Anticoagulation and Antiplatelet Therapy in Emergency Medicine: An Evidence Base
December 6, 1998
Anticoagulation and Antiplatelet Therapy in Emergency Medicine: An Evidence Based, State-of-the-Art Review Part II: Unfractionated Heparin (UFH), Low Molecular Weight Heparins, and Warfarin (LMWH)
Authors: Susan B. Promes, MD, Associate Residency Director, Department of Emergency Medicine, Alameda County Medical Center-Highland Campus, Oakland, CA, Assistant Professor of Clinical Medicine, University of California, San Francisco; Tammie Quest, MD, Department of Emergency Medicine, Alameda County Medical Center-Highland Campus, Oakland, CA; Gideon Bosker, MD, FACEP, Assistant Clinical Professor, Section of Emergency Services, Yale University School of Medicine, New Haven, CT, Associate Clinical Professor, Oregon Health Sciences University.
Peer Reviewer: Stephen P. Ernest, PharmD, Clinical Pharmacy Coordinator, Columbia Terre Haute Regional Medical Center, Terre Haute, IN.
Improving outcomes in acute coronary syndromes and venous thrombotic disease are well-defined goals for emergency medicine practice. In this regard, recent advances in anticoagulation therapy have the potential to make a profound therapeutic and pharmacoeconomic impact on the acute management of arterial and veno-occlusive syndromes. Although for many years, heparin has been the "workhorse" parenteral anticoagulant for the treatment of deep venous thrombosis and pulmonary embolism (PE), as well as being one of the primary ingredient for managing acute coronary ischemic syndromes, the landscape of anticoagulant therapy has witnessed a significant therapeutic shift with the introduction of low-molecular weight heparins (LMWHs) such as enoxaparin and related agents.
On the venous side of the thromboembolic equation, the LMWHs, in particular, offer opportunities for preventing (and, it is anticipated, will also gain approval for treating) deep venous thromboembolism (DVT) with convenient subcutaneous administration and less intensive laboratory monitoring, thereby permitting out-of-hospital management of eligible patients deemed to be safe and suitable for this kind of treatment protcol.
On the arterial side of the ischemic equation, heparin, as well as LMWHs, have been extensively evaluated in patients with unstable angina (UA) and non-Q-wave myocardial infarction (NQMI). The results with at least one LMWH have been impressive, not only in reducing recurrent ischemic events in patients with UA/NQMI, but from a pharmacoeconomic perspective, decreasing the need for recurrent percutaneous vascular interventions (PTCA and CABG).
When emergency physicians consider that LWMHs are currently under intense investigation for their effectiveness as co-therapeutic agents in antiplatelet/anticoagulant cocktails for acute coronary syndromes, it is clear that this drug class will play an increasingly pivotal role in our practice environment. The clinical challenge in the area of anticoagulation therapeutics is now well-defined: Recognizing specific indications for LMWHs such as enoxaparin, analyzing differences between unfractionated heparin (UFH) and LWMHs, and evaluating opportunities for combination antiplatelet/anticoagulation therapy have become essential for maintaining high, contemporary standards of clinical practice
Unfortunately, this is an area that is evolving very rapidly, and many of the seminal studies have been published in the non-emergency medicine literature. Complicating adoption of these agents into the emergency medicine arsenal is the fact that interventional cardiologists are developing their own therapeutic paradigms, which, in some cases, emphasize antiplatelet therapy over anticoagulation protocols.
With these issues in clear focus, the purpose of Part II of this two-part series is to present a comprehensive discussion current indications, outcomes, and pharmacoeconomic implications of anticoagulants such as heparin, LMWHs, and warfarin. Implications for intervention are discussed in detail.
—The Editor
Anti-Thrombin Agents: Unfractionated Heparin
Unfractionated heparin (UFH) is an effective anticoagulant that is widely used for a number of clinical indications. Although it has become the mainstay of parenteral anticoagulation, the compelling outcome and pharmacoeconomic data associated with low molecular weight heparins (LMWHs) such as enoxaparin suggest that heparin may soon be supplanted as the anti-thrombin agent of choice in emergency medicine practice. Heparin is ineffective after oral administration, but is well absorbed following intramuscular or subcutaneous injections.
A large anionic, sulfated glycosaminoglycan molecule weighing approximately 15,000-30,000 daltons and found in mast cells, heparin is commercially available as the sodium salt prepared from either porcine intestinal mucosa or bovine lung tissue. It is heterogeneous with respect to molecular size, anticoagulant activity, and pharmacokinetic activity. Moreover, heparin non-specifically binds to proteins and has a varying dose response. Bioavailability for UFH is approximately 30%. Elimination of UFH is biphasic and contributes to its inconsistent activity; there is a rapid hepatic phase followed by a slower renal clearance phase.
That the anticoagulant activity of heparin is heterogeneous can be explained by the following: 1) only one-third of the heparin molecule binds with antithrombin III; 2) the anticoagulant profile is influenced by the chain length of the heparin molecules; and 3) the molecular weight of heparin influences its clearance (i.e., higher molecular weight species are cleared more rapidly than those with lower molecular weight).1 In the United States, the potency of heparin is standardized according to its ability to prevent clotting in sheep plasma, and is expressed as USP Heparin Units. In other countries, International Units (IU) may be used. These units are not equivalent.
Mechanism and Dosing. Heparin markedly accelerates the rate at which antithrombin III (heparin cofactor) neutralizes thrombin and activated coagulation factor X (Xa). In the presence of heparin, this reaction is accomplished almost instantaneously. Heparin binds to antithrombin III, causing a conformational change in the molecule that promotes its interaction with thrombin and Xa. In the presence of heparin, antithrombin III also neutralizes activated coagulation factors in the intrinsic pathway (i.e., factors IX, XI, XII, and plasmin).2 (See Figure 1.) Patients with antithrombin III deficiency are resistant to heparin. In these patients, antithrombin III concentrate or fresh frozen plasma should be administered to replenish this factor, and then heparin therapy can be initiated.
With low-dose heparin therapy, anticoagulation appears to result from neutralization of activated factor X (Xa), which prevents the conversion of prothrombin to thrombin. Low doses of heparin (5000 units every 8-12 h SQ) have very little effect on thrombin and exert measurable antithrombogenic effects only if thrombin formation has not already occurred. In contrast, with full-dose heparin therapy, anticoagulation appears to result primarily from neutralization of thrombin, which prevents the conversion of fibrinogen to fibrin. Full-dose heparin therapy also prevents the formation of a stable fibrin clot by inhibiting activation of fibrin stabilizing factor.3
Low-dose heparin therapy is frequently used for prophylaxis of DVT and PE in patients who are immobilized for long periods of time. The dose is typically 5000 units subcutaneously every 8-12 hours. The low-dose heparin regimen, however, is usually not started for conditions managed in the emergency department (ED) setting.
The precise and optimal dose for "high-dose heparin therapy" is, to some degree, still a matter of debate. Typically, patients who require full anticoagulation with heparin are given an intravenous bolus injection of 5000-7500 units, followed by a continuous drip at a rate of 1000-2000 units per hour (standard care heparin). In some instances, bolus SQ or IM injections have been used; however, this method is not recommended due to erratic absorption.
The goal of anticoagulation therapy with heparin is to achieve as rapidly as possible a therapeutic activated partial thromboplastin time (APTT) of at least 1.5 times control, while minimizing side effects. To reduce the risk of bleeding complications, there is increasing support for the use of weight-adjusted heparin dosing nomograms in clinical practice. The time required to reach the therapeutic threshold decreases with this approach, and the percentage of patients reaching this threshold increases when a patient specific titration strategy is utilized.4-6
A randomized, clinical trial comparing standard vs. weight-based dosing regimens of heparin in patients with either UA or arterial or venous thromboembolism found that patients who received weight-based heparin as compared to standard-care heparin were more likely to achieve therapeutic APTT values within 24 hours of therapy (89% vs 77%, respectively). In addition, the weight-based group had a decreased risk of recurrent thromboembolism.7 Patients on the weight-adjusted heparin regimen received a starting dose of 80 units per kilogram as an intravenous bolus and an 18 unit per kilogram per hour infusion. In general, physicians do not give sufficient amounts of heparin initially; consequently, many patients are subtherapeutic at 24 hours. A PTT should be checked six hours after heparin is started. An adequate response is 1.5-2.5 times control.6,7
Toxicity. Heparin has the potential to induce bleeding by altering blood coagulation, impairing platelet function, and increasing vascular permeability.3 Absolute contraindications to heparin include active internal bleeding, malignant hypertension, CNS neoplasm, recent and significant trauma or surgery, and a history of heparin-induced thrombocytopenia.
Thrombocytopenia develops in approximately 3% of patients on heparin, usually after 3-5 days of therapy.8 Relative contraindications to heparin use include recent GI bleed or prior hemorrhagic stroke. The drug has a narrow therapeutic window and is the number one cause of drug-related deaths in the hospital.4 Significant bleeding is found in 7-30% of patients with a complication rate of 1-2% per day. Elderly patients and individuals taking aspirin are at greatest risk. The risk of heparin-related bleeding is influenced by a number of factors: 1) the dose and the anticoagulant response; 2) the method of administration (the risk of hemorrhage is greater with intermittent IV administration than with continuous IV administration); 3) the patient’s clinical condition; and 4) the concomitant use of antiplatelet or thrombolytic agents. Rarely, patients develop hypersensitivity or anaphylactic reactions. In some patients, transient alopecia develops several months after heparin administration.
UFH is listed as pregnancy risk category C. It has not been tested in animal reproduction studies and does not cross the placenta. Despite its category designation, heparin is used as a first-line drug for serious thromboembolic disease in pregnant women when it is clearly indicated. Heparin is not excreted in human milk.
Monitoring. The emergency physician should obtain a PTT and CBC (including differential and platelet count) on all patients before starting heparin; additional studies may be required to monitor therapy. The goal PTT should be between 1.5-2.5 times control. The physician should observe for a drop in the patient’s hemoglobin, since clinically significant bleeding is the most common side effect of heparin therapy. The platelet count must also be monitored because heparin currently is the most common cause of drug-related thrombocytopenia in hospitalized patients. If severe thrombocytopenia develops (platelets < 100,00/microliter), heparin should be discontinued and other measures for managing thrombosis- or ischemia-related conditions should be considered.
Thrombocytopenia associated with heparin therapy may take three different forms, each of which will vary depending on severity, time of onset, and incidence. For example, an acute and reversible decline in platelets may occur immediately after an intravenous infusion.9,10 Although this response is common, it tends to be mild and rarely causes clinically significant problems. This reduction in platelets is thought to occur secondary to aggregation and sequestration of platelets through direct interaction with heparin. A second type of thrombocytopenia can develop 2-4 days after initiation of heparin therapy. Typically, this also is a mild form and platelets do not drop below 100,000/microliter. This form of thrombocytopenia resolves spontaneously within five days without heparin discontinuation. The last type of thrombocytopenia is the most serious and occurs in less than 5% of patients. Platelet counts drop below 100,000/microliter but will return to normal if heparin is discontinued.
If a patient on heparin therapy begins to bleed, the physician should stop the heparin and transfuse the patient appropriately. Protamine sulfate can be used to reverse the effect of heparin, but this reversal strategy is not without side effects. Hypotension can occur when protamine is given rapidly, and anaphylactic reactions also have been described. Anaphylaxis most commonly occurs after repeated exposure or when the drug is given to patients who are allergic to fish, since protamine sulfate is obtained from fish in the salmon family. The dose of protamine required for reversal is based on the amount of heparin that has been administered and the amount of time that has elapsed since the last heparin dose. As rule, 1.0-1.5 mg of protamine sulfate should be administered for each 100 units of heparin that is being reversed and it should be adminstered slowly (i.e., no more than 50 mg should be given in a 10-minute period). For patients allergic to protamine sulfate, one can consider the use of desmopressin. Desmopressin can reverse the increase in bleeding time, but it is unclear if this agent can control hemorrhage.11
Indications: Venous Thrombosis and Pulmonary Embolism. There is substantial evidence that heparin prophylaxis reduces the rate of venous thromboembolism after major surgery, as well as in certain high-risk medical patients.12-15 According to the package insert, when used for this indication, the dose is 5000 units via deep subcutaneous injection every 8-12 hours. It is generally accepted that intravenous unfractionated heparin is required to establish rapid hypocoagulability in patients with a confirmed proximal venous thrombosis or PE.16,17 When administered subcutaneously, unfractionated heparin does not prolong the PTT enough to be therapeutic until 12 hours after administration.18 Therefore, this route of administration is not recommended for ED treatment. Achieving a PTT of 1.5-2.5 times control is the therapeutic goal. Patients will need to be anticoagulated (with an oral agent following heparin administration) for at least three months following DVT.
Because it is neither feasible nor desirable to maintain patients on IV heparin for an extended period of time, oral therapy with warfarin should be given concomitantly with heparin on hospital day 1. Other schedules have been described, but starting warfarin on hospital day 1 rather than later is safe and effective and decreases length of stay. UFH should be continued for 4-5 days until the desired effects of warfarin have been achieved (i.e., prothrombin time[PT] is prolonged to 1.3-1.5 times control, which is equivalent to an international normalized ratio [INR] of 2.0-3.0). Once warfarin has produced its desired effect, the heparin infusion can be discontinued. Patients with recurrent venous thromboembolism should be anticoagulated indefinitely. When a patient is hemodynamically unstable from a massive pulmonary embolism, treatment with both a thrombolytic agent and heparin is indicated.19
Acute Coronary Syndromes. The American Heart Association guidelines recommend the use of IV heparin for 48 hours along with aspirin for the treatment of UA in patients with intermediate or high risk for short-term complications of death and nonfatal MI.20 This recommendation is based on few studies.21-24 While the literature on the benefits of aspirin is strong, the existing trials on addition of heparin are not as conclusive as the above guidelines may suggest. Recent studies (Efficacy and Safety of Subcutaneous Enoxaparin [ESSENCE] Trial) comparing the efficacy of the LMWH enoxaparin to UFH suggest that enoxaparin should supplant heparin as the agent of choice in eligible patients with UA or NQMI. (See enoxaparin section for a detailed discussion.)25-27
The efficacy of heparin combined with non-selective thrombolytic agents (i.e., streptokinase) has been equivocal, at best. In angiographic studies, heparin has been shown to increase vessel patency when a selective thrombolytic agent (TPA) was used, but its effects have not been clinically overwhelming.28,29 Currently, heparin is recommended in patients receiving the selective thrombolytics agents ateplase and retevase.30 The goal APTT range is 50 to 70 seconds.31 Heparin should be administered in the ED to patients who will be undergoing a percutaneous coronary intervention upon leaving the ED.
Ischemic Stroke. Although trials are ongoing, the efficacy of heparin in acute ischemic stroke is not well established, and, at the present time, heparin cannot be recommended for routine use in patients with new, completed stroke. If the use of intravenous UFH is contemplated, it should be considered only after consultation with the neurologist and primary provider who will be managing the patient in the hospital. A non-contrast CT scan always should be performed prior to beginning therapy, and the CT scan should be read by a radiologist to identify possible hemorrhage. The recent literature recommends consideration of heparin therapy for a very select group of stroke patients: 1) those with minor stokes and no evidence of hemorrhage; 2) those with evolving clinical signs without evidence of hemorrhage on CT; 3) those whose stroke is caused by a large vessel thrombosis and who have no evidence of hemorrhage; and 4) patients who have a cardioembolic etiology for their stroke. In all cases, risk factors for possible conversion of a thrombotic to a hemorrhagic stroke should be considered in the clinical equation, including: the age of the patient, previous history of cerebral hemorrhage, hypertension, and other underlying factors.
Atrial Fibrillation. Atrial fibrillation (AF) is a major risk factor for systemic and cerebral embolism. It is believed that thrombotic events occur when a thrombus in the dilated left ventricle is dislodged in response to a change in cardiac rhythm. Consequently, patients with risk factors for thromboembolism who present with AF should be anticoagulated, assuming there are no contraindications.The most rapid way to achieve that end point is to begin heparin and then transition the patient to warfarin for long-term anticoagulant therapy. Although the long-term use of anticoagulants may increase the chance of hemorrhage, in high-risk subgroups of patients with AF, the benefits of reduced incidence of stroke and systemic emboli with warfarin exceed the risk of catastrophic bleeding, if anticoagulant therapy is appropriately monitored.32-34
Low Molecular Weight Heparin (LMWH): Enoxaparin, Ardeparin, and Dalteparin
Low molecular weight heparin (LMWH) is produced by partial chemical or enzymatic depolymerization of unfractionated heparin. The end-product is a heparin, which has a molecular weight varying from approximately 3000 daltons to about 9000 daltons, in marked contrast to UFH, which weighs considerably more. The decreased molecular weight accounts for the benefits of LMWH over UFH.
Although LMWHs have been used in Europe for more than 10 years, there are currently three LMWHs approved for use in the United States. They include ardeparin (Normiflo®), dalteparin (Fragmin®), and enoxaparin (Lovenox®). Each of these has unique properties based on their molecular weight; it should be stressed that no two LMWHs are alike.1,35,36 These LMWHs became available for use in the United States as early as 1993, when enoxaparin was approved by FDA. Dalteparin was approved by FDA in 1994. Both are indicated for use in the prophylaxis of DVT in patients undergoing surgical procedures, and well-designed trials are also available demonstrating efficacy of LMWHs such as enoxaparin for the treatment of DVT.
Mechanism and Dosing. Like UFH, LMWH exerts its anticoagulant activity by binding to antithrombin III (ATIII), which enhances its therapeutic effect. The heparin-ATIII complex then binds to and inactivates activated factor X (Xa) and factor II (thrombin). LMWH differs from UFH in that it exerts less of an inhibitory effect on thrombin and a greater inhibitory effect against Xa. LMWH has a higher anti-Xa:Anti-thrombin ratio than does UFH. The inactivation of factor Xa and thrombin inhibits the conversion of fibrinogen to fibrin. This inhibition blocks the final step in the coagulation cascade. (See Figure 1.)
Each of the LMWHs is administered by the subcutaneous route only. Therapeutic levels are obtained within 30 minutes after administration and last for about 24 hours. LMWH produces consistent and accurate anticoagulation when given according to a weight-based regimen. Care should be used in renal failure patients because the effect of the drug may be prolonged. Each of the LMWHs have a bioavailability of approximately 90%. (See Table 1.)
| Table 1. Comparison of UFH and LMWH | ||
| Effect | UFH | LMWH |
| Mean molecular weight | 15,000-30,000 daltons | 3000-9000 daltons |
| Anti-Xa:Anti-thrombin ratio | 1:1 | 2-4:1 |
| Protein binding | Significant | Minimal |
| Thrombocytopenia | Not rare | Rare |
| Bioavailability | Approx. 30% | Approx. 90% |
| Route of administration | SQ, IV, and IM | SQ |
| ___________________________________________________________ | ||
Although each of the LMWHs is FDA-approved for prophylaxis of DVT, only enoxaparin is approved for the prevention of ischemic complications of UA and non-Q-wave MI when given with aspirin. In addition, enoxaparin is expected to soon gain FDA approval for the treatment of acute DVT and PE.
Since emergency physicians rarely begin DVT prophylaxis, the dosing regimens for all three agents will not be discussed. However, because enoxaparin carries or is anticipated to carry multiple indications that can be managed in the ED, its full dosing pattern is presented. Recommended doses for enoxaparin, based on the package insert, are as follows: DVT prophylaxis for a patient receiving surgery, 30 mg SQ every 12 hours or 40 mg SQ once a day depending on the type of surgery; and UA and NQMI, 1 mg/kg actual body weight SQ every 12 hours given concurrently with aspirin 100-325 mg. The anticipated dosage-related labeling for inpatient treatment of DVT, with or without PE, is 1 mg/kg SQ every 12 hours, or 1.5mg/kg SQ once a day. And, for outpatient treatment of DVT without PE it is 1mg/kg every 12 hours.37,38 It should be stressed that each LMWH has its own dosing profile, and that one drug cannot be substituted for another.36,37, 39-42
Toxicity. The toxicity profile of LMWH is similar to UFH.43,44 Just as with UFH, LMWH should not be used in patients with a known bleeding disorder, thrombocytopenia, or known hypersensitivity to heparin. LMWH can cause thrombocytopenia but this does not occur as often as it does with standard heparin. LMWH should not be administered to patients who have had a recent lumbar puncture or spinal anesthesia. There have been case reports of spinal hematomas and paralysis following the use of LMWH. If an overdose of LMWH occurs, protamine sulfate can be used to neutralize the heparin. LMWH has a pregnancy Category B rating, and it is unclear whether metabolites are excreted in breast milk.
Monitoring. In general, there is no need to order coagulation tests on patients receiving LMWH, inasmuch as these tests will be normal. Anti-Factor Xa levels can be ordered but are not readily available and are very costly. Periodic CBC and stool guaiac tests are indicated to monitor for possible bleeding complications.
Thromboembolic Prophylaxis and Treatment With Low Molecular Weight Heparin: Outcome- and Cost-Effective Management in the Outpatient and In-Hospital Setting. From a clinical, outcome-effectiveness perspective, the availability of LMWHs provides a unique opportunity to manage thromboembolic conditions on an outpatient, in-home basis while reducing monitoring and human resource costs associated with in-hospital prophylaxis of DVT. Emergency physicians must become familiar with the LMWHs inasmuch as they will soon be prescribing such agents (which are presently awaiting imminent FDA approval for treatment of DVT), as well as arranging for outpatient treatment plans, for selected patients with DVT.
Although LMWHs such as enoxaparin represent an important advance in out-of-hospital management of venous thromboembolic disease, these pharmacotherapeutic strategies are only part of a larger movement to reduce total outcome costs. Similar home-based treatment and prophylaxis strategies for a wide variety of illnesses—from infections to malignancy—will become, in the near future, more firmly established in a healthcare environment that puts a premium on effective therapy implemented in a cost-optimizing manner.
With respect to LMWHs, perhaps the greatest clinical experience available, as well as the most studies, for agents approved for use in the United States, has been accumulated with enoxaparin sodium (Lovenox®). Enoxaparin is indicated for the prevention of DVT, which may predispose to the development of PE. Currently, the principle use of this medication is for patients who are undergoing hip replacement and other orthopedic surgical procedures involving the lower extremities. Prophylaxis with enoxaparin is provided during and following hospitalization. Other candidates suitable for enoxaparin therapy include individuals undergoing knee replacement surgery, as well patients who have had abdominal surgery and are at risk for thromboembolic complications.
From a patient selection perspective, those at risk for thromboembolic complications include patients who are older than 40 years, obese, undergoing surgery under general anesthesia lasting longer than 30 minutes, or who have additional risk factors, such as malignancy or a history of DVT or PE. Enoxaparin also is indicated for the prevention of ischemic complications of UA and NQMI, when concurrently administered with aspirin.
Deep Venous Thrombosis and Pulmonary Embolism. Ardeparin, dalteparin, and enoxaparin are all indicated for the prevention of DVT in patients undergoing surgery. There are also multiple, randomized studies comparing LMWH with the current standard of care, UFH, for the initial management of DVT.45-48 Study end points typically include venographic improvement, symptomatic recurrence of DVT with objective confirmation, or bleeding during treatment with heparin. In addition, in most studies, warfarin is usually started on the first day of treatment. In general, the studies found LMWH to be at least as safe and effective as UFH. There are two meta-analyses that found the risk of DVT recurrence, clinically significant bleeding, and mortality to favor LMWH for this indication.43,49 In one study, the relative risk of bleeding was reduced by 66% during the initial two weeks of therapy.49
As suggested, the use of LMWH antithrombotic agents for management of documented DVT presents unique cost and efficacy advantages that are of special importance to emergency physicians managing patients with DVT. DVT is a recognized clinical problem in Western countries, with an estimated annual incidence of 1 per 1,000 inhabitants.47 The morbidity and mortality of DVT is likely to grow as the population ages and requires surgical procedures (hip and knee replacements) and hospitalizations that predispose to DVT. The current DVT rate implies that each year approximately 250,000 Americans need to be hospitalized for 5-10 days of intravenous heparin therapy.47 The standard treatment for DVT is the constant infusion of heparin, with the goal of maintaining the APTT within a desired therapeutic range. Warfarin is initiated concomitantly with the regimen and maintained as the sole anticoagulant once an INR of 2-3 is achieved. This therapy is continued for three months or longer, depending on the underlying etiology of the thrombotic event. Recently, LMWHs have been rigorously studied as new pharmacologic modalities for treating DVT. The evaluation of LMWH in the management of thromboembolic disease has been primarily directed toward the degree of venographically proven clot reduction and/or the confirmation of symptomatic recurrent thrombosis. In one study, investigators compared enoxaparin at 1 mg/kg, subcutaneously, every 12 hours, with standard heparin adjusted for a therapeutic APTT of 1.5-2.5 of baseline. Bilateral lower-extremity venography was performed in all patients upon entry and repeated on day 10 of the protocol. The size of the thrombus was assessed qualitatively and quantitatively to demonstrate therapeutic efficacy. Perfusion lung scanning was performed in all patients within 48 hours of study entry and repeated if symptoms or signs of PE developed. Repeat venography revealed that one (1.5%) of 67 patients receiving enoxaparin had extension of the initial DVT compared with five (7.5%) of 67 patients who received standard heparin. None of the patients in the enoxaparin-treated group had PE, compared with two patients in the standard heparin group. There were no major bleeding problems in either of the two groups.50,51
Other studies, as well as two recent meta-analyses of randomized trials comparing LMWH agents with heparin, concluded that LMWHs administered subcutaneously in fixed doses adjusted for body weight and without laboratory monitoring were more effective and safer than standard heparin infusion in the management of acute DVT.39-42,48,51-62
From an emergency medicine perspective, one of the primary objectives, with respect to LMWH, is establishing the effectiveness, safety, and user-friendliness of this drug for managing DVT in the outpatient setting. To assess this issue, in one study, 500 patients with acute proximal DVT were randomized in an open-label study to either enoxaparin, 1 mg/kg SQ every 12 hours, or a constant infusion of standard heparin. The patients were categorized into three groups: 1) outpatients who were not admitted; 2) patients who had DVT admitted at night or on weekends, and who, for logistic reasons, could not be enrolled in this study immediately; and 3) patients who were hospitalized for other reasons, such as surgery, and in whom DVT was diagnosed subsequently. Of the 247 enoxaparin-treated patients, 149 were outpatients, 76 were hospitalized for 48 hours, and 22 were treated in the hospital. All 253 standard heparin patients except for two were managed in the hospital.50
The principle outcomes of this study were symptomatic recurrence of venous thromboembolism and bleeding during the period of administration of the study medications or within 48 hours after the completion of therapy. Symptomatic recurrent thromboembolism occurred in 13 (5.3%) of 247 enoxaparin-treated patients and 17 (6.7%) of 253 standard heparin-treated patients. A breakdown of the recurrent events revealed DVT in 11 (4.4%) of 247 patients in the enoxaparin group and 15 (5.9%) of 253 patients in the standard heparin group. Two patients in the standard heparin group had fatal PE on the day of randomization and on day 6 of the protocol, respectively. Major bleeding complications occurred during the first seven days of the study in five (2%) of the patients treated with enoxaparin and three (1.1%) of the patients managed with standard heparin. Two episodes of bleeding in the enoxaparin group were fatal; one patient had a subdural hematoma after a fall and the other had associated thrombocytopenia due to chemotherapy and radiation, and bled from an esophageal cancer.59-61
Based on results of these studies, LMWHs have been shown to be safe and effective in preventing recurrent thrombotic events when compared with the more precise heparin dosing schedules. Moreover, studies evaluating home treatment of DVT suggest that LMWHs administered subcutaneously, without laboratory monitoring, in a dose determined by body weight, will likely shift the management of DVT from the inpatient setting to the home environment. As these agents await approval for out-of-hospital management of venous thrombosis, a number of institutions have developed inclusionary and exclusionary protocols for patient assignment to LMWH treatment protocols.53-64 An approach developed by the Jefferson Hospital (Philadelphia) Antithrombotic Therapy Service presents a risk-averse algorithm for identifying patients who are suitable for this treatment pathway. (See Table 2.)
| Table 2. Proposed Inclusionary and Exclusionary Criteria for Outpatient Management of DVT | |
| Inclusion Criteria | |
| 1. Positive diagnosis of DVT by Doppler Ultrasound or venography | oYes oNo |
| Exclusion Criteria | |
| 1. Unable to provide informed consent | oYes oNo |
| 2. Geographic inaccessibility | oYes oNo |
| 3. Potential for medication noncompliance | oYes oNo |
| 4. Unable to support cost of drug | oYes oNo |
| 5. Pregnancy | oYes oNo |
| 6. Hereditary or acquired thrombotic disorders | oYes oNo |
| 7. Hereditary bleeding disorders | oYes oNo |
| 8. Active bleeding (PUD < 6 wk, GI, GU) | oYes oNo |
| 9. Concomitant medical problems (Acute CHF, estimated
creatinine clearance
< 30 &L/min increased LFTs) |
oYes oNo |
| 10. Hypoxia, Tachypnea | oYes oNo |
| 11. Suspected pulmonary embolism | oYes oNo |
| __________________________________________________________________ | |
Outcome Analysis and Implementation Strategies. The emergence of LMWH as an outpatient treatment alternative in appropriate subgroups of patients with DVT has important implications for emergency practice. Among the potential pharmacoeconomic advantages of this approach would be fewer hospital admissions, increased patient comfort, and decreased overall costs. A disadvantage is that patients would have to be carefully evaluated to identify those who would be more safely treated in the hospital. In addition, much of the responsibility for treatment would be shifted from medical personnel to the patient and family, requiring self-administration of anticoagulants, self-monitoring for safety and efficacy, and compliance with clinic appointments for dosage adjustments of oral anticoagulants. (See Table 3.)
| Table 3. Total Outcome Cost Comparison of DVT *Treatments Between Hospital and Home Settings | |
| Hospital Treatment | Home-Based Treatment |
| Preparation of IV solution | Preparation of LMWH syringes |
| Maintaining IV access | Patient education on self-administration and monitoring of LMWH therapy |
| Infusion-pump use | Patient education on self-administration and monitoring of LMWH therapy |
| Laboratory monitoring of APTT (time and materials) | Patient education on self-administration and monitoring of LMWH therapy |
| Nurse of physician time for UFH dosage adjustment | Periodic telephone calls from (or clinic visits with) treatment team |
| Hospital room charges | Visiting-nurse services |
| Education of patient on use and monitoring of warfarin (time and materials) | Education of patient on use and monitoring of warfarin (time and materials) |
| Monitoring of PT and INR (blood sampling, evaluation, and dosage adjustment) | Monitoring of Patient and INR (blood sampling, evaluation, and dosage adjustment) |
| Treatment of bleeding or thrombotic complications | Treatment of bleeding or thrombotic complications |
|
* DVT = deep vein thrombosis, LMWH = low-molecular-weight heparin, APTT = activated partial thromboplastin time, UFH = unfractionated heparin, PT = prothrombin time, INR = International Normalized Ratio. |
|
From a cost outcome perspective, the advantage of LMWHs are clear. Because of the lack of effect of LMWHs on thrombin, as well as the improved bioavailability, there is little interpatient or intrapatient variability in response to a given dose. Thus, LMWHs can be given in a dose specific for body weight, without laboratory testing and dosage adjustment customary for UFH. In addition, LMWHs are all effective on a once-daily or twice-daily schedule of subcutaneous injection.59-62,65
LMWH is sure to revolutionize the treatment for DVT. Two open label studies have been performed comparing outpatient LMWH to inpatient UFH.66,67 Neither study found a difference in recurrence rates or bleeding, but the LMWH groups had a much shorter hospital stay. These investigators also looked at outpatient treatment of thromboembolism with LMWH and found equal outcomes for inpatients and outpatients. Naturally, care must be taken to identify the proper patient for this therapy. Exclusion criteria in the above studies were broad: prior DVT, suspected PE, use of anticoagulants in the past 24 hours, life expectancy less than six months, potential for non-compliance, and geographic inaccessibility.
In order for outpatient treatment to be successful, a well thought out home care program must be in place. Patients must be carefully screened for inclusion in the treatment program. In addition, patients must be educated about administration of LMWH (enoxaparin) and/or arrangements made for a visiting nurse to go to the patient’s home and administer the drug. Finally, close follow-up must be guaranteed. It is not clear how long a patient should be on home therapy. Currently, the goal is to get the patient to a point when they are therapeutic on warfarin (INR 2.0-3.0) and then discontinue the use of LMWH.
Initial studies of LMWH for acute PE are also promising.37,38,68,69 The Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events (THESE) study group performed a multicenter, open label, randomized trial comparing UFH with once daily dosing of the LMWH, tinzaparin, in patients with acute PE. All patients were also started on warfarin early in their course. The two treatment options were equally efficacious and safe when the end points of recurrent thromboembolism, hemorrhage, and death were evaluated. A landmark study evaluating the efficacy of enoxaparin for DVT and PE has demonstrated that this LMWH is as efficacious and safe as UFH.37,38
LMWHs: Issues in Home-Based Treatment of DVT. As discussed, paradigm shifts in medication usage should be undertaken conservatively until more experience is gained with LMWHs. Initial treatment of DVT at home should follow a protocol in which all aspects of the treatment are clearly defined. This treatment protocol should be written in advance by a team of medical professionals experienced in the treatment of DVT. The protocol should include criteria for patient selection, drug selection, patient and caregiver education, monitoring, and LMWH dose preparation. Each medical facility choosing to begin treating patients with DVT at home will need to develop a protocol that fits its own practice patterns.
In particular, criteria must be developed to identify patients who qualify for home-based treatment of DVT. Most studies evaluating LMWH for outpatient therapy have excluded patients with a high risk of bleeding (malignant hypertension, peptic ulcer disease, recent surgery, known bleeding disorders, thrombocytopenia, high risk of falling), a high risk of recurrent thrombosis (previous CVT, pregnancy), and suspected PE. In addition, patients who resided a long distance from follow-up medical care, who were unable to care for themselves or did not have a competent caregiver in residence, and who were simply too ill to stay at home were not considered candidates for home-based treatment of DVT. Patients had to be willing to participate in their care, including self-administration of medications and follow-up for warfarin dosage adjustment when necessary. With these strict guidelines for patient selection, about 22-58% of patients who were screened in various studies were considered eligible for home-based treatment of DVT with a LMWH such as enoxaparin.55,58
Detailed instructions must be provided by the emergency medicine team. The patient or caregiver must be taught to administer the medication, monitor for adverse reactions and efficacy, and perform any other self-care deemed necessary (such as bed rest, leg elevation, and use of compression stockings). The patient or caregiver must know what steps to take in the event of a complication. Instruction should begin immediately after diagnosis and can be provided by a nurse, a pharmacist, or both. Written instructions should also be provided.
Monitoring in home-based treatment of DVT with LMWHs should include compliance, subcutaneous injection technique, local adverse effects from the injections, signs of bleeding, signs of recurrent thrombosis, and initiation and monitoring of warfarin therapy. Much of this monitoring can be done by the visiting nurse, who should see the patient daily during the initial treatment period of 5-9 days. It may also be useful for a nurse, a pharmacist, or a physician from the treatment team to telephone the patient or caregiver periodically to ensure that treatment is going as planned and that there are no complications. For patients selected to undergo home-based treatment with enoxaparin, the LMWH should be administered for at least five days, and warfarin can be started on the same day as the LMWH or the day after. Blood should be drawn daily to monitor the prothrombin time (PT) for the first few days; the INR should be between 2.0 and 3.0 for two consecutive days before the LMWH is stopped.
Acute Coronary Syndromes. LMWH is superior to aspirin alone in patients with UA.70,71 LMWH has also been compared to UFH in various trials.71-73 Most of the results are promising. The FRIC study, however, which looked at dalteparin in comparison to UFH, found no difference in efficacy between the two agents.73
Currently, there is compelling evidence from rigorous, well-designed, comparative trials suggesting that enoxaparin is an effective LMWH for acute coronary syndromes (UA and NQMI). TIMI 11A studied the best dosing regimen for enoxaparin when used for UA.74 But the most significant comparison of LMWH with UFH is the ESSENCE trial evaluating this agent in patients with non-Q-wave coronary events. This was a multicenter, randomized, double-blind study of more than 3000 patients with UA or NQMI. Groups were given aspirin and either enoxaparin 1 mg/kg SQ every 12 hours or IV UFH. Other antianginal therapy could be given at the physician’s discretion. The end points of the study were death, MI, or recurrent angina. Enoxaparin demonstrated a clinically significant 15% relative reduction in these triple end points on day 14, an effect that was sustained for 30 days.25-27
Perhaps, the most compelling evidence confirming pharmacoeconomic and clinical efficacy of enoxaparin in acute coronary syndromes was presented at the American College of Cardiology 47th Annual Scientific Session in March, 1998 in Atlanta, Georgia.26 At that meeting, the one-year follow-up data from the ESSENCE trial was reported. The investigators demonstrated that in 2915 patients of the original 3171 ESSENCE patients evaluated at one year, enoxaparin, dosed 1 mg/kg SQ q 12 hours for 2-8 days, provided superior efficacy. At one year, compared to heparin, there was a 13% reduction in the number of enoxaparin patients requiring coronary artery bypass grafting (CABG) or percutaneous coronary transluminal angioplasty (PCTA); a 15% reduction in the number of patients with death or MI; an 11% reduction in patients with death, heart attack, or recurrent angina; and a 6% reduction in the number of patients undergoing CABG, PTCA, or diagnostic catheterization.25,26 Of special note is that with only 2-8 days of initial therapy at the time of the ischemic episode, the reduction in death/MI/recurrent angina at one year (11%) was well-maintained, and was similar to the reduction (15%) observed at 30 days.
From an emergency medicine perspective, selection of enoxaparin as the preferred agent for managing coronary syndrome (UA or non-Q-wave infarction) patients may have important pharmacoeconomic implications for the institution or health plan caring for such patients. An important study examined the hospital billing data for 936 ESSENCE patients randomized to receive either enoxaparin or heparin in the United States.27 Physician fees were estimated from the Medicare Fee Schedule. During the initial hospitalization, major resource use was reduced with enoxaparin patients, with the largest effect seen with coronary angioplasty (15% vs 20% for heparin; P = 0.04). At 30 days, these cost-savings with enoxaparin persisted, with the largest reduction seen in diagnostic catheterization (57% vs 63% for heparin; P = 0.4) and coronary angioplasty (18% vs 22%; P = 0.08). The mean cost of a course of enoxaparin therapy in the United States was $155, whereas for heparin it was $80. However, the total medical costs (hospital, physician, and drug therapy) for the initial hospitalization were $11,857 for enoxaparin and $12,620 for heparin, representing a cost advantage of $763 (P = 0.18). At the end of 30 days, the cumulative cost savings associated with enoxaparin increased to $1172 (P = 0.04).27
Based on these data, enoxaparin joins the ranks of a select group of therapies that both improve clinical outcomes and reduce net treatment costs relative to older, established therapies (standard heparin) they are intended to replace. In actuality, a cost-savings analysis conducted at one-year post-enoxaparin treatment for acute coronary syndromes might reveal even greater cost-savings. Considering 1) that in the one-year ESSENCE follow-up data, enoxaparin, as compared to heparin, produced a 13% reduction in patients requiring CABG or PCTA, and 2) that CABG and PCTA are costly procedures, the evidence favoring enoxaparin as an initial therapy of choice in ED patients with acute coronary syndromes is quite compelling. It should also be stressed is that the efficacy of enoxaparin has been substantiated for patients managed both pharmacologically and non-pharmacologically (PCI), which currently places it in a favorable position as cmopared to the GP IIb/IIa inhibitors, where the supportive data is primarily in the area of acute coronary syndromes managed with PCI.
Clearly, emergency physicians must consider both the clinical outcome and pharmacoeconomic data of the ESSENCE trial when developing guidelines for initial ED treatment of UA or non-Q-wave infarction. Although unfractionated heparin has been beneficial for the past century, it is now time to change to LMWH, which has similar efficacy and safety. The cost of LMWH is for prophylaxis ranges from $140 to $245 per dose. The overall costs for treatment of acute DVT and PE are not clear. However, when approached from a cost:benefit perspective LMWH is promising. Hospital stays can be decreased, if not eliminated in certain cases, and there is no need to monitor these agents. Administration of enoxaparin is via the subcutaneous route (vs. the intravenous route for unfractionated heparin), which permits self administration and decreased nursing care. Emergency physicians can lead the way in promoting appropriate use of this safe, cost-effective treatment.
Warfarin
Warfarin (Coumadin®), a hydroxycoumarin compound, is the most widely used oral anticoagulant in North America.1 Emergency physicians encounter a significant number of patients taking warfarin, and must remain vigilant about detecting drug-related side effects, including minor and major hemorrhage. Warfarin is rapidly absorbed from the gastrointestinal tract and reaches maximal blood concentrations in 90 minutes. The drug’s circulating half-life is between one and two days.
Mechanism and Dosing. Warfarin, which, perhaps is better known to most ED physicians as Coumadin, competitively inhibits hepatic synthesis of Vitamin K-dependent coagulation factors II, VII, IX, and X. (See Figure 1.) Only the synthesis of new factors is affected. As a consequence, the anticoagulant effect is delayed until presently circulating factors have been degraded. Because the half-life of factor VII is the shortest (approximately 6 hours), anticoagulant effects may be seen as early as 8-12 hours after ingestion. The peak effect of warfarin, however, is not observed for 1-3 days because of the longer half-lives (which range from 24 to 60 hours) of the other Vitamin K-dependent factors. The duration of effect after a single dose of warfarin is 5-7 days.
Most patients requiring anticoagulation are initially started on heparin or LMWH. Administration of these agents is continued until therapeutic levels of warfarin are obtained days later. In the past, this has meant that the patients needed to be hospitalized for emergent anticoagulation, but with the emergence of LMWH as primary therapy for many ischemic and thrombotic syndromes, this will definitely change. Warfarin should be started early, preferably at the same time that treatment with heparin or LMWH is initiated. Doses greatly vary among patients, but an individual typically should be given an initial dose 10 mg po.75 Clinical and laboratory findings will help guide subsequent doses in order to obtain optimal therapeutic effects while minimizing the risk of hemorrhage.
Warfarin is strictly contraindicated in pregnancy. Fetal and neonatal hemorrhage have occurred, as have birth defects in offspring of women taking warfarin during pregnancy. Warfarin is not distributed into human milk.
Toxicity. The major complication experienced by patients taking warfarin is hemorrhage.76-78 This risk is amplified in patients with comorbid conditions. Minor bleeding episodes are common and include small bruises and bleeding gums after brushing teeth; these complications usually do not require drug cessation. Occult rectal bleeding, bleeding from hemorrhoids, microscopic hematuria, and menorrhagia will be encountered in a minority of patients. The ED physicians should thoroughly evaluate bleeding complications and check a CBC and INR. If the patient’s laboratory studies are outside the expected ranges and the patient has experienced extensive hemorrhage, anticoagulant therapy may need to be discontinued. There are a number of factors that affect a patient’s response to warfarin: 1) concomitant consumption of certain foods and drugs; 2) vitamin K deficiency; and 3) liver disease. (See Table 4.)3
| Table 4. A Partial List of Common Drugs that May Affect a Patient’s Response to Warfarin | |
| Enhanced Response | Reduced Response |
| acetaminophen | alcohol (chronic) |
| alcohol (acute intoxication) | antihistamines |
| anabolic steroids | barbiturates |
| antibiotics | corticosteroids |
| cimetidine | glututhimide |
| heparin | griseofulvin |
| ibuprofen | rifampin |
| metronidazole | spironolactone |
| salicylates | trazodone |
| thiazides | |
| tricyclics | |
| ________________________________________________________________ | |
Reversal. Vitamin K/phytonadione will correct the PT in approximately 4-6 hours. Fresh frozen plasma can be given emergently to reverse the anticoagulant effects of warfarin. If the patient’s hemoglobin/hematocrit is falling, transfusing the patient with packed red blood cells may be necessary.
Monitoring. The effect of warfarin can be monitored by obtaining a PT or INR. Both of these tests will be prolonged in a patient who is therapeutically anticoagulated on warfarin. In order to promote standardization of the PT for monitoring oral anticoagulation, the World Health Organization (WHO) developed the INR, which represents the PT ratio obtained by testing a given sample using the WHO reference thromboplastin. Generally speaking, the current recommendation is a goal INR of 2.0-3.0 for most conditions, although there are variations for specific conditions.79 In addition to ordering a PT and INR, the emergency physician may need to order a CBC to rule out bleeding in patients who present with signs or symptoms that suggest hemodynamic compromise, hemorrhage, or neurological deficits, or who are unstable for reasons that are not readily explainable.
Indications: Venous Thrombosis and Pulmonary Embolism. Warfarin is indicated for the long-term treatment of DVT and PE. If heparin is used, it should be started in the emergency department along with 10 mg of warfarin. Patients should remain on therapeutic doses of warfarin for at least three months with a first episode.80 Treatment with warfarin for more that three months is indicated in patients with recurrent venous thromboembolism or in patients in whom there are continuing risk factors for venous thromboembolism.81 Use of enoxaparin for outpatient management of DVT will likely become standard therapy. Warfarin also is used in conjunction with this agent.
Atrial Fibrillation and Valvular Heart Disease. Warfarin is also indicated in patients with mitral valve disease, high-risk patients with AF, and in patients with prosthetic mechanical valves in order to prevent thromboembolic complications such as transient ischemic attack or ischemic stroke. The goal INR for mechanical prosthetic valve is 2.5-3.5.
Acute Coronary Syndromes/Acute Myocardial Infarction. Warfarin currently has no role in the emergency treatment of acute coronary syndromes or myocardial infarction. The onset of action is not sufficiently rapid to afford clinical benefits during the acute phase of the illness.
Cerebral Embolism/Stroke. The value of anticoagulant therapy in patients with TIAs or stroke that is not due to cardioembolic disease (with or without AF) has not definitely been established, and therefore, routine use of warfarin is not recommended.
| Table 5. Dosing and Indications for Antiplatelet Agents and Anticoagulation Therapy | ||
| Drug or Drug Class* | Clinical Indications | Comments and Warnings |
| Cyclo-Oxygenase Inhibitor | ||
| Aspirin | Atrial fibrillation: 325 mg q day po
Angina: 81 mg q day po/pr Acute Myocardial Infarction: 160-325 mg q day po/pr Cerebral Ischemia: 81 mg q day po/pr |
Thrombocytopenia |
| ADP Receptor Inhibitors | ||
| Clopidogrel | Use in the case of "aspirin failures"
Coronary or Cerebral Ischemia: 75 mg q day po |
Rash
GI Upset |
| Ticlopidine | Use in the case of "aspirin failures"
Coronary or Cerebral Ischemia: 250 mg bid po |
Neutropenia
GI upset Thrombocytopenia |
| GIIB/IIA Receptor Inhibitor | ||
| Abciximab | Acute Coronary Syndromes with planned
PCI within 24 hours: 0.25 mg/kg IV bolus (10-60 minutes prior to procedure) then 0.125 mcg/kg/min IV drip for 12 hrs PCI only: 0.25 mg/kg IV bolus then 10 mcg/min IV drip for 18-24 hours or until 1 hour after PCI |
Must use with heparin.
Lasts 1-2 days. Readministration may cause hypersensitivity reaction. |
| Eptifibatide | Acute Coronary Syndrome:
180 mcg/kg IV bolus then 2 mcg/kg/min IV drip up to 72 hours PCI: 135 mcg/kg IV bolus then 0.5 mcg/kg/min IV drip for 20-24 hours |
Lasts approximately 2.5 hours |
| Tirofiban | Acute Coronary Syndrome or PCI:
0.4 mcg/kg/min IV for 30 min. then 0.1 mcg/kg/min IV |
|
| UFH | ||
| Heparin | Prophylaxis for DVT:
5,000 units q 8-12 hrs SQ Deep Venous Thrombosis, Pulmonary Embolism Unstable Angina or PCI: Bolus 5000-7500 units IV followed by IV drip 1000-2000 units per hour, titrate to therapeutic effect |
Thrombocytopenia |
| LMWH | ||
| Ardeparin | Prophylaxis for DVT (knee replacement):
50 units/kg bid SQ |
Do not use in patients who have
received an LP or spinal anesthesia. |
| Dalteparin | Prophylaxis for DVT (abdominal surgery):
2500 anti Factor Xa units qd SQ-low risk pts 5000 anti Factor Xa units qd SQ-high risk pts |
Use caution in renal or liver failure
patients. Do not use in patients who have received an LP or spinal anesthesia. |
| Enoxaparin | Prophylaxis for DVT (hip/knee replacement):
30 mg bid SQ Extended Prophylaxis for DVT (hip replacement) or general surgery: 40 mg qd SQ Unstable angina or Non-Q-wave MI: 1 mg/kg q 12 hours SQ Inpatient therapy for Deep Venous Thrombosis with or w/o Pulmonary Embolism: 1 mg/kg q 12 hours SQ or 1.5 mg/kg SQ qd Outpatient therapy of Deep Venous Thrombosis without Pulmonary Embolism: 1 mg/kg q 12 hours SQ Warfarin Atrial Fibrillation, Monitor PT/INR Deep Venous Thrombosis, or Multiple drug interactions Pulmonary Embolism: 5-10 mg po in ED then titrate dose to therapeutic effect |
Use caution in renal failure
patients and elderly. Do not use in patients who have received an LP or spinal anesthesia. |
| * It is important to remember that a complication
of all these agents is hemorrhage.
____________________________________________________________________________________ |
||
Direct Thrombin Inhibitors: Hirudin and Hirulog
Hirulog (bivalirudin), a molecule fashioned after hirudin, has been shown to have enhanced efficacy and safety over heparin in percutaneous coronary intervention (PCI).82 Unlike LMWHs, the activated partial thromboplastin time and activated clotting time appear to provide a reasonable approach for monitoring anticoagulation activity. Hirulog and and its related derivatives are the first parenteral anticoagulants introduced since the introduction of heparin in the early 1900s.
A naturally occurring anticoagulant found in leeches, Hirulog is composed of a single peptide chain of 65 amino acids with a molecular weight of about 7000 daltons. This compound is a potent thrombin-specific inhibitor that forms equimolar complexes with thrombin. Although Hirulog represents a new anticoagulant agent in the same class as heparin, in contrast to heparin, this anticoagulant does not require antithrombin III as a cofactor, it is not inactivated by anti-heparin proteins, it has no direct effect on platelets, and it may also inactivate thrombin bound to clot. Therapeutic effects must be monitored by ordering APTT levels. Recombinant technology allows for the production of r-hirudin in sufficient quantities for medicinal use.
Currently, there are a few studies that have evaluated Hirulog for prevention and treatment of thromboembolism, UA, and acute myocardial infarction.82 A large trial (CACHET: Comparison of Abciximab with Hirulog [and back-up with abciximab]) is designed to test the hypothesis of whether Hirulog, with IIb/IIIa blockade given on an ad hoc basis procedurally (PCI) will compare favorably with abciximab and low-dose, weight-adjusted heparin. Authorities who follow the field closely anticipate that Hirulog will likely gain approval for commercial use in late 1998.83 ED physicians should follow ongoing studies to determine their positioning in the context of ischemic heart disease and procedural interventions.
Summary
Antithrombotic therapy is currently the mainstay for the treatment of patients with thromboembolic diseases affecting the arterial and venous circulation. Continued research and drug development have produced new therapeutic classes that will play an integral role in emergency-based management of these classes. Among the most promising classes that will have an immediate impact are LMWHs such as enoxaparin, as well as GP IIa/IIIb inhibitors. Because the indications, risks, and protocols vary considerably among these agents, emergency physicians must keep abreast of current pharmacologic advancements.
References
1. Becker C, Ansell J. Antithrombotic therapy: An abbreviated reference for clinicians. Arch Intern Med 1995;155:149-161.
2. Olson ST, Bjork I. Regulation of thrombin activity by antithrombin and heparin. Sem Thromb Hemostasis 1984;120:373-409.
3. American Hospital Formulary Service. Drug Information 1998. Bethesda, MD: American Society of Hospital Pharmacists, 1998:1168.
4. Hull RD, Raskob GE, Rosenbloom DR, et al. Optimal therapeutic level of heparin therapy in patients with venous thrombosis. Arch Intern Med 152:1589-1595.
5. Raschke RA, Reilly BM, Guidtry JR, et al. A weight-based heparin dosing nomogram compared with a standard care nomogram. Ann Intern Med 1993;119:874-881.
6. Hirsh J, Dalen JE, Deyken D, et al. Heparin: Mechanism of action, pharmacokinetics, dosing considerations, monitoring, efficacy and safety. Chest 1992;104:337S-351S.
7. Bolan CD, Alving BM. Recurrent venous thrombosis in hypercoagulable states. Am Fam Physician 1991;44:1741.
8. Chong BH. Heparin-induced thrombocytopenia. Br J Haematol 1995;89:431-439.
9. Cola C, Ansell J. Heparin induced thrombocytopenia and arterial thrombosis: Alternative therapies. Am Heart J 1990;119:368-374.
10. Warkentin TE, Kelton JG. Heparin and platelets. Hematol Onc Clin North Am 1990;4:243-264.
11. Schulman S, Johnsson H. DDAVP and the bleeding time. Thromb Haemost 1991;65:242-244.
12. Clagett GP, Reisch JS. Prevention of venous thromboembolism in general surgery patients. Results of a meta-analysis. Ann Surg 1988;208:227.
13. Collins GA, Scrimgeour A, Yusef S, et al. Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin. N Engl J Med 1988;318:1162.
14. Dalen JE, Hirsh J. Third American College of Chest Physicians consensus on antithrombotic therapy. Chest 1992;102:391.
15. Kakkar VV, Corrigan TP, Fossard DP. Prevention of fatal postoperative pulmonary embolism by low doses of heparin: An International multicenter trial. Lancet 1975;2:45.
16. Hirsh J. Heparin. N Engl J Med 1991;324:1565-1574.
17. Wilson JR, Langman J. Heparin therapy: A randomized prospective study. Am Heart J 1979;97:155-158.
18. Hull RD, et al. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal vein thrombosis. N Engl J Med 1986;315:1109-1114.
19. Jeres-Sanchez C, Ramirez-Rivera A, de Lourdes Garcia M, et al. J Thromb Thrombolysis 1995;2:227-229.
20. Cummins RO (ed). Advanced Cardiac Life Support, Dallas, TX: American Heart Association; 1994:9-30.
21. Theroux P, Oumet H, McCans J, et al. Aspirin, heparin, or both to treat acute unstable angina. N Engl J Med 1988;319:1105-1111.
22. The RISC Group. Risk of MI deaths during treatment with aspirin and IV heparin with unstable coronary artery disease. Lancet 1990;336:827-830.
23. Theroux P, Waters D, Qui S, et al. Aspirin versus heparin to prevent myocardial infarction during the acute phase of unstable angina. Circulation 1993;88:2045-2048.
24. Loh E, Sutton, MS, Wun CC, et al. Ventricular dysfunction and the risk of stroke after myocardial infarction. N Engl J Med 1997;336:251-257.
25. ESSENCE Study (Effectiveness and Safety of Subcutaneous Enoxaparin in Non-Q Wave Coronary Events). N Engl J Med 1997;337:447-452.
26. Presentation at American College of Cardiology, 47th Annual Scientific Session, March 30, 1998. Atlanta, Georgia,
27. Mark DB, Cowper PA, Berkowitz SC, et al. Economic assessment of low-molecular weight heparin (Enoxaparin) versus unfractionated heparin in acute coronary syndrome patients: Results from the ESSENCE randomized trial. Circulation 1998;97:1702-1707.
28. GUSTO-I Investigators. Link between angiographic substudy and mortality outcomes in a large randomized trial of myocardial reperfusion: importance of early and complete infarct artery reperfusion. Circulation 1995;91:1923-1928.
29. Collins R, MacMahon S, Flather M, et al. Clinical effects of anticoagulant therapy in suspected acute myocardial infarction: Systemic overview of randomized trials. BMJ 1996;313:652-659.
30. Hsia J, Hamilton WP, Kleiman N, et al. A comparison between heparin and low dose aspirin as adjunctive therapy with TPA for acute myocardial infarction: Heparin-Aspirin Reperfusion Trial (HART) Investigators. N Engl J Med 1990;323:1433-1437.
31. Metz BK, Topol EJ. Heparin as an adjuvant to thrombolytic therapy in acute myocardial infarction. Biomed Pharmacother 1996;50:243-253.
32. Dunn M, et al. Antithrombotic therapy in atrial fibrillation. Chest 1989;95:118S-126S.
33. Ip JH, et al. Thrombosis and antithrombotic therapy in cardiovascular disease. Cardiovasc Rev Rep 1991;12:12-16.
34. Wipf JE, Lipsky BA. Atrial fibrillation: thromboembolic risk and indications for anticoagulation. Arch Intern Med 1990;150:1598-1603.
35. Fareed J, Jeske W, Hoppensteadt D, et al. Are the available low molecular weight heparin preparations the same? Semin Thrombosis Haemost 1996;22:77-91.
36. Hirsh J, Levine MN. Low molecular weight heparin. Blood 1992;79:1-17.
37. Spiro T. A multicenter clinical trail comparing once and twice daily subcutaneous enoxaparin and intravenous heparin in the treatment of acute deep venous thrombosis. Thromb Haemostasis 1997;(Sup):373-374, Abstract SC-1527.
38. Spiro TE. A multicenter clinical trial comparing once and twice-daily treatment of acute deep venous thrombosis. Blood 1997;90(10 Sup 1 pt 1):295a, Abstract 1305.
39. Lindmarker P, Holmstrom M, Granqvist S, et al. Comparison of once daily subcutaneous Fragmin with continuous intravenous unfractionated heparin in the treatment of deep venous thrombosis. Thromb Haemostat 1994;72:186-190.
40. Leizorovicz A, Simonneau G, Decousus H, et al. Comparison of efficacy and safety or low-molecular-weight heparins and unfractionated heparin in the initial treatment of deep venous thrombosis: a meta-analysis. BMJ 1994;309:299-304.
41. Lensing A, Prins M, Davidson B, et al. Treatment of deep venous thrombosis with low-molecular-weight heparins: A meta-analysis. Arch Intern Med 1995;155:601-607.
42. Levine M, Gent M, Hirsh J, et al. A comparison of low-molecular-weight heparin administered primarily at home with fractionated heparin administered in the hospital for proximal deep vein thrombosis. N Engl J Med 1996;334:677-681.
43. Lensing AW, Prins MH, Davidson BL, et al. Treatment of deep venous thrombosis with low molecular weight heparins. A meta analysis. Arch Int Med 1995;155:601-607.
44. Nurmohamed MT, Verhaeghe R, Haas S, et al. A Comparative Trial of low-molecular-weight heparin (enoxaparin) vs. standard heparin for the prophylaxis of post operative deep venous thrombosis in general surgery. Am J Surg 1995;169:567-571.
45. Weitz JI, Wood AJJ. Low molecular weight heparin. New Engl J Med 1997;337:688-698.
46. Clagett CP, Anderson Jr FA, Heit J, et al. Prevention of Venous Thromboembolism. Chest 1995;108:312S-334S.
47. Lensing A, Hirsh J, Buller H. Diagnosis of venous thrombosis, In:Colman R, Hirsh J, Marder V, Salzman E (eds). Hemostasis and Thrombosis: Basic Principles and Clinical Practice, 3rd ed. Philadelphia, PA: J.B. Lippincott, 1994:1297-1321.
48. de Valk H, Banga J, Wester W, et al. Comparing subcutaneous danaparoid with intravenous unfractionated heparin for the treatment of venous thromboembolism. Ann Intern Med 1995;123:1-9.
49. Siragusa S, Cosmi B, Piovella F, et al. Low-molecular-weight heparins and unfractionated heparin in the treatment of patients with acute venous thromboembolism: Results of a meta-analysis. Am J Med 1996;100:269-277.
50. Koopman M, Prandoni P, Piovella F, et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. N Engl J Med 1996;334:628-687.
51. Simonneau G. Subcutaneous fixed dose of enoxaparin versus intravenous adjusted dose of unfractionated heparin in the treatment of deep venous thrombosis. Thromb Haemostat 1991;65:754.
52. Meuleman D. Orgaran (Org 10172): its pharmacological profile in experimental models. Haemostasis 1992;22:58-65.
53. Pini M. Prophylaxis of venous thromboembolism: The old and the new. Haematologica 1995;80(sup 2):66-77.
54. Cziraky MJ, Spinler SA. Low-molecular-weight heparins for the treatment of deep-vein thrombosis. Clin Pharmacol 1993;12:892-899.
55. Schafer AI. Low-molecular-weight heparin--An opportunity for home treatment of venous thrombosis. N Engl J Med 1996;334:724-725. Editorial.
56. Gibaldi M, Wittkowsky AK. Contemporary use of and future roles for heparin in antithrombotic therapy. J Clin Pharmacol 1995;35:1031-1045.
57. Simonneau G, Charbonnier B, Decousus H, et al. Subcutaneous low-molecular-weight heparin compared with continuous intravenous unfractionated heparin in the treatment of proximal deep vein thrombosis. Arch Intern Med 1993;153:1541-1546.
58. Lindmarker P, Homstrom M, Granqvist S, et al. Comparison of once-daily subcutaneous Fragmin with continuous intravenous unfractionated heparin in the treatment of deep vein thrombosis. Thromb Haemost 1994;72:186-190.
59. Levine M, Gent M, Hirsh J, et al. A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med 1996;334:677-681.
60. Koopman MMW, Prandoni P, Piovella F, et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. N Engl J Med 1996;334:682-687.
61. Leizorovicz A, Simonneau G, Decousus H, et al. Comparison of efficacy and safety of low molecular weight heparins and unfractionated heparin in initial treatment of deep venous thrombosis: A meta-analysis. BMJ 1994;309:299-304.
62. Lensing AWA, Prins MH, Davidson BL, et al. Treatment of deep venous thrombosis with low-molecular-weight heparins. Arch Intern Med 1995;155:601-607.
63. Wittkowsky AK. Thrombosis. In: Young LY, Koda-Kimble MA, eds. Applied therapeutics: The clinical use of drugs. 6th ed. Vancouver, WA; 1995;12.1-12.25.
64. Creager MA, Dzau VJ. Vascular diseases of the extremities. In: Isselbacher KJ, Braunwald E, Wilson JD, eds. Principles of internal medicine. 13th ed. New York: McGraw-Hill; 1994:1135-1143.
65. Siragusa S, Cosmi B, Piovella F, et al. Low-molecular-weight heparins and unfractionated heparin in the treatment of patients with acute venous thromboembolism: Results of a meta-analysis. Am J Med 1996;100:269-277.
66. Levine M, Gent M, Hirsh J, et al. A comparison of low molecular weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep venous thrombosis. N Engl J Med 1996;334:677-681.
67. Kooperman MMW, Prandoni P, Piovella, et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low molecular weight heparin administered at home. N Engl J Med 1996;334:682-687.
68. Buller HR, Gent M, Gallus AS, et al. Low molecular weight heparin in the treatment of patients with venous thromboembolism. N Engl J Med 1997;337:657-662.
69. Simmonneau G, Sors, Charbonnier B, et al. Low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism. N Engl J Med 1997;337:663-669.
70. FRISC study group. Low-molecular-weight heparin during instability in coronary artery disease. Lancet 1996;347:561-568.
71. Gurfinkel EP, Manos EJ, Mejail RI, et al. Low molecular weight heparin versus regular heparin or aspirin in the treatment of unstable angina and silent ischemia. J Am Coll Cardiol 1995;26:313-318.
72. Cohen M, Demers C, Gurfinkel EP, et al. A Comparison of Low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. N Engl J Med 1997;337:447-452.
73. Klein W, Buchwald A, Hillis SE, et al. Comparison of low-molecular-weight heparin with unfractionated heparin acutely and with placebo for 6 weeks in the management of unstable coronary artery disease. Circulation 1997;96:61-68.
74. Antman E, et al. Dose ranging trial of Enoxaparin for unstable angina: Results of TIMI 11A. J Am Coll Card 1997;29:1474-1482.
75. Hull RD, Pineo GF. Current concepts of anticoagulation therapy. Clin Chest Med 1995;16:269-280.
79. Hirsh J. Oral Anticoagulant Drugs. N Engl J Med 1991;324:1865-1875.
76. Coon WW, Willis PW III. Hemorrhagic complications of anticoagulant therapy. Arch Int Med 1974;133:386-392.
77. Davis FB, Estruch MT, Samson-Corvera EB, et al. Management of anticoagulation in outpatients. Arch Intern Med 1977;137:197-202.
78. Petitti DB, Strom BL, Melmon KL. Duration of warfarin anticoagulant therapy and probabilities of recurrent thromboembolism and hemorrhage. Amer J Med 1986;81:255-259.
80. Research Committee of the British Thoracic Society. Optimum duration of anticoagulation for deep vein thrombosis and pulmonary embolism. Lancet 1992;340:873-876.
81. Hyers TM, Hull RD, Weg J. Antithrombotic therapy for venous thromboembolic disease. Chest 1992;102:408S-425S.
82. Bittl, JA, Stromy, J, Brinker JA, et al. Treatment with bivalirudin (Hirulog) as compared to heparin during coronary angioplasty for unstable or post-infarction angina. Hirulog Angioplasty Study Investigators. N Engl J Med 1995;333:764-769.
83. Topol, EJ. The future of antithrombotic and antiplatelet therapy for ischemic heart disesae. AHJ Vol 36: No 4. Part 2: S66-69.
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