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European Heart Journal Supplements (2001) 3 (Supplement J), J15J23

Issues in antithrombin therapy for UA/NSTEMI

J. S. Alpert1, A. J. Budaj2, E. P. Gurfinkel3 and T. D. Henry4

1University of Arizona College of Medicine, Tucson, Arizona, U.S.A.; 2Postgraduate Medical School, Warsaw,

Poland; 3Favoloro Foundation, Buenos Aires, Argentina; 4Hennepin County Medical Center, Minneapolis,Minnesota, U.S.A.

In September 2000, participants at the 4th Annual Experts

Meeting of the International Cardiology Forum convened

to discuss guidelines for the management of unstable

angina/non-ST-elevation MI, recently published by North

American and European task forces. Discussion of new

recommendations for antithrombin therapy focused on therole of low-molecular-weight heparin (LMWH). Although

most participants found the new guidelines largely consist-

ent with existing data, and sufficiently adaptable to most

clinical settings, there was concern that neither task force

specified LMWH as the antithrombin of choice for the

medical management of these patients. The new guidelines

continue to endorse the use of unfractionated heparin,

particularly for high-risk patients, despite the evidence for

the efficacy of LMWH in this setting. This is largely a

consequence of the dominant role assigned to the GP

IIb/IIIa inhibitors and to an early interventional strategy. It

was generally agreed that more data on the use of LMWH

in combination with GP IIb/IIIa antagonists would be

helpful, as well as more information to guide the transition

from medical management to the cath lab. The optimalduration of antithrombin therapy was also the subject of

discussion, particularly for patients unable to undergo

immediate revascularization.

(Eur Heart J Supplements 2001; 3 (Suppl J): J15J23)

2001 The European Society of Cardiology

Key Words: Unstable angina, antithrombin, heparin, low-

molecular-weight heparin, guidelines

Overview of the new guidelines

When the AHCPR published its 1994 guidelines[1], themainstay of anticoagulation for an acute coronary syn-drome presenting without ST-elevation was aspirin(ASA) and unfractionated heparin (UFH). Since thattime, there has been significant investigation into the useof other agents that exert their effects on platelets, thecoagulation cascade, or both, among them low-molecular-weight heparin (LMWH), the direct thrombininhibitors, thienopyridines, and platelet glycoprotein(GP) IIb/IIIa receptor antagonists. Clinical trials havedemonstrated the efficacy of several of these agents inthe setting of unstable angina and non-ST-elevationmyocardial infarction (UA/NSTEMI). Most pertinentto the discussion of therapy directed against the gener-ation of thrombin is LMWH. Trials that are now wellfamiliar to cardiologists have demonstrated that, in thissetting, LMWH is at least as efficacious as UFH(FRIC[2] and FRAX.I.S[3]) in preventing death or myo-cardial infarction, and in some studies significantly moreso (ESSENCE[4] and TIMI 11B[5]). The correspondingappearance of LMWH agents in the recently publishedguidelines is therefore not surprising.

After workshops held in September 1998, theInternational Cardiology Forum recommended thatLMWH be considered the antithrombin of choice in themedical management of non-ST-elevation ACS[6]. Boththe European[7] and North American[8,9] guidelines haveincorporated LMWH into their approach to medicaltherapy, but do not unconditionally recommend it as asubstitute for UFH. Consequently, much of the discus-sion in our workshops centred on the choice betweenLMWH and UFH, the data or need for data tosupport the use of LMWH in certain specific settings,and the differences among the three available agentswithin this class.

Low-molecular-weight heparin andunfractionated heparin

In the ACC/AHA guidelines, the recommendations forantithrombin and antiplatelet therapy are given together(Table 1). Aspirin (or a thienopyridine in certainpatients) remains the mainstay of therapy, with a choiceof LMWH or UFH added to this regimen. Note thatthis recommendation was assigned level of evidence B.

Although there is a wealth of data comparing the use ofLMWH and UFH in this setting, the ACC/AHA taskforce did not feel that there was A-level evidence from

Correspondence: Joseph S. Alpert, University of Arizona College ofMedicine, Tucson, Arizona, U.S.A.

1520-765X/01/0J0015+09 $35.00/0 2001 The European Society of Cardiology


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large, randomized, placebo-controlled trials demonstrat-ing the superiority of aspirin+ UFH or aspirin+ LMWHover aspirin alone. Nevertheless, the guidelines do pointout that a meta-analysis of all studies comparingaspirin+UFH or LMWH with aspirin alone does reveala significant benefit associated with antithrombin

therapy (relative risk reduction 65%).While there is ample discussion of LMWH versus

UFH in the text of these guidelines, there is no formalrecommendation made for choosing LMWH over UFH.

On the contrary, in the table of Class I recommen-dations for antithrombotic therapy (Table 2) there is aretreat from the use of LMWH in higher-risk patients,particularly those in whom a coronary intervention isimminent. The rationale for recommending iv heparin inthese patients is two-fold. First, it was felt that higher-

risk patients benefit from the addition a IIb/IIIa receptorantagonist to their medical regimen, and there arelimited data and less physician experience supporting the combination of LMWH therapy andIIb/IIIa inhibitors. Second, there are fewer data on theuse of LMWH in percutaneous interventions. Becausethe use of IIb/IIIa inhibitors is intimately tied to cardiaccatheterization, the words high risk have becomeassociated with an aggressive management protocolinvolving early catheterization, use of a IIb/IIIa inhibi-tor, and thus use of iv UFH.

This retreat from the use of LMWH is also seen in theESC document. The document begins with an endorse-

ment of LMWH therapy: in a table entitled Level ofevidence of the different therapeutic options (Table 3),the task force assigns A-level evidence to the benefits

Table 1 ACCtAHA recommendations for antiplatelet and anticoagulation therapy

Recommendation Level of evidence

Class I1. Antiplatelet therapy should be initiated promptly. Aspirin (ASA) is the

first choice and is administered as soon as possible after presentation andcontinued indefinitely.

A

2. A thienopyridine (clopidogrel or ticlopidine) should be administered topatients who are unable to take ASA because of hypersensitivity or majorgastrointestinal intolerance.

B

3. Parenteral anticoagulation with intravenous unfractionated heparin(UFH) or with subcutaneous LMWH should be added to antiplatelettherapy with ASA, or a thienopyridine.

B

4. A platelet GP IIb/IIIa receptor antagonist should be administered, inaddition to ASA and UFH, to patients with continuing ischaemia or withother high-risk features (see Table 2) and to patients in whom apercutaneous coronary intervention (PCI) is planned. Eptifibatide andtirofiban are approved for this use. Abciximab can also be used for

1224 h in patients with UA/NSTEMI in whom a PCI is planned withinthe next 24 h.

A

Class III1. Intravenous thrombolytic therapy in patients without acute ST-segment

elevation, a true posterior MI, or a presumed new left bundle-branchblock.

A

Table 2 Class I ACCtAHA recommendations for

antithrombotic therapy

PossibleACS

Likely/definiteACS

Definite ACS withcontinuing high-risk

features orplanned intervention

Aspirin Aspirin Aspirin+ +

sc LMWH iv heparinor +

iv heparin iv platelet GP IIb/IIIa antagonist

Table 3 Excerpt of a table from the ESC recommendations entitled Level of

evidence of the different therapeutic options

TreatmentEarly benefit:

reductionischaemia

Early benefit:prevention,MI, death

Sustainedeffect of

early benefit

Additionallong-term reduction

death, MI

Unfractionated heparin C B LMWH A A A C (in selected pts)Specific antithrombins A A

J16 J. S. Alpert et al.

Eur Heart J Supplements, Vol. 3 (Suppl J) August 2001


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of LMWH in reducing ischaemia and preventing deathand MI, with a sustained effect of this early benefit.Unfractionated heparin, in contrast, is assigned onlylevel of evidence C or B for early benefits, with no

evidence of a sustained benefit. Despite this difference, inthe flowchart entitled Recommended strategy in acutecoronary syndromes (Fig. 1), initial therapy includesaspirin, anti-anginal medication, and heparin, whichtraditionally refers to unfractionated heparin. As in theACC/AHA guidelines, this algorithm reinforces a tightassociation between high-risk features and an aggressivestrategy involving IIb/IIIa inhibition and cardiaccatheterization. The risk stratification implicit in thisflowchart involves a single decision-point, with higher-risk patients receiving a IIb/IIIa inhibitor and UFH, andundergoing angiography as soon as possible. Onceagain, there is a limited role assigned to LMWH.

What about the lower-risk patient? In the ACC/AHA

guidelines, as described above, a patient who does notexhibit high-risk features may receive either LMWH orUFH, and the lowest-risk patient can be given aspirinalone. In the ESC guidelines, it is stated that:

Low molecular weight heparin may be discontinuedwhen, after the observation period, no ECG changesare apparent and a second troponin measurement isnegative.

Following this algorithm, patients are thus divided intohigh-risk patients who receive a IIb/IIIa inhibitor,UFH, and are scheduled for catheterisation andlow-risk patients, who do not require further anti-

coagulation.As to the duration of antithrombin therapy, both taskforces refrain from offering definitive recommendations.In the ACC/AHA executive summary, there is no men-tion of the duration of therapy. In the complete ACC/AHA document, it is stated that the results of FRISCII[10], may make a case for the prolonged use of anLMWH in selected patients who are managed medicallyor in whom angiography is delayed. The ESC documentstates that, the evidence to support longer term treat-ment with low-molecular-weight heparin is less convinc-ing, but also suggests, based on FRISC II results, thatLMWH can be extended to 2 weeks, in patients inwhom revascularization is judged not to be feasible.

Similarly, there is limited mention of LMWH adminis-tered as an intravenous bolus. Both the ACC/AHAexecutive summary and the ESC guidelines are silent on

this issue, and there is a single mention in the fullACC/AHA document, included in the discussion ofenoxaparin dosing, that, the first dose may be precededby a 30-mg iv bolus, as was done in the TIMI 11B trial.

While there are no formal recommendations for dis-tinguishing among the different low-molecular-weightheparins, both sets of guidelines discuss the issue atlength. Both guidelines point out that the two trialsdemonstrating the superiority of LMWH over UFH inaspirin-treated patients were trials of enoxaparin,

whereas similar trials of dalteparin and nadroparindemonstrated equivalence. As stated in the ACC/AHAguidelines, Although it is tempting to compare therelative treatment effects of the different LMWH com-pounds [Fig. 2], the limitations of such indirectcomparisons must be recognized. Without a directhead-to-head comparison, neither task force felt thata formal recommendation for the preferred use ofenoxaparin could be made.

Other antithrombin agents

The guidelines focus appropriately on LMWH andUFH for antithrombin therapy, but other classes ofantithrombin agents are available. While the ACC/AHAexecutive summary does not mention these, there issome discussion in the full-length document of the directthrombin inhibitors (most notably hirudin), and theirindications for heparin-induced thrombocytopenia(HIT) and for the prophylaxis of deep-vein thrombosisin patients undergoing hip arthroplasty. Severalwarfarin studies are also discussed, with the conclusionthat, the role, if any, of long-term warfarin in patientswith UA/NSTEMI remains to be defined.

Similarly, the ESC guidelines describe level Aevidence that hirudin reduces death and MI in this

setting. Both the ESC and ACC/AHA discussions of thedirect thrombin inhibitors focus on the OASIS-2 trial, inwhich hirudin (specifically, lepirudin) was compared

No persistentST-segment elevation

AspirinNitrates

Beta-blockersHeparin

Elevated troponinRecurrent ischaemia

Haemodynamic/rhythmic unstabilityEarly post-MI unstable angina

Normal troponinon admission and 12 h

later

GP IIb/IIIa blocker

Cor. angiography

Stress testbefore or after

discharge

Figure 1 Adapted from ESC guidelines recommendedstrategy in acute coronary syndromes.

1.5

LMWH better

0.75

FRIC(dalteparin; n = 1482)

1

LIFH better

* Triple endpoint: death, MI, recurrent ischaemia urgent resuscitation

6

FRAXIS(nadroparin; n = 2357)

14

ESSENCE(enoxaparin; n = 3171)

14

TMI 11B(enoxaparin; n = 3910)

14

(P = 0.032)

(P = 0.029)

Day

LMWH in Unstable AnginaEffects on Triple Endpoints*

Figure 2 Low-molecular-weight heparin in unstable

angina: effect on triple end-points (reproduced from ACC/AHA recommendations with permission).

Issues in antithrombin therapy J17



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with UFH in the acute treatment of ACS presentingwithout ST-segment elevations[11]. The results of thistrial have been subject to diverse interpretations. On the

one hand, there was a significant reduction in the tripleend-point of death, MI, or refractory angina at 7 daysassociated with hirudin. On the other hand, the reduc-tion in the primary end-point of death or MI was notsignificant at either 7 or 35 days, and was associatedwith an increase in bleeding categorized as major but notlife-threatening. The ESC refers to the evidence as levelA based on a meta-analysis, performed by the OASISinvestigators, including all patients in GUSTO-IIb, theOASIS pilot study, and OASIS-2 who did not receivethrombolytic therapy. In this expanded trial population,hirudin was associated with a significant reduction indeath/MI at 35 days. Data from a substudy of the

OASIS-2 trial have suggested that these clinical benefitsare more pronounced in patients undergoing earlycardiac intervention[12]. Despite these data, hirudin isapproved in most countries for HIT, but not for ACS.

It should be noted that since the time of the guide-lines publication, the direct antithrombin bivalirudinhas received approval in several countries for use in ACSpatients undergoing PCI. This approval has been basedon the combined results of several clinical trials in whichbivalirudin was compared to UFH in this setting.

How do the guidelines differ?

Overall, there is little divergence between the recommen-dations of the two task forces. Both recommend theaddition of an antithrombin regimen to treatment withaspirin for all but the lowest-risk patient. Both assign alimited role to LMWH in ACS, a role influenced greatlyby the use of IIb/IIIa receptor antagonists and by theimminence of catheterization and thus, more generally,by the patients level of risk. While the table of anti-thrombin agents presented in the ESC guidelines wouldclearly lead to a recommendation of LMWH over UFH,these newer agents are excluded from the generalapproach to ACS outlined later in the document. Simi-larly, while the ACC/AHA guidelines present data

demonstrating the superiority of LMWH over UFH formedical management, the actual recommendationsretreat from the use of these agents in higher-riskpatients.

The general sense in our workshop was that the ESCdocument seems to focus more on LMWH, assigning ahigher level of evidence to the existing data, and relyingmore on the results of FRISC II for some of itsconclusions. It was felt that this increased focus is theresult of divergent practice environments in Europe andNorth America. In our group, indeed, physicianspracticing in Europe reported more LMWH use inUA/NSTEMI patients than their North Americancounterparts.

An increased emphasis on LMWH can similarly befound in other guidelines documents appearing inareas of the world outside of North America and

Europe. For example, guidelines recently publishedin Latin American reflect the increased use of newerantithrombin agents found in many of these countries.

Consensus documents published in Uruguay[13],Argentina[14], and many other countries, recommendLMWH for use in non-ST-elevation MI, citing A-levelevidence.

Are the guidelines consistent with currentpractice?

We found the recommendations for antithrombintherapy to be largely consistent with our currentpractices. Several of our workshop members, particu-larly those from Eastern European nations, reported

very routine use of LMWH, regardless of a patientsperceived level of risk. It was remarked that this wasperhaps driven by extremely limited use of revascular-ization techniques within those institutions. It appearedthat, where LMWH is available, and cardiac catheter-ization is not an issue (albeit secondary to resourcelimitations), LMWH is a clear choice for antithrombintherapy. Others reported more liberal use of anti-thrombin agents in low-risk patients (both LMWH andUFH) or the administration of at least a single dose ofsubcutaneous medication in cases where there is anysuspicion of ACS. Lastly, some physicians reported thatLMWH was not available at their institutions, thus theywere constrained to use UFH for antithrombin therapy.

We also found that where patients require transfer toanother facility, either for more intense monitoring orfor cardiac catheterization, additional issues related totransport come into play. In practice, the referringphysician, the receiving institution, and the level ofcommunication between the two will all determinemedical management during this period. Simplifyingmanagement under these circumstances may improveoutcomes, and any guidelines would need to be tailoredto the specific setting. This issue is especially pertinentto the antithrombin therapy, where the difficulty ofadministering UFH is compounded by periods of timewhere aPTT testing is not available, and where a

continuous intravenous infusion requiring titration isdifficult.Our group was divided over whether LMWH or UFH

is preferred during transport. On the one hand, there islittle guesswork when dosing subcutaneous LMWH, andthus the level of anticoagulation is less subject to thetransport team, weather conditions, and other real-lifeconditions that are not controlled by the physicians ateither end. Thus, many of our workshop participants feltmore comfortable placing a patient on a schedule ofsubcutaneous LMWH, as opposed to a UFH drip, priorto transport, especially when the timing of catheteriz-ation is uncertain. In this situation, an investigator whois not comfortable with the combined use of IIb/IIIa

inhibitors and LMWH may elect to defer IIb/IIIainhibition to the time of possible revascularization.Conversely, transported patients are often received by




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interventional cardiologists, who may want a patient toreceive as many hours of IIb/IIIa inhibition as possibleprior to catheterization, and do not feel comfortable

using the two agents together. Thus, many of ourparticipants would instruct a referring physician to begintherapy with a IIb/IIIa receptor antagonist and iv UFH.

In general, the guidelines seemed to apply most read-ily to the most aggressively interventional settings (e.g.certain tertiary care centres in the United States). Inthese settings, once a patient is labeled as cath-bound,he or she can truly be considered as being en route to thecardiac catheterization laboratory, and issues of trans-port and bridging therapy do not require as muchconsideration.

CommentaryWe found the two guidelines documents largely consist-ent with existing data, and sufficiently adaptable to mostclinical settings. Both documents are specific enough toguide therapy in many cases, yet broad enough to allowfor variations depending on available resources (such aslack of catheterization facilities) and, to a certain extent,physician and patient preferences.

Antithrombin therapy in high-risk patients

The concerns most frequently raised in our group,

however, were the retreat from the use of LMWH inhigher-risk patients, and the hesitancy on the part ofboth task forces to specify LMWH as the preferredantithrombin for the medical management of UA/NSTEMI. Data on the combined use of LMWH andIIb/IIIa receptor antagonists, as well as the use ofLMWH as a procedural anticoagulant, were extremelylimited at the time of the guidelines publication; there-fore, the recommendations for UFH in higher-riskpatients stem not from its efficacy in this population butrather from its use as the adjunctive therapy in trials ofboth IIb/IIIa inhibition and cardiac intervention. How-ever, the superiority of LMWH to UFH is even more

pronounced in higher-risk patients

[10,15]

, and thus itshould be given consideration as a choice of agent, evenwhen IIb/IIIa inhibition and/or cardiac catheterizationare under discussion.

The trials of IIb/IIIa receptor antagonists in UA/NSTEMI that most influenced the recommendationswere performed using UFH. The combined weight ofthese trials (discussed elsewhere in greater detail) wassummarized in a meta-analysis performed by Boersmaet al.[16], familiar now to most cardiologists. Becausethe protocols in PURSUIT[17] (eptifibatide), PRISM-PLUS[18] (tirofiban) and CAPTURE[19] (abciximab) allencouraged a period of medical management prior tocardiac catheterization, it was possible to analyze the

early effects of IIb/IIIa inhibition before an interventionwas performed. Generating KaplanMeier curves forthe combined patient population, the investigators

found a 34% relative risk reduction in the composite ofdeath and MI associated with IIb/IIIa inhibition, duringthe period of pharmacotherapy. The same meta-analysis

found a consistent and even greater protective effect ofthe IIb/IIIa receptor antagonists when continuedthrough PCI. Furthermore, subgroup analyses for theindividual trials of the IIb/IIIa inhibitors have demon-strated that this benefit is greater in troponin-positivepatients[20,21].

As there have been no head-to-head trials comparingLMWH with the combination of UFH and a IIb/IIIareceptor antagonist, it is difficult to compare the incre-mental benefits of each regimen over UFH alone. Atreating physician must keep in mind that, for medicallymanaged patients, there was a robust 20% relative riskreduction in death or MI associated with the use of

enoxaparin instead of UFH. In addition, this risk reduc-tion was maintained at 1-year follow-up[22]. This figurecannot be compared directly to the benefits seen in theIIb/IIIa trials, however, because many of those patientswent on to undergo cardiac catheterization, notrandomly, but at the discretion of the treating physician.Because of these confounding issues, we were unable toreach a definitive consensus on optimal treatment.

While it is tempting to speculate on combinationtherapy with aspirin, LMWH and a IIb/IIIa receptorantagonist as a possible ideal regimen, we founddiverse levels of comfort with this combination in ourworkshop. Some participants were concerned aboutcombination therapy because of the limited data or

lack of personal experience, while others were uneasywith the idea of using two novel agents without anestablished means of measuring anticoagulation. Whilesubcutaneous LMWH produces a reliable anti-Xaactivity in most patients[23], an estimation of anti-Xaactivity based on the timing of subcutaneous injectionswas perceived by some as less precise when comparedwith the aPTT testing used to dose UFH. On the otherhand, even those who consider the aPTT as a reliableguide to the instantaneous activity of UFH are alsofamiliar with the tremendous difficulty in achieving andmaintaining this aPTT within a desired range, especiallyearly in the course of therapy[4]. There is an increasedincidence of thromboembolic complications associatedwith aPTT values both above and below the therapeuticrange[24]. Thus, proponents of using LMWH routinely,even when a IIb/IIIa inhibitor is to be used, argued thatthere is little that is reassuring about aPTT testing otherthan its availability.

Regardless of the issues surrounding the IIb/IIIareceptor antagonists, the hesitancy to administerLMWH in high-risk patients stems in part from the lackof experience with these agents in the cardiac catheter-ization laboratory. Although many cardiologistsworldwide are already comfortable with the transitionfrom medical to interventional management in a patienton LMWH, and although there have been some rough

guidelines published on this subject[25], clinical trials ofLMWH as a procedural anticoagulant are only recentlybeing performed. We found that where patients are




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referred for angiography, their medical regimen is deter-mined by the interventional cardiologist, who often(including members of our workshop) is more comfort-

able with UFH. It was also pointed out, however, that inmany environments, even the most urgent PCI occursafter at least 8 hours, and that in trials comparingLMWH and UFH, the survival curves begin to divergebefore that time[4,5]. Thus, the imminence of catheteriz-ation should not be the only factor influencing thechoice of antithrombin therapy.

An additional concern is that a retreat from LMWHin higher-risk patients may incur additional costs oflaboratory work and hospitalization. Economic assess-ments of enoxaparin[26,27] have demonstrated an econ-omic benefit associated with using LMWH instead ofUFH, accounted for by reduced resource use and a

reduced need for coronary interventions

[28]

. Consideringthe expense of the IIb/IIIa inhibitors, a combinationof aspirin and LMWH may prove an effective andeconomically sound regimen, even for higher-riskpatients, in settings where resources are limited.

Antithrombin therapy in low-risk patients

At the other end of the spectrum, we noted that both setsof guidelines recommend the cessation of antithrombintherapy in the lowest-risk patient. In common practice,however, it is felt that a patient who has met the criteriafor admission has an indication for at least a brief course

of anticoagulation. According to the ESC guidelines,after a second negative troponin and no ECG changes,LMWH therapy can be discontinued; however, a60-year-old patient with transient and nonspecific ECGchanges and a good story for unstable angina may inpractice continue to receive some form of heparin evenafter cardiac enzymes have revealed no myocardialnecrosis. Given that many of these patients are at riskfor further events, and given the safe environment of thehospital for administering anticoagulant therapy, manyin our workshop felt that this more liberal use ofanticoagulants was appropriate. With respect to thechoice of agent, it was felt that at the lowest level of risk,there were few data to support the use of one agent overanother.

Other issues

Regardless of the choice of antithrombin agent, we feltthat more guidance was needed on both the duration oftreatment, and in the case of LMWH therapy theuse of an initial iv bolus.

The prolongation of either UFH or LMWH therapybeyond several days, or even beyond discharge, is notrecommended routinely by either set of guidelines. Thecontinuation of enoxaparin therapy in the outpatient

phase of TIMI 11B did not result in a significantimprovement in patient outcomes, but rather an increasein major bleeding. Similarly, in FRISC II, prolonged

dalteparin treatment in patients assigned to medicaltherapy resulted in an increase in event rates at 90 days.For several reasons, however, we would use caution in

dismissing the extended use of anticoagulants for allUA/NSTEMI patients based solely on these studies.First, TIMI 11B may not have been powered adequatelyto reveal a benefit of prolonged therapy, whereas suchoutpatient treatment has proved both safe and effectivein the setting of venous thromboembolic disease.Second, there may be subsets of patients who benefitfrom prolonged treatment, even if the study populationas a whole did not. In FRISC II, while the primaryend-point of death and MI at 90 days was reached moreoften in the prolonged-treatment group, there appearedto be an advantage to prolonged treatment at earliertime-points analyzed. Although the significance of this

finding has been widely debated since the publication ofFRISC II, the crossing of the survival curves at 2 weekshas been interpreted by some to justify the continuationof LMWH for 1 week following admission, as reflectedin the ESC recommendations. Certainly, the patientswho may benefit most from prolonged anticoagulationwith a LMWH include those who cannot undergorevascularization and those who are seen to have a largeclot burden on angiography; however, more data areneeded before setting a precise duration and patientpopulation for such extended therapy.

The issue of intravenous bolusing of LMWH ismentioned only once in the full-text version of theACC/AHA guidelines (as an optional dosing regimen

for enoxaparin), and is avoided entirely in the ACC/AHA executive summary and in the ESC guidelines.This dosing is not yet approved in many countries,although it has been investigated in several studies todate, including TIMI 11B; thus, it would be difficult tomake any formal recommendations. Some of the partici-pants in our workshop do, in practice, administer abolus of enoxaparin prior to subcutaneous treatment inpatients deemed to be at higher risk; this practice isgreatly influenced by the country of origin and theindividual institution. Because intravenous LMWH isactually being used, we felt that at least a discussion ofthis topic would be warranted in the guidelines, andperhaps further clinical trials.

We agreed that, because of the lack of head-to-headclinical trials, there were not enough data to recommendenoxaparin as the sole agent of choice for UA/NSTEMI.Nevertheless, it should be noted as detailedextensively in the text of both guidelines documents that it was the trials of enoxaparin exclusively thatdemonstrated the superiority of LMWH to UFH in thissetting. This important point could be overlooked byphysicians who only look at the formal recommen-dations put forth in either document. Caution should bemade, as in all clinical situations, to avoid choosing atherapy based upon a class effect, without a review of theoriginal data.

In this same vein, all trials of LMWH should not beconsidered together as one study, and attempting acombined analysis of these studies is not always




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appropriate. While a true meta-analysis of the two largetrials of enoxaparin (ESSENCE and TIMI 11B) waspossible[29], based on the similarity of the patient popu-

lations and outcomes, such an analysis is not appropri-ate for all trials of LMWH. It should be noted, forexample, that FRISC II did not compare LMWH withUFH, as implied by the inclusion of this trial in a figurelabelled, Comparisons of LMWH to unfractionatedheparins in patients with acute coronary syndromes, inthe ESC guidelines. Rather, in FRISC II, all patientsreceived dalteparin in the acute setting, and the riskreduction at 30 days was for the comparison of pro-longed dalteparin and placebo. While this correction isvery specific, it serves to illustrate one of the pitfallsof comparing different trials, and the importance ofreviewing trial designs carefully when interpreting their

outcomes.

New data

Although our workshops focused on the recommen-dations for antithrombin therapy, we spent some timediscussing the GUSTO IV ACS trial of the IIb/IIIareceptor antagonist abciximab. Although the trial resultshave not yet been published, they were presented orally

just prior to the ICF meeting[30], and it was difficult toavoid discussion of this trial and its potential impact onwhat we would recommend for the medical managementof UA/NSTEMI. This trial was designed to assess the

potential benefits of adding to the medical treatment ofUA/NSTEMI. To be enrolled in the study, patients wererequired to have angina at rest accompanied by ST-segment depressions, troponin elevations, or both; thus,they would meet the criteria for high risk as defined ineither set of guidelines. In addition, patients could not bescheduled to undergo cardiac intervention. To the sur-prise of many physicians, especially those familiar withpast trials of IIb/IIIa inhibition, there was no benefitseen to abciximab therapy. This lack of benefit wasconsistent across the numerous subgroups analyzed,including patients who presented with an elevated tro-ponin, and patients who presented with ST-segment

depressions. While it is diffi

cult to recommend makingchanges to the guidelines based on a single, unpublishedtrial, it is interesting to note that the patients in GUSTOIV ACS seem to meet the high-risk criteria set out inboth the ACC/AHA and ESC guidelines, and yet did notbenefit from IIb/IIIa inhibition. This trial was relevantto the discussion of antithrombin therapy because thedecision to use UFH in high-risk patients stems in partfrom the perceived benefits of a IIb/IIIa inhibitor in thissetting.

The GUSTO IV ACS trial was also relevant to thediscussion of antithrombin therapy because it included asubstudy analyzing the combined use of LMWH and aIIb/IIIa receptor antagonist[31]. The substudy was not

randomized, rather some of the centres involved in thestudy used the LMWH dalteparin instead of UFH as theconcomitant antithrombin agent. Rates of adverse

events were then compared across study centres thusbetween patients receiving UFH and a IIb/IIIa receptorantagonist and patients receiving LMWH and a IIb/IIIa

receptor antagonist. There was no excess of majorbleeding associated with either regimen. These results,also reported at the ESC, contribute to the growingbody of evidence that combination therapy with thenewer anticoagulants is safe.

At the time of the guidelines publications, the NICEtrials[32,33] had not yet been published, but many work-shop participants were familiar with the preliminaryresults of NICE-1, NICE-4, and the recently presentedNICE-3. These trials were designed to address someof the discussed above: namely, the safety of LMWH inthe cardiac catheterization laboratory, both with andwithout a IIb/IIIa receptor antagonist, and the safety of

combining LMWH and a IIb/IIIa receptor antagonist inthe medical management of UA/NSTEMI. In NICE-1, aregimen of intravenous LMWH, administered just priorto catheterization, produced no excesses of bleedingwhen compared to historical controls. In NICE-4, aregimen of enoxaparin and abciximab proved safe aswell, with a trend toward less thrombocytopenia whencompared to previous trials of abciximab[34]. TheNICE-3 trial was perhaps the most relevant to thediscussion of UA/NSTEMI. In this trial, patientspresenting with ACS, including those with higher-riskfeatures, were treated with LMWH only (no UFH wasused), followed by a IIb/IIIa receptor antagonist.Patients were referred for cardiac catheterization at the

discretion of the investigator, and at the time of cath-eterization, enoxaparin was supplemented if more than 8hours had elapsed since the last subcutaneous dose.Although this regimen does not precisely follow therecommendation of either set of UA/NSTEMI guide-lines, major bleeding rates in this trial fell within a rangeconsistent with historical controls.

At the time of the ICF meeting, the NICE trialsexhibited a wide range of influence on our own practices.Some of us reported that these regimens had alreadybeen implemented at their institutions. Some reportedthat the results, taken together, would push them moretoward using LMWH in higher-risk patients. Somewanted additional trial data particularly from ran-domized, controlled trials to feel more comfortableusing LMWH in these settings.

Areas where more guidelines or moredata are needed

As discussed above, some members of our workshop feltcomfortable using LMWH throughout all stages ofpatient management from initial medical therapy, tothe addition of a IIb/IIIa receptor antagonist (if one isdeemed appropriate), to cardiac catheterization. How-

ever, some felt that additional data were needed toestablish the safety of LMWH in these settings, and eventhose who felt that there were sufficient data already




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available agreed that specific guidelines for combi-nation therapy and for transitioning to interventionalmanagement would be very useful.

We also felt that there needed to be more data andguidance on the duration of antithrombin therapy. Asdiscussed above, given the benefits of LMWH in theacute setting, and the indications for prolonged use inother areas of cardiovascular disease, outpatient anti-thrombin therapy should not necessarily be dismissed.Even if antithrombin therapy is limited to acutehospitalization, the precise duration has been left poorlydefined. The duration of treatment, whether with UFHor LMWH, differs from trial to trial, ranging fromseveral days (as in ESSENCE) to 67 days (as in FRIC,FRAX.I.S, and other trials) and no consensus has beenreached.

Similarly, the guidelines do not address the possiblecontinuation of antithrombin therapy with UFH orLMWH after a successful PCI, and there are few trialsaddressing this question. To minimize the risk of bleed-ing, heparinization is routinely discontinued followingintervention. However, there may be benefits to contin-ued antithrombin therapy, especially in patients whowere found to have a large clot burden during angiog-raphy, and patients who may have underlying systemicdisease and therefore a continued state of hypercoagu-lability and/or inflammation. This is especially relevantwhere immediate revascularization is the norm, as theprocedure may take place before even a short course ofantithrombin therapy has been given. Once again, the

issue of anticoagulation after PCI is closely tied to theuse of IIb/IIIa inhibitors and thienopyridines, and anystudy or guidelines on this topic would need to takethese other agents into account. Along similar lines, theoptimal antithrombin therapy of higher risk patients inwhom no invasive procedure is feasible has not beenclearly defined. More data in these areas would beuseful.

Prolonged antithrombin therapy with warfarin ismentioned only in the text of the full-length ACC/AHAguidelines, and only to introduce the few pilot studies ofwarfarin post-ACS that have demonstrated any advan-tage over monotherapy with aspirin. Trials conductedsince the guidelines were published, however, may renewinterest in long-term anticoagulation, and are thereforeworth mentioning. The APRICOT-2 study[35], theresults of which were recently presented, compared aregimen of aspirin and warfarin to monotherapy withaspirin after successful thrombolysis. While the studywas not conducted on the UA/NSTEMI patient popu-lation, the decrease in death and MI that was seen withwarfarin use may spark re-interest in long-term anti-thrombin therapy, especially where there is risk ofrecurrent ischaemic events. WARIS II is an ongoingstudy of warfarin versus aspirin versus both in post-MIpatients; if positive, the results of this study mayquestion whether monotherapy with aspirin represents

optimal long-term anticoagulation for patients withischaemic heart disease. Lastly, in a recently publishedsubstudy of the OASIS-2 trial, 3712 patients were ran-

domly assigned to receive 5 months of either warfarin orstandard therapy following hospitalization for unstableangina[36]. There was a trend toward reduced rates of

ischaemia in the warfarin-treated population, and it wassuggested that this trend would have been significant ifnot for issues of patient compliance. More data andanalysis are therefore needed to settle the question oflong-term antithrombin therapy following ACS.

An issue related to the duration of antithrombintherapy is the relative timing of stress-testing and thecessation of heparinization. Our individual practicesdiffered as to the timing of these two events, and wefound little guidance in either the ACC/AHA or ESCrecommendations. Proponents of stress-testing whilecontinuing LMWH therapy argued that earlier testingmay be preferred, and that heparinization does not alter

the sensitivity of the test. Proponents of waiting forantithrombin treatment to end felt that the test wouldrepresent a more physiological assessment of the cor-onary arteries. Further discussion of this topic, andperhaps guidelines, may be warranted.

Lastly, while the ACC/AHA guidelines include specialsections on female, post-CABG, and elderly patients, aswell as on cocaine use and variant (Prinzmetals)angina, it was felt that there could be more detailedguidelines for patients who are obese or elderly, and inparticular patients with impaired kidney or liver func-tions. Care is often less well defined for these patientsubsets, because they are often the ones excluded fromclinical trials.

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