Welcome to Lesson 1 of this learning activity titled, Medication Review, DOACS vs. Warfarin. The content in this lesson was developed by myself, Kate Malish, and I will also be narrating this lesson. Doctors prescribe oral anticoagulants for two reasons, to prevent blood clots or to treat blood clots that have already formed. Preventing blood clots is paramount for patients with atrial fibrillation, those having hip or knee replacement surgery, patients with a mechanical heart valve, or those with certain conditions that place them at high risk for blood clots. While nothing can completely prevent all blood clots, these medications can make clots less likely to form. If a patient develops a blood clot anywhere in the body, such as a deep venous thrombosis or DVT, or pulmonary embolism known as PE, or has a stroke due to untreated atrial fibrillation, oral anticoagulants treat those blood clots by keeping them from growing bigger and moving to another part of the body. The major differences in oral anticoagulants include dosing regimen, amount of monitoring required, drug-drug and drug-food interactions, and reversal agents available. Dosing regimen depends on the medications and the indication. If you are taking a medication to treat a new blood clot, the first week or more of treatment might be different. Anticoagulants do not require regular blood tests, however, Warfarin requires blood tests on a scheduled basis. Although all anticoagulants have certain interactions with other drugs, Warfarin has the most. Certain medications, when taken along with these anticoagulants, can either lessen the effectiveness, which in turn increases risk of blood clots, or heighten the effectiveness, which in turn increases risk of bleeding. We will review drug interactions later in the course. Because anticoagulants increase bleeding risk, reversal agents are sometimes required. Warfarin has several reversal agents which are readily available in healthcare facilities. Conversely, DOACs have only one reversal agent per individual drug, and these agents are not readily available and are very expensive to obtain. We will begin to examine each drug individually, starting with the original oral anticoagulant, Warfarin. This is a diagram of the clotting cascade, to include the clotting factors which eventually allow a fibrin clot to form. These clotting factors are the main targets of anticoagulants, which work by inhibiting the clotting factor and essentially ending the clotting cascade, or breaking the chain, before it can form a clot. Warfarin works on several clotting factors, including factor 2, which is prothrombin, factor 7, 9, and 10. Warfarin is the oldest and most well-established oral anticoagulant in medicine. Its brand names are Coumadin and Jantovin. It inhibits the enzyme, which creates vitamin K, in our bodies. It also blocks factors 2, 7, 9, and 10 in the clotting cascade. The indications for Warfarin are numerous, to include reducing the risk of embolism after a myocardial infarction, prophylaxis and treatment of thromboembolic disorders such as DVT and PE, and prophylaxis and treatment of embolic complications from atrial fibrillation or cardiac valve replacement. It is important to note that Warfarin has no direct effect on an already established thrombus and does not reverse tissue damage created by this thrombus. The goal of Warfarin is to prevent further embolic complications. Looking at the pharmacology of Warfarin, it has a rather long onset of action compared to other oral anticoagulants. The onset of action is the length of time it takes for the drug to produce physiologic effects. For Warfarin, onset of action is measured by a person's INR, which stands for International Normalized Ratio. It is a lab value which shows how thin or thick the blood is. The average person's INR is 1.1 or below. The higher the INR, the more anticoagulated or thin your blood is. Patients with conditions requiring anticoagulation have a target INR between 2 and 3. Any level above 3.5 is generally too high and indicates the patient is too anticoagulated. Warfarin's initial effect on INR can be seen in 24 to 72 hours. However, full therapeutic effect is not seen until 5 to 7 days. This is because it takes 5 to 7 days for the body's clotting factors to completely break down. Warfarin has a very long half-life, which is a pharmacokinetic parameter that is defined as the time it takes for the concentration of the drug in the plasma, or the total amount in the body, to be reduced by 50%. Warfarin's half-life is 20 to 60 hours, which allows for varieties in dosing such as every other day or three times per week. There are many drug interactions with Warfarin, which is one of the major drawbacks to this medication. The more severe culprits include antibiotics such as Bactrim, phenytoin, barbiturates, and antifungals such as ketoconazole. Another important interaction with Warfarin is the food interaction. Foods high in vitamin K, such as leafy green vegetables, need to be eaten on a consistent basis so a clinician can adjust the Warfarin dose accordingly. This is one of the major patient counseling points for a physician or pharmacist. Patients do not need to totally eliminate these healthy foods, but simply keep consumption consistent. Other foods and products which contain vitamin K are green tea, chewing tobacco, and many oils such as canola, corn, olive, peanut, and safflower. Here is an abbreviated list of medications which enhance Warfarin's anticoagulant effect along with those which decrease the anticoagulant effect. It is imperative that a patient maintain transparency with his or her provider regarding any current or new medications they take. Dosing of Warfarin is often considered more of an art than a science. The initial starting dose in most patients is 5 mg daily. However, a lower or higher starting dose may be used depending upon patient-specific factors. Although an elevation in INR is usually seen in 24-48 hours after the first dose due to depletion of factor VII, this does not represent therapeutic anticoagulation because other vitamin K-dependent clotting factors with longer half-lives, factors II, IX, and X, must also be depleted. Accordingly, in patients at high risk for thromboembolism, overlap or bridging with a parenteral or IV anticoagulant may be necessary during initiation of Warfarin until a stable therapeutic INR is attained. Patients are often treated with unfractionated heparin or low molecular weight heparin while in the hospital, then bridged with Warfarin until they have a therapeutic INR and can be discharged only on Warfarin. As you can see, Warfarin comes in 9 different strengths to accommodate the various dosing regimens needed. Patients with hepatic impairment often require smaller doses or are contraindicated from taking Warfarin due to their impaired clotting factors and decreased metabolism of Warfarin. Patients older than 60 years often have a higher INR than expected and may require dose adjustments to a smaller dose. Similarly, those of Asian descent may also require lower doses due to decreased metabolism of the drug. This is an example of a Warfarin initiation nomogram targeting an INR range of 2 to 3, which is the normal target INR range for most patients requiring anticoagulation. Patients with a mechanical heart valve have a slightly higher target INR of 2.5 to 3.5. The two columns in this nomogram show standard dosing for patients not expected to be sensitive to Warfarin and reduced dosing for patients expected to be more sensitive, such as those patients previously mentioned who are greater than 60 years old, of Asian descent, or those with comorbidities or taking other medications which interact with Warfarin. After an initial dose, it is best practice to check the patient's INR in four days and adjust the dose according to that INR result. If the INR is sub-therapeutic, the dose should be increased, whereas if it is super-therapeutic, the dose should be decreased or even held until the INR returns to target levels. As you can see, this requires constant patient-provider communication to achieve best results. This slide shows the importance of monitoring Warfarin and its clinical effect. Once initiated in the hospital, daily INR monitoring is required, as well as noting any signs or symptoms of bleeding, such as bruising or external bleeding. Once a patient is discharged, monitoring can occur anywhere from every one to three days to weekly during the first month of therapy. Once a patient has achieved maintenance dosing and is stable on therapy, monthly appointments are possible to check INR and discuss any important changes in diet or medication regimen. It is important to mention that a well-established treatment plan for Warfarin reversal exists and is commonly used in medicine. The provider must first determine whether the patient is actively bleeding at the time of presentation. If they are not bleeding and the INR is less than 10, the provider should either withhold Warfarin dose until the INR is back within the therapeutic range, or in more serious cases, the provider should give 0.5 to 2 mg vitamin K as a rapid reversal agent. The INR should then be rechecked in eight hours, and a repeat dose of vitamin K may be warranted. If the patient is in fact bleeding upon presentation, the provider should determine whether the bleed is life-threatening or not, as this will determine the treatment strategy. If the bleed is life-threatening, fresh frozen plasma, or FFP, 15 mL per kilogram, or prothrombin complex concentrates, or PCC, 50 units per kilogram is given, which will effectively replace the patient's clotting factors. The INR is rechecked at six hours, and vitamin K may be given if the PCC did not contain Factor VII. One important quality of a medication is its therapeutic index, a comparison of the amount of drug that causes the therapeutic effect to the amount that causes toxicity. Ideally, a drug will have a wide therapeutic index, allowing more room for dosing adjustments or dosing error. Warfarin, however, has a very narrow therapeutic index, which is why constant monitoring is required. Slight adjustments in dosing can have large physiologic effects. This is where reversal agents become important. In the event a patient becomes too anticoagulated from Warfarin, as evidenced by high INR or overt bleeding, the drug should be immediately stopped and one of the following agents given. Oral or IV vitamin K is usually the initial reversal response. However, the patient may require fresh frozen plasma or prothrombin complex concentrates to help replace clotting factors. Finally, the patient may be given recombinant Factor VIIa. As you can see, Warfarin is a very valuable medication but does have its drawbacks. The need for more anticoagulant options was clear, which sparked development of direct oral anticoagulants, commonly known as DOACs. This concludes Lesson 1 of Medication Review, DOACs vs. Warfarin. Thank you for your participation.

Warfarin

mechanism of action

dosing

drug interactions

direct oral anticoagulants