Warfarin administration and monitoring

# 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.
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)."  Current recommendations on chronic warfarin management are mainly based on the RE-LY trial which was published in 2009 with modifications due to subsequent practice guidelines by the American College of Chest Physicians in 2012. Randomized controlled trials suggest that non-pharmacist led clinics can achieved good anticoagulation.

# Initial dosing of warfarin
Dosing can be estimated with  .
Meta-analysis Meta-analyses found improved response from genotype-Guided dosing
- When compared to a "clinical adjusted dosing regime" group that used an algorithm, the time to first therapeutic was reduced by 2.17 days (2 studies, I2 = 64%) and major bleeding reduced by 0.56 (95%CI: 0.36-0.89, P = 0.01, 6 studies, I2 = 25%). Studies used, and their citations for the clinical adjusted group were not provided.
- An earlier meta-analysis found benefit, but did not subgroup by methods of dosing in the control groups.

# 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%.
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): 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 /.

### Typical and best practice
Expected TTR values in various settings are
- Self-management - 72%
- Community physicians - 57%
- Community physicians best practice (Orbit-AF trial) 66% 
- Anticoagulation Clinic - 69% (best practice) 
Using multidose drug dispensing (MDD) - 79%
- Using multidose drug dispensing (MDD) - 79%
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.

## 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".
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.

## 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:
- 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
- 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. The importance of choice of pill size is not clear.

# Concomitant vitamin K to reduce erratic control
Daily oral vitamin K may improve control in some patients.

# Management of Warfarin Related Bleeding
The management of bleeding among patients on warfarin includes:
- 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