J Thromb Thrombolysis (2009) 28:220–223 DOI 10.1007/s11239-008-0256-4
Anticoagulation: where we are and where we need to go Geoffrey D. Barnes Æ James B. Froehlich
Published online: 18 July 2008 Springer Science+Business Media, LLC 2008
Abstract Although a commonly prescribed medication, warfarin has unique pharmacologic properties that make dosing challenging for many primary care physicians. When a patient’s international normalized ratio (INR) is out of the therapeutic range, they are at increased risk for thrombotic or hemorrhagic complications. We have reviewed the current literature for quality improvement techniques to minimize adverse outcomes and improve anticoagulation care. The use of anticoagulation clinics, computer-guided dosing and patient self-monitoring have been demonstrated to reduce adverse events or improve patient and provider satisfaction. Additional techniques, including genetic-based dosing, concurrent vitamin K administration and development of risk-assessment tools, have been discussed, but not fully developed or assessed in the literature. We identify tools that can be implemented today as well as those currently under development for the improvement in anticoagulation care. Keywords Anticoagulation Warfarin Anticoagulation clinic
yet to be optimized [1]. Some studies have suggested that patients taking warfarin are out of their therapeutic range up to 50% of the time [2–4]. A recent meta-analysis of 71,000 anticoagulated patients found that 44% of hemorrhagic events occurred at INRs above therapeutic range while 48% of thromboembolic events occurred at INRs below the therapeutic range [5]. For this reason, any factors that improve a patient’s time in therapeutic range and thereby decrease the frequency of adverse events should be a priority. A few studies have examined factors that improve outcomes in this patient population. Anticoagulation services, computerized software for tracking INR results and recommending dosing changes, as well as the use of patient self-monitoring of INR values, have all been suggested as practical strategies that can achieve these goals [6–8]. However, the number of patients currently not being managed by anticoagulation services is unknown, so the overall impact of this change cannot be accurately estimated. Furthermore, little is known about other factors that may improve or worsen outcomes for patients receiving anticoagulation.
Introduction Steps to improve the situation Warfarin is one of the most commonly prescribed medications. This is due to its effectiveness in preventing thromboembolism in patients with venous thrombosis and stroke in patients with atrial fibrillation. In spite of over 50 years of clinical experience, warfarin’s management has
G. D. Barnes (&) J. B. Froehlich University of Michigan Cardiovascular Center, 1500 East Medical Center Drive, SPC 5853, Ann Arbor, MI 48109-5853, USA e-mail:
[email protected]
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The first step in any quality improvement effort is to identify what benchmarks should be measured to assess quality of care. Following this, perceived and actual barriers to improving care must be explored and interventions to overcome these barriers must be designed. After implementing specific interventions to achieve the end goals, their effectiveness must be assessed and continual changes made to optimize outcomes [9]. In the case of anticoagulation, we see two treatment goals: (1) increased time in INR therapeutic range and (2) reduced adverse
Anticoagulation: where we are and where we need to go Table 1 Potential tools to improve patient outcomes • Organized anticoagulation clinics • Computer-aided warfarin dosing • Patient self-monitoring • Genetic-based warfarin dosing (needs further study) • Development and use of risk assessment tools • Oral vitamin K supplementation for patients taking warfarin (needs further study)
events. Achieving these goals has been the topic of a large body of research in the last 10 years. Three primary techniques have been identified (Table 1): 1. 2. 3.
Use of anticoagulation services. Use of computerized software for data tracking, including algorithms for dosing recommendations. Patient self-monitoring of INR.
All three of these interventions have been found to be as effective or more effective than standard anticoagulation care in a number of studies [1, 6–8, 10–13]. Nevertheless, limitations in application exist. Specifically, some physicians feel that separate anticoagulation services detract from or fragment patient care [14]. However, a well organized and implemented anticoagulation service can manage the day-to-day aspects of anticoagulation such as arranging for INR checks and making dosing adjustments while leaving the overarching responsibility of choosing the timing, method and degree of anticoagulation to the primary physician. This structure has been found to maximize the time patients interact with the health care system while minimizing the administrative task-work required by the primary physician’s office [1]. Additionally, patient satisfaction and knowledge of safe INR range is higher when under the care of an anticoagulation service as compared to standard care by their primary physician [7, 15]. Reimbursement for anticoagulation services is often quite limited and complicated by questions of which providers (MD, RN, NP, medical assistant, etc.) can be reimbursed for providing services. Frequently the cost falls to an institution or large group of providers [1]. Estimates from various studies indicate that savings could be as high as $860–1320 per patient-year, mostly due to decreased emergency room visits and hospital admissions [16, 17]. However, such ‘‘theoretical’’ savings are often not obvious or attractive to hospital administrations resulting in resistance to the added direct costs of such care. Additional and more recent data on cost-effectiveness of anticoagulation clinics may motivate health insurance providers to cover the costs of such clinics. A billing code for anticoagulation care was recently created, but the extent to which this will be reimbursed by third party payers, and exactly what form of care would qualify, is yet to be determined.
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Computerized software to track warfarin dosing, INR values, and make dose adjustment recommendations is another tool that improves time in therapeutic range and reduces adverse events. Studies have shown that well designed computer software is as effective as experienced practitioners when completing this task [12, 13]. Another study demonstrated greater time in the therapeutic range for patients managed with computer software compared with standard care [6]. The use of such software allows for better record keeping, more robust data tracking and the ability to incorporate a patient’s individual trend into dosing recommendations. In fact, one study showed that primary care office staff members were happy to incorporate some duplication of data entry for the confidence software data tracking and dose adjustment recommendations provide [6]. A large concern for many practices is the cost of such software. An estimate of $160 per patient per year cost primarily is related to initial set up, and decreases with the increasing size of the population of patients followed. The intervention least commonly used today is patient self-monitoring of INR. Nonetheless, some studies have suggested that this intervention may be the most beneficial in reducing adverse events and improving the time in therapeutic range [4, 18–20]. A major limitation to patient self-monitoring is the perception that self-monitoring is not feasible for many patients. However, some studies suggest the opposite. One study of university-based patients showed that 78% of patients initially randomized to selfmonitoring completed the study while monitoring their own INR [19]. In another study of 325 patients aged 65 or older randomly assigned to self-monitoring or standard care, 59% were able to participate in self-monitoring for the duration of the study [18]. Appropriate patient selection and patient education will only increase the number of eligible patients for this potentially beneficial intervention. Other interventions show promise, but have not been adequately validated in the literature (Table 1). These include better bleeding risk stratification tools, the use of vitamin K supplements to decrease daily variability while taking warfarin, and the use of genetic testing for warfarin response prediction. One review of risk stratification tools identified five different tools to assess bleeding risk, none of which were associated with sufficient likelihood ratios to adequately predict bleeding risk [21]. The HEMORR2 HAGES tool showed the most promise for predicting major bleeding, but not for minor bleeding [22]. Clearly, better bleeding risk assessment tools are needed. Some have suggested that taking daily vitamin K could decrease the day-to-day variability of blood vitamin K levels and allow for more predictable warfarin dosing and less time out of therapeutic range [23]. Lastly, a few genetic mutations (CYP2C9*2, CYP2C9*3 and VKORC1)
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have been associated with altered metabolism of warfarin, and changes in clinical response [24]. One randomized trial of a genetic dosing prediction tool showed no difference for percent of INRs in therapeutic range but did decrease the number of blood draws and dosing changes [25]. Another recent study developed a warfarin dosing tool for orthopaedic surgery patients using eight factors including genotype [26]. The National Heart, Lung and Blood Institute is initiating a trial of gene-based warfarin dosing compared to standard dosing approach. Outcomes will include time in therapeutic range, bleeding and thrombotic events and should help to understand the role of genotyping in warfarin dosing.
Measurement of effectiveness As with any good quality improvement initiative, the effectiveness of interventions must be measured, monitored and continually improved upon. Currently, there are few if any databases that monitor clinical processes and outcomes in patients managed on anticoagulation. Such a database would allow for the identification of specific practices that lead to improved patient outcomes and measurements of cost-effectiveness. If outcomes can be improved in a costeffective manner, then strong arguments can be made to health insurance providers to cover the cost of these interventions. Patient and physician demand for interventions such as self-monitoring tools, computerized software and establishment of anticoagulation services will drive the practice of anticoagulation management forward in next 5–10 years. Newer interventions discussed above, such as genetic testing and vitamin K supplementation, still require evaluation and testing to determine efficacy for improving clinical outcomes. Finally, novel oral antithrombotic agents (direct antithrombin inhibitors, factor Xa inhibitors, etc.) are in various stages of development. While the introduction of these agents into routine clinic practice is likely years away, anticoagulation clinics will likely play a critical role in the integration of these newer agents into anticoagulation care. Although our hope is that these newer agents will minimize many of the clinical issues inherent with warfarin use, new monitoring strategies and issues will arise (e.g. monitoring of liver enzymes, peri-procedural bridging). Over the next few years, we hope to begin filling the many knowledge gaps that exist in anticoagulation care including the start of the genetic-based dosing study noted above and a database of patient enrolled in anticoagulation clinics evaluating patient and process of care features associated with improved outcomes. Specifically, we hope to better understand:
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G. D. Barnes, J. B. Froehlich
• • • •
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Does genetic testing alter outcomes? Who really needs to be bridged with heparin when initiating warfarin therapy, and how best to do so? What is the best way to risk stratify patients for warfarin-associated bleeding? What components of anticoagulation clinics improve outcomes and how can they be implemented in a costeffective manner? Which patients need heparin bridging during periprocedural cessation of warfarin therapy, and how best to do so?
For such a common therapeutic intervention that has existed for over 50 years, the paucity of such clinical data is impressive. It should not be acceptable that patients are out of the therapeutic window up to 50% of the time. We must find ways to improve this deficiency, to reduce adverse events, and do so in a cost-effective manner. Investing in quality improvement studies is essential to achieving this goal. Acknowledgement The authors wish to thank Fred Spencer, M.D. for his assistance in reviewing this manuscript.
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