To provide practical strategies supported by the best available evidence for managing out-ofrange international normalized ratios (INRs) for patients on long-term warfarin therapy.# BACKGROUND:
- Warfarin can be challenging to manage due to its narrow therapeutic range, variable doseresponse among patients and common interactions with drugs, diet, alcohol, and other factors. 2. In patients who are taking warfarin, thromboembolic events and bleeding are strongly related to the time in therapeutic range (TTR). This is the proportion of treatment time that the INR is within the target therapeutic range (typically 2.0 to 3.0 or 2.5-3.5 for patients with mechanical mitral valve replacements). 3. Clinicians may underdose warfarin due to a perceived greater risk of harm from bleeding associated with supratherapeutic INR values. However, subtherapeutic anticoagulation has been shown to increase the frequency and severity of thromboembolic events. 4. Good INR control, defined empirically as a TTR >60%, may be best achieved by appropriately addressing both high and low INR values using a consistent approach (paper-based dosing nomogram or computerized decision support program).

# APPROACH TO OUT-OF-RANGE INR VALUES:
- For each out-of-range INR value, attempt to identify the cause. See the section below, "Summary of Common Causes of Out-of-Range INRs". 2. Determine whether a one-time change in the dose is all that is required or if a change in the maintenance dose is required or both.
- A change in the maintenance dose should be considered if there are at least two consecutive out-of-range INR values (in the same direction) in a patient with previously stable, in-range INRs and for which there is no identified temporary cause. - A one-time change in the dose is appropriate for patients in which a transient cause is identified.

# MANAGING SINGLE OUT-OF-RANGE INR VALUES
- For patients with previously in-range INR values who present with a single slightly outof-range INR (e.g. INR 0.5 above or below the target range), there are two management options:
- Continue current maintenance dose and repeat INR in 1-2 weeks, OR 2. Make a one-time dose change (increase or hold by 12 to 1 single dose) and resume current maintenance dose. Repeat INR in 1-2 weeks - The specific approach is influenced by the magnitude of the out-of-range value, previous experience of similar values in the patient and whether the patient has strong risk factors for thrombosis/stroke or bleeding.

# MAINTENANCE DOSING ALGORITHMS:
There are many warfarin dosing algorithms available. Physicians should become familiar with one approach in order to develop experience and consistency in making dosing changes. 

# SUMMARY OF COMMON CAUSES FOR OUT-OF-RANGE INRs:
Table 1 and Table 2 summarize common causes and management strategies for LOW and HIGH INRs, respectively.

# Table 1: Common Causes of LOW INRs and Management Strategies COMMON CAUSES OF LOW INRS MANAGEMENT STRATEGIES MISSED DOSES, NON-COMPLIANCE, or ERRORS IN DOSING
- Review the doses of warfarin actually taken over the past several weeks.
- If patient is receiving more than one strength of tablet, consider adjusting dose to enable use of a single strength to avoid confusion.  

# ANTIPLATELET AGENTS:
Antiplatelet agents (acetylsalicylic acid , clopidogrel, prasugrel, ticagrelor) and Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) significantly increase the risk of bleeding when combined with warfarin but generally do not change the INR. The indication and clinical necessity of using these agents should be carefully weighed against the increased bleeding risk and should be avoided unless specifically indicated. Refer to the Clinical Guide: Warfarin for more information.

# OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
- Warfarin - Warfarin: Point-of-Care INR Monitoring

# Date of Version: 07August2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein.