LEUVEN, BELGIUM. Warfarin (Coumadin) has a long history and much experience has been gained over the past 30 years to ensure safe and effective use of this drug. Recently three new oral anticoagulants – dabigatran (Pradaxa), rivaroxaban (Xarelto), and apixaban (Eliquis) – have entered the market as replacements for warfarin. The major advantage of the new anticoagulants is that, unlike warfarin, they do not require regular monitoring to ensure that their anticoagulation effect is optimal. Several clinical trials have been done to establish their benefit in preventing ischemic stroke and the risks (major bleeding and hemorrhagic stroke) associated with their use. Summary of these trials.

However, while guidelines for the use of warfarin are well established, this is not the case for the newer anticoagulants. A group of European cardiologists/electrophysiologists has now released a set of guidelines for the use of the new anticoagulants in patients with non-valvular atrial fibrillation (AF). Highlights are:

• It is recommended that patients on the new anticoagulants carry a card giving details about their treatment and other medications they may be taking. It is also recommended that patients undergo testing for liver and kidney function at least once a year and more frequently if they have reduced kidney function or have been prescribed dabigatran. Finally, patients should see their doctor at regular intervals, preferably every 3 months, for on-going review of their treatment.
• The new anticoagulants do not require routine monitoring of coagulation. The value of measuring activated partial thromboplastin time (aPTT) to provide a qualitative assessment of the presence of dabigatran, or prothrombin time (PT) to provide an assessment of the presence of rivaroxaban and apixaban is questionable, and INR monitoring is not applicable to patients on the new anticoagulants.
• It is expected that the new anticoagulants will have less interactions with foods, but interactions with other drugs will still be a problem. Not surprisingly, bleeding risk increases significantly if the new anticoagulants are taken in conjunction with other anticoagulants, platelet inhibitors or NSAIDs. Combining them with aspirin increases bleeding risk by at least 60%. Several drugs strongly potentiate the effect of the new anticoagulants and should be used with extreme caution or not at all. Among these drugs are dronedarone (Multaq), antifungal drugs such as ketoconazole and itraconazole, and HIV protease inhibitors (ritonavir). Other drugs weaken the anticoagulation effect. Most important among these are rifampicin, carbamazepine, phenytoin, phenobarbital, and the herb St. John's Wort. Some drugs potentiate the coagulation effect, but this may be countered by reducing the dose of anticoagulant. Among these drugs are verapamil and quinidine. Finally, some drugs potentiate the anticoagulant effect. But, unless two or more of these drugs are taken in combination with other potentiating drugs, anticoagulant dose does not need to be changed. Among this category of drugs are diltiazem, amiodarone, and certain antibiotics (cyclosporine, clarithromycin, erythromycin). NOTE: For a more complete list of drug interactions see the complete article[1].
• Special precautions need to be taken when switching between different anticoagulant therapies, especially when switching from one of the new anticoagulants to warfarin[1].
• The standard dose for dabigatran is 110 or 150 mg twice a day, for rivaroxaban it is 15-20 mg once a day, and for apixaban 5 mg twice a day. NOTE: Dosages are reduced for patients with impaired kidney function. It is very important to follow the dosing schedule and to follow instructions regarding missed doses[1].
• Chronic kidney disease is a risk factor for both thromboembolic events (ischemic strokes) and bleeding in AF patients. Use of the new anticoagulants is not recommended in patients with a creatinine clearance of less than 30 mL/min or in dialysis patients.
• There are currently no specific antidotes for the new anticoagulants and no effective and readily available protocols for dealing with severe bleeding complications, although some success has been achieved with the use of dialysis and blood transfusions. The effect of an accidental overdose can sometimes be mitigated by the prompt use of activated charcoal.
• Some forms of surgery require the discontinuation of anticoagulation. The last dose should generally be taken 24 to 48 hours prior to surgery depending on the extent of the surgery and the patient's creatinine clearance level. Anticoagulation can generally be restarted 6 to 8 hours after the completion of surgery, but in some cases a wait period of 72 hours or more is required. For AF patients undergoing catheter ablation, anticoagulation with warfarin (INR between 2.0 and 3.0) would still seem to be the safest option. Patients with both AF and coronary artery disease require special consideration and different protocols may be needed depending on whether the patient has suffered a heart attack or not[1].
• In the case of AF patients whose episode has lasted more than 48 hours (or is of unknown duration), anticoagulation is required for 3 weeks before and 4 weeks after cardioversion. If there is doubt about the patient's compliance with their anticoagulation protocol, transesophageal echocardiography should be performed prior to cardioversion.
• Patients suffering an ischemic stroke should not receive thrombolytic therapy with recombinant tissue plasminogen activator or should wait for this therapy for at least 48 hours after taking the last dose of the new anticoagulants. NOTE: Thrombolytic therapy is not effective if given more than 3 hours after stroke occurred. There is no established protocol for dealing with a hemorrhagic stroke (intracranial bleeding) occurring in a patient taking one of the new anticoagulants.
• Patients with cancer are at an increased risk for thromboembolic events and some cancer therapies may increase bleeding tendency. Because of the wealth of experience in using heparin and warfarin in cancer patients and the complete lack of experience using the new anticoagulants, they are not recommended for cancer patients.

Heidbuchel, H, et al. EHRA practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: Executive summary. European Heart Journal, Vol. 34, 2013, pp. 2094-2106
Reference 1

Editor's comment: The guidelines for the use of the new anticoagulants in AF patients should be required reading for all afibbers prescribed dabigatran, rivaroxaban or apixaban. An excellent executive summary of the guidelines can be downloaded (see Reference 1) and the full report here.