeding is not severe and the risks of continuing the drug outweigh the benefits, the drug should be discontinued. Heparin activity will cease in less than four hours due to its short half-life. If the bleeding is life-threatening, the heparin should be discontinued and a slow infusion of protamine sulfate should be administered (1 mg for every 100 units of heparin the patient received over the previous four hours, to a maximum of 50 mg). Unfortunately, protamine also has risks, including anaphylaxis. It also has a shorter half-life than heparin, so multiple doses may be necessary.
Heparin-induced thrombocytopenia is a problem that causes platelet levels to drop, often quickly. If this occurs, the heparin should be discontinued, but a platelet transfusion should not be performed because it can lead to microangiopathic thrombosis. If the patient continues to need anticoagulation therapy, the anticoagulant hirudin may be used instead.
BIVALIRUDIN: A SYNTHETIC ANALOGUE
Bivalirudin is a synthetic analogue of reconstituted hirudin. It is used along with aspirin in patients with unstable angina who are scheduled for PCI. Bivalirudin is also used in patients who would normally undergo heparin therapy but cannot due to previous episodes of HIT.
Bivalirudin is contraindicated in patients who have major active bleeding or a previous hypersensitivity reaction to the drug. The dose should be adjusted for renal impairment. Extreme caution should be used when giving the drug to patients with a history of bleeding disorders.
Bivalirudin’s major side effect is bleeding. However, the rate of significant hemorrhage is less than that of equivalent therapy with heparin. In the REPLACE-2 (Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical Events) trial, patients were randomized to either bivalirudin plus a glycoprotein IIb/IIIa inhibitor or heparin plus a glycoprotein IIb/IIIa inhibitor and then underwent PCI. The clinical endpoints were similar in both groups; however, the risk of major hemorrhage was 2.4% in the bivalirudin group and 4.1% in the heparin group. In the Bivalirudin Angioplasty Trial, patients were randomized to bivalirudin or heparin groups and all the clinical endpoints were similar except the risk of major hemorrhage. In the bivalirudin group, the risk was 3.5%; in the heparin group, it was 9.3%.
If a patient does develop major hemorrhage while on bivalirudin, the medication should be discontinued. Bivalirudin has no antidote. It works as a direct thrombin inhibitor, and in patients with normal renal function its half-life is 25 minutes. About 25% of the drug can be cleared by hemodialysis.
COMBINATION THERAPY
Today, patients are often on several antiplatelet and anticoagulant medications at the same time. Common combinations seen in outpatient therapy are aspirin and clopidogrel and aspirin and warfarin. In the emergency department and on inpatient units, even more combinations of medications may be used. For example, a patient with acute myocardial infarction may be on aspirin, heparin, and a glycoprotein IIb/IIIa inhibitor concurrently.
Clinicians must be aware of drug interactions and realize that combination therapy increases the risk of hemorrhage. To treat a patient with multiple complications from a combination of antiplatelet and anticoagulant medications, the recommendations in this article should be followed. Each problem drug should be discontinued and each complication treated with an appropriate antidote. Once the complications resolve, the original drug can be resumed or a new one substituted.
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Suggested Reading
Bailitz J: Antithrombotic therapy and its complications. In Wolfson AB, et al. (eds): Hardwood-Nuss’ Clinical Practice of Emergency Medicine, 4th ed, Lippincott, Williams & Wilkins, 2005, p. 796.
CAPRIE Steering Committee: A randomized, blinded trial of clopidogrel versus aspirin in patients at risk of ischemic events (CAPRIE). Lancet 348(9038):1329, 1996.
De Vane PJ: Letter from Wyeth-Ayerst Pharmaceuticals to health care professionals. Food and Drug Administration (Web site), March 21, 2001. Available at www.fda.gov/medwatch/SAFETY/2001/cordarone_deardoc.pdf. Accessed February 27, 2007.
Gibler B, et al.: Practical implementation of the guidelines for unstable angina/non-ST-segment elevation myocardial infarction in the emergency department. Circulation 111(20):2699, 2005.
Lincoff AM, et al.: Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 289(7):853, 2003.
Weber J, et al.: Anticoagulants, antiplatelet agents, and fibrinolytics. In Tintinalli J, et al. (eds): Emergency Medicine: A Comprehensive Study Guide, 6th ed, McGraw-Hill, 2004, p. 1354. |
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