Journal of Clinical Pharmacy and Therapeutics, 2012, 37, 375377

doi: 10.1111/j.1365-2710.2011.01324.x

Commentary

Warfarin therapeutic monitoring: is 70% time in the therapeutic range the best we can do?
E. Lader* MD FACC FACP FAHA, N. Martin* BA, G. Cohen* MD FACC, M. Meyer* RN MSN, P. Reiter* MD FACC, A. Dimova* MD FACC and D. Parikh* MD FACC
*Mid Valley Cardiology, Kingston and Department of Medicine, New York University School of Medicine, New York, NY, USA

Received 2 October 2011, Accepted 7 November 2011

Keywords: anticoagulation, international normalized ratio, outcomes and process assessment, warfarin

SUMMARY Heavier than air ying machines are impossible. Lord Kelvin, President, Royal Society of England, 1895 What is known and Objective: Warfarin, an oral anticoagulant, which has been in clinical use for over sixty years, remains a challenge for clinicians to utilize, given the multiplicity of items which can limit its efcacy. Our objective is to review the evidence and comment on whether INR control can be better than has been currently reported in various studies. Comment: The duration of time a patients international normalized ratio (INR) is maintained within the therapeutic range (time in the therapeutic range, TTR) for his or her particular indication for the drug impacts the effectiveness and safety of warfarin therapy. Maintaining a therapeutic INR while on warfarin is difcult, and numerous studies employing various strategies conrm the challenge, but not the impossibility of achieving a TTR above 70%. What is new and Conclusion: Maintaining a therapeutic INR requires a dedicated multi-faceted approach. With diligence, skill and various therapeutic strategies, a TTR >70% can be achieved.

to examine our own experience in an exploration of this provocative statement. COMMENT The earliest clinical users of these oral anticoagulants noted that there were wide variations in the dose requirements for individual patients1. Numerous and complex food and drug interactions complicate dosing strategies2, and more recently appreciated genetic polymorphisms 3 serve to further increase the clinicians challenge. Yet it is clear the stakes are high: if the TTR is less than around 60%, some data suggest that much of the benet of utilizing warfarin is lost and we might as well be using aspirin4! An early strategy aimed at improving TTR was based on the hypothesis that a clinic or service, which focused solely on managing the dosage of warfarin, could achieve better results than a practitioner who was likely to be distracted by a broader array of health issues on a daily basis. A number of studies have been conducted to determine the validity of this assumption, but not all reported their results in the format of TTR. A paper from 1993 found that over 70% of patients in the anticoagulation clinic maintained their INR within the therapeutic range more than 50% of the time, with a substantial reduction in bleeding and thrombotic events compared with prior to enrollment5. A 1998 article found a TTR level of 37% in the usual medical care group improved to 40% in the anticoagulation clinic group, with a signicant reduction in bleeding incidents and healthcare costs6. A randomized trial comparing anticoagulation clinics to care by family physicians showed an improvement of TTR from 59% to 63%7. A 2005 article studied the effect of a clinical pharmacy anticoagulation service using a centralized telephonic approach and showed a TTR of 635% compared with 552% TTR in the group managed with usual care, with a reduction in complications8. A very recent paper from an Italian anticoagulation clinic caring for elderly patients quoted a TTR of 62%9. Anticoagulation clinics work, but reported TTR does not seem to break the 70% barrier. Dosing algorithms, either utilized by humans or imposed by computers, presume that by substituting a standard dosing strategy and eliminating the subjective and sometimes unpredictable choices in dosing made by the clinician, the TTR can be improved. Dosing algorithms may be more useful during initiation of treatment when a steady-state dose is being determined,

WHAT IS KNOWN AND OBJECTIVE First described as responsible for the sweet clover disease in cattle in the 1920s, warfarin and its related compounds have been used in clinical medicine as anticoagulants since the 1940s. Published data and clinical experience, however, have demonstrated time and time again how challenging it is to maintain the degree of anticoagulation within the desired therapeutic range (time in the therapeutic range, TTR). Indeed, despite herculean efforts and a number of clinical strategies, it has appeared impossible to achieve a TTR much >70%. Dare we state, invoking thoughts of Lord Kelvin, that maintaining the TTR with warfarin >70% is impossible? Our objective is to comment on these strategies on the basis of published research and

Correspondence: Ellis Lader, MD, 111 Marys Avenue, Kingston, New York, NY 12401, USA. Tel.: 845 331 6600; Fax 845 339 3629; e-mail: ewlader@verizon.net

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although a standardized approach to dealing with the commonly seen uctuations in INR that occur during warfarin maintenance dosing should be helpful as well. It may not be possible to fully evaluate the usefulness of algorithms in terms of our TTR challenge, however, because studies examining algorithms used with initial warfarin dosing did not report their effectiveness as TTR, but rather in terms of how well their use predicted the correct dosing. It also may not be possible to separate the benets of algorithm use from that of participating in a specialty clinic, as many clinics reported using algorithms as part of their management strategies. Algorithms may be simple 10 or complex. Algorithms that include genetic testing were quite complex 11 and only marginally effective in predicting a correct warfarin dose. The cost of genetic testing and the delay in receiving the results of such testing may limit the use of these strategies. They may improve the time to achieve the therapeutic range, but not the TTR itself. In general, the use of algorithms offered only a modest improvement in control compared with the non-use of algorithms, but the TTR, when reported, did not approach 70%12. The use of patient INR self-monitoring, using a drop of blood from a nger and employing a hand-held device analogous to home glucose monitoring, has been proposed as a strategy to improve TTR. Once a home INR is obtained, the patient can either adjust his or her own warfarin dosing according to an algorithm (back to the algorithm!) or call his or her own physician for subsequent dosing and retesting orders. A recent metaanalysis reviewed the effects of self-monitoring 13 and concluded there were fewer thromboembolic events and lower mortality with no increased risk of bleeding in patients utilizing self-monitoring. TTR improved slightly in the self-monitoring group, but not signicantly (619661%), and were on average less than our challenge of 70%, although several centres did break that barrier13,14. The ease of obtaining an INR, obviating the need to travel to a laboratory or clinic for the blood test, might improve compliance with testing, theoretically improving INR control. Increased frequency of testing, likely due in part to the convenience of obtaining the test, might also improve INR control. In trials evaluating self-testing, there was a clear increase in the frequency of INR determinations14. It should be noted, however, that a large proportion of patients evaluated in these trials could not or would not be trained in the use of the self-monitoring devices, especially the elderly. We would suspect the technologically savvy and obsessive patient would be the ideal individual for this management strategy. The cost of the device and testing supplies, insurance coverage and patient selection will clearly limit the widespread use of this technique. This technique was felt not to be cost-effective based on an analysis in the United Kingdom15. Most recently, dosing strategies that include data from patient genotyping have been evaluated. There are two genes that are currently thought to play a role in a patients metabolism of warfarin: cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1)16. Recently, the United States Food and Drug Administration updated its warfarin product label to include information on pharmacogenetics. The label now includes specic instructions on how to use a patients genotype to predict the therapeutic dose. Of course, to be genotyped, a patient must undergo genetic testing that costs around $400 per patient17. Is genetic testing worthwhile? In a 2011 retrospective cohort study of 1378 patients, Finkelman et al. 17 compared a pharmacogenetic algorithm to other dosing strat-

egies and found it was signicantly better at predicting the correct warfarin dose (52% of patients within the therapeutic dose range) than any of the other methods evaluated, including empiric dosing (putting everyone on 5 mg/day of warfarin), a formal clinical algorithm, and two different dosing tables based on genotype. The pharmacogenetic algorithm used genotype along with multiple clinical factors (age, body surface area, African American race, amiodarone usage, target INR, smoking status and warfarin indication) to determine the patients therapeutic dose. Using clinical factors along with genotype may be the best way to predict a therapeutic warfarin dose. However, it may still not be that simple. Both pharmacogenetic algorithms and genetic tables may be less accurate in dose predictions for African Americans. And there are other genes that are being identied as being inuential with respect to warfarin dosing. CYP4F2, GGCX, EPHX1 and ApoE may all affect warfarin dosing. Even using pharmacogenetic algorithms, 48% of patients were not dosed well enough to be in their therapeutic range17. In our own cardiology practice, we attempted to improve the TTR of our patients requiring anticoagulation with warfarin using a standard quality improvement technique18. Following a team meeting including physicians and nurses involved in managing our patients warfarin, we identied and then implemented 6 strategies listed in Table 1. We compared a baseline 250 patient sample TTR and repeated a 250 patient sample at 6 and 24 months following the adoption of these strategies. Our patients TTR improved nonsignicantly (Fig. 1), highlighting the challenge of maintaining the INR within the therapeutic range. The report from the ACTIVE W trial, besides indicating that if the TTR was below 65%, the benet of warfarin therapy over aspirin was lost, also reported that a full quartile of centres in the study was able to achieve a TTR over 733% (mean 78%)4. It should be noted that these results were obtained within the context of a clinical trial by centres that were presumably expert in Table 1. Strategies for improvement in INR control in Warfarin patients
Direct contact with the patient receiving instructions Readback of dose and blood test instructions Warfarin dose titration by algorithm Review of concurrent medications Review of diet Review of alcohol use

67 % Therapeutic 66 65 64 63 62 61 60

P = ns

P = ns

P = ns

Fall 2007

Spring 2008

Fall 2009

Fig. 1. Percentage of patients with INR within the therapeutic range at three surveys.

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the use of oral anticoagulants, and therefore may not be representative of normal clinical practice. But they showed it could be done! Curiously, the United States Food and Drug Administration has weighed in on TTR, recommending that the novel oral anticoagulant rivaroxaban not be approved for use in atrial brillation, because the warfarin control group in the ROCKET AF trial had a TTR of only 55%, stating that warfarin, when used skillfully, would have had a higher TTR and would have looked better, when compared to rivaroxaban19. Our review of the literature as well as our own experience indicates it is indeed a challenge to successfully manage warfarin dosing. The difculty maintaining an INR within the therapeutic range is related to genetic polymorphisms, numerous dietary and medication interactions, patient compliance issues and variation in the skill and experience of practitioners doing the prescribing. Although the new oral anticoagulants, which are now or will soon become available, should make anticoagu-

lation management much easier, their cost and limited (so far) indications suggest we will be dealing with warfarin for some time to come. Moreover, the history of post-marketing drug withdrawals suggests that a long period of clinical use of new agents is necessary before their proper riskbenet balance can be assessed. Multiple strategies have been devised to minimize the difculty in managing warfarin and achieve uniformity in INR control with variable degrees of success. WHAT IS NEW AND CONCLUSION Breaking the 70% TTR barrier is a major challenge. Rather than risk being remembered as the individual who said No one can achieve a TTR greater than 70%, we opine that evidence suggests that by utilizing a variety of management strategies, achieving a TTR over 70% may be difcult but not impossible. A heavier than air machine can y! We have even made it to the moon! Planets beyond our solar system .Year XX70?

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Journal of Clinical Pharmacy and Therapeutics, 2012, 37, 375377