Complications from atherosclerotic coronary arterydisease are the principal cause of death worldwide.Many therapeutic strategies have been developedto reduce the burden of this disease. Systemic antithrombotictherapy, typically with unfractionatedheparin, has long been a mainstay in the managementof acute coronary syndromes (ACS) despite severallimitations, including intravenous administrationand unpredictable pharmacokinetics necessitatingfrequent monitoring. In recent years, newer agentswithout these limitations have been developed andevaluated in clinical trials. This review focuses onnovel antithrombotic therapies for ACS, particularlyfondaparinux sodium, a synthetic inhibitor of clottingfactor Xa.
(Am J Manag Care. 2006;12:S435-S443)
Atherosclerotic coronary artery disease(CAD) continues to pose anenormous burden worldwide and isthe principal cause of death in the developedworld. It is estimated that in the UnitedStates alone, more than 700 000 individualswill have a new coronary attack, and about500 000 will have a recurrent attack in theyear 2006.1
Acute coronary syndromes (ACS), whichinclude unstable angina (UA) and myocardialinfarction (MI) with (STEMI) or without(NSTEMI) ST-segment elevation, present aunique challenge to clinicians because of thehigh rate of mortality and morbidity associatedwith these conditions. Recent statisticsby the American Heart Association (AHA)indicate that approximately 25% of men and38% of women will die within 1 year of havingan initial recognized MI, and people whosurvive the acute stage have an increasedrisk of illness and death that is up to 15times higher than that of the general population.1,2 The economic impact of ACS is alsovery high, costing Americans more than$400 billion this year, according to AHAestimates.1
The treatment of ACS typically includesthe use of antithrombotic agents, along withseveral other classes of medication. Whenusing antithrombotic therapy, however,providers have always had to perform a careful"balancing act" between efficacy andreduction in ischemic events with increasedrisk of bleeding because reducing the probabilityof thrombotic events has meant anunavoidable increase in the risk of bleedingcomplications.3 However, some recent trialsindicate that with the use of a new type ofanticoagulant, it may now be possible to preventthrombosis without a significant increasein the risk of bleeding.4,5
Our understanding of the pathophysiologyof CAD has evolved significantly in thepast few years, and it is now thought thatatherosclerosis represents a chronic inflammatoryresponse to the deposition andmodification of lipids within large-andmedium-sized arteries throughout the vasculature.6 ACS arise after the rupture of aninflamed atherosclerotic plaque, exposingprothrombotic contents of the vascularmatrix to the blood.
After plaque rupture, circulating plateletsadhere to, and are activated by, the exposedcomponents of the vascular matrix. Tissuefactor is also exposed to plasma after plaquerupture, initiating the thrombotic cascadevia its interaction with coagulation factorVII. Activated factor VII (factor VIIa) moleculesactivate small amounts of factor X thatcombine with factor Va to produce thrombin(factor IIa). Thrombin then serves to amplifythe response to the injury by further activationof platelets.
These interactions result in the assemblyof the prothrombinase complex on the surfaceof activated platelets and the generationof large amounts of thrombin that catalyzethe production of fibrin and cause the clinicalmanifestations of thrombosis and ACS.7Thrombin generation is downregulated viaa variety of mechanisms, most notably theserine protease inhibitor antithrombin III (ATIII), which inactivates circulating coagulationfactors, including factor Xa andthrombin.8
Current Antithrombotic TherapyUnfractionated heparin (UFH). In addition
to other standard therapies, such asnitrates, antiplatelet agents, beta blockers,and angiotensin-converting enzyme inhibitors,aldosterone antagonists andantithrombotic drugs have been a mainstayof short-term therapy for ACS for manyyears. Despite limited published evidence,UFH continues to be widely used as the initialanticoagulant for most ACS.9 UFH is aheterogeneous mixture of linear polysaccharidesthat activates ATIII, dramaticallyenhancing its ability to inhibit thrombin andfactor Xa. The heparin and ATIII interactionoccurs via a specific pentasaccharidesequence (present on only 30%-50% of theUFH molecules) that induces a conformationalchange in ATIII. Thrombin (factor IIa)inhibition requires a subsequent nonspecificinteraction with the residual heparin moleculeto bring the inhibitor and the clottingfactor into close proximity. A covalent interactionbetween factor IIa and ATIII theninhibits thrombin and allows heparin to disassociate(Figure 1). Inactivation of factorXa, on the other hand, is less dependent onthe nonspecific "bridging" interaction tofacilitate the interaction with ATIII, and isabout 10 times less sensitive to UFH thanthrombin.8,10
The clinical evidence supporting the useof UFH in the setting of ACS is far fromdefinitive. Trials comparing UFH with aplacebo or aspirin alone in NSTEMI haveproduced mixed results.10 There is, however,some direct evidence supporting the use ofUFH in combination with aspirin in ACS. Ina meta-analysis of 6 randomized trials (n =1353) in which the combination of UFH andaspirin was compared with aspirin alone,UFH was found to provide a 33% relativereduction in the risk of cardiovascular deathand recurrent MI (relative risk [RR] = 0.67;95% confidence interval [CI], 0.44-1.02).11
With regard to STEMI, there is no clearconsensus regarding the role of UFH, despitemore than 40 years of experience with thedrug.9 When an invasive approach involvingimmediate cardiac catheterization and interventionis planned, the use of UFH iswarranted. Among patients treated with fibrinolytics,however, recommendations foranticoagulation tend to be based on expertopinion rather than clinical evidence.Administration of UFH is generally recommendedwith fibrin-specific agents or whenpatients are at high risk for thromboemboliccomplications, and coadministration withstreptokinase is said to be "reasonable."9
UFH is typically administered intravenouslyin the setting of ACS. Because ofadherence to plasma proteins and cell surfaces,as well as complex clearance pharmacokinetics,there is significant variability inthe bioavailability of and response to UFH,mandating frequent monitoring of activatedpartial thromboplastin time.12 Furthermore,approximately 1% of patients treated withUFH for 5 or more days will develop heparin-inducedthrombocytopenia (HIT), leavingthem at significant relative (odds ratio, 20-30) and absolute risk (30%-75%) for thromboticcomplications.13,14 HIT arises as aresult of an interaction between UFH andplatelet factor 4 (PF4), which increasesthrombin production and may lead tothrombosis.14
Another complication with the use ofUFH is bleeding. In the trials that establishedUFH as an adjunct to aspirin in ACS, metaanalysisreveals a small, nonsignificant increasein major bleeding (RR = 1.88, 95% CI,0.60-5.87; = .28).11,15 It should be noted,however, that these trials were performedbefore the widespread use of invasive procedures,and the associated periproceduralbleeding, in ACS.
Low molecular weight heparins (LMWH).
LMWH, produced by depolymerizing UFH,are more homogeneous molecules, approximatelyone third of which possess an ATIIIbinding pentasaccharide sequence. Thesmaller size of LMWH makes these moleculesless able to form a bridge betweenATIII and factor IIa, therefore the clinicaleffects are more dependent on the antifactorXa properties of these drugs (Figure1). These smaller molecules exhibit lessadhesion to plasma proteins and cell surfaces,hence they have more reliable pharmacokinetics.Additionally, they are less likely toform immune complexes with PF4 and tocause HIT.
Since the introduction of these drugs, severaltrials have suggested that they aresomewhat more efficacious with similarrates of significant bleeding when comparedwith UFH in the setting of high-risk ACS.12LMWH have also gained popularity becausethey are administered subcutaneously and,in most cases, require no monitoring.16,17 Itshould be noted, however, that LMWH mustbe used with caution in patients with renaldysfunction and that, unlike UFH, there isno reversal agent. Additionally, although lesscommon, treatment with LMWH is also associatedwith HIT.13,14
Factor Xa Inhibition:Fondaparinux Sodium
Discovering the exact mechanism ofaction of the heparinoids led to the developmentof compounds that inhibit factor Xa inthe coagulation cascade.18 Among these novelcompounds, fondaparinux sodium has beenparticularly promising, having been shownto be safe, efficacious, and cost-effectivein a number of clinical scenarios, includingthe treatment and prophylaxis of deep veinthrombosis and pulmonary embolism.19-22
Fondaparinux is a synthetic pentasaccharide(Figure 2) that binds ATIII, resulting ina 340-fold increase in the rate of factor Xainhibition over the basal rate (Figure 3).8,23The compound is administered subcutaneouslyand is rapidly absorbed, with linearpharmacokinetics providing effective anticoagulationwith once-daily dosing and noapparent need for monitoring. It is excretedunchanged in the urine and must be dose-adjustedin patients with renal dysfunction.Fondaparinux does not bind significantly toother plasma proteins or produce the high-affinityimmunoglobulins that are responsiblefor HIT.8 Although fondaparinux wouldtheoretically appear to be a good choice forthe treatment of HIT, there are, as of yet, limiteddata regarding its use in this setting.13,14
OASIS-5: Fondaparinux Versus Enoxaparinin NSTEMI or UA
Two large clinical trials have been publishedrecently in which fondaparinux wasevaluated in the setting of ACS. In the FifthOrganization to Assess Strategies in AcuteIschemic Syndromes (OASIS-5) trial,420 078 patients admitted with ACS weretreated with either fondaparinux or enoxaparin,an LMWH.
Patients presenting within 24 hours ofsymptom onset who had serologic evidenceof MI or electrocardiographic evidence ofischemia were eligible for enrollment.Exclusion criteria included STEMI, contraindicationsto antithrombotic therapy, orserum creatinine levels of ≥3.0 mg/dL. Patientswere treated with 2.5 mg of fondaparinuxdaily or with 1 mg/kg of enoxaparintwice daily. Fondaparinux was administereduntil hospital discharge or for 8 days(whichever occurred first), whereas enoxaparinwas administered for 2 to 8 days oruntil the patient was in a clinically stabilizedcondition.
The primary objective of the study was toestablish that therapy with fondaparinuxwas noninferior to enoxaparin with respectto death, MI, or refractory ischemia at 9days. Secondary outcomes included evaluatingthese same end points at 30 days andagain at the end of the study. The main safetyoutcome was bleeding at 9 days.
The enrolled patients were of relativelyhigh risk, more than half with suspected MI,but most were treated conservatively,because only about 34% of each groupunderwent percutaneous coronary intervention(PCI) during the initial hospitalization.Otherwise, the patients received aggressivemedical therapy, including aspirin in 97% ofcases, clopidogrel in about 70%, and statintherapy in 79%. Approximately 9% ofpatients in both arms of the trial had diseaseof sufficient severity to warrant coronaryartery bypass grafting.4
At 9 days of follow-up, fondaparinux metthe noninferiority criterion, with 5.8% ofpatients in both arms experiencing the primaryend point. At 30 days, there was atrend favoring patients randomized to fondaparinuxwith respect to the combination ofdeath, MI, and refractory ischemia. Thistrend was driven by a small but significantreduction in mortality among patientsrandomized to fondaparinux (2.9% vs 3.5%;= .02). These differences held up at 180days as well, when mortality was significantlylower among patients randomized tofondaparinux than those treated with enoxaparin(5.8% vs 6.5%; = .05).
With respect to safety, there was anexcess of bleeding complications in theenoxaparin arm at 9 days, 30 days, and atthe end of the study (Table 1). The authorsnoted that, regardless of the treatment strategy,bleeding complications were associatedwith significantly higher rates of death, reinfarction,and stroke. Among the subgroup ofpatients who underwent PCI (n = 6899), outcomeswere similar at 9, 30, or 180 days offollow-up, regardless of the anticoagulationstrategy employed. Bleeding, however, wassignificantly lower among patients randomizedto fondaparinux (Table 2). A clinicallysignificant increase in guiding-wire thrombusformation was noted in the fondaparinuxarm (29 vs 8 episodes), but other complicationsof PCI, such as groin hematomas, werelower among these patients.4
OASIS-6: Fondaparinux VersusEnoxaparin in STEMI
Also published this year were the resultsfrom the Sixth Organization for theAssessment of Strategies for IschemicSyndromes (OASIS-6) trial,5 in whichpatients presenting with STEMI within 24hours of symptom presentation were randomizedto receive antithrombotic therapywith fondaparinux or to "usual care." Thistrial was quite complex, because "usual care"could mean UFH or no antithrombotic therapy(placebo).
Additionally, patients were, at the discretionof the enrolling provider, treated with avariety of reperfusion therapies, includingPCI or thrombolysis with either a fibrin-specificor nonspecific drug. Given these significantdifferences, patients in the trial wereplaced into 1 of 2 large groups. The first(stratum 1) included patients without astrict indication for antithrombotic therapy,typically patients receiving nonfibrin-specificlytics (streptokinase). Stratum 2 includedpatients in whom antithrombotic therapywas indicated (fibrin-specific lytics, PCI,or no reperfusion therapy).5
In stratum 1, a daily subcutaneous dose of2.5 mg of fondaparinux was compared with aplacebo for up to 8 days (or hospital discharge).Patients in stratum 2 were alsotreated with 2.5 mg/day of fondaparinux orplacebo for up to 8 days. Given the firm indicationfor anticoagulation among thesepatients, however, patients in the stratum2-placebo arm were treated with an infusionof UFH, whereas those in the fondaparinuxarm received a matching infusion of a placebo.In both cases, these infusions were continuedfor 24 to 48 hours. Thus in stratum 2,fondaparinux was compared with UFH, andin stratum 1, the comparator was placebo.5
The primary outcome measure was deathor recurrent MI at 30 days. Secondary outcomeswere death or recurrent infarction at9 days, 3 months, or 6 months. As withOASIS-5, bleeding complications were themain safety outcome.5 A total of 12 092patients were enrolled in the trial, with 5658qualifying for stratum 1 and 6434 forstratum 2.
A comparison of baseline characteristicsindicated that, for the most part, patients inthe 2 strata were similar, with a small excessof patients in stratum 1 presenting withheart failure, and fewer patients receivingaspirin or a thienopyridine or having undergoneprevious revascularization. Reperfusionwith thrombolytic therapy (typicallystreptokinase) was most common in stratum1 (78%), whereas PCI was more common instratum 2 (53%). About 23% of patients didnot receive reperfusion therapy. The medianduration of therapy was 8 days in stratum 1.In stratum 2, UFH was administered for amedian of 45 hours and the study drug (orplacebo) for a median of 7 days.5
With respect to the primary outcome,randomization to fondaparinux resulted ina significant reduction in the rate of deathor reinfarction at 30 days (9.7% vs 11.2%;= .008). Significant reductions were alsonoted at 9 days and at the end of the study(Table 3). Bleeding complications were uncommonin all treatment arms, with the lowestincidence occurring in patients receivingfondaparinux. However, when safety outcomesamong patients undergoing PCI wereanalyzed in detail, it was noted that therewas a trend toward more severe bleeding(16 vs 9), as well as significantly more guidingcatheter thrombosis (22 vs 0; <.001),in the fondaparinux arm, compared with theUFH arm. Nevertheless, these events werequite rare, occurring only 16 or 22 timesamong 1890 patients.5
In both OASIS-5 and OASIS-6, therapywith fondaparinux for approximately 8 dayswas efficacious and safe. Of particularimportance were the low rates of severebleeding in patients treated with fondaparinuxin both studies. However, it should benoted that, although the benefit found inthese trials may reflect the biochemicalsuperiority of the drug, it might also be dueto other factors, such as the longer durationof therapy with fondaparinux or interactionswith other evidence-based therapies. Furthermore,according to the results of thesestudies, therapy with fondaparinux is lesslikely to be of benefit among ACS patientstreated with an early invasive strategy. In allother patient groups studied, however, fondaparinuxappears to offer a significantadvantage over other anticoagulants, especiallywith regard to its ability to minimizethe risk of bleeding complications. In summary,these large clinical trials clearly suggestthe excellent safety and efficacy offondaparinux, making it a potential therapeuticoption in the management of patientspresenting with ACS.
Thomas May contributed to the writing of this article.
Address correspondence to: Charles L. Campbell, MD, University ofKentucky, Gill Heart Institute, 900 South Limestone St, 326 Charles T.Wethington Bldg, Lexington, KY 40536-0200. E-mail: firstname.lastname@example.org.
1. Thom T, Haase N, Rosemond W, et al. Heart Diseaseand Stroke Statistics—2006 Update: A Report from theAmerican Heart Association Statistics Committee andStroke Statistics Subcommittee. 2006;113:e85-e151.
The Heart, Arteries and Veins.
2. Hurst W. 10th ed. NewYork, NY: McGraw-Hill; 2002.
Eur Heart J.
3. Moscucci M, Fox KAA, Cannon CP, et al; for theGRACE Investigators. Predictors of major bleeding inacute coronary syndromes: the Global Registry ofAcute Coronary Events (GRACE). 2003;24:1815-1823.
N Engl J Med.
4. The Fifth Organization to Assess Strategies in AcuteIschemic Syndromes Investigators. Comparison of fondaparinuxand enoxaparin in acute coronary syndromes.2006;354:1464-1476.
5. The OASIS-6 Trial Group. Effects of fondaparinux onmortality and reinfarction in patients with acute ST-segmentelevation myocardial infarction: the OASIS-6 randomizedtrial. 2006;295:1519-1530.
N Engl J Med.
6. Ross R. Atherosclerosis—an inflammatory disease.1999;340:115-126.
Arterioscler Thromb Vasc Biol.
7. Monroe, DM, Hoffman M, Roberts HR. Platelets andthrombin generation. 2002;22:1381-1389.
Eur J Clin Invest.
8. Alban S. From heparins to factor Xa inhibitors andbeyond. 2005;35(suppl 1):12-20.
9. Antman EM, Anbe DT, Armstrong PW, et al.ACC/AHA guidelines for the management of patientswith ST-elevation myocardial infarction: a report of theAmerican College of Cardiology/American HeartAssociation Task Force on Practice Guidelines(Committee to Revise the 1999 Guidelines for theManagement of Patients with Acute MyocardialInfarction). 2004;110:e82-e292.
10. Hirsh J, Raschke R. Heparin and low-molecular-weightheparin: the Seventh ACCP Conference onAntithrombotic and Thrombolytic Therapy. 2004;126(3 suppl):188S-203S.
11. Oler A, Whooley MA, Oler J, Grady D. Addingheparin to aspirin reduces the incidence of myocardialinfarction and death in patients with unstable angina. Ameta-analysis. 1996;276:811-815.
12. Peterson JE, Mahaffey KW, Hasselblad V, et al.Efficacy and bleeding complications among patients randomizedto enoxaparin or unfractionated heparin forantithrombin therapy in non-ST-segment elevation acutecoronary syndromes: a systematic overview. 2004;292:89-96.
13. Warkentin TE, Greinacher A. Heparin-inducedthrombocytopenia: recognition, treatment, and prevention:the Seventh ACCP Conference on Antithrombotic andThrombolytic Therapy. 2004;126(3 suppl):311S-337S.
14. Jang IK, Hursting MJ. When heparins promotethrombosis: review of heparin-induced thrombocytopenia.2005;111:2671-2683.
15. Eikelboom JW, Anand SS, Malmberg K, Weitz JI,Ginsberg JS, Yusuf S. Unfractionated heparin and low-molecular-weight heparin in acute coronary syndromewithout ST elevation: a meta-analysis. 2000;355:1936-1942.
N Engl J
16. Cohen M, Demers C, Gurfinkel EP, et al; for theEfficacy and Safety of Subcutaneous Enoxaparin inNon-Q-Wave Coronary Events Study Group. A comparisonof low-molecular-weight heparin with unfractionatedheparin for unstable coronary artery disease. 1997;337:447-452.
17. The SYNERGY Trial Investigators. Enoxaparin vsunfractionated heparin in high-risk patients with non-STsegmentelevation acute coronary syndromes managedwith an intended early invasive strategy: primary results ofthe SYNERGY randomized trial. 2004;292:45-54.
18. Califf RM. Fondaparinux in ST-segment elevationmyocardial infarction: the drug, the strategy, the environment,or all of the above? 2006;295:1579-1580.
N Engl J Med.
19. Wertz J. Fondaparinux in pulmonary embolism [correspondence].2004;350:619.
Arch Intern Med.
20. Turpie AGG, Bauer KA, Eriksson BI, Lassen MR; forthe Steering Committee of the PentasaccharideOrthopedic Prophylaxis Studies. Fondaparinux vsenoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of4 randomized double-blind studies. 2002;162:1833-1840.
Am J Ther.
21. Spruill WJ, Wade WE, Leslie RB. A cost analysis offondaparinux versus enoxaparin in total knee arthroplasty.2004;11:3-8.
22. Sullivan SD, Davidson BL, Kahn SR, Muntz JE,Oster G, Raskob G. A cost-effectiveness analysis of fondaparinuxsodium compared with enoxaparin sodiumas prophylaxis against venous thromboembolism: use inpatients undergoing major orthopaedic surgery. 2004;22:605-620.
Curr Opin Hematol.
23. Gallus AS, Coghlan D. Heparin pentasaccharide.2002;9:422-429.