Anticoagulation and Antiplatelet Therapy in Emergency Medicine: An Evidence Base
Anticoagulation and Antiplatelet Therapy in Emergency Medicine: An Evidence Based, State-of-the-Art Review
Part I: Aspirin, Glycoprotein IIb/IIIa Inhibitors, and ADP Platelet Receptor Antagonists
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.
Anticoagulation. Antiplatelet therapy. Vascular death risk reduction. These are some of the most critical, yet complex, rapidly evolving, controversial, and difficult-to-manage areas in the field of emergency medicine. In fact, from an emergency medicine perspective, a comprehensive understanding of the clinical role that antiplatelet agents and anticoagulants play in mortality reduction and disease prevention has become an area of intense investigation. New therapeutic agents—among them, aspirin, glycoprotein IIb/IIIa inhibitors, enoxaprin, warfarin, and others—represent powerful, proven additions to the arsenal for management of patients at risk for vascular-related disorders. As a result, the increasing role these agents have come to play in managing life-threatening ischemic, arterial, and veno-occlusive syndromes presents new challenges for emergency medicine specialists.
Of special importance is the understanding that these new agents have been investigated in a wide and diverse range of patient subsets. Moreover, all drugs that belong to the same class are not created equal. And, certain classes of drugs, as well as agents within those classes, appear useful only for specific clinical indications, among them: percutaneous coronary intervention (PCI) procedures (angioplasty, stenting, etc.), prevention and treatment of venous thromboembolism, prevention of MI and stroke, atrial fibrillation, unstable angina, non-ST-segment elevation MI, non-Q-wave myocardial infarction, or classical MI with ST-segment elevation.
For example, in some cases, a drug may show risk reduction of recurrent ischemic events only in patients who undergo PCI, but not in those treated with only pharmacologic therapy. Not surprisingly, linking agents, or antiplatelet/anticoagulant "cocktails," to specific conditions has become a formidable clinical challenge that requires interpretation of sometimes imperfect, and, sometimes, even conflicting clinical trials. Moreover, when pharmacoeconomic, safety, and efficacy considerations enter into the equation, selecting an outcome-effective anticoagulant or antiplatelet drug can tax even the most analytical mind.
One of the most important priorities for the emergency physician is to recognize indications (DVT, unstable angina, acute MI) that justify acute intervention with these agents in the emergency department (ED). Although general indications for antiplatelet and anticoagulation therapies are widespread, ranging from cardioprevention and unstable angina to non-Q-wave MI and stroke reduction, the optimal agent or class, and its overall effectiveness for specific subgroups and combinations of drugs are still a matter of debate and a subject of ongoing investigation. Interestingly, existing antiplatelet agents, when used alone, have not been found to be clinically effective in the area of veno-occlusive disease, although this may change as future studies report outcomes with newer agents and trials designed to evaluate combined therapy.
In addition, ED physicians must also be able to identify—and in some cases, it may be argued, even screen ED patients for—those individuals (i.e., high-risk patients with chronic atrial fibrillation, patients with recent MI and left ventricular failure, and individuals with coronary artery disease risk factors) who can benefit from the addition of a prevention-oriented antiplatelet agent or anticoagulant on an outpatient basis in order to reduce their risk for such conditions as embolic infarction, stroke, or MI. When patients present to the ED with problems unrelated to arterial or venous occlusive disease, but who, nevertheless, require and may benefit from prevention-oriented drug intervention, physicians should be prepared to refer such individuals for antiplatelet or anticoagulation therapy. Finally, important paradigm shifts also are occurring in the area of DVT treatment. With trials showing the efficacy of low molecular-weight heparins (LMWHs), such as enoxaprin, for treatment of selected patients with DVT, consideration of outpatient treatment for this condition may soon become standard practice in emergency medicine.
To achieve these goals and maximize outcomes associated with anticoagulant and antiplatelet therapy, this two-part review will provide a detailed discussion of current antiplatelet agents (oral and intravenous), as well as old and newer approaches to anticoagulation therapy. Part I of this monograph will examine indications and clinical effectiveness of three classes of antiplatelet agents currently approved by the FDA, the cyclooxygenase inhibitor (aspirin), the ADP platelet inhibitors, and ticlopidine clopidogrel, as well as a new class of agents, the GPIIb/IIIa receptor antagonists (abciximab, tirofiban, eptifibatide). Because there are clinically significant differences among these drug classes, and among the drugs within each class, the authors provide detailed analysis of mechanism of actions, indications, drug toxicity, and cost. In addition, considerations related to use of these agents during pregnancy and lactation will be examined.
In part II, the authors turn to the venous side of the thrombosis equation, and examine anti-fibrin drugs, including unfractionated heparin and the exciting new opportunities associated with low molecular heparin preparations (ardeparin, dalteparin, and enoxaparin). A review of indications for warfarin and a brief synopsis of newer, direct thrombin inhibitors also will be presented.
— The Editor
Introduction: Role and Significance of Coagulation Disorders in Emergency Medicine
Under normal physiologic conditions, blood components do not interact with an intact vascular endothelium. However, exposure of circulating blood to disrupted or dysfunctional endovascular surfaces initiates a series of complex biochemical events that give rise to the rapid deposition of platelets, erythrocytes, leukocytes, and insoluble fibrin, producing an initial hemostatic plug. Not surprisingly, platelet aggregation is believed to play a major role in the pathogenesis of arterial thrombosis and its associated clinical conditions, including myocardial infarction (MI), stroke, and other ischemia-related diseases. From a therapeutic perspective, evidentiary-based trials have documented that inhibition of platelet aggregation reduces the incidence of both primary and secondary ischemic complications of atherothrombotic disease.
The importance of platelet function, aggregation, and inhibition is related to its central role in normal hemostasis, which can be characterized as a balance between thrombus formation and dissolution. Vascular thrombosis is a dynamic process, in which clot formation and dissolution occur almost spontaneously. The overall extent of thrombosis and the associated circulatory compromise, therefore, is determined by forces that shift the "balance" in one direction or another. In particular, platelets both mediate and participate as cellular components in "white thrombus" formation; these thrombi develop in high-pressure arteries, where circulating platelets adhere to areas of abnormal epithelium. In contrast, venous thrombi consist of a loosely packed network of erythrocytes and fibrin with islands of aggregated platelets (red thrombus). As would be expected, clinical strategies for prevention and/or treatment of arterial thrombotic disease varies considerably from agents used for managing patients with venous thrombosis.
Broadly speaking, these pathophysiological differences explain the clinical observation that anti-fibrin drugs, such as heparin, low molecular weight heparin (LMWH), and warfarin, are effective in syndromes (DVT and PE) associated with venous thrombosis, whereas aspirin and antiplatelet therapies are the mainstay of treatment and prevention for arterial thrombotic syndromes. Moreover, it should be emphasized that, in addition to these well-known medications, there are newer antithrombotics that appear to potentiate the effectiveness of existing treatments for both arterial and venous thrombotic disease. Accordingly, combination or cocktail therapies using multiple agents are likely to hold significant promise. (See Table 1.)
| Table 1. Vascular and Ischemic Disorders: Therapeutic Options |
| Acute myocardial infarction |
| aspirin, enoxaparin (non-Q wave MI), heparin (with certain thrombolytics) eptifibatide, tirofiban |
| Acute pulmonary embolism |
| heparin, enoxaparin, coumadin |
| Atrial fibrillation |
| aspirin, clopidogrel, ticlopidine, heparin, warfarin |
| Deep venous thrombosis |
| heparin, enoxaparin, ardeparin, dalteparin |
| Documented deep venous thrombosis |
| heparin, enoxaparin, coumadin |
| Unstable angina |
| aspirin, clopidogrel, ticlopidine, enoxaparin, heparin, abciximab (with planned PCI), eptifibatide, tirofiban |
| Percutaneous coronary intervention (PCI) |
| heparin, abciximab, eptifibatide, tirofiban |
| TIA/Ischemic stroke |
| aspirin, clopidogrel, ticlopidine, heparin |
| ___________________________________________________________________ |
Inhibition of platelet aggregation, coagulation, clot formation, and thrombus reactivity have become the most important and effective prevention-oriented strategies in patients at risk for cardiovascular disease and stroke. From a pathophysiological perspective, a growing thrombus of aggregated platelets causes reduced arterial blood flow and leads to end-organ ischemic and/or occlusive clinical syndromes. Overall, the site, size, and composition of thrombi forming within the arterial circulatory systems is determined by: 1) alterations in blood flow; 2) the thrombogenicity of endovascular surfaces; and 3) the concentration and reactivity of hemostatic proteins and cellular elements.
It should be emphasized that an extremely complex series of events—precipitated by a number of biochemical mediators and physical stressors—is responsible for transforming an atheroma into a highly thrombogenic surface that fosters platelet aggregation and subsequent in situ thrombosis. In this regard, collagen from the exposed subendothelium, tissue factor on the surface of macrophages, adenosine diphosphate (ADP) from red blood cells that are lysed as they pass through stenotic arteries that produce turbulent flow, and the action of shear stress (disruption of laminar flow) all activate platelets and lead to the expression of the active form of the glycoprotein (GP) IIb/IIIa receptor on their surface. These receptors permit platelets to aggregate by attaching to one of several macromolecular ligands. As thrombosis evolves, local thrombin generation acts as an ongoing stimulant for platelet activation and subsequent aggregation.
Aspirin: Cyclooxygenase Inhibitor Par Excellence
Aspirin has become the standard antiplatelet agent for prevention of a wide range of ischemic syndromes. It is used for secondary prevention of MI (both acutely in combination with thrombolytic agents and for long-term oral prophylaxis), for prevention of thromboembolic disease in low-risk patients with chronic atrial fibrillation, as adjunctive therapy with heparin for unstable angina, for TIA prophylaxis, and for many other conditions. Specifically, long-term aspirin therapy reduces the risk of critical cardiovascular and cerebrovascular events (death, stroke, MI, unstable angina) by an average of about 25% compared to placebo.1-3 Furthermore, it has been shown that aspirin reduces the risk of abrupt vessel closure during percutaneous revascularization. The reasons for aspirin’s widespread use are well known. It is simple to administer, it is safe at low doses, and it is cost effective. In fact, to date, no other antiplatelet agent has demonstrated the risk-benefit ratio and low cost that aspirin affords. (See Table 2.) And yet, despite the benefits of aspirin therapy, experts still do not universally agree as to whether different doses of aspirin have varying magnitudes of clinical benefit, or what the ideal dose of aspirin should be for a particular clinical condition.
| Table 2. Antiplatelet Agents: Indications and Cost of Therapy | ||
| Agent | Indications |
|
| Cyclo-oxygenase Inhibitor | ||
| Aspirin | 2° prevention of MI/ Stroke; Acute coronary and Cerebral ischemia Syndromes Low risk patient subgroups or lone atrial fibrillation |
|
| ADP platelet receptor Inhibitor | ||
| Ticlopidine | Aspirin failures; |
|
| Clopidogrel | Peripheral vascular disease |
|
| GP IIb/IIa Inhibitor | ||
| Abciximab | Unstable angina only when PCI planned within 24 hrs |
|
| Eptifibatide | Unstable angina, non-Q wave MI, |
|
| Tirofiban | adjuvant of PCI |
|
| Drug only cost, does not include monitoring
and administration costs
< $ = < $5.00 $$ = $80-100 $$$ = ~$130044 _________________________________________________________________________ |
||
Mechanism of Action and Onset of Action. The antiplatelet effect of low-dose aspirin therapy (30-325 mg/d) is due to acetylation of platelet cyclooxygenase. This reaction is irreversible, and studies have shown that aspirin can induce inhibition of this enzyme at doses as low as 30 mg/d.1,2 Without cyclooxygenase, platelets are unable to make thromboxanes, which are pro-aggregatory and cause vasoconstriction, but cyclooxygenase inhibition also prevents platelets from generating prostacyclins, which cause vasodilation and help maintain GI mucosal integrity. While the inhibition of platelet-derived thromboxanes is the principal antithrombotic mechanism of aspirin, the concomitant reduction of prostacyclins is thought to limit aspirin’s value in arterial occlusive disease. At low doses, however, it is thought that inhibition of thromboxanes can occur without inhibiting prostacyclins, therefore allowing the beneficial effects of aspirin to predominate, while minimizing GI side effects.
One of the principal pharmacokinetic advantages of aspirin is its rapid onset of action, which explains its usefulness in acute coronary occlusive syndromes. One-dose therapy with aspirin produces acute inhibition of platelet function within 60 minutes of administration, an effect that lasts about nine days, which represents the approximate half-life of a platelet. Enteric coating will delay onset of inhibition by about 3-4 hours.3 Currently, there is no oral antiplatelet preparation available that has an onset of action as rapid as "plain" aspirin. This quick onset of action represents a major advantage over other agents for treatment of acute ischemic vascular syndromes. Aspirin is rapidly absorbed by both oral and rectal routes.
As far as monitoring, in patients on chronic aspirin therapy, a routine CBC should be ordered periodically to rule out occult bleeding, and a stool guiac test should be performed. Bleeding time will be prolonged in patients taking aspirin.
Dosing. Aspirin dosing is controversial, with various studies or editorials confirming, recommending, or reporting that aspirin doses from 30 to 1400 mg/d are effective for specific clinical conditions.4 Most studies and consensus panels, however, recommend aspirin dosages between 81 and 325 mg/d.5 (See Table 3.)
| Table 3. Minimum Recommended Dose of Aspirin for Common Indications | |
| Thrombotic Disorder | Minimum Effective
Daily Dose |
| Stable Angina | 81 mg |
| Unstable Angina | 81 mg |
| Acute Myocardial Infarction | 160-325 mg |
| Transient Ischemic Attack | 81 mg |
| Atrial Fibrillation (warfarin contraindicated or young/lone atrial fibrillation) | 325 mg |
| Atrial Fibrillation (in addition to warfarin in case of failure) | 325 mg |
| Secondary Prevention of MI | 81-162 mg |
| _________________________________________________________________________ | |
There is also conflicting information with respect to the relationship between aspirin dose and side effects, although lower doses appear to be associated with a lower risk of hemorrhagic complications. Moreover, women seem to be at higher risk for aspirin-related complications. When the the objective is secondary prevention of MI, the goal is to use the lowest dose of aspirin required to inhibit thromboxane, yet spare prostacyclin production. Although the mechanism of gastrointestinal side-effects is not well understood, these complications are thought to be related, at least in part, to inhibition of prostacyclin, which is thought to occur at higher aspirin doses.6 There have been intriguing reports of "booster" dosing of aspirin, in which patients taking 81 mg/d of aspirin for long-term prevention, take one 325 mg aspirin tablet every 15 days, in order to enhance cardiprotection. Although one study suggests enhanced outcomes with this dosing pattern, additional trials are required to establish the efficacy of this approach.
Toxicity. Although aspirin-related side effects are rarely seen within the context of acute administration within the ED setting, physicians must be aware of possible complications of chronic therapy. Aspirin, which has a Class D pregnancy rating, is unsafe in pregnancy; its safety in lactating women is unknown or controversial.
The side effects of aspirin are primarily related to dose but may also be related to length of use.7 Pooled data from 21 clinical trials suggest that patients on long-term aspirin therapy have 1.5-2.0 times the risk of hematemesis or melena.8 Both short- and long-term aspirin use may produce gastric erosions and hemorrhage, but long-term use increases the frequency and severity of disease. Aspirin-induced gastric injury, as detected by endoscopy, has been found to be greatest in the first week and tapers off within 2-8 weeks of continuous ingestion.
Aspirin is primarily associated with gastric rather than duodenal ulceration. Antacids, buffering agents, H-2 blockers, proton pump blockers, misiprostol, and enteric coating may reduce gastrointestinal injury, although these agents generally do not need to be administered when aspirin is given in the acute setting.9 Aspirin, alone, usually does cause generalized, systemic bleeding except in cases of concomitant anticoagulant use, hemophilia, and uremic states.10-12 The incidence of severe neutropenia with aspirin is approximately 0.02%. If a patient on aspirin develops severe bleeding, packed red blood cells and platelets should be administered. Aspirin-related antiplatelet clinical effects last about nine days, which is the average life of a platelet.
Indications for Aspirin Therapy. The primary indications for acute administration of aspirin in the ED setting include acute myocardial infarction (AMI), unstable angina in low-risk patients with atrial fibrillation, and ischemic cerebrovascular syndromes that have failed warfarin therapy or in patients who are poor candidates for warfarin. However, emergency physicians should also be prepared to counsel other individuals with coronary heart disease (CHD) risk factors who access the ED for non-cardiac problems, but who may benefit from the prevention-oriented benefits of aspirin therapy.
Primary vs. Secondary Prevention. In this regard, aspirin has been evaluated for its effectiveness in both primary and secondary prevention of MI. There have been only a few major trials published to explore the issue of primary prevention. In men, aspirin reduces the incidence of MI, but the net effect on stroke and cardiovascular death remains inconclusive. It should be stressed that the U.S. Physicians Health Study (USPHS)11 and the British Doctors Trial (BDT)13 give conflicting results. The USPHS revealed about an 18% reduction of all vascular events (nonfatal MI, nonfatal stroke, or cardiovascular death) among those on aspirin (325 mg qod), with a 33% reduction in non-fatal MI. The BDT noted no significant difference in combined end points of important cardiovascular events, thereby casting the role of aspirin for primary prevention into serious doubt. With regard to primary prevention of stroke, aspirin affords no benefit and may, in fact, be harmful. There was a small increase in hemorrhagic stroke rate in healthy individuals.
An important ingredient in many cocktails for cardioprevention, aspirin is still under-used for secondary prevention against recurrent MI. ED physicians should attempt to identify these individuals in the process of taking a drug history in patients with known cardiovascular disease. As emphasized, the use of aspirin for primary prevention in healthy individuals is still somewhat controversial, although most experts recommend its inclusion in cardioprotective regimens in high-risk subgroups. The 1988 American Physicians Health Study was prematurely stopped because of a 40% reduction in first, non-fatal MIs. The British Male Doctors study, however, did not show a reduction in first MIs, thus generating a controversy about the use of aspirin in primary prevention. The Thrombosis Prevention Trial (TPT) also does not support the widespread use of aspirin for primary prevention, because, even in high-risk men, the overall reduction in ischemic heart disease (IHD) events was a modest 20%, and aspirin had no effect on total mortality. Moreover, there are few data on women, at least one-half of the target population.
Low-intensity warfarin was also evaluated in TPT, and its cardioprotective effects for primary prevention were similar to aspirin. However, because warfarin was associated with an excess of dissecting and ruptured aortas, it cannot be recommended for primary prevention, especially in combination with aspirin. However, the case for using aspirin to prevent recurrent MI and coronary events in men at high risk is very strong. The appropriate dose is 81 mg of aspirin per day, with some experts recommending 162 mg/d. So who is eligible for aspirin therapy? Probably, most individuals older than age 50 with no contraindications, diabetics, those with a history of coronary heart disease, stable or unstable angina, history of MI, coronary angioplasty, or coronary bypass graft. The use of aspirin for primary prevention in women at low risk for CAD is not settled because the risk of causing hypertensive hemorrhage is slightly greater in patients on aspirin than those off of aspirin.14,15
In general, then, routine aspirin use for primary prevention in healthy individuals may afford no benefit, while placing patients at mild-to-moderate risk for hemorrhagic events. Primary preventive measures, such as lowering cholesterol, blood pressure, estrogen replacement therapy in women, and cessation of smoking, may have more of an effect on prevention of CHD than aspirin alone. However, low-dose aspirin therapy (81 mg/d) is indicated in all individuals who can tolerate the drug with a history of stroke/TIA, MI, angina, documented CHD, and probably, in other risk groups, such as diabetics and individuals with peripheral vascular disease.
Because emergency services are increasingly being integrated into comprehensive health management plans, emergency physicians should identify such high-risk subgroups requiring cardioprevention and ask about aspirin use as part of a drug history. Meta-analysis data suggest that total morbidity and mortality is significantly reduced when aspirin is used for secondary prevention in these subgroups.16 In patients with a history of cardiovascular or cerebrovascular ischemic events, a meta-analysis of 25 trials, suggest vascular event rates are reduced by about 25%, with the most significant reduction observed in non-fatal MI (32%). In addition, a 20% reduction in risk of stroke has been observed with aspirin.16
Acute Coronary Syndromes. The primary indication for acute aspirin administration in the ED is acute coronary artery syndromes. In general, aspirin should be administered to all individuals with known or suspected ischemic coronary syndromes as first-line therapy.17 If it is unclear whether the patient took their daily aspirin dose, just give it. The side effects are minimal, and the benefit may be substantial.
The Second International Study of Infarct Survival (ISIS-2) demonstrated that 160 mg of aspirin daily, given up to 24 hours after the onset of suspected AMI and continued for one month afterward reduced mortality by 23%.This benefit was maintained for two years and equaled that produced by IV streptokinase.18 Other agents, such as thrombolytics and anticoagulants may be combined with aspirin, but aspirin must never be forgotten and should be part of any mortality-reducing pathway for managing patients with acute coronary syndromes.
Non-Valvular Atrial Fibrillation (AF). The overall risk of stroke in non-valvular AF is estimated to be about 4.5% per year.19 Older individuals and those with hypertension, diabetes, previous stroke, heart failure, and coronary heart disease are at greater risk for thromboembolic events than those without these risk factors.
It should be stressed that warfarin, not aspirin, represents first-line therapy for chronic AF in high-risk patients (advanced age, prior TIA/stroke, hypertension or diabetes, left ventricular dysfunction, congestive heart failure, left atrial enlargement). However, summary data demonstrates that aspirin alone may be appropriate first-line therapy in those at low risk.20 Persons younger than 75 years, with no high-risk factors ("low-risk"), benefit from aspirin alone, with an acceptable 0.5% primary event-per-year rate of thromboembolic events. Although less effective than warfarin, aspirin has been shown to reduce the risk of stroke by 18-44%.21 Nevertheless, because high-risk individuals have a much higher primary event rate with aspirin alone vs. warfarin (4.8% vs 3.6%, respectively), aspirin therapy alone is recommended in high-risk patients only if they are intolerant of, or poor candidates for warfarin therapy.
In summary, the Stroke Prevention in Atrial Fibrillation (SPAF) III study has shown that aspirin is effective for preventing cerebrovascular events in low-risk AF patients. On the other hand, patients with chronic AF who are at high risk for embolic events (i.e., those with two or more risk factors from among the following: hypertension, valvular heart disease, elderly, women > 75 years, hypertension, prior stroke, and CHF or LV dysfunction) should be treated with warfarin to achieve an INR in the range of 2.0 to 3.0. Those at low risk (i.e., they do not have any of the risk factors cited above) can be treated with aspirin alone.
The value of antithrombotic therapy in patients with LV dysfunction was evaluated in the Studies of Left Ventricular Dysfunction (SOLVD) trial. The purpose of this investigation was to analyze the SOLVD database to assess the effects of antithrombotic therapy on risk for sudden cardiac death. A multivariate analysis revealed that antiplatelet therapy (primarily aspirin) was associated with a 24% reduction in sudden cardiac death risk, and anticoagulant (warfarin) therapy was associated with a 32% reduction in risk. Interestingly, antiplatelet therapy was not associated with a decreased risk in sudden death in a subset of 923 patients thought to have nonischemic heart failure, but anticoagulant therapy was still associated with a reduced risk in this group. Eligible candidates who have sustained an MI accompanied by an ejection fraction less than 35% will benefit most from warfarin-based anticoagulant therapy.22
Valvular Heart Disease. Aspirin alone is not sufficient to prevent thromboembolic complications of valvular heart disease.23 However, In combination with full-dose warfarin, aspirin has been shown to improve the efficacy above warfarin alone. Unfortunately, the additional benefit is associated with a significant increase in bleeding. In patients who have failed warfarin (i.e., have experienced a thromboembolic event while on warfarin), it is reasonable to add aspirin, even though there is an increased risk of hemorrhagic complications. Patients intolerant of warfarin also may take aspirin.
Peripheral Vascular Disease/Intermittent Claudication. Generally speaking, aspirin should be recommended in all patients with claudication symptoms. Aspirin decreased morbidity and mortality associated with peripheral vascular disease. Patients with claudication have as high as 60% mortality over 10 years, which is due mostly to MI and stroke. Additionally, antiplatelet therapy has been shown to demonstrate a reduced need for surgery.24
Venous Thromboembolism. The efficacy of aspirin for prevention of venous thromboembolic disease is uncertain. Currently, there is no conclusive data to date to support the use of aspirin for this indication. The Pulmonary Embolism Prevention Trial is currently in progress.5
ADP-Platelet Receptor Inhibitors: Ticlopidine (Ticlid®) and Clopidogrel (Plavix®)
Ticlopidine (Ticlid®) and clopidogrel (Plavix®) are two agents that affect platelet activity (including aggregation) through inhibition of ADP platelet activation. Although these agents usually are not used for acute intervention in the ED, they are becoming widely accepted as a "second-line" antiplatelet therapy, especially in patients who cannot tolerate aspirin or who have failures on aspirin therapy.25 Moreover, because these medications can cause side effects, ED physicians must be aware of their indications and potential problems.
Compared to aspirin, these agents have been shown to offer convincing, clinically significant benefits with respect to reduction of ischemic events related to certain end points. However, whether these drugs offer outcome-effective advantages over aspirin is more difficult to evaluate when one considers cost of therapy and possible toxicity, especially in the case of ticlodipine. In this regard, ticlopidine should be used cautiously, based on recent reports that individuals taking this drug are at risk for acquiring thrombotic thrombocytopenic purpura (TTP), as well as neutropenia and agranulocytosis. The new antiplatelet agent clopidogrel is similar to ticlopidine and provides protection against recurrent MI that is similar or slightly better than aspirin, but it is not associated with the hematological risks seen with ticlopidine.
Reversal agents are available. Methylprednisolone normalizes bleeding time in patients taking ticlopidine. If significant bleeding develops, a platelet transfusion may be used, except in cases of ticlopidine-induced TTP. Ticlopidine carries a Pregnancy Class B rating, based on animal studies. No adequate and well controlled studies are available in women. The drug is excreted in human breast milk. (See Table 4.)
| Table 4. Antiplatelet Agents: Complications, Monitoring, and Pregnancy Profile | |||
| Agent | Major Complications | Monitoring | Pregnancy |
| Cyclo-oxygenase Inhibitor | |||
| Aspirin | GI Bleeding | None | Class D |
| ADP platelet receptor Inhibitor | |||
| Ticlopidine | Neutropenia, ITP, TTP | CDC w/diff q 2 weeks for first 90 days; thereafter, with s/s of infection | Class B |
| Clopidogrel | Rash, diarrhea, abdominal pain | None | Class B |
| GPIIb/IIa Inhibitor | |||
| Abciximab | Generalized bleeding | None | Class C |
| Eptifibatide | Note: required concomitant heparin | Class B | |
| Tirofiban | therapy must be closely monitored to prevent excess bleeding | Class B | |
| ________________________________________________________________________ | |||
From an emergency medicine perspective, use of ADP platelet receptor inhibitors is limited by the rapidity of onset of action, which is slower than it is for aspirin. Because both agents require several days to achieve maximal therapeutic effects, their use is limited in acute ischemic syndromes.26 The onset of action of ticlopidine increases gradually over a period of four days, with a total duration of activity of about 14 days. Clopidogrel has an onset of action within about two hours and a total duration of activity of about five days. (See Table 5.) Nevertheless, emergency physicians will encounter an increasing number of patients who present on these agents or who may require, on a selected basis, initiation of these agents on discharge from the ED.
| Table 5. Antiplatelet Drugs: Pharmacokinetics | ||
| Agent |
|
|
| Cyclo-oxygenase Inhibitor | ||
| Aspirin |
|
|
| ADP platelet receptor Inhibitor | ||
| Ticlopidine |
|
|
| Clopidogrel |
|
|
| GPIIb/IIa Inhibitor | ||
| Abciximab |
|
|
| Eptifibatide |
|
|
| Tirofiban |
|
|
| ____________________________________________ | ||
Mechanism of Action and Dosing. Ticlopidine and clopidogrel are thienopyridine derivatives structurally unrelated to other platelet inhibitors. Structurally, ticlopidine and clopidogrel are nearly identical; specifically, clopidogrel is the (S) active enantiomer of ticlopidine. This structural alteration seems to account for clinically significant differences in potency and toxicity.25
Both agents block platelet-platelet adhesion. This action is mediated by selective and irreversible inhibition of ADP to its platelet receptor, thereby affecting the ADP-dependent activation of the GPIIb/IIIa complex. The GPIIb/IIIa complex is required for subsequent fibrinogen binding and, ultimately, thrombus formation. Both agents may take several days to reach maximum effect and both undergo hepatic metabolism.26,27 From a compliance perspective, clopidogrel, which is dosed at 75 mg/d has potential advantages over ticlopidine, which is dosed 250 mg po bid with food.28
Toxicity. As emphasized, the side-effect profile of ticlopidine has been the major factor limiting its use. Ticlopidine has a number of toxic, even potentially life-threatening, effects with which the ED physician should be familiar. Diarrhea, which is encountered in 20-22% of patients, and transaminitis, observed in up to 8% of patients, are the most frequently noted drug-related toxicities. Agranulocytosis, although rare, is one of the most dreaded drug-related complications. In clinical trials with ticlopidine, the overall incidence of neutropenia (ANC < 1200) was 2.4%. Severe neutropenia (ANC < 450) occurred in 0.8% of patients. Mild to moderate neutropenia (ANC 451-1200) occurred in 1.6%. The onset of neutropenia may be sudden, and usually occurs between three weeks and three months after initiation of therapy. Unfortunately, some cases have been detected after three months or longer of drug therapy.
In addition, thrombocytopenia (< 80,000) may be induced in the form of immune thrombocytopenia (ITP) or thrombotic thrombocytopenia purpura (TTP); neutropenia may also complicate these clinical presentations. Fatalities have been reported. Because ticlopidine is metabolized by the liver, it is contraindicated in patients with severe liver impairment. Other contraindications include: active bleeding, hemostatic disorder, and baseline hematopoietic disorder.28
In contrast to ticlopidine, clopidogrel has relatively few side effects and is similar to aspirin in its safety profile. The most common adverse reactions associated with clopidogrel include rash, abdominal pain, or dyspepsia; each are reported in about 4-5% of patients. Severe neutropenia may occur but is exceedingly rare. The incidence of severe neutropenia with clopidogrel is similar to that with aspirin (0.04% vs 0.02%), and it is much lower than the 0.8% incidence seen with ticlopidine. No cases of TTP have been reported.29
Monitoring. When considering the cost-benefit ratio of ticlopidine, the costs of vigilant monitoring of drug therapy must be included in the equation for drug selection. In this regard, monitoring the complete blood count (CBC), including a differential (neutrophil and platelet counts) is essential in all patients taking ticlopidine. Blood monitoring should be performed once every two weeks for the first three months of therapy. After 90 days, complete blood counts are recommended only when the patient has signs or symptoms of infection. Patients who have a 30% or greater drop in neutrophil count, must be monitored more closely, and considered for alternative therapy (i.e., clopidogrel). Patients who stop therapy for any reason must continue to have their blood monitored for at least two weeks, given the long half-life of the drug.28 Clopidogrel, in contrast, does not require blood monitoring. Both agents prolong bleeding time.
Indications: Cerebral Ischemia/Stroke. Both ticlopidine and clopidogrel have demonstrated efficacy in reducing risk of recurrent cerebral ischemia and stroke. Although there may be indications for using these agents as initial therapy, their primary role is in patients who have experienced thromboembolic events while on aspirin therapy (i.e., "aspirin failures") and in individuals who require MI or stroke prophylaxis but are intolerant of aspirin. A recent worldwide survey of 185 neurologists in North America and Western Europe who are field leaders in the area of stroke prevention found significant differences in management styles for aspirin failures.30 More than two-thirds responded that in the setting of aspirin failure, they would stop aspirin and begin another agent such as ticlopidine or some other anticoagulant. The literature supports the position that as an alternative to aspirin, ADP platelet receptor inhibitors are the most effective oral agents, although there are important differences in the relative efficacy and indications for ticlopidine and clopidogrel in stroke and MI prevention.
The clinical data for both clopidogrel and ticlopidine show that both agents are effective in the secondary prevention of cerebral ischemia and stroke.31 The ticlopidine-based TASS Trial (3069 patients) evaluated patients for a 2-5 year period, and demonstrated a 48% reduction in fatal and non-fatal stroke the first year and about a 24% overall reduction per 100 patients followed for five years (ticlopidine vs aspirin). When composite outcomes of stroke, MI, and vascular death are considered vs. placebo in a meta-analysis trial, risk reductions are 25% for aspirin and 33% with ticlopidine.32
In the clopidogrel vs. aspirin CAPRIE Trial (19,185 patients), clopidogrel showed an overall (i.e., when all patient subgroups were combined) relative-risk reduction of 8.7% above the accepted 25% reduction using aspirin therapy, for the combined end points of ischemic stroke, MI, or vascular death.33 Because of the results of the CAPRIE Trial, clopidogrel carries an expanded indication for prevention of recurrent MI. Interestingly, however, the CAPRIE efficacy data for clopidogrel are not as impressive as the TASS data, especially for stroke prevention.
At least one other aspect of the CAPRIE trial requires special mention. Of special note is the fact that in the MI subgroup in the CAPRIE study, there was actually a slightly higher incidence of all end point (fatal/non-fatal MI or stroke, or other vascular deaths) vascular events observed in the clopidogrel treated patients vs. those on aspirin. Inclusion into the MI group required clinical signs, symptoms, EKG, and laboratory confirmation of MI within 35 days prior to randomization to either aspirin or clopidogrel. Although there was a slight reduction in fatal/non-fatal recurrent MI and fatal stroke in the qualifying MI subgroup (11,630 patients), the increase in "other vascular deaths" was significantly greater in the clopidogrel vs. aspirin group. Other vascular deaths, according to the CAPRIE protocol, were defined as "any deaths that were clearly non-vascular and did not meet the criteria for fatal stroke, fatal myocardial infarction, or hemorrhage. Deaths considered by the Central Validation Committee to be directly related to the qualifying event were classified as other vascular."33 Accordingly, it would be difficult to justify, at present, to use clopidogrel as the sole agent of choice for overall vascular event/death in patients with recent MI, unless they are unable to tolerate or have failed aspirin therapy.
While these agents appear to offer significant advantage over aspirin in selected patient populations, the cost:benefit ratio should be considered. Cost decision-analysis modeling indicates with respect to cerebral ischemia/infarction, five-year treatment with ticlopidine would reduce the number of lifetime strokes in 100 high-risk patients by two stroke events at an incremental cost compared to aspirin of $31,200-55,000 per quality-adjusted life-year gained.34 In summary, while the use of the ADP receptor inhibitors can, with qualifications, be recommended for targeted patient subgroups, these agents are expensive when compared to aspirin. The cost per month for aspirin is $3.14 (Bayer), $113.93 for ticlopidine, and $86.76 for clopidogrel.35
Acute Coronary Syndromes. Clopidogrel and ticlopidine are less effective than aspirin, but they may be considered as second-line or alternative therapy when aspirin cannot be tolerated. The delayed onset of action may account, in part, for the inferior results compared to aspirin for management of acute coronary syndromes. Studies, however, do suggest that some antiplatelet therapy is better than none at all.36
Peripheral Vascular Disease. Both agents can be considered reasonable alternatives to aspirin in patients with intermittent claudication.23 Improved morbidity and mortality has been observed in patients on ticlopidine for the indication of intermittent claudication compared to placebo. Although not well quantified, improvement in clinical outcomes with ticlopidine is primarily observed in the area of cardiovascular and neurovascular events, which is consistent with the data in the area of TIA and stroke reduction reported in the TASS trial.36 Clopidogrel also has been shown to have a relative-risk reduction of vascular events compared to aspirin of 23.8%.
| Table 6. 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 2.1/2 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 q day SQ-low risk pts 5000 anti Factor Xa units q day 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 q day 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 |
Use caution in renal failure
patients and elderly. Do not use in patients who have received an LP or spinal anesthesia. |
| Warfarin | Atrial Fibrillation, Deep Venous Thrombosis, Pulmonary
Embolism:
5-10 mg PO in ED then titrate dose to therapeutic effect |
Monitor PT/INR
or Multiple drug interactions |
| * It is important to remember that a complication
of all these agents is hemorrhage.
_________________________________________________________________________________________________________ |
||
GP IIb/IIIa Receptor Antagonists: Abciximab (ReoPro®), Eptifibatide (Integrilin®), and Tirofiban (Aggrastat®)
Platelet aggregation and thrombus formation may occur despite aspirin use. The glycoprotein (GP) IIb/IIIa receptor antagonists represent the latest generation of powerful platelet inhibitors. With 40,000-80,000 GP IIb/IIIa receptors per platelet, it is not surprising that antagonists to this receptor have demonstrated clinical success in acute coronary syndrome trials.37-39 Accordingly, incorporation of GP IIb/IIIa receptor blockers into medical stabilization and mortality-reducing regimens for unstable angina is expected to enhance the safety and reduce the number of invasive procedures. At present, there are multiple trials investigating the adjunctive role of GP IIb/IIIa receptor inhibitors in combination with fibrinolytic therapies, including tPA. It has also been suggested that platelet aggregation around residual thrombus—a phenomenon that is not resolved by current therapies—may contribute to fibrinolytic therapy failures.
Preliminary results with GP IIb/IIIa receptor antagonists are generally favorable when combined with thrombolytics. As a result, these antiplatelet drugs may offer some additional benefits by permitting lower doses of thrombolytic agents such as tPA to be used in MI (with or without heparin) and, ultimately, by permitting fewer patients to undergo invasive therapy. Although preliminary economic considerations suggest GIIb/IIIa antagonists may be cost-effective by reducing the need for emergent revascularization procedures and the length of hospital stay, a definitive pharmacoeconomic analysis is still awaited.
Unfortunately, drawing definitive conclusions about the current role of GP IIb/IIIa inhibitors for emergency practice is exceptionally difficult, because many of the studies used to support these agents show conflicting or inconsistent results—sometimes related to gender and geographical differences with respect to clinical trial outcomes. In addition, the studies were performed using different treatment regimens in slightly different patient subgroups. Among the trials used to identify the role of GP IIb/IIIa inhibitors are the CAPTURE,38 EPISTENT,39 EPIC,40 and EPILOG41 trials. Development of oral agents in the GP IIa/IIIb drug class—among them, xemilofiban, orbofiban, sabrafiban—is currently in progress.
Mechanism and Dosing. In the presence of platelet activation by fibrinogen or von Willebrand factor, the GP IIb/IIIa receptors on platelets undergo structural modification, which facilitates platelet aggregation and subsequent thrombus formation. There are currently three GP IIb/IIIa agents available for clinical use, and they differ considerably in indications, dosing, and outcomes. In the case of abciximab and tirofiban, heparin should accompany infusion, with strict attention to dosing per manufacturer recommendations to avoid excess bleeding events.
Abciximab (ReoPro®). Abciximab is the Fab fragment of the chimeric human-murine monoclonal antibody 7E3, which is produced by continuous perfusion in mammalian cell culture. The Fab fragment is extracted and, when given to human subjects, it blocks the GP IIb/IIIa receptor and, therefore, platelet aggregation. Abciximab is administered by intravenous infusion and has a half-life of 10 minutes. Continuous infusion must be maintained for antiplatelet effect. Although abciximab remains in the circulation for two weeks, platelet function returns within 48 hours. It is a non-competitive inhibitor, accounting for a longer half-life than is observed with other agents in its class.
Abciximab is intended for use in combination with aspirin and heparin.42,43 According to the package insert, it is dosed as a 0.25 mg/kg IV bolus administered 10-60 minutes prior to cardiac catheterization, which is then followed by continuous infusion of 0.125 mcg/kg/min (to a maximum of 10 mcg/min) for 12 hours.
Eptifibatide (Integrilin®). Eptifibatide is derived from the venom of the southeastern pygmy rattlesnake. This cyclic heptapeptide reversibly binds to platelets in a dose- and concentration-dependent manner.
A competitive inhibitor, eptifibatide (in contrast to abciximab) does not maintain inhibition after infusion. Available only as an infusion, 84% platelet inhibition has been observed after a 15 minute infusion. Plasma elimination half-life is approximately 2.5 hours after bolus plus infusion. In clinical trials that have shown eptifibatide to be effective, most patients also received both heparin and aspirin. However, the manufacturer’s package insert does not require heparin or aspirin for eptifibatide use.
The dose for managing patients with acute coronary syndromes is 180 mcg/kg bolus with an infusion of 2 mcg/kg/min until discharge or CABG for up to 72 hours. When used for patients undergoing a percutaneous coronary intervention (PCI), the infusion should be decreased to 0.5 mcg/kg/min at the time of procedure, followed by continued infusion for 20-24 hours after PCI, for up to a maximum of 96 hours.
Tirofiban (Aggrastat®). Tirofiban is a non-peptide extraction from the venom of an African snake, the saw-scaled viper. Platelet inhibition occurs within five minutes, and bleeding time returns to normal within 3-4 hours after discontinuation of infusion. The elimination half-life is two hours. The recommended dose is 0.4 mcg/kg/min for a 30 min infusion, then 0.1 mcg/kg/min (one-half the dose for severe renal insufficiency).
Toxicity. Bleeding is the major complication with all agents in this class. The incidence of major bleeding end points (intracranial hemorrhage, a > 5 mg/dL decrease in hemoglobin, or > 15 mg/dL drop in hematocrit) for all three agents ranges between 2.0% and 5.2%. (CP10-14) Minor bleeding episodes are reported to be between 4% and 11%.37-41 In patients on warfarin in whom PCI is imminent, it is recommended that warfarin be discontinued (and reversed with fresh frozen plasma [FFP] and Vitamin K), and titratable heparin be started. In all cases, in order to reduce the incidence of bleeding complications, heparin should be carefully dosed and monitored, precisely as recommended by the manufacturer of each agent.
Thrombocytopenia is a potentially life-threatening side effect. Mild to severe thrombocytopenia may occur with all three drugs and ranges between 0.5% and 3.2%. It must be stressed that the data may be confounded by the mandatory use of heparin with these agents, and that some reports may reflect heparin-induced thrombocytopenia. Data are limited regarding readministration of agents for subsequent ischemic episodes, but readministration may lead to hypersensitivity, anaphylaxis, thrombocytopenia, or diminished effectiveness.44-46 Data for use of GIIb/IIIa inhibitors with thrombolytic agents are under investigation (GUSTO-IV). Preliminary results suggest that alteplase may be safer with respect to bleeding than streptokinase when given with eptifibatide.
Abciximab is designated Pregnancy Class C; animal studies have not been conducted. It is not known whether abciximab is excreted into human milk or absorbed systemically after ingestion. Eptifibatide and tirofiban are designated Class B. It is not known if these drugs are excreted into human milk or absorbed systemically after ingestion. Use with caution.
Indications: Acute Coronary Syndromes and Percutaneous Coronary Intervention. Based on results from a number of clinical trials,37-41 GP IIb/IIIa inhibitors have been approved for treatment of diverse patient populations with ischemic syndromes. Eptifibatide is approved for patients with unstable angina (UA)/non-Q-wave MI (NQMI), regardless of the mode of patient management. It is also indicated for treatment of patients undergoing elective, urgent, or emergency PCI. Abciximab is approved for treatment of patients scheduled to undergo PCI (including those with refractory unstable angina awaiting PCI), while tirofiban HCl is approved for treatment of patients with UA/NQMI (who may be managed either medically or with PCI).
Abciximab, which is approved only as adjunctive therapy for unstable angina when percutaneous coronary intervention is planned within 24 hours, has been studied in three trials. A key inclusionary criterion was that the decision for percutaneous coronary intervention was made prior to starting the drug infusion.44-46 In addition, all patients enrolled had previous angiographic studies that demonstrated a potential "culprit" lesion. Progression to MI or death after intervention was less than 5% with abciximab compared to 9% with placebo, when evaluated at a 30-day end point.38
It should be stressed that when abciximab was evaluated in the CAPTURE Trial (1265 patients) the primary efficacy end point was a composite of death from any cause, nonfatal MI, or urgent repeat intervention or CABG for recurrent ischemia (11.3% for abciximab and 15.9% for placebo) at 30 days. However, at six months in the CAPTURE Trial, there appeared to be minimal, statistically borderline differences between those treated with abciximab and those in the placebo arm.
The finding of only borderline benefit with abciximab at six months is not in agreement with the EPIC Trial (1400 patients) or EPISTENT Trial (2399 patients) results presented at the European Society of Cardiology Meeting in August 1998;39 these studies, in fact, did demonstrate significant reductions in death/MI/recurrent revascularization end points at six months in specific patient subgroups.39-41 For example, in the EPISTENT Trial, the improved end points with abciximab were observed primarily in the group of patients who had received the drug and had PCI/stent therapy; in contrast, in those who received abciximab plus PCI (PTCA) treatment, the differences between drug and placebo had only borderline significance.
Overall, abciximab administration to patients undergoing stent implantation reduced the composite end point at 30 days by 51% and by 47% at six months compared to stenting alone. From a practical, emergency intervention perspective, it appears as if abciximab is most advisable in patients who undergo PCI and stent implantation. In the EPIC Trial, the reduction in MI/death/revascularization was significant only in abciximab patients who received a bolus of the drug plus infusion. Improved end points, including reduction in restenosis, persisted for three years. Other studies have failed to confirm such protracted benefits. The different outcomes among the studies has been explained by the variations in study design. In CAPTURE, patients received abciximab for only one hour after PCTA compared with 12 hours in EPIC and EPILOG. These findings suggest that the infusion of abciximab for 12 hours after PCTA may be critically important in producing a benefit that is sustained over the long term.
Unfortunately, the data for eptifibatide (Integrilin®) are even more ambiguous, and in some ways problematic, from a cautionary perspective.47 In U.S. and Canadian studies (3827 patients), the combined death/MI rate at 30 days was 15% for placebo and 11.7% for eptifibatide (22% reduction). However, in Western European studies (3697 patients), there was only a 7% relative reduction (14.8% combined adverse end point in placebo, 13.8% with eptifibatide). More disturbing, however, is the finding that in Latin American (396 patients) and Eastern European (1541 patients) trials, there was a net increase in adverse, combined end points with eptifibatide.47 In overall worldwide outcome data, in male patients there was a 16.9% negative end point rate in those on placebo, and in only 13.9% in the eptifibatide treatment arm.
However, in worldwide outcomes evaluating women, negative combined end points were observed in 13.7% of females on placebo, and in 14.9% on the eptifibatide arm (i.e., a net increase of 8% in adverse events in the treatment arm). Once again, the Western and Eastern European study groups, as well as the Latin American trials, showed a marked adverse effect of the drug in women. Moreover, the PURSUIT Trial suggests that the greatest benefits with eptifibatide were observed in patients undergoing PCI, not in those managed pharmacologically. Given the gender-specific efficacy, the differences in responsiveness to PCI and non-PCI subgroups, and some of the discrepancies between regional outcomes with eptifibatide, it is probably prudent at the present to limit use of this agent in favor of other modalities (i.e., abciximab or enoxaparin) until additional studies provide clarification.
The tirofiban data are also sufficiently ambiguous to demand further investigation before this agent can be recommended for routine use. In the RESTORE Trial (2141 patients) at 30 days, there were no statistically significant difference in the incidence if the composite end point (death/MI or any repeat intervention) between the groups receiving tirofiban HCl and placebo (12.2% in the placebo group vs. 10.3% in the tirofiban group, P = 0.16). The PRISM study (3200 patients) also failed to demonstrate significant benefit of tirofiban over heparin. In contrast, the PRISM-PLUS Trial (1550) patients showed a 19% (P = 0.024) risk reduction at six months for tirofiban plus heparin vs. heparin alone (for death/MI/repeat revascularization).48
In summary, the jury is still out on exactly how prominent a role tirofiban and and eptifibatide should play in ED-based antiplatelet management. There may be a place for these agents, but additional clarification is required. Clearly, among the GP IIa/IIIb receptor antagonists per se, the overall data are more compelling for abciximab, especially in certain subgroups (i.e., those undergoing stent-related procedures as part of PCI). However, when this class is compared to the wide range of end point benefits demonstrated for enoxaprin at the one-year end point (ESSENCE), enoxaprin (Lovenox®) seems to be emerging as the initial agent for consideration in patients with acute coronary syndromes (UA/NQMI). The ED role of the GIIb/IIIa receptor antagonists has yet to be defined.
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