Preparing for the Post-warfarin Generation of Antithrombotics

The drawbacks of today's entrenchedantithrombotic therapies are wellknown. Most clinicians and evenmany patients realize that the anticoagulanteffects of warfarin are highly unpredictable.This vitamin K antagonist was first developedin the 1940s but remains the mostwidely used oral anticoagulant in NorthAmerica.¹ It is a leading cause of drug-relatedemergency department visits and drug-relatedadverse events in hospitals and inthe community.^2-4 Given its inherent bleedingrisk, some hesitancy in prescribing warfarinis not unexpected. Physicians areespecially reluctant to use anticoagulation inelderly patients because of bleeding risk,despite the fact that these patients are athighest risk for stroke.

Some health systems help clinicians keeptheir patients within warfarin's narrow therapeuticwindow by providing coordinatedclinical infrastructures for education, therapeuticmonitoring, and dose adjustment.Attempts to improve anticoagulation deliveryand encourage home patient monitoringmust continue. But even assuming increasedinvestments in anticoagulation clinics andother efforts to maximize outcomes withwarfarin, the practical problems related toeveryday clinical use of this drug will likelycontinue to stymie any major progress inreducing stroke or venous thromboembolism(VTE). This is why about half of warfarin-eligible patients with atrial fibrillation(AF) still do not receive anticoagulationtherapy.^5-7 And among AF patients who doinitiate warfarin, dosing often remains inadequateto provide real protection againststroke.⁸ Aspirin is a safer alternative to warfarinfor stroke prevention, but it is muchless effective in patients with risk factors.⁹

Anticoagulant therapy in patients at riskfor deep vein thrombosis (DVT) and pulmonaryembolism (PE) is similarly encumbered.Extended thromboprophylaxis inhigh-risk situations, such as after orthopedicsurgery, can be accomplished with warfarinbut, again, the convenience of oral therapy isseverely limited by the variable effects—caused in part by interactions with food andmedications—and the related requirementfor careful coagulation monitoring to avoidserious adverse effects.¹⁰ Low-molecular-weightheparin (LMWH) or unfractionatedheparin also effectively lowers the risk ofVTE, but these agents require parenteraladministration, which has become increasinglyproblematic because the recommendedduration of prophylaxis has been steadilylengthening in patients with risk factors, suchas surgery, immobilization, trauma, recurrentevents, cancer, or inherited thrombophilia.^1,11With heparin, coagulation monitoring is alsooften required and heparin-induced thrombocytopeniais an additional risk that must beconsidered. Several newer agents, such asdirect thrombin inhibitors (eg, desirudin, bivalirudin,and argatroban) and fondaparinuxsodium (ie, short-acting synthetic pentasaccharide),have also been used for anticoagulation,but these parenteral agents areinconvenient for extended outpatient use.^1,12This is one reason why, based on their abilityto block both circulating and clot-boundthrombin, most of the injectable directthrombin inhibitors have been developed foruse in specific inpatient settings, such as inthe management of heparin-induced thrombocytopeniaand during percutaneous coronaryinterventions.^13,14 Fondaparinux, on theother hand, has been studied in the preventionof VTE after major orthopedic surgery aswell as in the treatment of acute VTE.^15,16

This litany of problems associated withwarfarin, the heparins, and the injectabledirect thrombin inhibitors makes clear thecontinuing need for novel antithromboticstrategies. The preceding review article anddiscussion in this supplement explored theextent and the consequences of this long-standing need for alternatives, especially inambulatory patients requiring stroke andDVT/PE prevention. This final article willintroduce the pharmacology and emergingclinical profiles of antithrombotic agentsthat may soon simplify and improve preventionof arterial and venous thrombosis inday-to-day clinical practice. Many anticoagulantdrug classes have advanced to variousstages of clinical evaluation, if not approval(Table). A number of innovative antiplateletdrugs and drug combinations have alsorecently been tested for use in stroke.Targeted local delivery of various anticoagulantsor genes modulating coagulation tohighly thrombogenetic sites is anotherattractive strategy of the future.¹⁷ This articlewill focus on specific agents that havemoved closest to clinical release and thatshow the most promise as practical replacementsfor warfarin in the prevention ofstroke and DVT/PE.

Oral Direct Thrombin Inhibitors

Over the past decade, researchers haveelucidated many of the complex steps of thecoagulation cascade, and they have usedmolecular modeling and structure-baseddrug design to create new classes of drugsthat target specific steps in this pathway.Because of its role as a central regulator incoagulation, most notably the activation ofplatelets and the cleavage of fibrinogen tofibrin, thrombin has been a prime target inthe search for better oral anticoagulants.^18,19Unlike heparin, which acts by indirectthrombin inhibition, several of the directthrombin inhibitors appear to have animproved benefit-to-risk ratio as well as amore attractive pharmacokinetic and pharmacodynamicprofile.¹² Also, the directthrombin inhibitors do not require antithrombinas a cofactor and do not bind toplasma proteins, which leads to a morepredictable anticoagulant effect and lessinterpatient variability in response.²⁰ Twooral direct thrombin inhibitors deservespecial mention because of their developmentas prodrugs to allow convenient oraladministration.

Ximelagatran. Ximelagatran is an oraldirect thrombin inhibitor being developed asan anticoagulant for the prevention andtreatment of thromboembolism. A pro-drug,it is rapidly absorbed and biotransformedinto its active form, melagatran. The activedrug has a half-life of 4 to 5 hours and can beadministered twice daily. Plasma levels ofmelagatran increase linearly in relation tothe dose²¹ and the pharmacokinetic profileis predictable and stable over time, with noapparent effect because of age, obesity, ethnicorigin, mild-to-moderate hepatic dysfunction,or food intake.¹² Melagatran is notmetabolized through the hepatic cytochromeP450 enzyme system, so it has a low potentialfor drug interactions.²² Clearance is predominantlythrough the kidney, suggesting aneed for dose reduction in patients withsevere renal dysfunction.²³ This is a pharmacokineticand pharmacodynamic profile thatsuggests the possibility of oral administrationwith rapid onset of action and without aneed for routine therapeutic monitoring—ahypothesis that has now been tested in severalcontrolled settings against traditionalwarfarin therapy with anticoagulation monitoring.

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Several large phase 3 trials have nowdemonstrated the safety and efficacy oftwice-daily oral ximelagatran in the preventionof stroke in AF patients and in the preventionof VTE after orthopedic surgery. Inthe Stroke Prevention using the OralThrombin Inhibitor in Patients with nonvalvularAF (SPORTIF) trial, one open-labeland the other double-blind, fixed-dose ximelagatran(36 mg twice daily) was at least aseffective as strictly controlled warfarin forthe prevention of stroke and systemicembolism.^24,25 The studies, which enrolled atotal of more than 7000 patients, weredesigned as noninferiority trials. In theopen-label trial during a 17.4-month studyperiod, 56 patients (2.3%) taking warfarindeveloped stroke or systemic embolism versus40 patients (1.6%) in the ximelagatrangroup (absolute risk reduction, 0.7%; = .1).Various composite end points occurred atsimilar rates (Figure 1), but the combinedincidence of minor and major hemorrhageswas lower with ximelagatran than with warfarin(29.8% vs 25.8%; relative risk reduction14%; = .007).²⁴

Preliminary results from SPORTIF V suggestoutcomes similar to those of SPORTIFIII.²⁵ In this double-blind study, the rate ofstroke and systemic embolism was 1.6% inximelagatran-treated patients, and 1.2% inpatients treated with warfarin. Rates ofintracranial hemorrhage (0.6% in eachgroup) and major bleeding complications(ximelagatran 2.4% vs warfarin 3.1%) werenot clinically or statistically different.

In both SPORTIF III and SPORTIF V,approximately 6% of patients developed anincrease in alantine aminotransferase, aliver function test, while receiving ximelagatrantherapy. This observation, althoughasymptomatic and reversible in 2 to 4 weekswhether or not therapy is continued, needsto be evaluated further. Liver function testmonitoring will likely be necessary duringthe first 6 to 12 months of ximelagatrantherapy.

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Ximelagatran has also been comparedwith other antithrombotic agents afterorthopedic surgery. In European trials, oralximelagatran was preceded by subcutaneousmelagatran, whereas the US trials involvedonly oral prophylaxis. As reported in recentreviews of 6 major trials, ximelagatran hasdemonstrated similar or superior efficacyand safety compared with LMWH or well-controlledwarfarin therapy.^12,26 In a majorUS study of more than 1200 patients undergoingtotal knee replacement, for example,the incidence of total VTE was significantlylower in patients receiving ximelagatran 36mg than in patients receiving warfarin(20.3% vs 27.6%, = .003) (Figure 2). Therates of hemorrhagic complications with the2 drugs were similar (major bleeding rates,ximelagatran 0.8%, warfarin 0.7%).²⁷

Given evidence of efficacy and safetyequivalent to warfarin, ximelagatran has thepotential to become the anticoagulant ofchoice for patients with AF or those undergoingorthopedic surgery.^12,26,28,29 Becausethe clinical trials to date have all comparedthis direct thrombin inhibitor with warfarinadministered and monitored under what aregenerally considered ideal conditions, theactual risk-benefit advantages of fixed-doseximelagatran in the real-world setting ofclinical practice may be even greater thandemonstrated in these formal study settings.In SPORTIF III, for example, patients takingwarfarin were maintained within the internationalnormalized ratio therapeutic range66% of the time—a rate that, as emphasizedthroughout the discussion in this supplement,is higher than typically seen in communitysettings and comparable withanticoagulation clinic management. However,a full review of the clinical evidence invarious populations, including further evaluationof this agent's liver effects, is still warranted.Also, the higher cost of this agentwill necessitate new comparisons of the relativecost advantages of switching to ximelagatranversus investing in more aggressive orinnovative anticoagulation compliance programswith warfarin. Such evaluations mayhelp identify risk-targeted populations inwhom ximelagatran would be most costeffective.

Dabigatran etexilate. After oral administration,this prodrug is rapidly converted toits active form, known experimentally asBIBR 953ZW, after oral administration. Thehalf-life of the active thrombin inhibitor is15 hours and the drug is renally eliminated.Preliminary dosing trials with dabigatranetexilate indicate that once- or twice-dailyoral dosing may be possible, and the agent isnow in phase 2 trials.¹² As with ximelagatran,this oral direct thrombin inhibitor hasthe potential to become a replacement forwarfarin in various clinical settings. Giventhe medical community's long history ofdosing and compliance problems with warfarin,the possibility of a once-a-day fixed-doseoral direct thrombin inhibitor isespecially attractive.

Once-weekly SubcutaneousPentasaccharide

Fondaparinux and idraparinux are syntheticanalogs of the active pentasaccharidesequence in heparin and LMWH that bindsto antithrombin. With their higher affinityfor antithrombin than the naturally occurringpentasaccharides, these agents lead tohigh levels of factor Xa inhibition andmarked levels of antithrombotic activity inanimal models.³⁰ Several large clinical comparativetrials in the setting of orthopedicsurgery have shown fondaparinux to lowerrates of VTE significantly compared withLMWH with comparable bleeding rates.^15,31,32Although fondaparinux has a half-life of only17 to 21 hours and requires daily subcutaneousadministration, idraparinux has a plasmahalf-life of 80 hours,³³ opening the door tothe possibility of once-weekly subcutaneousinjections. Other attractive pharmacokineticfeatures of this agent relative to warfarininclude its lack of drug or food interactionsand the ability to offer a fixed-dose regimenwith no coagulation monitoring.¹

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In a recent phase 2 evaluation, once-weeklyadministration of this second-generationsynthetic factor Xa inhibitor (4different dose levels) was as effective as warfarinin reducing the thrombotic burden inpatients with proximal DVT.³⁴ In 614 evaluablepatients, the rates of normalization anddeterioration did not differ among the 5treatment groups. There was a clear doseresponse in major bleeding rates in patientstaking idraparinux ( = .003), but patients atthe lowest dose (2.5 mg) had less bleedingthan patients taking warfarin ( = .03). Aphase 3 open-label comparison of idraparinuxwith dose-adjusted warfarin is currentlyunder way in patients with AF.³⁵ If these andother larger phase 3 trials show idraparinuxto be equivalent to warfarin in efficacy, andat least as safe, then this once-weekly agentmay become a suitable alternative to warfarin.Clinical settings requiring intermediate-length therapy (ie, therapy for weeks ormonths after orthopedic surgery) might bebest suited to an agent requiring weeklyinjections. In the setting of AF, for example,such an agent might be most useful in managingnoncompliant patients or those withimpaired gastrointestinal absorption.³⁵

Aspirin plus Clopidogrel

In clinical practice, adjusted-dose warfarintherapy is associated with 52% relativerisk reduction for stroke in AF patients comparedwith no warfarin therapy.³⁶ Despite itslower efficacy, aspirin 325 mg daily is stillconsidered an alternative to oral anticoagulationin certain low-risk patients (ie, thosewith certain contraindications to warfarin).⁹Aspirin permanently inactivates a keyenzyme in platelet arachidonic acid metabolism,thereby limiting production of thromboxaneA₂, which normally amplifies plateletactivation signals and leads to irreversibleaggregation.³⁷

Clopidogrel is a thienopyridine that inhibitsplatelets by selective inhibition ofreceptors for adenosine diphosphate—inducedplatelet aggregation.³⁸ Until recently, clopidogrelhad mainly been used in high-riskpatients with coronary and cerebrovasculardisease who could not take aspirin or afterintracoronary stent placement.³⁷

Thus, although the combination of aspirinplus clopidogrel is now widely used inpatients with acute coronary syndromes, theefficacy of this combination in stroke preventionin patients with AF remains to bedetermined in head-to-head trials with warfarinand aspirin alone. Such trials havebeen initiated.³⁹ If the combination ofantiplatelet agents proves to have advantagesin efficacy or safety over aspirin alonein patients with AF, this regimen maybecome a new standard of therapy forpatients at lower risk for stroke or ineligiblefor anticoagulant therapy; if the combinationcompares well with dose-adjusted warfarinor with newer agents such asximelagatran, then even broader usage in AFpatients may be warranted.³⁵

Summary

Several antithrombotic agents in developmenthave the potential to greatly simplifythe management of patients with AF or atrisk for DVT/PE. Ximelagatran has alreadycompleted several phase 3 clinical studiesin both of these high-risk, high-cost clinicalsettings and is poised to become the firstpractical alternative to warfarin. Althoughthe exact therapeutic roles of ximelagatranand other novel antithrombotics furtherback in the pipeline remain to be determined,the impact of these nonwarfarinalternatives on the current labor-intensivesystem of anticoagulation clinics seems certain.Most important, the introduction ofsafer and equally effective oral anticoagulantsthat do not require monitoring mayincrease the percentage of high-riskpatients who actually receive preventivetherapy. If the institutional energy andresources previously spent on anticoagulationclinics, thrombotic disease management,and quality benchmarking can nowbe redirected to the delivery of the new generationof easier-to-administer and saferantithrombotic agents, the potential toincrease rates of preventive therapy initiationand adherence in managed care populationsmay be within reach. Given theproven clinical value of anticoagulation, thispotential increase in the rate of prophylaxissuggests the possibility that, even in theface of a rapidly aging US population, we arenonetheless entering into a period ofreduced morbidity, mortality, and costsfrom stroke and DVT/PE.

Am J Manag Care.

1. Nutescu EA. Antithrombotic therapy for the treatmentof venous thromboembolism. 2003;9(5 suppl):S103-S114.

JAMA.

2. Gurwitz JH, Field TS, Harrold LR, et al. Incidenceand preventability of adverse drug events among olderpersons in the ambulatory setting. 2003;289:1107-1116.

Ann Emerg Med.

3. Hafner JW Jr, Belknap SM, Squillante MD, BucheitKA. Adverse drug events in emergency departmentpatients. 2002;39:258-267.

Pharmacoepidemiol DrugSaf.

4. Zaidenstein R, Eyal S, Efrati S, et al. Adverse drugevents in hospitalized patients treated with cardiovasculardrugs and anticoagulants. 2002;11:235-238.

Heart.

5. Perez I, Melbourn A, Kalra L. Use of antithromboticmeasures for stroke prevention in atrial fibrillation. 1999;82:570-574.

AnnIntern Med.

6. Go AS, Hylek EM, Borowsky LH, Phillips KA, SelbyJV, Singer DE. Warfarin use among ambulatory patientswith nonvalvular atrial fibrillation: the Anticoagulationand Risk Factors in Atrial Fibrillation (ATRIA) study. 1999;131:927-934.

ArchIntern Med.

7. McCormick D, Gurwitz JH, Goldberg RJ, et al.Prevalence and quality of warfarin use for patients withatrial fibrillation in the long-term care setting. 2001;161:2458-2463.

J Thromb Thrombolysis.

8. Samsa GP, Matchar DB, Phillips DL, McGrann J.Which approach to anticoagulation management is best?Illustration of an interactive mathematical model to supportinformed decision making. 2002;14:103-111.

J Am CollCardiol.

9. Fuster V, Ryden LE, Asinger RW, et al. ACC/AHA/ESCguidelines for the management of patients with atrial fibrillation:executive summary. A Report of the AmericanCollege of Cardiology/American Heart Association TaskForce on Practice Guidelines and the European Societyof Cardiology Committee for Practice Guidelines andPolicy Conferences (Committee to Develop Guidelinesfor the Management of Patients with Atrial Fibrillation):developed in Collaboration with the North AmericanSociety of Pacing and Electrophysiology. 2001;38:1231-1266.

Chest.

10. Ansell J, Hirsh J, Dalen J, et al. Managing oral anticoagulanttherapy. 2001;119(1 suppl):22S-38S.

J Am Coll Cardiol.

11. Hirsh J, Fuster V, Ansell J, et al. American HeartAssociation/American College of Cardiology Foundationguide to warfarin therapy. 2003;41:1633-1652.

Drugs.

12. Eriksson BI, Dahl OE. Prevention of venous thromboembolismfollowing orthopaedic surgery: clinicalpotential of direct thrombin inhibitors. 2004;64:577-595.

Expert RevCardiovasc Ther.

13. Bates ER. Bivalirudin: an anticoagulant option forpercutaneous coronary intervention. 2004;2:153-162.

Thromb Res.

14. Warkentin TE. Management of heparin-inducedthrombocytopenia: a critical comparison of lepirudinand argatroban. 2003;110:73-82.

Arch Intern Med.

15. Turpie AG, Bauer KA, Eriksson BI, Lassen MR.Fondaparinux vs enoxaparin for the prevention ofvenous thromboembolism in major orthopedic surgery:a meta-analysis of 4 randomized double-blind studies. 2002;162:1833-1840.

Ann Intern Med.

16. Buller HR, Davidson BL, Decousus H, et al.Fondaparinux or enoxaparin for the initial treatment ofsymptomatic deep venous thrombosis: a randomizedtrial. 2004;140:867-873.

Semin Hematol.

17. Moll S, Roberts HR. Overview of anticoagulantdrugs for the future. 2002;39:145-157.

Am J Cardiovasc Drugs.

18. Weitz JI, Crowther MA. New anticoagulants: currentstatus and future potential. 2003;3:201-209.

Ann Pharmacother.

19. Nutescu EA, Wittkowsky AK. Direct thrombininhibitors for anticoagulation. 2004;38:99-109.

Chest.

20. Weitz JI, Hirsh J. New anticoagulant drugs. 2001;119:95S-107S.

Eur J Clin Pharmacol.

21. Eriksson UG, Bredberg U, Gislen K, et al. Pharmacokineticsand pharmacodynamics of ximelagatran, anovel oral direct thrombin inhibitor, in young healthymale subjects. 2003;59:35-43.

Clin Pharmacokinet.

22. Bredberg E, Andersson TB, Frison L, et al.Ximelagatran, an oral direct thrombin inhibitor, has alow potential for cytochrome P450-mediated drug-druginteractions. 2003;42:765-777.

Clin Pharmacokinet.

23. Eriksson UG, Johansson S, Attman PO, et al.Influence of severe renal impairment on the pharmacokineticsand pharmacodynamics of oral ximelagatran andsubcutaneous melagatran. 2003;42:743-753.

Lancet.

24. Olsson SB; Executive Steering Committee on behalfof the SPORTIF III Investigators. Stroke Prevention withthe Oral Direct Thrombin Inhibitor Ximelagatran Comparedwith Warfarin in Patients with Non-valvular AtrialFibrillation (SPORTIF III): randomised controlled trial. 2003;362:1691-1698.

Circulation.

25. SoRelle R. Interleukin-18 predicts coronary events. 2003;108:e9051-e9065.

Drugs.

26. Evans HC, Perry CM, Faulds D. Ximelagatran/melagatran:a review of its use in the prevention of venousthromboembolism in orthopaedic surgery. 2004;64:649-678.

N Engl J Med.

27. Francis CW, Berkowitz SD, Comp PC, et al.Comparison of ximelagatran with warfarin for the preventionof venous thromboembolism after total kneereplacement. 2003;349:1703-1712.

Stroke.

28. Hankey GJ, Klijn CJ, Eikelboom JW. Ximelagatranor warfarin for stroke prevention in patients with atrialfibrillation? 2004;35:389-391.

Curr Opin Cardiol.

29. Reiffel JA. Will direct thrombin inhibitors replacewarfarin for preventing embolic events in atrial fibrillation? 2004;19:58-63.

J Intern Med.

30. Koopman MM, Buller HR. Short- and long-actingsynthetic pentasaccharides. 2003;254:335-342.

N Engl J Med.

31. Eriksson BI, Bauer KA, Lassen MR, Turpie AG,Steering Committee of the Pentasaccharide in Hip-Fracture Surgery Study. Fondaparinux compared withenoxaparin for the prevention of venous thromboembolismafter hip-fracture surgery. 2001;345:1298-1304.

Lancet.

32. Lassen MR, Bauer KA, Eriksson BI, EuropeanPentasaccharide Elective Surgery Study (EPHESUS)Steering Committee. Postoperative fondaparinux versuspreoperative enoxaparin for prevention of venous thromboembolismin elective hip-replacement surgery: a randomiseddouble-blind comparison. 2002;359:1715-1720.

Blood.

33. Herbert JM, Herault JP, Bernat A, et al. Biochemicaland pharmacological properties of SANORG34006, a potent and long-acting synthetic pentasaccharide. 1998;91:4197-4205.

J Thromb Haemost.

34. PERSIST Investigators. A novel long-acting syntheticfactor Xa inhibitor (SanOrg34006) to replace warfarin forsecondary prevention in deep vein thrombosis. A phaseII evaluation. 2004;2:47-53.

Am J Manag Care.

35. O'Donnell M, Weitz JI. Novel antithrombotic therapiesfor the prevention of stroke in patients with atrial fibrillation. 2004;10(3 suppl):S72-S82.

Am J Manag Care.

36. Go AS. Efficacy of anticoagulation for stroke preventionand risk stratification in atrial fibrillation: translatingtrials into clinical practice. 2004;10(3suppl):S58-S65.

Eur Heart J.

37. Patrono C, Bachmann F, Baigent C, et al. Expertconsensus document on the use of antiplatelet agents.The task force on the use of antiplatelet agents inpatients with atherosclerotic cardiovascular disease ofthe European Society of Cardiology. 2004;25:166-181.

Nature.

38. Hollopeter G, Jantzen HM, Vincent D, et al.Identification of the platelet ADP receptor targeted byantithrombotic drugs. 2001;409:202-207.

J Cardiovasc Electrophysiol.

39. Hohnloser SH, Connolly SJ. Combined antiplatelettherapy in atrial fibrillation: review of the literature andfuture avenues. 2003;14(9suppl):S60-S63.

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