Discussions of anticoagulation therapyoften begin with a review of 3 rathernoncontroversial facts. As summarizedhere, these might be dubbed "the GoodFact," "the Bad Fact," and "the Ugly Fact."
First, evidence that anticoagulation therapyreduces the risk of major and costlymedical events is overwhelming. Meta-analysesindicate that oral anticoagulationwith dose-adjusted warfarin reduces the riskof stroke by about 60% versus placebo inpatients with atrial fibrillation (AF).1,2 Bycomparison, aspirin offers only modest protection(approximately 20% risk reduction)against future stroke in these patients.2-4Similarly, therapy with heparin for 1 weekplus oral anticoagulation continuing for atleast 3 months has been shown to reduce therisk of recurrent deep vein thrombosis(DVT) and pulmonary embolism (PE) byabout 80% to 90%.5 Extended therapy withwarfarin further reduces the risk of venousthromboembolism.6-8
Second, although the benefits of oral anticoagulationin patients are clear, the risk ofbleeding and the potential for seriousintracranial hemorrhage are equally welldocumented. In particular, the risks of warfarin-related major bleeding increases as theintensity of anticoagulation increases and ishigher in the elderly, in patients with a historyof bleeding, and in patients with seriouscomorbid conditions.9,10 To balance the benefitsand risks of anticoagulation, therapeuticmonitoring has become a necessaryadjunct to warfarin therapy. Recommendationson how to select patients and make thecrucial periodic adjustments of warfarindosage in individual patients with varyingdegrees of thrombotic and bleeding risk—and how to combine oral anticoagulationwith concomitant therapy, such as rate controlin AF or heparin in DVT/PE—are nowspelled out in various anticoagulation treatmentguidelines.11-14
The third fact about anticoagulation thatwill not often be disputed is that healthcareproviders still do not provide sufficient anticoagulationfor some patients. Only abouthalf of eligible AF patients, for example,receive anticoagulation.15 A recent review of9 studies found the rate of warfarin use in eligiblehigh-risk patients ranges from 22% to79%.16 Equally troubling was the finding thatup to 60% of those receiving warfarin hadinternational normalized ratios (INRs) belowthe recommended therapeutic range.16 Thebarriers to the initiation and proper long-termuse of dose-adjusted warfarin therapyinclude: the fear of bleeding events, theinconvenience of continuous prothrombintime monitoring, and the possibility of druginteractions and complex interindividualpharmacokinetics that will further confounddosing. From the patient's perspective, theneed for continuous anticoagulation monitoringcontributes to widespread noncompliance,especially in patients with languagebarriers, disabilities, or rural residences.
To help overcome these barriers to evidence-based oral anticoagulation, a varietyof approaches have been adopted, with anticoagulationclinics and patient educationwith self-testing and/or self-managementbeing commonly employed tactics. Anticoagulationclinics now represent the goldstandard for long-term warfarin therapy—essentially coming closest to emulating theefficacy rates seen in the randomized clinicaltrial settings—and these clinics areacknowledged to improve quality, reducecomplications, and reduce total health system costs.17-21 One recent 2004 analysis in alarge health maintenance organization inGeorgia calculated the per member permonth costs for an outpatient pharmacyanticoagulation service for AF patients to be$62, an amount that the authors concludedwas justified based on the percent of timepatients were kept within their INR goal(60%) and the cost savings because of preventedcomplications, such as stroke orintracranial bleeding.21 Although less established,patient self-management of warfarintherapy has recently emerged as an alternativeor an add-on to anticoagulation clinics.These innovative strategies, which haveincluded home use of portable coagulometersand creation of Web-based virtual anticoagulationclinics, have in some cases beenfound to be safe and cost-effective alternativesto usual care or to the classic anticoagulationclinic model.22-25
Having recited these 3 facts, many discussionsand review articles on anticoagulationend at this point, perhaps adding a callfor investments in research, anticoagulationprograms, or improvements in efforts toboost warfarin adherence.
From the health system perspective, thecosts of therapy, monitoring, and relatedanticoagulation management programs mustnow become a critical part of the extendeddiscussion. The economic rationale forinvesting in the primary and secondary preventionof stroke and DVT/PE has alwaysbeen clear. After all, the clinical and economicburdens of stroke and PE are knownto be huge. On a national level, the directcosts of stroke alone have been estimated at$33 billion per year.26 A recent review ofinternational studies indicated that the long-termper-patient costs of stroke ranged from$18 538 to over $200 000, with severestrokes costing 11% to 71% more than minorstrokes because of longer acute care stays.27In the United States, the increasing size ofthe elderly population, a group at muchhigher risk of AF and stroke, makes the cost-effectivenessargument for anticoagulationeven stronger.16
However, although the possibility of cost-effective,if not cost-saving, warfarin preventivetherapy might seem intuitive with suchhigh disease-related costs, the various pharmacoeconomicstudies evaluating this questionshow that the actual cost effectivenessdepends on an amalgam of factors, such asstroke risk, bleeding risk, patient preferences,patient age, rates of appropriate use,and local costs of anticoagulation management.16,28-32 In the end, health systems mustbase their decisions to invest in stroke andvenous thromboembolism prevention ontheir analysis of local demographics, eventrates, costs, and available anticoagulationresources and talent. As made clear in thefew ambitious attempts to develop a decision-making tool for anticoagulation managementcosts and outcomes,33,34 estimatingthe cost effectiveness of any single healthsystem's anticoagulation program can be anextraordinarily complex undertaking. Withwarfarin as the sole oral agent, furtherinvestments in anticoagulation educationsoon reach a point of diminishing returns.
The economics of anticoagulation mayquickly be radically altered by the introductionof new anticoagulant and antiplatelettherapies now emerging from clinical trials.Agents such as the oral direct thrombininhibitor ximelagatran, the subcutaneouslyinjected synthetic pentasaccharide idraparinux,and the combination of clopidogreland aspirin are now being tested againstdose-adjusted warfarin. If these therapiesare proved to be safer than and as effectiveas warfarin, they may eliminate the need fortherapeutic monitoring and thereby greatlyincrease the willingness of both cliniciansand patients to initiate and maintain long-termanticoagulation therapy. One or moreof these agents may soon signal the end of anera for warfarin.35 But as newer therapiesenter the clinic and pharmacy, questionsabout the cost effectiveness of anticoagulationwill remain. In fact, because the newagents may improve anticoagulation initiationand adherence rates (vs health systeminvestments in anticoagulation clinics orpatient education), discussions about theeconomics of anticoagulation have neverbeen more relevant.
Clinicians and administrators in managedcare settings need to anticipate the arrival ofthese new agents by assessing their currentsituation. This assessment should include anhonest appraisal of the current institutionalrates of anticoagulation in key populationsand the local resources already being spentto improve this rate (eg, staff for anticoagulationclinic or patient education and selfmonitoringprograms). A baseline assessmentof missed prevention opportunities (eg, percentof warfarin-eligible patients not receivinganticoagulation) will provide anobjective measure of the potential upside forimproved outcomes with the new anticoagulants.Although these new therapies will bemore costly than warfarin, they may also cutoverall medical budgets by reducing theneed for therapeutic monitoring and avoidingadverse events. Costs for treatment ofcertain bleeding side effects may also bereduced. Finally, and most important, if thepromise of early trials is borne out, the newnonwarfarin anticoagulants may also eventuallyease clinician hesitancy to prescribeanticoagulants and, in the process, increaseoverall population anticoagulation usage andadherence and thereby reduce event ratesand event severity. This potential forimprovement in patient outcome—fewerserious strokes and PEs—is where real economicgains will likely be found.
The AmericanJournal of Managed Care
This supplement to was based on aroundtable discussion on the healthcareeconomics of effective anticoagulation. Thediscussion was held on April 2, 2004, in SanFrancisco. The purpose of the discussionwas to provide readers with a starting pointto undertake their own local and institutionaldiscussions of issues related to the economicsof anticoagulation.
The review article by Ann K. Wittkowsky,PharmD, CACP, FASHP, provides details onthe epidemiologic and economic scope ofstroke and PE and formally introduces theabove-mentioned essential facts about anticoagulation.Dr Wittkowsky emphasizes thecurrent extent of suboptimal warfarin use,reminding readers that this gap betweenanticoagulation guidelines and clinical practicecan be measured in 2 distinct ways:underutilization (the number of eligiblepatients not receiving warfarin) and undercoagulation(the percentage of patients takingwarfarin but not at INR goal). As directorof anticoagulation services at the Universityof Washington Medical Center, long-timeauthor and educator in the field ofantithrombotic pharmacotherapy, and recipientof the 2003 American Society of Health-System Pharmacists Drug Therapy ResearchAward for her work in the pharmacogenomicsof warfarin, Dr Wittkowsky was anatural choice to chair the session and setthe stage for discussion.
The roundtable of experts was then invitedto share their ideas on the economic consequencesof stroke and DVT/PE, the extentand the costs of nonadherence to nationalguidelines for anticoagulation, the primarycauses of anticoagulant underuse, and thebest ways to improve adherence to anticoagulationguidelines. The edited summary ofthis discussion provides managed care decisionmakers with a diverse range of opinionsand insights on the stubborn challenges withthe anticoagulation services prevalent inmost healthcare settings today.
In a post-meeting interview, Jaime Caro,MDCM, was given an opportunity to expandon his comments related to the economics ofanticoagulation. In particular, he shared theresults of a new Medicare-based study measuringthe national economic burden ofstroke in AF. In describing a related study,Dr Caro explains how he compared thenational cost outcomes in typical clinicalscenarios, including care with anticoagulationclinics, usual medical care, and no anticoagulation.His conclusion that only 11% ofthe potential anticoagulation benefit is currentlybeing obtained supports his belief thatit will be difficult to overcome the inherentdifficulties of prescribing warfarin in clinicalpractice.
Finally, in the concluding article by DrWittkowsky, the main pharmacologic agentscurrently being evaluated as possiblereplacements for warfarin are brieflyreviewed. The arrival of these agents maypowerfully reshape the clinical and economicstatus quo with warfarin-based anticoagulation.The new anticoagulants are, as onediscussant termed it, "a disruptive technology"that just might close the longstandinggap between the promise of anticoagulationas demonstrated in clinical studies and thecurrent practice of anticoagulation as evidenced in underutilization and under-coagulation.Will direct thrombin inhibitors reallyreplace warfarin as a first-line anticoagulantto prevent stroke and DVT/PE? Will morethan half of patients with AF finally get properpreventive therapy? Uptake of these newagents will depend on the final evidence ofsafety and efficacy, but it will also hinge ondiscussions about the economics of anticoagulationthat are just now beginning inmanaged care organizations around thecountry.
1. Warfarin versus aspirin for prevention of thromboembolismin atrial fibrillation: Stroke Prevention in AtrialFibrillation II Study. 1994;343:687-691.
Ann Intern Med.
2. Hart RG, Benavente O, McBride R, Pearce LA.Antithrombotic therapy to prevent stroke in patients withatrial fibrillation: a meta-analysis. 1999;131:492-501.
Am J Manag Care.
3. Go AS. Efficacy of anticoagulation for stroke preventionand risk stratification in atrial fibrillation: translatingtrials into clinical practice. 2004;10(3 suppl):S58-S65.
Arch Intern Med.
4. AFI. The Atrial Fibrillation Investigators. The efficacyof aspirin in patients with atrial fibrillation. Analysis ofpooled data from 3 randomized trials. The AtrialFibrillation Investigators. 1997;157:1237-1240.
Am J RespirCrit Care Med.
5. Hyers TM. Venous thromboembolism. 1999;159:1-14.
N Engl J Med.
6. Kearon C, Gent M, Hirsh J, et al. A comparison ofthree months of anticoagulation with extended anticoagulationfor a first episode of idiopathic venous thromboembolism. 1999;340:901-907.
N Engl J Med.
7. Schulman S, Granqvist S, Holmstrom M, et al. Theduration of oral anticoagulant therapy after a secondepisode of venous thromboembolism. The Duration ofAnticoagulation Trial Study Group. 1997;336:393-398.
N Engl J Med.
8. Ridker PM, Goldhaber SZ, Danielson E, et al. Long-term,low-intensity warfarin therapy for the prevention ofrecurrent venous thromboembolism. 2003;348:1425-1434.
9. Oden A, Fahlen M. Oral anticoagulation and risk ofdeath: a medical record linkage study. 2002;325:1073-1075.
10. Levine MN, Raskob G, Landefeld S, Kearon C.Hemorrhagic complications of anticoagulant treatment. 2001;119(1 suppl):108S-121S.
J Am Coll Cardiol.
11. Fuster V, Ryden LE, Asinger RW, et al.ACC/AHA/ESC guidelines for the management ofpatients with atrial fibrillation: executive summary. AReport of the American College of Cardiology/AmericanHeart Association Task Force on Practice Guidelines andthe European Society of Cardiology Committee forPractice Guidelines and Policy Conferences (Committeeto Develop Guidelines for the Management of Patientswith Atrial Fibrillation): developed in Collaboration withthe North American Society of Pacing andElectrophysiology. 2001;38:1231-1266.
Ann Intern Med.
12. Snow V, Weiss KB, LeFevre M, et al. Managementof newly detected atrial fibrillation: a clinical practiceguideline from the American Academy of FamilyPhysicians and the American College of Physicians. 2003;139:1009-1017.
13. Geerts WH, Heit JA, Clagett GP, et al. Preventionof venous thromboembolism. 2001;119(1 suppl):132S-175S.
J Am Coll Cardiol.
14. Hirsh J, Fuster V, Ansell J, Halperin JL. AmericanHeart Association/American College of CardiologyFoundation guide to warfarin therapy. 2003;41:1633-1652.
15. Buckingham TA, Hatala R. Anticoagulants for atrialfibrillation: why is the treatment rate so low? 2002;25:447-454.
Am J ManagCare.
16. Bushnell CD, Matchar DB. Pharmacoeconomics ofatrial fibrillation and stroke prevention. 2004;10(3 suppl):S66-S71.
Eff Clin Pract.
17. Hamby L, Weeks WB, Malikowski C. Complicationsof warfarin therapy: causes, costs, and the role of theanticoagulation clinic. 2000;3:179-184.
18. Samsa GP, Matchar DB. Relationship between testfrequency and outcomes of anticoagulation: a literaturereview and commentary with implications for the designof randomized trials of patient self-management. 2000;9:283-292.
19. Macik BG. The future of anticoagulation clinics. 2003;16:55-59.
JtComm J Qual Improv.
20. Gill JM, Landis MK. Benefits of a mobile, point-of-careanticoagulation therapy management program. 2002;28:625-630.
J Manag Care Pharm.
21. Anderson RJ. Cost analysis of a managed caredecentralized outpatient pharmacy anticoagulationservice. 2004;10:159-165.
J Thromb Thrombolysis.
22. Lafata JE, Martin SA, Kaatz S, Ward RE.Anticoagulation clinics and patient self-testing forpatients on chronic warfarin therapy: a cost-effectivenessanalysis. 2000;9(suppl 1):S13-S19.
Am JGeriatr Cardiol.
23. Cheung DS, Heizer D, Wilson J, Gage BF. Cost-savingsanalysis of using a portable coagulometer for monitoringhomebound elderly patients taking warfarin. 2003;12:283-287.
Jt Comm J Qual Saf.
24. Kelly JJ, Sweigard KW, Shields K, Schneider D. JohnM. Eisenberg Patient Safety Awards. Safety, effectiveness,and efficiency: a Web-based virtual anticoagulation clinic. 2003;29:646-651.
J Thromb Haemost.
25. Gadisseur AP, Kaptein AA, Breukink-Engbers WG,van der Meer FJ, Rosendaal FR. Patient self-managementof oral anticoagulant care vs management by specializedanticoagulation clinics: positive effects onquality of life. 2004;2:584-591.
Heart Disease andStroke Statistics—2004 Update.
26. American Heart Association. Dallas, Tex: AmericanHeart Association; 2003.
27. Payne K, Huybrechts K, Caro JJ. The economic burdenof stroke: an international review of long-term cost-of-illness estimates. Abstract presented at: 5th WorldStroke Congress; June 25, 2004; Vancouver BritishColumbia, Canada.
28. Gustafsson C, Asplund K, Britton M, Norrving B,Olsson B, Marke LA. Cost effectiveness of primary strokeprevention in atrial fibrillation: Swedish national perspective. 1992;305:1457-1460.
29. Gage BF, Cardinalli AB, Albers GW, Owens DK.Cost-effectiveness of warfarin and aspirin for prophylaxisof stroke in patients with nonvalvular atrial fibrillation. 1995;274:1839-1845.
Arch Intern Med.
30. Eckman MH, Falk RH, Pauker SG. Cost-effectivenessof therapies for patients with nonvalvular atrial fibrillation. 1998;158:1669-1677.
31. Lightowlers S, McGuire A. Cost-effectiveness ofanticoagulation in nonrheumatic atrial fibrillation in theprimary prevention of ischemic stroke. 1998;29:1827-1832.
Arch Intern Med.
32. Wolf PA, Mitchell JB, Baker CS, Kannel WB,D'Agostino RB. Impact of atrial fibrillation on mortality,stroke, and medical costs. 1998;158:229-234.
J Thromb Thrombolysis.
33. 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.
34. Thomson R, Parkin D, Eccles M, Sudlow M,Robinson A. Decision analysis and guidelines for anticoagulanttherapy to prevent stroke in patients with atrialfibrillation. 2000;355:956-962.
35. Donnan GA, Dewey HM, Chambers BR. Warfarinfor atrial fibrillation: the end of an era? 2004;3:305-308.