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Low Molecular Weight Heparins in the
Management of Acute Coronary Syndromes
James J. Ferguson III, MD
St. Luke's Episcopal Hospital, Texas Heart
Institute, Baylor College of Medicine, T
he University of Texas Health Science Center at Houston, Houston, Texas, USA
Recent years have witnessed a veritable explosion in the number of therapeutic options available to us for the management of patients with acute coronary syndromes. In the old days we had aspirin, heparin, nitrates, beta blockers and thrombolytic therapy (for acute MI). These restricted thrombo-regulatory capabilities severely limited the efficacy of therapy. Recurrent events were frequent, and coronary intervention was a hazardous undertaking. But now we have a lot more options.
In addition to vastly improved interventional capabilities (with IIb/IIIa antagonists and user-friendly stents), we now have low molecular weight heparins, safer thienopyridines, thrombin inhibitors, even more IIb/IIIa antagonists, and newer generation fibrinolytics. Numerous trials have shown the benefit of these forms of therapy over traditional therapy with aspirin and unfractionated heparin. In some respects the messages are confusing, but in one area they all agree: we can do better than aspirin and UF heparin.
A lot of recent attention has been directed at LMW heparins. In many countries, they are the primary first-line therapy in ACS patients. In the United States, the use of LMW heparins has lagged somewhat behind. The present paper will review coagulation, discuss the LMW heparins and how they work, and finally (rather than providing a rote recitation of the already-well-known results of the LMWH clinical trials) synthesize the available information to provide perspective on how LMW heparins can be used in modern-day clinical practice.
COAGULATION AND ANTITHROMBOTIC RX: HEPARIN
AND LMW HEPARINS
The coagulation process consists of three primary steps: initiation, amplification, and propagation . At the site of initial vessel injury, two things happen in parallel: first, platelets adhere and are activated; secondly, tissue injury exposes tissue factor, initiating the thrombotic cascade. Importantly, these two processes proceed in closely-linked harmony. As platelets are activated, they secrete their granule contents (activating adjacent platelets), change their shape and membrane structure, and finally aggregate or accumulate at the site of injury. The thrombotic cascade proceeds as large pre-assembled "packages" of key coagulation elements are assembled on the activated platelet membrane (amplification) and beget further thrombin and fibrin formation (propagation).
Heparin is a glycosaminoglycan composed of a mixture of polysaccharides that have molecular weights ranging from 3000 to 40,000 daltons . Heparin binds avidly to endothelial cells, macrophages, and plasma proteins. On its own, heparin has little, if any, anticoagulant effect. However, when heparin is added to plasma and associates with antithrombin (AT), this association markedly increases the anticoagulant activity of heparin (up to 1000-fold) and greatly enhances the endogenous activity of AT. AT is a naturally occurring protein mainly found along the endothelial lining and, as part of the endogenous mechanisms regulating thrombin formation, capable of inhibiting multiple steps in the coagulation cascade, including blocking the action of thrombin and factor Xa. At low rates of thrombin generation, AT can inhibit the amplification phase of coagulation and block the positive feedback loops in which thrombin participates. In the presence of a stronger stimulus, however, thrombin generation will exceed the capacity for inactivation by AT and the accelerative process of coagulation will proceed. Augmentation of AT activity results in an increase in the threshold level of thrombin activity that can be inhibited and prolongs the time required for thrombin generation and clot formation.
Unfractionated heparin has a number of significant limitations (). UFH is highly protein-bound, and consequently provides a relatively unreliable degree of anticoagulation. In addition, dependence on AT severely limits the anticoagulation action of heparin because heparin must bind to both AT and thrombin to promote their interaction. Longer heparin molecules can link AT and thrombin, in much the same way as fitting a key into a lock; shorter ones cannot, because they cannot simultaneously bind to AT and thrombin. The interaction between heparin and AT is blocked by a number of proteins (including platelet factor 4). Consequently, a site of injury that contains activated platelets may be resistant to the action of heparin. In addition, thrombin that is bound to fibrin is resistant to the effects of heparin and the heparin-AT complex.
LMW heparins are created by subjecting the parent UF heparin molecule to one of a number of enzymatic processes that cleave longer UF heparin chains into shorter ones. Depending on the process used, the resulting structure may vary . Hence the overall "family" of LMW heparins, which are recognized by the FDA as distinct pharmaceutical compounds. As previously mentioned, the shorter chain LMW heparin molecules do not facilitate the inhibition of thrombin by AT, however the heparin AT complex is a potent inhibitor of activated Factor Xa; and this inhibition is not chain-length dependent. The end result is that UF heparin has more specific activity downstream, at the level of thrombin (Factor IIa), while LMW heparins have more specific activity upstream, at the level of Factor Xa. Given the accelerative nature of coagulation, upstream inhibition of coagulation is inherently more efficient. LMW heparins also are less protein bound than UF heparin, and less susceptible to platelet factor 4. Consequently, they provide a more reliable degree of anticoagulation than is achievable with UF heparin. LMW heparins also have a lower risk of heparin-induced thrombocytopenia (HIT) and heparin-induced thrombosis-thrombocytopenia syndrome (HITS), and do not require concomitant activated partial thromboplastin time (aPTT) monitoring to adjust dosing.
LMW HEPARINS IN ACS
The four large-scale active-controlled trials of UFH vs LMWH are listed in [4-10]. Bleeding complications in recent major LMW heparin trials are listed in . Two recent meta-analyses have also provided some perspective on the role of LMW heparins vs. UFH in the management of ACS [11,12]. However, both suffer from the limitations inherent in any meta-analysis that combines the data from very different clinical circumstances. These studies (and the other placebo-controlled trials such as FRISC I and FRISC II) [13-14] involve different populations, different inclusion criteria, different countries, different management strategies, and different endpoints. Meta-analysis has its place, but as far as UFH and LMWH, any such analysis is potentially deeply flawed. The only way to truly compare LMWH and UFH is to put them head-to-head. In two trials that compared enoxaparin to UFH, enoxaparin was superior. In two trials that compared nadroparin or dalteparin to UFH, they were not superior. That is the totality of the head-to-head data at this point. As noted in the meta-analyses, LMWH carries additional substantial convenience benefits that can significant facilitate their application. I, at least, remain "convinced" by the TIMI 11b and ESSENCE data, and personally believe that LMWH will emerge as the standard of care in the very near future, for both convenience and efficacy reasons.
Recently, the long-term (1 year) outcomes from the TIMI 11b/ESSENCE meta-analysis have suggested that the initial benefits are sustained out to 1 year . The authors also noted the high number of subsequent clinical events that transpired over time in both groups. The superiority of enoxaparin over UFH was largely a function of risk; in low-risk patients (0-2 risk factors, assesses by the TIMI risk scale ) there was virtually no difference between UFH and enoxaparin (HR 0.96, p=0.69; n=2101); in medium risk patients (3-4 risk factors) there was moderate benefit (HR 0.87, p=0.04; n=3696); in high-risk patients (5-7 risk factors) there was substantial benefit (HR 0.80, p=0.03; n=849). More than two-thirds of the patients in the pooled analysis fell into the medium-or high-risk categories. Interestingly, despite the perception that ESSENCE and TIMI 11B are "American" trials, almost one-half of the patients in TIMI 11B (and approximately 35% in the two trials combined) were European patients. Actually, only about 15% of the patients in TIMI 11B (and approximately 21% in the two trials combined) were from the United States.
Applying the data to Clinical Practice
So exactly which evidence are we supposed to use as we endeavor to practice so-called "evidence-based medicine"? It is true that the randomized evidence that we have favors the use of enoxaparin, but it is also true that the benefits of convenience (BID SQ dosing, lack of need for coagulation monitoring) are shared with the other agents. As previously mentioned, to truly distinguish between the individual LMWH preparations will require head-to-head trials. Until that time we have to work with the evidence we have. There are 8 commercially-available LMW heparins available worldwide, for a variety of indications. In the US, two drugs, enoxaparin and dalteparin are FDA-approved for use in ACS. Dalteparin is widely used in Europe, and has recently entered the US marketplace. At the present time there is only one direct head-to-head trial of LMW heparins in ACS, the EVET trial , which compared tinzaparin (once a day) to enoxaparin (twice a day) in 438 patients. In that study, recurrent ischemic endpoints were significantly lower with enoxaparin. We need larger-scale, efficacy-powered randomized trials to assess the additive role of adjunctive therapies (such as IIb/IIIa antagonists) above and beyond LMW heparins.
Three major issues remain as barriers to the more widespread uptake of LMW heparins in ACS patients: 1) Are they safe to combine with GP IIb/IIIa antagonists?; 2) How do we use LMW heparins in conjunction with an invasive management strategy?; and 3) What about the incremental cost?
In answer to the first question, data are beginning to emerge from preliminary studies such as ACUTE I , ACUTE II , NICE 3  and NICE 4  that suggest that LMW heparins are at least as safe and effective as UFH when combined with GP IIb/IIIa antagonists (). Further data will be available from the ongoing A-to-Z study, and this issue will be explored prospectively in the larger scale, randomized, efficacy-powered SYNERGY study of enoxaparin vs. UFH in high-risk ACS patients, described below. SYNERGY will also help to directly confront the second question, adding to existing data on in-cath-lab procedural use of LMW heparins from NICE 1, NICE 4, and a recent Dalteparin pilot study . Additional data from Collet et al.  and NICE 3  have provided observational experience in bringing patients forward to the catheterization laboratory and interventional procedures on LMW heparin, without the use of UF heparin. Despite these observational data, the "optimal" initial antithrombotic therapy in invasively managed ACS patients has yet to be defined. LMW heparins are safe and effective, but despite the results of ESSENCE and TIMI 11B, we do not yet know whether they are truly better in the context of an invasive management strategy because, as yet, we have no direct, randomized, active control, efficacy-powered data.
Cost is another issue that assumes ever-increasing importance in modern-day health care. And yes, LMW heparins cost more than UFH. In low risk patients they provide no outcome benefit, so why use them? In these patients, the major impetus favoring LMW heparins is one of convenience. They are easily administered, do not require monitoring, and do not require the level of nursing and medical attention seen with intravenous UFH. The incremental drug cost of LMWH is more than offset by avoiding intravenous infusions and aPTT monitoring . At the high risk end of the spectrum, the cost-benefit of reducing clinical events tips the balance even further in favor of LMWH.
The observational data from NICE 4 and NICE 3 provided valuable background safety information, but did not address the fundamental question of "Is combination therapy truly better?", especially in light of the trend in US practice strongly favoring an aggressive management strategy of early cardiac catheterization and coronary revascularization, frequently including adjunctive use of GP IIb/IIIa antagonists. The recently initiated SYNERGY study (Superior Yield of the New strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa inhibitors) is designed to provide definitive evidence concerning the comparison of enoxaparin and UFH in the setting of invasively managed, high-risk ACS patients . This large-scale prospective, randomized, open-label, multicenter study will evaluate the efficacy and safety of enoxaparin versus UFH in high-risk patients who present with unstable angina or NSTEMI and in whom an early invasive treatment strategy (including "upstream" and/or procedural GP IIb/IIIa inhibitors) is planned ( ).
The study population will include approximately 8000 patients enrolled at 500 sites worldwide, primarily in the United States and Canada. Patients will be included in this trial if they are at least 18 years-old, have ischemic pain at rest lasting > 10 minutes and occurring within 24 hours before enrollment, and at least two of the following: electrocardiographic changes, age > 60 years, and abnormal cardiac markers within 24 hours before enrollment. Electrocardiographic changes are defined as new or presumably new ST-segment depression > 0.1 mV (> 1 mm) or transient (<30 minutes) ST-segment elevation > 0.1 mV (> 1 mm) in at least 2 contiguous leads. Abnormal cardiac markers are defined as elevated troponin I or T levels greater than the established criteria at each site or creatine kinase myocardial band (CK-MB) levels greater than the site's upper limit of normal (ULN). The SYNERGY trial is the largest trial currently planned for the acute therapy of patients with unstable angina and NSTEMI. It also will be the first large trial in this patient population since the publication of the revised ACC/AHA5 and ESC6 unstable angina/NSTEMI guidelines last year.
Additionally, the ongoing A to Z trial will examine the early and long-term management of ACS patients, including a randomization to UFH versus enoxaparin (on a background of ASA and the Ib/IIIa antagonist tirofiban) with either invasive or conservative therapy.
A number of clinical trials have highlighted the inadequacies of UFH in the management of ACS patients. While unfractionated heparin does provide incremental clinical benefit above and beyond aspirin, it is difficult to adjust, and potentially very unreliable. The low molecular weight heparins have a number of significant theoretical advantages, including subcutaneous administration, a more reliable degree of anticoagulation, and no need for ongoing hematologic monitoring to titrate therapy. It is true that the results of some of the randomized trials comparing UFH and LMWH have been mixed, the results of the two large-scale enoxaparin trials show significant benefit over UFH. A number of unresolved issues (largely related to making the transition to the catheterization laboratory) have limited the more aggressive uptake of LMWH into general clinical practice, but data will shortly be forthcoming that may help provide guidance as to how to better handle this circumstance. We will also hopefully have large-scale efficacy-powered trials of combination therapy underway shortly.
Should enoxaparin broadly replace UFH in ALL patients? Before we can make that leap of faith, two other key "what about " questions arise. What about the cath lab and an invasive management strategy? What about IIb/IIIa antagonists? As is painfully obvious, despite the robust clinical results of the TIMI 11B/ESSENCE meta-analysis, the question of what to do with these findings and how to apply them to modern-day practice are much more complex and convoluted than simply "A is better than B". Showing the superiority of enoxaparin over UFH in this pooled analysis is not necessarily sufficient to change the "standard of care" that we proudly maintain is so evidence-based. The problem with actually trying to practice "evidence-based" medicine is that as we look for evidence relating to a new therapy versus "standard" therapy, the current "standard" is continuously moving forward, and in trials done just a few years ago can lag significantly behind currently available options.
Similarly, if we are unwilling to consider a change in the "standard" of care because the standard against which a new form of therapy (such as LMW heparin) was tested did not account for all of our modern-day therapeutic options, we handcuff ourselves because the "standard" never really moves forward, and any new trials that include more up-to-date advances will themselves once again be out of date two-to-three yeas from now. We will never be able to catch the tortoise unless we can shift our perspective outside the "A-to-B" comparison and take into account the real-time shifts in the so-called "control" arm.
Another thorny issue is whether there are meaningful clinical differences between the individual LMW heparins, which are structurally unique compounds. That issue was not specifically addressed in ESSENCE or TIMI 11B, but these are in fact the only two large scale active-control trials that have shown a LMW heparin (in this case enoxaparin) to be superior to UFH, in contrast to FRIC and FRAXIS and other placebo-controlled studies. The inferiority or non-inferiority of one compound in relation to another can really only be objectively assessed with direct head-to-head studies. Until those are available, we have only the evidence from clinical trials, and our own individual experience to guide us.
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