The Wonder of Warfarin: What This Last Year Has Taught Us

For 65 years, warfarin has been widely used as an effective medication in the prevention of venous thromboembolism for a variety of disease states, including atrial fibrillation, as well as for the secondary prevention of deep vein thrombosis and pulmonary embolus. Although novel oral anticoagulants have received FDA approval recently (4 agents total at this time), warfarin's role remains firmly planted in the world of anticoagulation. 

Specific advantages—reversibility, ability to monitor the degree of anti-coagulation, consistent drug levels regardless of renal function, and low cost—will likely ensure that warfarin remains a relevant therapeutic option for years to come despite the approval of novel agents. Being the new kid on the block will be a challenge as clinicians’ long history of experience and success with warfarin has created a high level of comfortability that will take years to develop with the novel agents.

Our experience led to the launch of this column a year ago, and intent to discuss common scenarios related to warfarin and the clinical rationale and decision-making that was involved with those situations. Certainly every case with warfarin is unique (evidenced by the extraordinarily large interpatient variability in daily dose), but we think the lessons presented from the cases can be helpful in almost all scenarios related to warfarin. Although there is a large variability between patients, the well-understood pharmacokinetics and pharmacology of warfarin, combined with careful patient assessment and logical clinical reasoning, allows even the most difficult situations to be handled appropriately to minimize potential risk to patients. 

A Look Back

In this final article we leave you with some of our most important takeaways related to the clinical use of warfarin. Exploring warfarin through these monthly articles has led to long and in-depth discussions related to the pharma-cokinetic and pharmacologic profile of this “wonder” drug, as well as how these factors can be influenced by, and applied to, various clinical scenarios. 

Despite its long-term dependability, we still encounter situations that teach us how to best use this medication. And, our discourse has led to a deeper understanding for us individually. Even though we are comfortable with warfarin, we encourage practitioners to continue learning about this medication in order to maximize efficacy and minimize risk. In farewell, we hope you have enjoyed reading these articles as much as we have enjoyed writing them.

Our Findings

• Warfarin is a racemic mixture of R- and S-warfarin and differences in the isomers leads to different clinical effects. S-warfarin is about 2.5 times as potent as R-warfarin and thus is responsible for the majority of the anticoagulant effects. S-warfarin is metabolized by CYP 2C9 whereas R-warfarin is metabolized by CYP 3A4; only those drugs interacting through CYP 2C9 and impacting S-warfarin are likely to lead to clinically relevant drug-drug interactions.

• When adjusting doses of warfarin we prefer to adjust based on the total weekly dose (TWD) rather than the daily dose. Evidence from clinical trials shows that adjusting warfarin doses using a systematic approach increases time in the therapeutic range. Therefore, in most situations, we adjust the TWD by 10%-15% for international normalized ration (INR) values within 0.5 points of the goal INR range or by 15%-20% for values more than 0.5 points away from the INR goal.

• It is unlikely that the majority of patients will be able to take the same dose each day of the week (eg, 5 mg daily). In cases where additional (or fewer) half- or full-tablet doses are utilized, we prefer to spread out the different doses throughout the week. For example, instead of doing 5 mg daily except 7.5 mg on Monday, Tuesday, and Wednesday, we would prefer, instead, to dose warfarin at 5 mg daily except 7.5 mg on Mondays, Wednesdays, and Fridays. To this aim we also feel that there should not be more than 2 different doses that a patient would have to take (would recommend against 2.5 mg, 5 mg, and 7.5 mg doses to be taken) in order to minimize confusion and the potential for incorrect dosing. 

• In an effort to limit the burden of frequent clinic visits for INR monitoring, the monitoring interval can be extended in very selected patients; it should not be universally applied to all patients. Patients should be on stable doses of warfarin and exhibit a long history of consistently therapeutic INR values; concomitant medications and comorbidities should also be stable. A reliable method of communication should be established in cases of questions, comments, or concerns. If such a strategy is pursued, we prefer to slowly lengthen the INR monitoring interval as opposed to increasing directly to the desired interval. Finally, clinicians should not be hesitant to reduce the monitoring interval should the situation suggest more frequent monitoring is needed.

• Home INR monitoring may become more widespread as costs decrease for the monitoring machine and test strips. Changes in insurance billing may allow primary care clinicians to be reimbursed for coordinating chronic disease states without in-office visits, which may also further increase the incidence of home INR monitoring. As with extended INR intervals, home INR monitoring should only be offered to select patients. A reliable method of communication should be established prior to starting home monitoring. Also, a protocol outlining frequency of testing, who is responsible for calling in and receiving INR results, and INR values that trigger automatic in-office assessment should be developed. Home INR monitoring should not be a substitute for in-office physician assessment and counseling, but may serve as a bridge between in-clinic INR visits to ensure the maintenance of therapeutic INR values.

• There is relatively little "new" information emerging about warfarin outside of drug-drug interactions with novel drugs approved by the FDA. Staying up to date with CHEST guidelines will prove helpful to clinicians, especially regarding the pharmacology and pharmacokinetics of warfarin, drug interactions, food interactions, and more.ν

Eric A. Dietrich, PharmD, BCPS, graduated from UF College of Pharmacy in 2011 and completed a 2-year fellowship in family medicine where he was in charge of a coumadin clinic. He now works for the UF Colleges of Pharmacy and Medicine. 

Louis Kurtizky, MD, is a family physician affiliated with the University of Florida Family Medicine Residency Program, where he commonly co-manages warfarin cases with his colleagues. 

Reference:

1.  Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: CHEST Evidence-Based Clinical Practice Guidelines. 2012;141(2 suppl).