Although only part of the entire treatment regimen,antithrombotic therapy represents a large portionof the total costs associated with acute coronarysyndromes (ACS) treatment. Unfractionated heparin(UFH), the mainstay of antithrombotic therapy, carriesthe risk of bleeding and associated interventions, andmust be closely monitored. UFH therapy also has anincreased risk of heparin-induced thrombocytopenia(HIT) and osteoporosis. These drawbacks promptedthe development of newer antithrombotic agents,particularly low molecular weight heparins (LMWH)and factor Xa inhibitors. LMWH have several clinicaladvantages over UFH and has been demonstrated tobe more effective than UFH in ACS.
Because UFH is inexpensive, newer therapiesneed to demonstrate economic attractiveness overUFH. In addition to acquisition costs, it is important toconsider the cost of all key components throughoutthe continuum of care. Health economic analysesshow that the clinical advantages of the LMWHenoxaparin are also likely to result in net cost-savingbenefits, due to reductions in diagnostic catheterization,percutaneous transluminal coronary angioplasty,and intensive care unit length of stay. Fondaparinux,an indirect inhibitor of factor Xa, does not require routinemonitoring or multiple daily dosing, and isunlikely to interact with HIT antibodies. Large randomizedclinical trials have shown that fondaparinuxis at least as safe and efficacious as enoxaparin orUFH in the prevention of venous thromboembolism(VTE) and treatment of deep vein thrombosis or pulmonaryembolism. Data from 2 recently publishedtrials are similarly indicating noninferiority of fondaparinuxin ACS patients. Health economic analysis offondaparinux treatment is currently limited to VTE scenariosbut point to a cost benefit associated with fondaparinuxcompared with enoxaparin.
(Am J Manag Care. 2006;12:S444-S450)
The arterial thrombosis responsible foracute coronary syndromes (ACS)begins with the rupture of the atheroscleroticplaque, exposing components ofthe arterial subendothelium that attract andbind platelets to the damaged arterial surface.The bound platelets secrete substancesthat promote vasoconstriction, attract otherplatelets that increase the size of the thrombusat the site of injury, and trigger theformation of clotting factor Xa. The lattercatalyzes the transformation of prothrombinto thrombin, which then converts fibrinogento fibrin, stabilizing the developingthrombus.1
Because of the key role of thrombosis inACS, antithrombotic therapy is central to itstreatment.1-3 Although it is but one part ofthe entire treatment regimen, antithrombotictherapy represents a sizeable portion ofthe total costs associated with ACS treatment.4 Newer, more cost-effective antithromboticagents could, therefore, significantlyease the economic burden associated withthe treatment of ACS.
Although unfractionated heparin (UFH)has been the mainstay of anticoagulant therapyfor nearly 60 years,5-7 it has a narrowtherapeutic window and carries the risk ofhemorrhage and its attendant costs fortransfusion and other associated interventions.8 Moreover, the dose-response characteristicsof UFH vary significantly frompatient to patient.8 As a result, its anticoagulanteffect must be closely monitored,introducing its own costs for personnel andlaboratory work.4,8 Additionally, UFH requirescontinuous intravenous infusion inacute treatment of ACS, necessitating theprolonged hospitalization of patients whomight otherwise be well enough for discharge.9 UFH also carries the risk of heparininducedthrombocytopenia (HIT) andosteoporosis.4,8 These drawbacks haveprompted the development of newer antithromboticagents, including low molecularweight heparins (LMWH) and factor Xainhibitors, such as fondaparinux.
LMWH have been a major boon toantithrombotic therapy, because they haveseveral advantages over UFH. LMWH areproduced by the chemical degradation ofUFH into component peptides of varyinglength and molecular weight.10 The introductionof these heparin derivatives has hada significant impact on antithrombotic/anticoagulanttherapy,7,8 and they have becomeincreasingly popular for the prevention andtreatment of venous thromboembolism(VTE) and for the management of ACS.8,9Their longer plasma half-lives permit onceortwice-daily dosing,11 providing the optionof continuing antithrombotic therapy on anoutpatient basis after hospital discharge.In addition, their greater bioavailabilityand more predictable dose-response characteristics,compared with UFH, lessen theneed for coagulation monitoring and doseadjustment.9-14
LMWH—Safety and Efficacy.
The advantagesof LMWH have prompted their investigationin the treatment of ACS, and theyhave proved safer and more effective thanUFH in several different patient populations.4,8,15-20 As a result, the 2002 guidelinesof the American College of Cardiology/American Heart Association (ACC/AHA)and the European Society of Cardiologyrecommend LMWH, in combination withaspirin or clopidogrel, for the treatment ofunstable angina (UA) and non-ST-segmentelevation myocardial infarction(NSTEMI).21,22 The 2005 updated ACC/AHA/SCAI [Society for Cardiovascular Angiographyand Interventions] guidelines forpercutaneous coronary intervention (PCI)state that LMWH are reasonable alternativesto UFH in patients with UA/STEMI undergoingPCI.23 Most studies of LMWH in ACShave focused on enoxaparin, and there isconsiderable evidence that, especially in theacute setting, enoxaparin is more effectivethan UFH.15,16,24 The Efficacy and Safety ofSubcutaneous Enoxaparin in Non-Q-waveCoronary Events (ESSENCE) trial, for example,found enoxaparin to be superior to UFHat both 30-day and 1-year follow-up ofpatients with UA and NSTEMI.24,25
Several other clinical trials have alsoyielded favorable results regarding the safetyand efficacy of enoxaparin in ACS. For example,both the National Investigators Collaboratingon Enoxaparin (NICE) 1 and NICE4 trials found that enoxaparin alone or inconjunction with a glycoprotein IIb/IIIa(GpIIb/IIIa) inhibitor provided safe and effectiveanticoagulation in patients undergoingPCI, with infrequent episodes of bleeding.26Additionally, a meta-analysis of the clinicaldata from the ESSENCE and Thrombolysis inMyocardial Infarction 11B (TIMI 11B) trialsshowed that, compared with UFH, enoxaparinwas associated with a 20% lower riskof death and serious cardiac ischemicevents, without significant increase in thefrequency of major bleeding.24 A systematicoverview of combined data from theESSENCE, A to Z, and SYNERGY [SuperiorYield of the New Strategy of Enoxaparin,Revascularization, and Glycoprotein IIb/IIIaInhibitors] trials found a statistically significantreduction in favor of enoxaparin overUFH in the combined end point of death ormyocardial infarction (MI) at 30 days.27Moreover, the Assessment of the Safety andEfficacy of a New Thrombolytic Regimen(ASSENT)-3 trial, in which a combined regimenof tenecteplase with enoxaparin, UFH,or the GpIIb/IIIa inhibitor abciximab wasused for the medical management of patientswith acute MI, found a lower rate for each ofthe end point components of 30-day mortality,reinfarction during initial hospitalization,or recurrent ischemia for tenecteplase incombination with enoxaparin than in combinationwith UFH.28
Results from the SYNERGY trial showednoninferiority of enoxaparin compared withUFH at 30 and 90 days,29 and later extendedout to 6 months and 1 year.30 The investigatorsnoted a modest increase in bleedingwith enoxaparin with a statistically significant increase in TIMI major bleeding (9.1%vs 7.6% for UFH; <.008).29 A subgroupanalysis of the impact of prerandomizationantithrombotic therapy showed that patientswho continued to take enoxaparinafter randomization had a lower rate ofdeath or MI than those who continued onUFH.31
BecauseUFH is quite inexpensive, newertherapies need to demonstrate economicattractiveness to ensure adoption of the newtherapy in practice. Here, economic attractivenessmeans that the newer therapy is asgood or better clinically with net cost saving(economically dominant), or the newertherapy is better and more costly, but theextra health benefit is deemed worth theadditional cost (cost-effective). Health economicanalyses show that the clinicaladvantages of enoxaparin are also likely toresult in net cost-saving benefits (Figure 1).8Although the acquisition cost of treatment-doseLMWH for ACS is approximately 25-foldgreater than for UFH,32 this does not necessarilymean that using an LMWH instead ofUFH leads to an increase in the overall costof treatment. In order to obtain a realisticassessment of all costs involved in treating apatient, it is not appropriate to look at acquisitioncosts alone. Instead, one must considerthe cost of all key components throughoutthe continuum of care.
Regarding the use of anticoagulants inACS, comprehensive evaluations have beencompleted. Several health economics analysesbased on the ESSENCE trial have consideredvarious other components of carebesides drug acquisition costs.33-37 One ofthese analyses found that diagnostic catheterization,percutaneous transluminal coronaryangioplasty, and intensive care unitlength of stay were significantly lowerwith enoxaparin than with UFH at 30-dayfollow-up, which resulted in significant costsavings (cumulative total cost savings, $1172;= .04).33 In the Analysis of Coronary UltrasoundThrombolysis Endpoints in AcuteMyocardial Infarction (ACUTE) trial, thepercentage of rehospitalizations—a largecontributor to additional treatment costs—was much lower with enoxaparin (1.6%)than with UFH (7.1%) (= .002),17 althoughit was similar in the ESSENCE trial.33 Basedon ESSENCE, lower costs of medical resourcesassociated with enoxaparin, comparedwith UFH, reflect downstream savingsof lower revascularization costs, secondaryto fewer ischemic events.33-37 For example,in the US cohort, Mark et al found a mean30-day cumulative saving of $929 in hospitalcosts (<.02) and $317 in physician fees(<.03) in favor of enoxaparin.33 There wasan accompanying drop in resource use suchas percutaneous transluminal angioplastyand coronary artery bypass graft (-6% and -3%respectively). The higher acquisition cost ofenoxaparin, compared with UFH, is evidentlycompensated for by savings in medicalresource costs. Such cost savings, in additionto improved clinical effectiveness, makeLMWH therapy a dominant strategy overUFH therapy in the treatment of ACS.33-38
Fondaparinux is an indirectinhibitor of factor Xa, binding stronglyand selectively to antithrombin III (ATIII)to modify the latter's conformation andpotentiate its inactivation of factor Xa byapproximately 300-fold.39 Fondaparinux is asynthetic pentasaccharide, synthesized basedon the ATIII-binding sequence of both UFHand LMWH. Because it does not inactivatethrombin itself, fondaparinux is unlikely tointerfere with thrombin's postulated wound-healingproperties.40 In contrast to UFH,fondaparinux does not require routine monitoringof its anticoagulant effect. Additionally,a long half-life of 17 to 21 hourspermits once-daily dosing.41 Its syntheticnature and high selectivity for factor Xamake fondaparinux unlikely to interact withthe antibodies responsible for HIT in patientswho carry such antibodies.40,42 Because of itsrenal elimination, however, fondaparinux iscontraindicated in patients with severe renaldysfunction (creatinine clearance <30mL/min), and it should be used with care inpatients with moderate renal dysfunction(creatinine clearance 30-50 mL/min).41
Fondaparinux—Safety and Efficacy.
Fondaparinux has shown efficacy in each ofthe major areas for which enoxaparin isindicated. Efficacy has been demonstratedin the prevention of VTE after major orthopedic43and abdominal44 surgery, as well asin older patients with acute medical conditions.45 In addition, fondaparinux has shownefficacy in the treatment of acute deep veinthrombosis (DVT)46 and pulmonary embolism(PE),9 and in the management of patientswith ACS.13,47 A meta-analysis of the datafrom 4 major randomized trials comparingfondaparinux with enoxaparin in majororthopedic surgery found that the use of fondaparinuxresulted in an overall risk reductionof VTE greater than 50% during the first11 days after surgery, without increasing therisk of clinically relevant bleeding.43 Furthermore,the results of 2 large, randomized,controlled trials indicated that fondaparinuxis at least as safe and efficacious as enoxaparinor UFH in the treatment of DVT46 andPE,9 respectively.
Fondaparinux has also shown promise ina number of studies investigating its use inACS. In phase II of the Pentasaccharide asan Adjunct to Fibrinolysis in ST-ElevationAcute Myocardial Infarction (PENTALYSE)study, in which 3 dose levels of fondaparinuxwere compared with UFH in patientsgiven aspirin or alteplase for evolving MI,60% to 69% of the fondaparinux-treatedpatients showed full arterial patency at 90minutes (as reflected by TIMI [Thrombolysisin Myocardial Infarction] grade 3 flow) comparedwith 68% of those treated with UFH.48There was also a trend toward less reocclusionand fewer revascularizations with fondaparinux.The 2004 ACC/AHA guidelinesfor the management of ST-segment elevationMI (STEMI) noted this comparability in thePENTALYSE study, and suggested that factorXa inhibitors could constitute future therapeuticoptions for patients with STEMI.2
More recently, 2 large-scale, randomizedtrials have demonstrated the noninferiorityof fondaparinux versus enoxaparin andUFH in the treatment of ACS. In the FifthOrganization to Assess Strategies in AcuteIschemic Syndromes (OASIS-5) trial, whichinvolved more than 20 000 patients with UAor NSTEMI, fondaparinux produced resultscomparable to that of enoxaparin for thecomposite outcome measures of death, MI,or refractory ischemia, as well as producinga significantly lower rate of major bleedingthan enoxaparin, with these effects persistingthroughout the 180-day follow-up periodof the study.13 In the Sixth Organization forthe Assessment of Strategies for IschemicSyndromes (OASIS-6) trial, which includedmore than 12 000 patients with STEMI,fondaparinux produced a relative reductionin the risk of death of 17% at 9 days, 14% at30 days, and 12% at the study end point of 3to 6 months, compared with placebo orUFH, and was associated with no greatermajor bleeding than either of the latter 2drugs.47 No benefit was found for patientsundergoing PCI; however, the authors suggestthat fondaparinux may be a usefultreatment after PCI, with UFH used duringthe procedure.
Economic data with fondaparinux atthis time are limited to VTE. One of the fewhealth economic studies that have been conductedin this area investigated its use inorthopedic surgery and found cost savingswith fondaparinux over enoxaparin, whichgrew from $61 per patient at 30 days afterhospital discharge to $155 at 5 years in aclinical trial-based analysis.49 In a morerecent study involving patients undergoinghip fracture surgery, the use of fondaparinuxwas associated with 30 fewer episodes ofVTE per 1000 patients, at a savings of $361per patient at 3 months (Figure 2) and anestimated savings of $466 per patient at 5years.50 Although no health economic dataon fondaparinux in ACS are currently available,the use of fondaparinux instead ofenoxaparin is likely to result in overall costsavings because of several factors, such as itslower dose in ACS as well as the lower ratesof bleeding reported in recent trials.13,47
Because antithrombotic therapy comprisesthe largest portion of the costs associatedwith the treatment of ACS, it istherefore important to find the most cost-effectivetreatment that is both safe andeffective. Although UFH represents standardtherapy, newer treatments such as LMWH orfactor Xa inhibitors are efficacious alternativesthat are less costly in terms of overalltreatment costs, including not only acquisitionscosts but also monitoring expenses andcosts of bleeding and other side effects.According to recent trials, fondaparinuxappears to be equivalent to enoxaparin interms of efficacy in ACS patients; recentanalyses suggest that it may even turn out tobe cost saving due to lower rates of bleedingand lower drug dosages required.
Kenneth Lane and Thomas May contributed to the writing of this article.
Address correspondence to: Edith A. Nutescu, PharmD, Department ofPharmacy Practice, University of Illinois at Chicago, College of Pharmacy,833 S. Wood St., RM 164, MC886, Chicago, IL 60612. E-mail:firstname.lastname@example.org.
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