Use of Warfarin in Nonvalvular Atrial Fibrillation

Michael B. Bottorff, PharmD: We’ve been using warfarin for atrial fibrillation and stroke prevention for quite some time, now. It’s an indirect acting anticoagulant. The way it works is that it blocks the hepatic synthesis of 4 vitamin K-dependent clotting factors—those are II, VII, IX, and X. The result of that is that it takes (for many patients) a fair amount of time (sometimes days to weeks) to become therapeutic because of existing clotting factors that are already in the bloodstream.

Warfarin has a number of drug interactions. It has a very complex metabolism. There are at least 3 cytochrome P450 pathways (3A4, 2C9, 1A2), and a number of other drugs go through those pathways and interfere with warfarin. So, many people would consider warfarin to be the most likely drug to have a drug interaction of those that we use in regular practice. Because of that vitamin K dependency for the clotting factors and the effectiveness of warfarin, variations in the vitamin K content of diet can have a significant effect on what you’re dosing requirements are for warfarin.

The therapeutic effectiveness of warfarin is known to be associated with achieving a therapeutic INR (international normalized ratio) in the range of 2 to 3. If you get an INR that is less than 2, the risk for stroke goes up. If you have an INR greater than 3 to 3.5, the risk for bleeding goes up. Unfortunately, there are so many factors that interfere with warfarin’s effectiveness. In many patients, that INR bumps around and changes a lot.

One reason people like to use warfarin is the so-called availability of a reversing agent, again, because of that vitamin K dependency. Vitamin K is considered the reversing agent, but if you look at the way that it works by helping the liver resynthesize those hepatic-dependent clotting factors, that takes a fair amount of time. And so, the ability of vitamin K to reverse warfarin may take as long as 12 to 18, or maybe even 24 hours. Most people would not consider that an immediate reversing agent. In the last several years, we’ve now had the availability of 3- and 4-factor prothrombin complex concentrates. Those act fairly quickly, but they also run the risk of making you hypercoagulable. We do have reversibility capabilities for warfarin, but I wouldn’t say that it’s optimal.

We’ve used warfarin for quite some time. There are some of advantages in that we knew how it works. We know the INR was associated with its benefits, so we could monitor patients and adjust their dosing accordingly. But, the disadvantages include a very slow onset of effect. It has a very long half-life, so if you do have a major problem and stop it, that bleeding complication is there for quite some time. There’s a lot of variability—some of that related to drug metabolism, and some of that related to genetic variability in managing warfarin patients that could result in as much as a 20- or 25-full difference in dosing requirements from patient-to-patient.

Other disadvantages for warfarin would include that long list of drug interactions that we’ve talked about. And another disadvantage would be the need to have a stable vitamin K content in one’s diet to not contribute to more dosing variability.

Given those disadvantages of warfarin, it was exciting to see the DOACs (direct oral anticoagulants) come on the market as available agents for consideration in patients with atrial fibrillation. All of them have clinical trials comparing themselves to warfarin. Unfortunately, there are no trials comparing them to each other, but we do have those comparative trials against warfarin. In general, it would be fair to say that those agents are at least as good as warfarin, and in some cases, are better for stroke prevention. And they are at least as good as warfarin, or better, for major bleeds.