Cases & Commentaries
Watch the Warfarin!
- Understand best practices for safe discharge of patients on warfarin.
- Describe recent advances in anticoagulation monitoring for ambulatory patients.
- Discuss patient safety risks of anticoagulation.
Case & Commentary—Part 1:
A frail 80-year-old man with a past medical history of dementia, falls, and atrial fibrillation presented to the hospital with confusion and weakness. Based on his examination, laboratory tests, and chest x-ray, he was diagnosed with community-acquired pneumonia. He was treated with ceftriaxone and doxycycline (antibiotics) for his pneumonia. He was on long-standing anticoagulation with warfarin for his atrial fibrillation, and this medication was continued while he was in the hospital.
After 48 hours he was clinically improved and back to his baseline, according to his daughter. Of note, his international normalized ratio (INR) was 2.4 at the time of discharge so he was appropriately anticoagulated on the warfarin. He was prescribed oral doxycycline for 5 more days for his pneumonia. There were no changes made to any of the medications he was taking before the hospitalization, including the warfarin.
A week later, in routine laboratory testing with his primary care doctor, he was found to have an INR of 4.0 (an abnormally high level that is associated with an increased risk of bleeding). Fortunately, even though he had fallen twice in the previous week, he had no significant bleeding.
Warfarin is a commonly prescribed oral anticoagulant, with 30 million prescriptions written per year in the United States alone.(1) When taken correctly, it effectively reduces the risk of thromboembolism, including the risk of stroke in patients with atrial fibrillation (the indication for this patient).(2) Unfortunately, warfarin has unpredictable, weight-independent therapeutic effects due to complexities of metabolism, diet, and interaction with other medications.(3) As a result, patients must have regular measurements of their international normalized ratio (INR) and frequent adjustments of warfarin dosing to keep their INR in a therapeutic range, most commonly between 2.0 and 3.0. Subtherapeutic (below-target) INRs result in an increased risk for thromboembolism, while supratherapeutic INRs raise the bleeding risk.(4) Patients face particular risk for both subtherapeutic and supratherapeutic INR levels during hospitalization due to the initiation or continuation of warfarin in the context of medication changes, acute illness, dietary adjustments, and care transitions; INR control has correspondingly been shown to be worse in the peri-hospitalization period.(5) Warfarin is responsible for 8% of all adverse drug events following hospital discharge, including more than one-in-six visits to emergency departments among elderly patients for adverse drug events.(6,7) The patient described in this case was fortunate in that his INR, though approaching dangerously high levels, had not yet led to any bleeding.
In the presented case, it is worth noting several aspects of warfarin care that were appropriately managed. The medical team correctly continued the patient's warfarin on admission; patients in whom warfarin is held (often a temptation of inpatient physicians borne out of a concern for excessive anticoagulation) often experience drops in their INR values to dangerously low levels and are at risk for thromboembolic events until the medication is restarted.(8) The medical team was also correct to check the patient's INR at discharge, since they had treated the patient with antibiotics (ceftriaxone and doxycycline) that may increase INR levels.(9) And finally, the outpatient physician was correct to recheck the INR at 1 week, even though the previous value was therapeutic at 2.4. Patients who have been on chronic warfarin with a stable and therapeutic INR usually have their INR rechecked at 28 (or more) day intervals (3), but in this case the hospitalization was recognized as a potentially destabilizing event and so the INR was rechecked early.
The excessively high INR and elevated bleeding risk in this case do, however, highlight several important aspects of safely discharging patients on warfarin. For the case patient, who was chronically taking warfarin, the medical team could have scheduled an earlier follow up with the primary care doctor specifically for INR testing in the setting of recent acute illness and new antibiotic prescriptions.(10) It is reasonable to recommend that patients who had changes in their warfarin dose, had new medications started, or experienced medical issues that might affect the INR be scheduled to get a follow-up INR within a week of discharge. Although the patient's INR on discharge was therapeutic, the medical team should have anticipated that it was likely to increase since he had only been in the hospital for two days and was being prescribed medications known to interact with warfarin. The medical team probably should have also either spoken directly with the primary care doctor at the time of discharge, or immediately faxed a discharge summary or letter to convey the last measured INR, the new medication list, and the recommended period of follow-up; these steps are particularly important to coordinating care if the inpatient and outpatient electronic medical records are not fully integrated.(5)
Finally, while this patient was on chronic warfarin, patients newly started on warfarin are at a much higher risk of complications, including major hemorrhage, than those continued on it.(11) For new patients especially, an inadequate understanding of warfarin—by both patients and caregivers—can significantly impair adherence and result in harm.(12) The inpatient team should thus carefully communicate not just with the outpatient team in arranging follow up, but also with patients or their caregivers regarding how best to take warfarin safely, using standardized education forms and checklists, which can significantly improve adherence and reduce adverse outcomes.(13)
Case & Commentary—Part 2:
His warfarin was adjusted and ultimately his INR returned to the target range of 2.0 to 3.0. Unfortunately, this required multiple visits to the primary care doctor's office for blood tests. As the patient was debilitated and easily confused because of his dementia, the need for repeated visits placed a substantial burden on his daughter, who was his main caretaker.
At the end of the patient's fourth visit in 2 weeks to see the primary care doctor, his daughter was frustrated with the process. She asked the primary care doctor, "Is this the only way to manage his blood thinners? Is there a better way? Will there be a better and easier way in the future?"
There have been many efforts directed at improving the safe use of warfarin, including the use of point-of-care machines that allow patients to check their own INR at home (as opposed to having to go to a lab or a clinical office). These machines are accurate, acceptable to patients, and effective when used in conjunction with self-management.(14) The use of dedicated anticoagulation clinics has also been shown to improve INR control.(15) Algorithms have been developed to standardize warfarin dose titration, with some shown to improve overall time patients spend in therapeutic INR range.(16) Some of these algorithms have been computerized and deployed over the Internet, providing instructions directly to patients and improving time in therapeutic range even more than an anticoagulation management service or "Coumadin clinic."(17) Taken collectively, these developments signal a movement towards a more standardized, streamlined, and patient-centered approach to anticoagulation, which could improve the quality and convenience of warfarin therapy. Though the case patient may not have been a good candidate for self-monitoring given his dementia, a caregiver such as his daughter could potentially be taught how to use a home INR machine and adjust his warfarin dose.
However, the most revolutionary changes may come from the development of newer oral anticoagulants, from factor Xa inhibitors such as rivaroxaban and apixaban to direct thrombin inhibitors such as dabigatran. These drugs have few drug–drug interactions, are not subject to variations in diet, and, unlike warfarin, provide stable levels of anticoagulation at a fixed dose and, most importantly, require no dose adjustments or INR monitoring. Dabigatran, which was approved by the US Food and Drug Administration in 2010 for patients with atrial fibrillation, has been shown to be as effective as, if not more effective than warfarin in preventing stroke in atrial fibrillation, with potentially fewer bleeding complications.(18) Though dabigatran is far more expensive per pill than warfarin, preliminary analysis has shown it to be reasonably cost effective, largely due to the high indirect costs associated with INR testing and monitoring.(19)
Unfortunately, these newer oral anticoagulants have significant limitations of their own. Dabigatran, taken twice daily, requires a higher level of adherence than warfarin (taken daily), and patients who do not take it on schedule may have compromised efficacy. In addition, the anticoagulant effect of these newer agents is irreversible, unlike warfarin, which can complicate management for patients who develop acute bleeding complications. Finally, dabigatran is renally cleared and therefore not recommended for people with severe renal insufficiency (20), ensuring that warfarin will continue to be an important anticoagulant for specific populations. For many patients, however, including the patient in this case, the new anticoagulants will present attractive alternatives to chronic warfarin therapy. Should the case patient's warfarin continue to be a management challenge, changing to dabigatran may be a reasonable alternative.
In summary, the best practices for the management of warfarin at hospital discharge should focus on the following factors:
- Ensuring close and timely follow-up after discharge.
- Improving communication between the inpatient and outpatient settings regarding changes in other medications, clinical status, and warfarin treatment plan.
- Educating patients and their caregivers to improve their understanding of and adherence to the warfarin regimen, particularly among patients newly started on warfarin.
- Standardizing systems of care through lab integration and improved communication between inpatient and outpatient settings to improve the safe use of warfarin within a health care system.
- Switching from warfarin to newer oral anticoagulants, particularly for patients with unstable INRs or those in whom lab monitoring has proven to be a significant burden.
Margaret Fang, MD, MPH
Associate Professor of Medicine in Residence
University of California, San Francisco
Department of Medicine
Division of Hospital Medicine
Raman Khanna, MD
Assistant Professor of Medicine
University of California, San Francisco
Department of Medicine
Division of Hospital Medicine
Faculty Disclosure: Dr. Fang and Dr. Khanna have declared that neither they, nor any immediate member of their families, have a financial arrangement or other relationship with the manufacturers of any commercial products discussed in this continuing medical education activity. In addition, the commentary does not include information regarding investigational or off-label use of pharmaceutical products or medical devices.
1. Wysowski DK, Nourjah P, Swartz L. Bleeding complications with warfarin use: a prevalent adverse effect resulting in regulatory action. Arch Intern Med. 2007;167:1414-1149. [go to PubMed]
2. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007;146:857-867. [go to PubMed]
3. Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G; American College of Chest Physicians. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 suppl):160S-198S. [go to PubMed]
4. Fang MC, Chang Y, Hylek EM, et al. Advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation. Ann Intern Med. 2004;141:745-752. [go to PubMed]
5. van Walraven C, Forster AJ. Anticoagulation control in the peri-hospitalization period. J Gen Intern Med. 2007;22:727-735.
[go to PubMed]
6. Forster AJ, Murff HJ, Peterson JF, Gandhi TK, Bates DW. The incidence and severity of adverse events affecting patients after discharge from the hospital. Ann Intern Med. 2003;138:161-167. [go to PubMed]
7. Budnitz DS, Shehab N, Kegler SR, Richards CL. Medication use leading to emergency department visits for adverse drug events in older adults. Ann Intern Med. 2007;147:755-765. [go to PubMed]
8. Garcia DA, Regan S, Henault LE, et al. Risk of thromboembolism with short-term interruption of warfarin therapy. Arch Intern Med. 2008;168:63-69. [go to PubMed]
9. Visser LE, Penning-van Bees FJ, Kasbergen AA, et al. Overanticoagulation associated with combined use of antibacterial drugs and acenocoumarol or phenprocoumon anticoagulants. Thromb Haemost. 2002;88:705-710. [go to PubMed]
10. Raebel MA, Witt DM, Carroll NM, Magid DJ. Warfarin monitoring in ambulatory older individuals receiving antimicrobial therapy. Pharmacotherapy. 2005;25:1055-1061. [go to PubMed]
11. Garcia DA, Lopes RD, Hylek EM. New-onset atrial fibrillation and warfarin initiation: high risk periods and implications for new antithrombotic drugs. Thromb Haemost. 2010;104:1099-1105. [go to PubMed]
12. Kimmel SE, Chen Z, Price M, et al. The influence of patient adherence on anticoagulation control with warfarin: results from the International Normalized Ratio Adherence and Genetics (IN-RANGE) Study. Arch Intern Med. 2007;167:229-235. [go to PubMed]
13. Metlay JP, Hennessy S, Localio AR, et al. Patient reported receipt of medication instructions for warfarin is associated with reduced risk of serious bleeding events. J Gen Intern Med. 2008;23:1589-1594. [go to PubMed]
14. Bloomfield HE, Krause A, Greer N, et al. Meta-analysis: effect of patient self-testing and self-management of long-term anticoagulation on major clinical outcomes. Ann Intern Med. 2011;154:472-482. [go to PubMed]
15. Sullivan PW, Arant TW, Ellis SL, Ulrich H. The cost effectiveness of anticoagulation management services for patients with atrial fibrillation and at high risk of stroke in the US. Pharmacoeconomics. 2006;24:1021-1033. [go to PubMed]
16. Kim YK, Nieuwlaat R, Connolly SJ, et al. Effect of a simple two-step warfarin dosing algorithm on anticoagulant control as measured by time in therapeutic range: a pilot study. J Thromb Haemost. 2010;8:101-106. [go to PubMed]
17. Ryan F, Byrne S, O'Shea S. Randomized controlled trial of supervised patient self-testing of warfarin therapy using an internet-based expert system. J Thromb Haemost. 2009;7:1284-1290. [go to PubMed]
18. Connolly SJ, Ezekowitz MD, Yusuf S, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-1151. [go to PubMed]
19. Freeman JV, Zhu RP, Owens DK, et al. Cost-effectiveness of dabigatran compared with warfarin for stroke prevention in atrial fibrillation. Ann Intern Med. 2011;154:1-11. [go to PubMed]
20. Ansell J. Warfarin versus new agents: interpreting the data. Hematology Am Soc Hematol Educ Program. 2010:221-228. [go to PubMed]