The Pharmacy Student's Guide to Dosing Warfarin
Imagine it's your first week of an APPE rotation at an anticoagulation clinic. You're excited and a little nervous. You've been brushing up on your Lovenox. You've read all you can about Eliquis and Xarelto and Pradaxa (oh my!). You're ready to impress.
Then there's the elephant in the room that is warfarin. Sure, you know lots about it. You can rattle off facts about VKORC1, and R and S enantiomers. You know that the pills are color coded by strength.
But how do you actually dose warfarin? If you're like most of us, you probably don't feel adequately prepared to jump right into managing wafarin therapy with what you learned in the classroom.
Because it's so different from patient to patient, and because the NAPLEX may not drill into the specifics of it, the dosing of warfarin is pushed off for you to learn somewhere during your practice experience.
I'm not saying that is wrong, but it doesn't help you out one bit on your APPE rotation either. Your preceptor (fair or not) will likely complain about the status of schools "these days" and how she can't believe you haven't been taught this.
If only there was some sort of concise guide targeted to pharmacy students to help them avoid this lowly state. Oh wait...
For starters, you have to understand how we measure and assess anticoagulation with warfarin. We do this with the International Normalized Ratio (INR). The INR is a "normalized" version of the Prothrombin Time (PT). Don't mix this up with the activated Partial Thromboplastin Time (aPTT). Confused yet? Me too.
- aPTT: measures the intrinsic pathway of clotting (use with heparin)
- PT/INR: measures the extrinsic pathway of clotting (use with warfarin)
- The PT is the only clotting test available that measures Factor VII
- anti-Xa: specifically measures inhibition of Factor Xa
- Depending on the institution, either the anti-Xa or the aPTT is used to monitor LMWH therapy (ie. Lovenox).
So how are the PT and INR related? Basically, PT levels vary between individuals (and over time). Your "normal" PT level will be different than mine. But we need the PT to monitor warfarin because we have to have something that measures Factor VII (warfarin specifically inhibits Factors II, VII, IX, and X).
So a bunch of statisticians got together and "normalized" the PT value by putting it in a math equation. This spits out the INR, which helps compare apples to apples between patients. Now we can set broad therapeutic goals that apply to everyone. For almost every indication, we shoot for an INR of between 2.0 and 3.0. For certain mechanical heart valves, we'll use 2.5 - 3.5.
Understand that the INR is still an "estimate." It's not that different than using Cockroft-Gault to estimate kidney function. Your real PT/INR is dynamic, and changing from moment to moment. We just use the samples from a single point in time (blood draws) to estimate it. We will come back to this idea later when we talk about common dosing errors.
Basic Dosing of Warfarin
For starters, warfarin is in a category of drugs where we think about the total weekly dose, not so much the daily dose. This means that we think of a patient taking 5mg every day as taking 35mg per week (5mg x 7 days...because math). All of the adjustments we make to warfarin therapy are based on the weekly dose.
And for most minor elevations or reductions to the INR, we reduce or increase the dose by about 10 - 15%.
So with our patient taking 35mg a week, if they have an INR of 3.4, we might consider cutting back to 30 - 32.5mg per week. It's a good idea to think about the tablet strength(s) the patient has. Let's assume our patient here has 5mg tabs, so our dosing increments can be adjusted by either 5mg (1 tab) or 2.5mg (1/2 tab).
In an ideal world, you'd like to keep the patient on only one tablet strength to minimize dosing errors. Warfarin tablets are color coded among all manufacturers, so if patients know they are always taking "a peach pill" then you reduce the risk of them taking the white ones that mistakenly got dispensed by their pharmacy.
If you really want to overachieve, it may be helpful to remember which strengths of warfarin correspond to which colors.
Warfarin Tablet Colors Pneumonic:
Please Let Georgia Brown Bring Peaches to Your Wedding
1mg - Pink
2mg - Lavender
2.5mg - Green
3mg - Brown
4mg - Blue
5mg - Peach
6mg - Teal
7.5mg - Yellow
10mg - White
Common Warfarin Dosing Errors
Armed with the above information, let's talk about what NOT to do.
1. Do not heavily load the patient's dose towards one part of the week. Remember than an INR measurement that we see is a single point in time and it changes from hour to hour. If a patient is getting 50mg per week, you don't want the sig to be "10mg PO Mon - Fri; then off for weekend." You also wouldn't want it to be "5mg PO Mon - Thurs, then 10mg Fri - Sun."
You want to try to spread the dose out as evenly as possible throughout the week. Heavily loading the dose on one end leads to a patient being under-treated in one part of the week and over-treated in the next. For our 50mg patient, we might try something like "7.5mg Mon - Sat, 5mg on Sun." It's not exactly perfect, but remember, we want to try to make this easy for the patient. You can complete this entire regimen with only 5mg tabs.
2. Speaking of loading--in general it's recommended NOT to give a loading dose with warfarin. Patient's being treated with warfarin need to be bridged with heparin/LMWH anyway, and loading with warfarin does not remove this need. Loading doses of warfarin can make it difficult to stabilize the patient's INR when you are initiating, and can potentially increase the bleeding risk.
3. Don't get trigger happy chasing the INR. Remember, warfarin inhibits the synthesis of Factors II, VII, IX, and X (and also protein C and protein S). It doesn't do anything with the existing factors. So, it takes a while for the full effect of a dose of warfarin to be realized. How long? That is determined by the half lives of Factors II, VII, IX, and X. In general, It takes about a week to see the full effect of a single dose of warfarin.
When you are initiating a patient on warfarin, it's natural to see their INR of 1.1 on day 2 and want to increase the dose. You have to fight this urge. You've gotta give warfarin time to work. The institution where you are practicing will likely have some basic guidelines on initiating warfarin, so when in doubt use those. We will give our own spin on initiating warfarin in Part II of this post.
4. Starting doses that are too high in certain patient populations. In addition to the hundreds of drug and food interactions, warfarin is very highly protein bound. This means that patients with low albumin have more "active" warfarin compared to patients with normal albumin. You have to take that into account when initiating warfarin therapy.
Low albumin typically shows up in patients that are elderly, malnourished, or those with liver disease. It's not a bad idea to start these patients off at 2.5mg daily until you get a better picture of how their INR responds. Also keep in mind the potential drug interactions with highly protein bound drugs.
So Long, and Thanks for All the Fish