Dr. Garas is an Interventional Cardiology Fellow at Emory University, Atlanta, GA. He received his MD in 1995 from the University of Missouri.

Dr. Marshall is an Associate Professor of Medicine at Emory University and the Director of the Catheterization Laboratory at Crawford Long Hospital, Atlanta, GA.

Atherosclerotic coronary artery disease (CAD) is the most common cause of morbidity and mortality in the United States. According to the American Heart Association, in 1997 there were 466,101 deaths attributed to coronary artery disease. ¹ It constitutes the largest health expenditure in the United States. Around the world, coronary artery disease is quickly becoming the most common cause of morbidity and mortality. The worldwide economic impact of coronary disease is staggering and is on the rise.

Acute coronary events are triggered by rupture or disruption of an atherosclerotic plaque and a subsequent thrombotic process in the coronary artery. Disrupted plaques, which can result in decreased coronary blood flow or obstruction, are a fundamental step in the pathogenesis of acute coronary syndromes (ACS) and are found beneath 75% of the thrombi responsible for acute coronary syndromes. Percutaneous coronary intervention (PCI) is inherently thrombogenic. Deep vessel wall injury induced by balloon dilatation and stent implantation triggers thrombosis resulting in thrombin generation, platelet activation, and a profound, systemically detectable inflammatory response. This is a complex, multifactorial process that involves simultaneous and interrelated pathways. These pathways are initiated by exposure to substances in damaged cells and ruptured plaque. As the coagulation cascade is initiated by tissue factor and collagen, platelet adhesion, activation, and aggregation occur in a parallel process. Thrombin plays a central role in thrombogenesis through activating platelets, converting fibrinogen to fibrin, amplifying coagulation by activating factors V and VIII, and stabilizing the fibrin clot through activation of factor XIII. Antithrombotic therapy, therefore, is critical in the treatment of ACS and during PCI. Antithrombotic therapy includes antiplatelet agents, anticoagulants, and fibrinolytics. This article will review the antithrombotic agents: unfractionated heparin (UFH), low molecular weight heparins (LMWHs), and direct antithrombins (figure 1).

Unfractionated heparin

Unfractionated heparin is the mainstay of therapy for ACS and PCI. It was discovered in 1916 from a liver extract. The name is derived from the Latin word hepar, which means liver. Commercial preparations are a mixture of glycosaminoglycans ranging in molecular weight from 3000 to 30,000 daltons. Only about one-third of all the heparin molecules have the pentasaccharide sequence necessary to attach antithrombin (AT). By attaching to AT, heparin enhances its activity by a thousand times. Thrombin that is already fibrin-bound, however, is protected from this inactivation. Heparin activity can be monitored using activated partial thromboplastin time (aPTT) or activated clotting time (ACT). It is important to note that there are two devices used to measure ACT: the Hemochron (International Technidyne Corp., Edison, NJ) and HemoTec (Medison Perfusion, Inc., Parker, CO) devices. The Hemochron device tends to yield higher values (30 to 50 sec) for any given level of systemic anticoagulation than the HemoTec device.

UFH in ACS

In unstable angina, heparin has been shown to reduce myocardial infarction (MI) and mortality. ² Heparin is superior to aspirin alone in preventing recurrent ischemic symptoms in patients with unstable angina. ³ Continuous intravenous (IV) heparin administered in the acute period after unstable coronary artery disease reduces the likelihood and severity of subsequent ischemic events. Heparin is also recommended for all patients presenting with acute MI, if no contraindications exist. ⁴

UFH in PCI

Since the advent of PCI, heparin has remained the primary antithrombotic therapy for the prevention of periprocedural ischemic complications. There are no large prospective, placebo-controlled trials evaluating the efficacy of heparin during PCI. Two small trials showed improved outcome with heparin therapy in patients presenting with unstable angina due to thrombus containing lesions by angiography. ^5,6 While ACT measurements are commonly made during coronary angioplasty to guide heparin dosing, the optimal dosing regimen has never been clearly defined. In a recent study by Chew et al ⁷ in which they evaluated data from 6 randomized trials encompassing 5216 patients, an ACT in the range of 350 to 375 seconds provided the lowest ischemic event rate.

Conclusions concerning UFH

Heparin remains a very attractive antithrombotic agent; it is relatively inexpensive, most clinicians are very familiar with it, and it has a readily available antidote (protamine sulfate). However, heparin is associated with a number of limitations. Heparin must rely on antithrombin to exert inhibitory effects on thrombin. In some cases, it is difficult to achieve a target ACT in patients who have received prior heparin infusions. The degree of nonspecific binding can vary from patient to patient since the concentration of heparin-binding proteins increases in acute illness, such as ACS. Patients with ACS require higher doses of heparin to achieve target ACT levels during PCI. Platelet factor 4 inhibits heparin, thus reducing its effectiveness, and clot-bound thrombin is not inhibited by the heparin-antithrombin complex. Heparin exhibits nonlinear pharmacokinetic and pharmacodynamic characteristics, with heparin's half-life increasing in a nonlinear fashion as the dose increases. Newer antithrombotic agents have to improve on the pitfalls noted with heparin in order to be helpful and gain widespread acceptance.

Low molecular weight heparins

Low molecular weight heparins provide more reliable anticoagulation and less need for patient monitoring and dosage adjustment than with standard UFH; therefore, they are well suited for long-term anticoagulation or outpatient therapy. Low molecular weight heparins are gaining acceptance as an alternative to UFH during ACS. Additionally, there are multiple studies under way to elucidate their role in PCI and ST-elevation MI. When compared with UFH, LMWHs have fewer side effects, such as heparin-induced osteopenia and heparin-induced thrombocytopenia (HIT). They also provide consistent bioavailability due to less binding to plasma proteins, platelet factor 4, endothelial cells, and macrophages. In addition, they provide better subcutaneous delivery and longer half-life that permits dosing once or twice daily. ⁸ In general, these advantages provide for a more predictable response that requires no aPTT monitoring.

Low molecular weight heparin preparations are formed by controlled enzymatic or chemical depolymerization, producing saccharide chains of varying lengths but with a mean molecular weight of approximately 5000 daltons. The LMWHs approved for use in the United States include enoxaparin, dalteparin, nadroparin, and tinzaparin. They all have greater anti-Xa:IIa ratios compared with UFH. In addition, the LMWH preparations used have a varying degree of anti-Xa:IIa activity, which may in part explain the differences observed in their respective outcomes. Consequently, LMWHs should not be considered as a single class of agents.

Approximately 15,000 patients were enrolled in 6 large randomized clinical trials of LMWHs, including enoxaparin, dalteparin, or nadroparin. The results of these trials have been generally very encouraging, especially for enoxaparin. Comparing these trials is difficult because of the differences between agents and trial designs (Table 1).

Low molecular weight heparins in ACS

Two trials of enoxaparin substantiated the role of LMWHs in patients with ACS. ^9-11 In the ESSENCE (Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q wave Coronary Events) trial, 3171 patients received either enoxaparin given as 1 mg/kg subcutaneously without a bolus or UFH, in addition to aspirin. Heparin dosage was adjusted to maintain aPTT between 55 and 85 seconds regardless of the reagent used by each institution. Compared with UFH, enoxaparin decreased the composite end point (death, MI, and revascularization) at day 14 (16.6% vs. 19.8%, P = 0.019) and at day 30 (19.8% vs. 23.3%, P = 0.016). The rate of major bleeding was similar between groups; however, enoxaparin was associated with a higher rate of minor bleeding at day 30.

Results of the TIMI-11B (Thrombolysis In Myocardial Infarction) trial further support a role for enoxaparin in patients with ACS. ¹⁰ A total of 3910 patients with unstable angina or non-Q wave MI were randomized to receive enoxaparin 30-mg bolus (IV) followed by 1 mg/kg subcutaneously every 12 hours or UFH 70-U/kg (IV) bolus followed by 15 U/kg/hour continuous infusion. During the short-term phase, UFH was continued for a mean of 3 days and enoxaparin for 4.6 days. The long-term phase consisted of fixed enoxaparin 40 mg every 12 hours for patients weighing <65 kg and 60 mg every 12 hours for those weighing more, or placebo. The primary end point was a composite of death, MI, and recurrent angina requiring urgent revascularization. At 48 hours, day 8, and day 14, patients randomized to enoxaparin showed a significant reduction in the composite end point compared with those treated with UFH (day 14, 12.4% vs. 14.5%, P = 0.048). Notably, only 50% of patients receiving weight-based UFH were within target aPTT range at 24 to 48 hours. In fact, more patients were subtherapeutic (18.9%) at 24 hours than in the ESSENCE trial. At day 43 after continued long-term dosing, no additional benefit was observed; however, enoxaparin was associated with a higher rate of major bleeding (2.9% vs. 1.5%, P = 0.021).

Meta-analysis of the data from both the TIMI-11b and ESSENCE trials showed a 20% reduction in the composite of death or MI at 8 days ( P = 0.02) and persisting at 14 days ( P = 0.02). ¹¹ At 1 year, the rate of death, MI, and urgent revascularization remained significantly lower in enoxaparin-treated patients (23.3% vs. 25.8%, P = 0.008). However, within both studies, there was a modest increase in minor hemorrhage associated with the use of LMWH mostly at injection sites.

Other LMWHs have not fared as well in randomized trials. The FRISC (Fragmin during Instability in Coronary Artery Disease) trial randomized ACS patients to receive dalteparin or placebo. The primary end point of death and MI at 6 days was lowered in patients treated with dalteparin as compared with placebo (1.8% vs. 4.8%). ¹² In the subsequent FRISC-2 trial, the use of dalteparin compared with placebo appeared to reduce the rates of death or MI within the first 30 days. However, by 90 days, the curves had converged and the difference was no longer significant. ¹³ In the FRAXIS (FRAXiparin in the Ischemic Syndromes) study, patients with ACS were randomly assigned to receive either UFH or nadroparin for 2 durations of therapy. There was no difference between the two groups in the primary end point of death, MI, or recurrent angina at 14 days ( P = 0.85). ¹⁴

LMWHs in PCI

An increasing number of patients with ACS are being treated with LMWHs prior to coronary angioplasty. The use of LMWH during PCI remains investigational. The FRISC-2 trial is noteworthy in the context of PCI, as it was the first study to demonstrate a benefit for invasive management and revascularization among patients with ACS. Some of the benefit seen is thought to be due to the extended pretreatment with dalteparin. ¹³ The REDUCE (reduction of restenosis after PTCA, early administration of reviparin in a double-blind unfractionated heparin and placebo-controlled) study randomized 625 patients undergoing elective PCI to receive reviparin or UFH. The study was designed to detect a difference in restenosis and, consequently, the results were negative. Interestingly, during initial hospitalization, there was a significant reduction in the frequency of salvage stent placement among patients treated with reviparin compared with UFH (6% vs. 2%). The occurrence of major clinical events (death, MI, need for reintervention or bypass surgery) was not reduced ( P = 0.707). ¹⁵

Several registry studies have been performed recently, including NICE 1, 3, and 4 (the National Investigators Collaborating on Enoxaparin study) as well as a registry of dalteparin in patients undergoing PCI. Several findings from these studies are noteworthy. In NICE 1, enoxaparin was given IV in combination with a GP IIb/IIIa inhibitor. In the dalteparin registry, dalteparin was used at one of several doses, each in combination with abciximab. The registries are notable for relatively low rates of ischemic events, which appeared to be very much in keeping with those observed in previous randomized trials of UFH with GP IIb/IIIa antagonists. The rates of bleeding also appeared to be comparable.

These studies should be interpreted with caution. First, there were no control groups in these registry studies, making comparison with UFH impossible. Second, the rigor with which events are ascertained may differ between registries and randomized controlled trials. Thus, the interpretation is that LMWHs probably can be used during PCI, but whether they are better than or worse than standard therapies involving UFH and GP IIb/IIIa antagonists remains to be determined.

LMWHs in ST-elevation MI

There are several completed and ongoing trials evaluating the use of LMWHs in the setting of ST-elevation MI. The HART-II (Heparin and Aspirin Reperfusion Therapy) trial investigated the use of LMWHs in patients receiving tissue plasminogen activator (tPA) for acute MI. This trial showed a trend toward improved coronary patency at 90 minutes in patients receiving LMWH. ¹⁶ Another trial, the ASSENT-3 (Assessment of the Safety and Efficacy of a New Thrombolytic Regimen) study, showed that tenecteplase plus enoxaparin reduces the frequency of ischemic complications of an acute MI. ¹⁷

Conclusions concerning LMHs

There is convincing evidence that LMWHs, more specifically enoxaparin, can be used effectively in the treatment of acute coronary syndromes. Preliminary data in the settings of PCI and ST-elevation MI are promising and suggest potential roles for the LMWHs. As these data emerge, we may begin to feel more comfortable with the idea of using LMWHs in conjunction with other therapies that currently are regarded as standards of care in patients with CAD. More data are needed, particularly randomized and double-blinded therapy trials to determine whether the LMWHs will become established as the first line of therapy (Table 1).

Direct thrombin inhibitors

Direct antithrombins inhibit thrombin without requiring the cofactor antithrombin. They exhibit a concentration-dependent anticoagulant effect. They can block both fluid-phase and clot-bound thrombin, and they are not inactivated by platelet factor 4. These properties of the direct antithrombins provide hope in the pursuit of an ideal anticoagulant, but whether these theoretical benefits will translate into clinical efficacy remains in question.

The prototype of the direct thrombin inhibitors is hirudin, originally isolated from the saliva of the medicinal leech. Lepirudin and desirudin are recombinant agents, and bivalirudin is a synthetic derivative of hirudin. These agents may differ in their pharmacodynamic, pharmacokinetic, and safety profiles, and therefore each of them may produce different clinical outcomes.

Direct antithrombins in ACS

As part of the GUSTO IIb (Global Use of Strategies to Open Occluded Coronary Arteries) study, more than 8000 patients were randomized to treatment with hirudin or UFH. The primary end point of death or MI at 30 days was not notably different between treatment groups (8.3% vs. 9.1%). ¹⁸ In the OASIS-1 (Organization to Assess Strategies for Ischemic Syndromes) pilot study, the combined end point of death, MI, or refractory angina occurred in 4.4% of patients treated with low-dose hirudin, 3.0% of patients treated with moderate-dose hirudin, and 6.5% of patients treated with UFH. ¹⁹ Consequently, OASIS-2 was performed in which approximately 10,000 patients were randomized to treatment with this moderate dose regimen of hirudin or UFH. The primary end point of death or new MI at 7 days occurred in 3.6% of those treated with hirudin and 4.2% of those treated with heparin ( P = 0.08). The composite end point of death, MI, or refractory angina occurred in 5.6% of those treated with hirudin and 6.7% of those treated with UFH. Major bleeding was more common with hirudin (1.2% vs. 0.7%). ²⁰

Direct antithrombins in PCI

There have been 2 major trials of direct antithrombins in patients undergoing PCI, both of which were conducted in an era when stents and GP IIb/IIIa inhibitors were not used. In a comparison study of hirudin with heparin in the prevention of restenosis after coronary angioplasty (HELVETICA), there was a reduction in a composite cardiovascular end point in hirudin versus UFH treated patients at 96 hours, but the differences were no longer apparent at 30 weeks. ²¹

The Bivalirudin Angioplasty Trial (BAT) was a randomized, double-blind trial of 4312 patients with ACS undergoing percutaneous transluminal coronary angioplasty. ²² The final analysis of adjudicated data is based on the intent to treat population of 4312 patients. The clinical efficacy end point was defined as a composite of death, clinical or enzymatically defined MI, or repeat revascularization. All patients were given aspirin in an oral dose of 300 to 325 mg prior to coronary angioplasty and daily thereafter. Patients were randomized to receive either: bivalirudin (a bolus of 1 mg/kg, a 4-hour infusion of 2.5 mg/kg/hr followed by a 0.2-mg/kg/h infusion for up to an additional 20 hours) or UFH (a bolus of 175 U/kg, followed by 18- to 24-hour infusions of 15 U/kg/hr). The composite end point of death, MI, revascularization, or major hemorrhage was significantly reduced in patients treated with bivalirudin ( P <0.001).

The incidence of death, MI, or revascularization was 7.9% for heparin-treated patients and 6.2% for bivalirudin-treated patients ( P = 0.039). The absolute difference was maintained at 90 days ( P = 0.012). Based on these recently adjudicated results, the FDA has granted approval for the use of bivalirudin during PCI. ²³

Direct antithrombins in ST-elevation MI

Several large trials have evaluated the utility of direct thrombin inhibitors as adjunctive therapy in patients with ST elevation treated with thrombolytic therapy. After the TIMI 9A, GUSTO IIa, and HIT-3 (Hirudin for Improvement of Thrombolysis) trials were terminated prematurely, the doses of both hirudin and UFH were reduced and the TIMI 9B, ²⁴ GUSTO IIb, ¹⁸ and HIT-4 ²⁵ trials were undertaken. In the TIMI 9B trial, the composite primary end point occurred in 12.9% of hirudin-treated patients and 11.9% of heparin-treated patients ( P = NS). In the GUSTO IIb trial, death or MI at 30 days occurred in 9.9% of those treated with hirudin and 11.3% of those treated with heparin ( P = 0.06). Taken together, the TIMI 9B and GUSTO IIb findings suggest little, if any, benefit of routinely using hirudin over UFH as an adjunctive therapy in patients treated with thrombolytic therapy and aspirin. Other smaller trials using different agents have produced similar mixed results.

Conclusions concerning direct antithrombins

Direct antithrombins provide significant theoretical advantages over UFH. Initial clinical trial results have been disappointing. More recent data, especially those from the bivalirudin angioplasty trial, provide renewed optimism in this class of agents. Additionally, hirudin has been shown to be a safe alternative to heparin in patients diagnosed with HIT. Further studies are under way to assess the use of direct antithrombins in a number of clinical settings, including a trial to evaluate bivalirudin in the modern PCI era using stents and GP IIb/IIIa receptor blockers (Table 2).

Conclusion

Unfractionated heparin remains the standard antithrombotic agent used in ACS and during PCI. Two newer classes of antithrombotic agents, LMWHs and direct antithrombins, provide promising alternatives. Data are accumulating, especially with enoxaparin and bivalirudin, which may lead to a change in our choices of adjunctive antithrombotic agents in the near future.