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(Circulation. 2001;103:2310.)
© 2001 American Heart Association, Inc.

Cardiovascular Drugs

The Search for Replacements for Unfractionated Heparin

Elliott M. Antman, MD

From the Cardiovascular Division, Brigham and Women’s Hospital, Boston, Mass.

Correspondence to Elliott M. Antman, MD, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail eantman{at}rics.bwh.harvard.edu

	Introduction

Top Introduction Direct Antithrombins Low-Molecular-Weight Heparins Long-Term Treatment References

 
Antithrombotic therapy is central to the management of patients presenting with an acute coronary syndrome (ACS). In addition to powerful new antiplatelet therapies, multiple agents capable of inhibiting thrombin are now available to clinicians (Figure).

View larger version (98K): [in this window] [in a new window]   Figure 1. Activated coagulation cascade and platelet aggregation in patients with an ACS. A, With disruption of a vulnerable plaque, tissue factor (TF) is exposed and ultimately complexes with activated factor VII (VIIa). TF:VIIa complex converts factor X to its active form (Xa). Through a multiplier effect, a single molecule of factor Xa leads to downstream production of many molecules of thrombin through its participation in prothrombinase complex along with factor V and calcium (Ca++) on a phospholipid surface, such as membrane of activated platelets (Plt). Thrombin is a potent agonist for platelet activation via binding to thrombin receptor on platelets. Aggregates of platelets are formed by cross-bridging via attachments of ligands such as fibrinogen (FGN) to the GP IIb/IIIa receptors on adjacent platelets. B, Sites of action of antithrombin and antiplatelet agents. Relative strength of actions at various positions is shown semiquantitatively by size of font in diagram. Thus, UFH has similar inhibitory action against thrombin and factor Xa, whereas LMWH has greater relative inhibitory capacity against factor Xa than thrombin. Direct antithrombins have little effect on generation of thrombin but are potent inhibitors of thrombin that has been formed. In contrast, TFPI and related compounds act more proximally in coagulation cascade to inhibit formation of factor Xa and limit downstream production of thrombin. Combinations of antithrombins shown and antiplatelet agents (bottom of diagram) are effective in reducing propensity to thrombus formation at the site of a disrupted vulnerable plaque.

Although familiar to the vast majority of clinicians, unfractionated heparin (UFH) has the disadvantages of a variable anticoagulant effect (necessitating frequent monitoring of the activated partial thromboplastin time [aPTT]), sensitivity to platelet factor 4, a relative inability to inhibit clot-bound thrombin, and the potential to cause thrombocytopenia and the heparin-induced thrombocytopenia syndrome (HITS). Novel pharmacological regimens most extensively investigated in clinical trials as alternatives to UFH include the direct antithrombins and the low-molecular-weight heparins (LMWHs).¹

	Direct Antithrombins

Top Introduction Direct Antithrombins Low-Molecular-Weight Heparins Long-Term Treatment References

 
Direct antithrombins inhibit thrombin without requiring the cofactor antithrombin. All of the direct antithrombins exhibit a concentration-dependent anticoagulant effect. In vitro observations have identified some differences among the agents (eg, binding characteristics to thrombin, ability to inhibit generation of thrombin), but it is unclear whether such differences have any important impact on their clinical use. Because clot-bound thrombin is less effectively inhibited by UFH (because attachment of fibrin to the fibrin-binding domain makes the heparin-binding domain inaccessible), it was proposed that the direct antithrombins had an advantage over UFH because of their greater ability to block both fluid-phase and clot-bound thrombin. This "thrombin hypothesis" was the inspiration for several randomized trials.

After the TIMI 9A, GUSTO IIa, and HIT 3 trials, which tested hirudin as an adjunct to fibrinolytic therapy, were terminated prematurely, the doses of both hirudin and UFH were reduced and the TIMI 9B² , GUSTO IIb,³ and HIT 4⁴ trials were undertaken. Pooled data from GUSTO IIb and TIMI 9B showed that hirudin was more effective at achieving and maintaining the target aPTT range. By careful adjustment of the doses of both hirudin and UFH, major bleeding could be reduced. There was no difference in mortality, however, in UFH- versus hirudin-treated patients; there was a 14% reduction in reinfarction by 30 days in patients treated with hirudin.⁵ A post hoc analysis of the GUSTO IIb data suggested that hirudin was more beneficial as an adjunct to streptokinase than to tissue plasminogen activator (tPA); this was not observed, however, in TIMI 9B.^{2 6} There were no significant differences between hirudin and UFH as adjuncts to streptokinase with respect to TIMI 3 flow rates or 30-day mortality in HIT 4, although the proportion of patients achieving complete ST-segment resolution at 90 minutes tended to be higher in the hirudin group.⁴

Potential explanations for the lack of significant benefit of hirudin in the trials noted above include:

1. UFH is capable of inhibiting the coagulation cascade upstream from thrombin and thus has an advantage over hirudin by decreasing both thrombin generation and activity. In contrast, hirudin has a greater ability to inhibit thrombin activity. Once the thrombin-inhibitory capacity of hirudin is exceeded (ie, higher concentrations of thrombin relative to the concentration of hirudin), thrombosis may occur.^{5 7}

2. The ability of hirudin to inhibit clot-bound thrombin is only 50% as potent as its ability to inhibit fluid-phase thrombin, which minimizes its potential advantage over UFH.⁷

3. UFH is a catalytic inhibitor of thrombin capable of dissociating from the antithrombin:thrombin complex, enabling a single molecule of UFH to catalyze the action of multiple molecules of antithrombin. In contrast, hirudin binds tightly in a 1:1 stoichiometric fashion to thrombin in both the fluid phase and the clot-bound phase. It is potentially possible to "exhaust" the supply of hirudin, permitting thrombin molecules to remain enzymatically active. Increasing the concentration of hirudin to inhibit more thrombin appears to be associated with unacceptable bleeding rates.⁵

The HERO investigators hypothesized that direct antithrombins must be administered before initiation of fibrinolytic therapy to maximize inhibition of thrombin activity. This concept is being tested in the HERO-II trial comparing bivalirudin with UFH as adjunctive therapy to patients receiving streptokinase for ST-segment–elevation myocardial infarction (MI).⁸ It has also been proposed that bivalirudin is a safer direct antithrombin than hirudin, because thrombin slowly cleaves the Arg₃-Pro₄ bond of bivalirudin, reexposing the catalytic site of thrombin and allowing hemostasis to occur.⁹

Pooled data from trials of ACS patients with ST-segment–elevation MI showed a significant reduction in the rate of death or MI favoring hirudin over UFH during the first 72 hours (relative risk 0.72, P=0.0002).¹⁰ The treatment effect lessened progressively over time such that the relative risk was 0.83 (P=0.004) at 7 days and was 0.90 (P=0.057) at 35 days.¹⁰ These observations are consistent with a potent effect of hirudin on thrombin activity while the antithrombins were being compared in a head-to-head fashion. After discontinuation of hirudin, which has no effect on generation of thrombin other than blocking the autofeedback amplification of thrombin on factors V and VIII, there may have been a rebound activation of the coagulation cascade, lessening the difference in event rates in hirudin- and UFH-treated patients by 35 days.

There have been 2 major trials of direct antithrombins in patients undergoing PTCA, both of which were conducted in an era when stents and intravenous glycoprotein (GP) IIb/IIIa inhibitors were not used. In the HELVETICA trial, there was a reduction in a composite cardiovascular end point in hirudin- versus UFH-treated patients at 96 hours, but this was no longer significant at 30 weeks.¹¹ In a bivalirudin study, although there was no difference between bivalirudin- and UFH-treated patients in the incidence of a composite cardiovascular end point, bleeding was less frequent with bivalirudin.¹² Also, a prespecified subgroup analysis of high-risk patients (postinfarction unstable angina) showed a lower incidence of the composite end point in patients treated with bivalirudin.

In the TRIM study, patients with an ACS and no ST-segment elevation received a 72-hour treatment with a low, medium, or high dose of inogatran or UFH.¹³ Although a dose-dependent prolongation of the aPTT was observed in inogatran-treated patients, the primary end point of death, recurrent infarction, and refractory or recurrent ischemia was not reduced.

	Low-Molecular-Weight Heparins

Top Introduction Direct Antithrombins Low-Molecular-Weight Heparins Long-Term Treatment References

 
LMWH preparations are formed by controlled enzymatic or chemical depolymerization, producing saccharide chains of varying length but with a mean molecular weight of 5000 Da.¹ In addition to the critical pentasaccharide for attachment of a heparin fragment to antithrombin, an additional 13 saccharide residues are necessary to allow the heparin fragment to simultaneously attach to the heparin-binding domain of thrombin and create a ternary complex. Only the critical pentasaccharide sequence is required, however, for binding to antithrombin and inhibition of factor Xa. Thus, by creating a mixture of short-chain and long-chain fragments, preparations of varying anti-Xa:anti-IIa activity may be developed. Additional features of LMWHs of particular clinical relevance are a decreased sensitivity to platelet factor IV; a more stable, reliable anticoagulant effect via the subcutaneous route; and lower rates of thrombocytopenia and HITS.

The LMWH preparations tested in ACS patients vary in anti-Xa:anti-IIa activity, ionic nature (sodium or calcium salt), chemical structure on the reducing and nonreducing ends of the chains, and release profile of tissue factor pathway inhibitor (TFPI).¹ Given these differences and variation in clinical effectiveness in other conditions such as venous thromboembolism,¹⁴ regulatory authorities have insisted that LMWHs not be considered a single class of agents and require that the treatment effect of each LMWH preparation be evaluated independently.^{1 15}

Consistent with the pooled data from trials of UFH, there was a significant reduction in the rate of death or MI in aspirin-treated patients with unstable angina/non–ST-segment–elevation MI given dalteparin versus placebo (FRISC¹⁶ ). Trials of LMWHs versus UFH in combination with aspirin are more difficult to interpret. In analyses that pool all LMWHs versus UFH, some authors have concluded that there is no evidence of superiority of LMWH over UFH with respect to prevention of death or MI.¹⁷ In addition to chemical differences in LMWHs and uncertainty about the relative antithrombotic potencies of the doses of the different LMWHs tested in the trials, however, one must also consider differences in severity of illness of patients enrolled and definitions of the composite primary end points, which raises questions about the advisability of pooling all LMWHs as a class.

The FRIC¹⁸ and FRAX.I.S¹⁹ trials were designed as superiority trials comparing dalteparin and fraxiparine, respectively, versus UFH in patients with non–ST-segment–elevation ACS. The enrollment windows after the qualifying episode of ischemic discomfort for FRIC and FRAX.I.S. were 72 and 48 hours, respectively. Neither trial showed superiority over LMWH. Possible explanations include the relatively low anti-Xa:anti-IIa ratio of dalteparin in FRIC and the reduced severity of illness of the patients enrolled in both trials.

In contrast to the dalteparin and fraxiparine studies, ESSENCE²⁰ and TIMI 11B²¹ independently showed superiority of enoxaparin (anti-Xa:anti-IIa ratio of 3.8:1) over UFH with respect to a composite cardiovascular end point. Detailed analyses revealed that the treatment benefit of enoxaparin appeared early (within 48 hours) when a direct head-to-head comparison with UFH was occurring, was present even in patients who had optimal levels of anticoagulation with UFH, was of a similar magnitude in patients who were treated exclusively medically and in those who underwent a percutaneous revascularization procedure after a period of initial medical stabilization, and was evident in troponin-positive patients even if creatine kinase–MB levels were not elevated.²² After discontinuation of treatment, a rebound increase in ischemic episodes on ST-segment monitoring is seen more frequently with UFH than enoxaparin.²² Although the unit cost of treatment with enoxaparin is greater than that of UFH, enoxaparin therapy was found to be an economically dominant strategy because it reduced the rate of events and the need for revascularization procedures.²³ A simple bedside risk score clearly shows that the treatment effect of enoxaparin increases progressively as a patient’s level of risk increases.²⁴

A prespecified meta-analysis of the 2 enoxaparin trials showed stable 20% reductions in death/MI/urgent revascularization and death/MI favoring enoxaparin through 43 days.²⁵ The benefits of enoxaparin were achieved by similar proportionate reductions in each of the elements of the composite end points, indicating that the results were not driven by any single element. At 1 year, the rate of death/MI/urgent revascularization remained significantly lower in enoxaparin-treated patients (23.3% versus 25.8%, P=0.008).

Possible explanations for the clinical trial findings of superiority of enoxaparin over UFH, in contrast to the findings with dalteparin and fraxiparine, include its greater anti-Xa:anti-IIa ratio compared with dalteparin, the greater severity of illness in the patients enrolled, and extension of its antithrombotic actions to include inhibition of platelet aggregation by suppression of the release of von Willebrand factor.²⁶ Important differences between the findings of the enoxaparin trials versus those with other LMWHs may be obscured not only by pooling of the trials but also by focusing on the comparative rates of death/MI at extremely early time points when the low rate of events results in <60% power to demonstrate even a 20% reduction in death/MI with a LMWH (eg, only 276 total events were analyzed out of 12 171 patients collectively enrolled in the studies pooled by Eikelboom et al¹⁷ ).

It has been argued that the benefits of enoxaparin were biased by a high rate of revascularization procedures and periprocedural MIs, especially after CABG.²⁷ It seems unlikely that differences in periprocedural MIs explain the benefits of enoxaparin, for several reasons. For both the ESSENCE and TIMI 11B trials, the Kaplan-Meier curves for death/MI/urgent revascularization separated early (within 48 to 72 hours) before many of the revascularizations occurred. Construction of such curves censors a patient’s follow-up once any element of the composite end point occurs, so that procedure-related MIs after a prior spontaneous MI or referral for urgent revascularization would not contribute to the comparison of the 2 antithrombin treatments. Furthermore, as presented to the FDA, only 0.6% of patients in ESSENCE experienced an end point through 30 days after a first revascularization procedure.²⁸ Such subtleties are not reflected in simple counts of the number of MIs and revascularization procedures in the trials.²⁷ Definitive proof of superiority of enoxaparin versus UFH for the prevention of the hard end point of death or MI in the absence of procedures would require a large trial in which patients were treated only medically during the acute phase of management of unstable angina/non–ST-segment–elevation MI—a difficult trial to conduct in the present era, in which there is mounting evidence of the benefits of proceeding to an early invasive strategy.

Major bleeding appears to be similar in patients treated with LMWHs versus UFH, but minor episodes of bleeding, such as ecchymoses at injection sites, are more common.²⁵

LMWHs have been investigated in patients with ST-segment–elevation MI. The rate of TIMI 3 flow tended to be higher in tPA-treated patients receiving enoxaparin compared with UFH in the HART II trial (presented at the American College of Cardiology [ACC] 2000 Scientific Session). Additional supportive evidence of the importance of inhibition of the coagulation cascade at a proximal location is the attainment of comparable TIMI 3 flow rates in tPA-treated patients given a specific factor Xa inhibitor versus UFH in the PENTALYSE study (presented at ACC 2000). Compared with UFH, enoxaparin treatment was associated with improved late angiographic findings, higher rates of complete ST resolution, and improved clinical outcomes among patients treated with streptokinase (AMI-SK Trial, presented at the American Heart Association [AHA] 2000 Scientific Sessions). Similarly, compared with UFH, dalteparin treatment was associated with fewer coronary occlusions, a lower incidence of coronary thrombus, and fewer reinfarctions during the first week among patients treated with tPA (ASSENT-Plus Trial, presented at AHA 2000). Ongoing evaluations of enoxaparin versus UFH include an angiographic study in patients receiving full-dose TNK and those receiving reduced-dose TNK in combination with abciximab (ENTIRE–TIMI 23 trial) and a comparison of clinical events with full-dose TNK (ASSENT 3 and ASSENT 3 PLUS studies).

Some clinicians have delayed a switch from UFH to LMWHs in their practices because of uncertainty about administration of LMWHs in patients undergoing catheterization and those receiving intravenous GP IIb/IIIa inhibitors. The available data are quite encouraging in these areas. Pilot studies reported safety data comparable to those seen historically with UFH when enoxaparin was used as the antithrombin in patients undergoing percutaneous coronary interventional procedures in both the absence (NICE 1) and presence (NICE 4) of abciximab.²⁹ The NICE 3 study reported similar non-CABG major bleeding rates when enoxaparin was combined with either tirofiban, eptifibatide, or abciximab compared with previously reported experience with UFH (presented at the European Society of Cardiology 2000 Annual Congress). Compared with UFH plus tirofiban, the coadministration of enoxaparin and tirofiban was associated with more consistent inhibition of platelet aggregation and lower bleeding time in the ACUTE 1 study, supporting the notion that combining an LMWH with an intravenous GP IIb/IIIa inhibitor may provide enhanced efficacy and safety in patients with an ACS.³⁰

	Long-Term Treatment

Top Introduction Direct Antithrombins Low-Molecular-Weight Heparins Long-Term Treatment References

 
Because clinical events continue to occur over the first year after hospitalization or an ACS without ST-segment elevation, LMWHs have been studied during chronic-phase treatment. In trials, such as TIMI 11B, in which high-risk patients generally underwent revascularization procedures during the index hospitalization or shortly thereafter, predominantly low-risk patients remained available for study during the chronic phase; no incremental benefit of an additional month of enoxaparin injections was seen in such patients.²¹ Data from the FRISC II trial suggest that some benefit in preventing death/MI over 90 days can be achieved with dalteparin in high-risk patients (eg, troponin-positive) who cannot be managed by an early invasive strategy.³¹ Oral anticoagulation with warfarin at a low level of intensity does not reduce the rate of clinical events in patients with a variety of ACS presentations treated with aspirin over the long term.³² Oral anticoagulation at a moderate or high level of intensity (INR >2.4) in the presence of aspirin, however, reduces the rate of clinical events, but at the expense of a slight increase in the risk of bleeding.³²

Conclusions
The currently available intravenously administered direct antithrombins provide a more consistent anticoagulant effect and short-lived benefit over UFH. Hirudin, approved for anticoagulation in patients with HITS, is not more convenient than UFH, because aPTT monitoring and dose adjustment is needed to minimize bleeding. Bivalirudin has been approved for anticoagulation during angioplasty procedures in patients with unstable angina, offering clinicians effective antithrombin support for the procedure with a reduced risk of bleeding. The appropriate dose of bivalirudin when GP IIb/IIIa inhibitors are administered remains to be established. Hirudin and another direct antithrombin, argatroban, are approved for anticoagulation in patients with HITS. There is no direct inhibitor of the anticoagulant effect of direct antithrombins; their effect is dissipated by cessation of the infusion and clearance of the drug.

All LMWHs offer a convenience advantage over UFH. The available data suggest that when dalteparin or fraxiparine is used in patients with non–ST-segment–elevation ACS, efficacy findings are similar to those for UFH. Superiority over UFH has been seen in patients treated with enoxaparin.²⁵ Stoichiometric neutralizing doses of protamine reverse 100% of the anti-IIa effect of LMWHs and 67% of the anti-Xa effect.³³

A major drawback to all the forms of antithrombotic therapy discussed above is the generalized systemic nature of drug administration. Unacceptable levels of hemorrhage occur in many patients even in the face of therapeutic efficacy. A logical avenue of investigation is local delivery of antithrombotic agents in high concentration at the site of vascular damage. Given the central role of tissue factor in initiating the coagulation cascade at sites of vascular injury, interest has arisen in inhibiting tissue factor. Adenoviral gene transfer of recombinant TFPI in animal models has been shown to prevent local arterial thrombus formation and the hyperplastic intimal response after balloon-induced injury without causing hemostatic impairment.³⁴ Local drug delivery via stents coated with immobilized drug or coated with a drug-releasing polymer matrix offers the possibility of focal therapeutic drug effect within target tissues without the bleeding risk arising from systemic drug administration.³⁵ Finally, it may be possible to reduce the cost of production of new antithrombotic agents by their expression in biological factories, such as the milk of transgenic animals.³⁶

Despite its current widespread use across the spectrum of ACS, it seems likely that UFH will be used less frequently in the future as the role of newer antithrombin agents is clarified by additional research.

	Footnotes

 
Dr Antman has received research grant support from Aventis, Novartis, Centocor, and Lilly.

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Top Introduction Direct Antithrombins Low-Molecular-Weight Heparins Long-Term Treatment References

 
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				M. S. Sabatine, D. A. Morrow, A. Dalby, M. Pfisterer, T. Duris, J. Lopez-Sendon, S. A. Murphy, R. Gao, E. M. Antman, E. Braunwald, et al. Efficacy and Safety of Enoxaparin Versus Unfractionated Heparin in Patients With ST-Segment Elevation Myocardial Infarction Also Treated With Clopidogrel J. Am. Coll. Cardiol., June 12, 2007; 49(23): 2256 - 2263. [Abstract] [Full Text] [PDF]

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