Warfarin administration and monitoring
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
The optimal dose of warfarin among patients on chronic anticoagulation represents a balance between the highest thrombosis prevention and the lowest risk of bleeding. In order to optimize the efficacy to safety ratio, dosing of warfarin requires INR monitoring with a target INR range of 2-3. The quality of management of a group of patients is measured with the time in therapeutic range.[1]
The 2012 American College of Chest Physicians (ACCP) clinical practice guidelines "suggest using validated decision support tools (paper nomograms or computerized dosing programs) rather than no decision support (Grade 2C)."[2] Current recommendations on chronic warfarin management are mainly based on the RE-LY trial[3] which was published in 2009 with modifications due to subsequent practice guidelines by the American College of Chest Physicians in 2012.[2] Randomized controlled trials suggest that non-pharmacist led clinics can achieved good anticoagulation.[4]
Initial dosing of warfarin
Dosing can be estimated with http://www.warfarindosing.org [5].
A meta-analysis found improved response from genotype-Guided dosing.[6]
Adjustment of Warfarin Dose According to INR
An retrospective analysis of the RE-LY trial found that adherence to a dosing protocol improved quality of anticoagulation and explained almost 90% of the variation in quality. In addition, for each 10% increase in algorithm-consistent dosing adverse clinical outcomes decreased by 6%.[7]
| INR Value | Response per RE-LY[3] | Alternative by ACCP[2] |
|---|---|---|
| ≤ 1.5 | ↑ weekly dose by 15% Repeat INR in 7-10 days. |
Patients with stable INRs at baseline, now with a single subtherapeutic INR value: no routine bridging with heparin |
| 1.51-1.99 | If unexplained, ↑ weekly dose by 10% Repeat INR in 7-10 days. |
Patients with stable INRs at baseline, now with a single out-of-range INR of < 0.5 below or above therapeutic: no change and retest 1-2 weeks |
| 2-3 | No dose adjustment* | |
| 3.01 - 4 | "Do not hold warfarin. If high on 2 consecutive occasions, decrease weekly dose by 10%" | Patients with stable INRs at baseline, now with a single out-of-range INR of < 0.5 below or above therapeutic: no change and retest 1-2 weeks |
| 4.01 - 4.99 | Hold dose for 1 day, then ↓ weekly dose by 10% Repeat INR in 7-10 days. |
Patients with INRs 4.5 - 10 and with no evidence of bleeding: ACCP suggests against the routine use of vitamin K |
| 5 - 8.99 | Hold dose until INR therapeutic, then ↓ weekly dose by 15% Repeat INR in 1 day. | |
| ≥ 9.0 | Hold warfarin and give vitamin K 5.0-10mg PO. Monitor more frequently and repeat vitamin K if necessary | Patients with INRs > 10.0 with no evidence of bleeding: ACCP suggests that oral vitamin K be administered |
| * Per ACCP, "For patients taking VKA therapy with consistently stable INRs, we suggest an INR testing frequency of up to 12 weeks rather than every 4 weeks". One definition of consistent stability is no change in dose for 6 months.[8] | ||
Based on the existing medical research and clinical practice guidelines, institutions have algorithms to standardize the chronic administration of warfarin. Examples are:
- Warfarin by Wichita is a harmonization of the RE-LY and ACCP recommendations
Monitoring
Time in therapeutic range
There are three different methods for calculating TTR.
- Percent of visits in range (Traditional Method): Total number of visits with INR in range divided by total number of visits.
- Percent of visits on Given Date (Cross Section Method): Total number of patients in range on the last reading prior to selected date divided by total active patients on selected date.
- Percent of Days in Range (Rosendaal Method):[1] The most popular and complex calculation. It looks at the amount of time between visits to determine how long the patient might have been within range. In simple terms, it is the number of days in range divided by total days between visits. For example, if the patient was tested at 2.5 on day 1 and then on day 30 retested at 3.5, one can assume that the patient slowly moved from 2.5 to 3.5 over the 30 days. Therefore on approximately day 15, they were likely over 3.0 and were out of range for 15 days making their TTR 50%. The Rosendaal Method is available online at http://qitools.github.io/warfarin/.
Expected TTR values in various settings according to a 2006 Systematic Review:[9]
- Community Physicians - 57%
- Anticoagulation Clinic - 66%
- Self-management - 72%
Oral anticoagulants provide a > 2-fold decrease in vascular events on patients when compared to an anti-platelet agent. However, a TTR of > 58% is needed to be confident that patients will benefit from an oral anticoagulant agent over an anti-platelet agent.[10]
Optimal frequency of testing
An observation study stated, "Our results suggest that a maximum interval of 28 days after obtaining the first or second in-range value and consideration of a longer interval after obtaining the third or greater consecutive in-range value may be appropriate".[11]
Per ACCP clinical practice guidelines, "For patients taking VKA therapy with consistently stable INRs, we suggest an INR testing frequency of up to 12 weeks rather than every 4 weeks". One definition of consistent stability is no change in dose for 6 months.[8]
Point of care testing
According to a systematic review, of randomized controlled trials, that compared varioius methods of management to traditional venipuncture with decisions by a health care provider[12]:
- Traditional venipuncture: time in therapeutic range (TTR): 64%
- Patients self-testing and self-management: 4.2% increase in TTR
- Patients self-testing but management by a health care provider: 7.2% increase in TTR
- Point of care testing and management in health care practitioners' offices: 6.1% increase in TTR
Pill selection
Recommendations exist for consistent use of one pill size by anticoagulation clinics.[13] The importance of choice of pill size is not clear.[14][15]
Concomitant vitamin K to reduce erratic control
Daily oral vitamin K may improve control in some patients.[16]
Management of Warfarin Related Bleeding
The management of bleeding among patients on warfarin includes:[2]
- Rapid reversal of anticoagulation with the administration of four-factor prothrombin complex concentrate (PCC), PLUS
- Slow IV injection of 5 to 10 mg vitamin K
References
- ↑ 1.0 1.1 Rosendaal FR, Cannegieter SC, van der Meer FJ, Briët E (1993). "A method to determine the optimal intensity of oral anticoagulant therapy". Thromb Haemost. 69 (3): 236–9. PMID 8470047.
- ↑ 2.0 2.1 2.2 2.3 Holbrook A, Schulman S, Witt DM, Vandvik PO, Fish J, Kovacs MJ; et al. (2012). "Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines". Chest. 141 (2 Suppl): e152S–84S. doi:10.1378/chest.11-2295. PMC 3278055. PMID 22315259.
- ↑ 3.0 3.1 Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A; et al. (2009). "Dabigatran versus warfarin in patients with atrial fibrillation". N Engl J Med. 361 (12): 1139–51. doi:10.1056/NEJMoa0905561. PMID 19717844. Review in: Ann Intern Med. 2010 Jan 19;152(2):JC1-2
- ↑ Entezari-Maleki T, Dousti S, Hamishehkar H, Gholami K (2016). "A systematic review on comparing 2 common models for management of warfarin therapy; pharmacist-led service versus usual medical care". J Clin Pharmacol. 56 (1): 24–38. doi:10.1002/jcph.576. PMID 26100092.
- ↑ Lenzini PA, Grice GR, Milligan PE, Gatchel SK, Deych E, Eby CS; et al. (2007). "Optimal initial dose adjustment of warfarin in orthopedic patients". Ann Pharmacother. 41 (11): 1798–804. doi:10.1345/aph.1K197. PMID 17911206.
- ↑ Kheiri B, Abdalla A, Haykal T, Osman M, Ahmed S, Hassan M; et al. (2018). "Meta-Analysis of Genotype-Guided Versus Standard Dosing of Vitamin K Antagonists". Am J Cardiol. doi:10.1016/j.amjcard.2017.12.023. PMID 29402419.
- ↑ Van Spall HG, Wallentin L, Yusuf S, Eikelboom JW, Nieuwlaat R, Yang S; et al. (2012). "Variation in warfarin dose adjustment practice is responsible for differences in the quality of anticoagulation control between centers and countries: an analysis of patients receiving warfarin in the randomized evaluation of long-term anticoagulation therapy (RE-LY) trial". Circulation. 126 (19): 2309–16. doi:10.1161/CIRCULATIONAHA.112.101808. PMID 23027801.
- ↑ 8.0 8.1 Schulman S, Parpia S, Stewart C, Rudd-Scott L, Julian JA, Levine M (2011). "Warfarin dose assessment every 4 weeks versus every 12 weeks in patients with stable international normalized ratios: a randomized trial". Ann Intern Med. 155 (10): 653–9, W201–3. doi:10.7326/0003-4819-155-10-201111150-00003. PMID 22084331. Review in: Ann Intern Med. 2012 Mar 20;156(6):JC3-3
- ↑ van Walraven C, Jennings A, Oake N, Fergusson D, Forster AJ (2006). "Effect of study setting on anticoagulation control: a systematic review and metaregression". Chest. 129 (5): 1155–66. doi:10.1378/chest.129.5.1155. PMID 16685005.
- ↑ Connolly SJ, Pogue J, Eikelboom J, Flaker G, Commerford P, Franzosi MG; et al. (2008). "Benefit of oral anticoagulant over antiplatelet therapy in atrial fibrillation depends on the quality of international normalized ratio control achieved by centers and countries as measured by time in therapeutic range". Circulation. 118 (20): 2029–37. doi:10.1161/CIRCULATIONAHA.107.750000. PMID 18955670.
- ↑ Rose AJ, Ozonoff A, Berlowitz DR, Ash AS, Reisman JI, Hylek EM (2011). "Reexamining the recommended follow-up interval after obtaining an in-range international normalized ratio value: results from the Veterans Affairs study to improve anticoagulation". Chest. 140 (2): 359–65. doi:10.1378/chest.10-2738. PMID 21310837.
- ↑ Health Quality Ontario (2009). "Point-of-Care International Normalized Ratio (INR) Monitoring Devices for Patients on Long-term Oral Anticoagulation Therapy: An Evidence-Based Analysis". Ont Health Technol Assess Ser. 9 (12): 1–114. PMC 3377545. PMID 23074516.
- ↑ Ebell MH (2005). "Evidence-based adjustment of warfarin (Coumadin) doses". Am Fam Physician. 71 (10): 1979–82. PMID 15926414.
- ↑ Wong W, Wilson Norton J, Wittkowsky AK (1999). "Influence of warfarin regimen type on clinical and monitoring outcomes in stable patients in an anticoagulation management services". Pharmacotherapy. 19 (12): 1385–91. PMID 10600087.
- ↑ Manning DM (2002). "Toward safer warfarin therapy: does precise daily dosing improve international normalized ratio control?". Mayo Clin Proc. 77 (8): 873–5. doi:10.4065/77.8.873-a. PMID 12173723.
- ↑ Boonyawat K, Wang L, Lazo-Langner A, Kovacs MJ, Yeo E, Schnurr T; et al. (2016). "The effect of low-dose oral vitamin K supplementation on INR stability in patients receiving warfarin. A randomised trial". Thromb Haemost. 116 (3). doi:10.1160/TH16-04-0320. PMID 27346552.