The new oral anticoagulants: Reasonable alternatives to warfarin
ABSTRACTDabigatran (a direct thrombin inhibitor) and rivaroxaban, apixaban, and edoxaban (direct activated factor X inhibitors) are increasingly being used in clinical practice. Compared with vitamin K antagonists, they are more convenient, do not require laboratory monitoring, have limited drug and food interactions, and have fixed dosages suitable for most patients. But the shortcomings of these agents can jeopardize their efficacy and increase the risk of bleeding. Their future role in preventing and treating thromboembolic disease will depend on building clinical experience, but current evidence indicates that they are reasonable alternatives to vitamin K antagonists.
KEY POINTS
- The new oral anticoagulants have favorable pharmacologic properties and similar efficacy and safety as vitamin K antagonists.
- The new agents are indicated for preventing stroke and systemic embolism in patients with nonvalvular atrial fibrillation and preventing and treating deep vein thrombosis and pulmonary embolism (the indications regarding venous thromboembolism differ somewhat among agents).
- Except for dabigatran, lack of an antidote in case of bleeding or emergency surgery is a major drawback.
- Be cautious when using these drugs in patients with renal or liver disease and in those taking an inhibitor or inducer of the P-glycoprotein transporter or the cytochrome P450 enzymes.
SWITCHING FROM VITAMIN K ANTAGONISTS TO THE NEW AGENTS
Important issues to consider when switching anticoagulant agents are the delayed onset of action after initiating treatment and the persistent anticoagulant effect after stopping it. In both cases, the international normalized ratio can be used to monitor the anticoagulant effect of the drugs. Renal failure should also be considered, as it can prolong the plasma half-life of the agents.1,39
MANAGING BLEEDING
Dabigatran is the only new anticoagulant with an antidote commercially available: idarucizumab can completely reverse the anticoagulant effect of dabigatran within minutes.
The other new oral anticoagulants lack antidotes, which can present a major problem if a patient has a major bleed or needs emergency surgery. Giving vitamin K is probably useless in this situation. In general, patients taking one of the new oral anticoagulants who present with bleeding should be treated with traditional measures—eg, oral activated charcoal to retard absorption of recently ingested drugs and cauterization and packing of localized bleeding sites. Dialysis may be useful for patients taking dabigatran40 but probably not the other drugs, because they are more highly protein-bound.
Other measures to consider include giving:
- Fresh frozen plasma, which may have some potential for reversing the action of thrombin inhibitors and factor Xa inhibitors but lacks data in humans41
- Activated prothrombin complex concentrate for reversing thrombin inhibitors
- Nonactivated prothrombin complex concentrates and factor Xa analogues for reversing anti-factor Xa agents42–44
- Recombinant factor VIIa, but serious adverse effects—disseminated intravascular coagulation and systemic thrombosis— limit its usefulness.45
More research is needed to assess the efficacy and safety of these measures.46,47
STOPPING THERAPY BEFORE SURGERY
How long to withhold a new oral anticoagulant before patients undergo surgery depends on the type and urgency of the procedure, the indication for anticoagulation, the patient’s renal function, and the drug used.
For procedures with a low risk of bleeding (eg, laparoscopy, colonoscopy), dabigatran should be stopped at least 48 hours before the procedure, and factor Xa inhibitors at least 24 hours before. More time should be allowed for patients with renal failure to clear the drug, according to creatinine clearance.
For procedures entailing a high bleeding risk (eg, major surgery, insertion of pacemaker or defibrillator, neurosurgery, spinal puncture), any new oral anticoagulant should be stopped at least 48 hours before the procedure, with a longer time needed for patients with renal failure.
If urgent surgery is needed and performed within a few hours after the last dose of a drug, bleeding complications should be anticipated.
Resuming anticoagulation therapy after surgery should also be individualized depending on the procedure, the indication for anticoagulation, and renal function. In most patients, if good hemostasis is achieved, the drug may be resumed 4 to 6 hours after surgery. Generally, the first dose should be reduced by 50%, after which the usual maintenance dose can be resumed.39
OTHER POSSIBLE USES
Cardioversion. Anticoagulation with dabigatran before and after cardioversion in patients with atrial fibrillation48 appears as effective and safe as anticoagulation with warfarin.49 There are insufficient data for the other new oral anticoagulants.
Heparin-induced thrombocytopenia. The new oral anticoagulants do not affect the interaction of platelets with platelet factor 4 or antibodies to the platelet factor 4-heparin complex, indicating that they may be an appropriate option for anticoagulation in patients with heparin-induced thrombocytopenia.50–53
Other conditions. The new oral anticoagulants have demonstrated efficacy in preventing or treating thromboembolic disease in patients with cancer54 and critical illnesses,55 and in treating acute coronary syndrome56–58 and other conditions.59 However, their role in these settings is not well established.60,61
SITUATIONS TO AVOID
Valvular heart disease. The new oral anticoagulants should not be prescribed for patients with a prosthetic heart valve or other significant valvular heart disease because of an increased risk of thrombotic complications with dabigatran and the lack of evidence of efficacy and safety of factor Xa inhibitors.62–64
Concurrent thrombolytic therapy along with any of the new oral anticoagulants poses a very high risk of bleeding. Some cases in which dabigatran was used successfully in this situation have been reported, but definitive recommendations are lacking.65
Elderly patients. The safety of the new oral anticoagulants in the elderly is of concern because of the high prevalence of renal failure and other comorbidities and the underrepresentation of this population in many clinical trials assessing these drugs. Data on interactions with foods or other drugs in this population are also scant.66
CHOOSING AN ORAL ANTICOAGULANT
New oral anticoagulants are now a viable alternative to vitamin K antagonists for preventing and treating thromboembolic disease.67,68
When oral anticoagulation is indicated, the choice of drug should be individualized. Cost is an important consideration: direct costs of the new drugs are substantially higher than those of vitamin K antagonists and heparin, but their cost-effectiveness may be comparable or superior to that of warfarin or enoxaparin when clinical efficacy and savings in avoiding coagulation tests are considered.18
Many experts estimate that the new oral anticoagulants are not remarkably superior to vitamin K antagonists, and thus patients whose coagulation is well controlled and stable on a traditional drug would probably not benefit much from changing.1,18
There is currently no conclusive evidence to determine which new oral anticoagulant drug is more effective and safe for long-term treatment, as head-to-head studies of the different medications have not yet been performed.17,69,70 However, there are factors to consider when choosing a drug:
- Rivaroxaban and edoxaban can be taken once daily and so may be better choices for patients who may have difficulties with compliance.
- Dabigatran should be avoided in patients with dyspepsia because of gastrointestinal adverse effects.13
- Dabigatran should be avoided in patients at risk of myocardial infarction because of a possible additional increase in risk.1,71
