SeriesOral anticoagulants for stroke prevention in atrial fibrillation: current status, special situations, and unmet needs
Introduction
Oral anticoagulation is the cornerstone in the prevention of stroke in atrial fibrillation. Vitamin K antagonists (VKA) have been the traditional anticoagulants. These compounds block the vitamin K dependent liver production of the plasma coagulation factors II (prothrombin), VII, IX, and X. They have a relatively narrow therapeutic window, the clinical consequences of which are compounded by a variable dose-effect response both within and between patients. This is mainly related to unpredictable and variable metabolism due to genetic variation and food and drug interactions. Therefore, VKA need close monitoring: overdosing can result in life-threatening bleeding and underdosing in stroke. An international and uniform laboratory standard of the intensity of anticoagulation, the international normalised ratio (INR), is widely used, replacing the non-standardised prothrombin time. Patients on chronic VKA therapy spend less than two-thirds of the time within the therapeutic INR window of 2·0–3·0.1 Time outside the therapeutic window is highly correlated with worse outcomes.2 Of all patients with atrial fibrillation who should be on oral anticoagulation according to clinical practice guidelines,3 only about half are currently being treated, even in high-income countries.4
In the past decade several oral direct inhibitors of thrombin (dabigatran) and of factor Xa (rivaroxaban, apixaban, edoxaban) have been developed and studied in large clinical trials of patients with atrial fibrillation (table 1). These non-VKA oral anticoagulants (NOACs) have predictable pharmacological effects and relatively few drug and food interactions compared with VKA. This feature has allowed the drugs to be developed using fixed doses without the need for routine anticoagulation monitoring. They have a fast onset of activity (2–3 h to peak effect) and a relatively short duration of action, which in case of bleeding or planned surgery is another advantage over VKA. On the other hand, despite similar half-lives of about 12 h for all four drugs, dabigatran and apixaban were developed with twice per day dosing versus once per day dosing (for atrial fibrillation) with rivaroxaban and edoxaban. The short half-life has advantages related to rapid recovery of haemostatic ability in the case of bleeding or need for procedures, but at the same time can be problematic in case of poor adherence.9 Adherence to NOACs in atrial fibrillation (75% in the case of dabigatran10) does not seem to be different from that of warfarin.11 But when NOACs are given once a day, one missed dose results in low trough drug concentrations. Thus, adherence might be more of a concern compared with VKA, since there is no routine measurement of whether the drugs are being taken and no monthly interaction with the health-care team regarding the treatment. Furthermore, an antidote for NOACs is not yet clinically available, although reversal agents are in phase 2 of clinical development (see below). This is by contrast with VKA, where for warfarin there is a well established reversal strategy with vitamin K and coagulation factor replacement, although this approach has not been shown to be effective at improving outcomes in patients with severe bleeding. Finally, with substantial renal clearance for each of the NOACs, and in particular for dabigatran, the drugs have not been clinically tested in patients with stage IV chronic kidney disease (estimated creatinine clearance <30 mL/min) and thus should not be used in this population, pending further study.
In atrial fibrillation NOACs have been at least as effective as warfarin in preventing stroke (and significantly better for higher dose [150 mg] dabigatran and for apixaban), with less life-threatening bleeding.12 The safety advantage persists over time,13 and is particularly notable for intracranial haemorrhage (see below).
In the past 5 years, NOACs have been found to be effective at preventing thrombotic events after acute coronary syndromes by comparison with placebo against a background of dual antiplatelet therapy (DAPT), at least in the case of rivaroxaban. But here bleeding was excessive in the context of adding the anticoagulant on top of DAPT, which is the standard of care.14
Because of their efficacy, safety, ease of administration, and lack of need for monitoring, NOACs are expected to replace VKA in most patients, as long as health-care systems and patients are willing and able to bear the extra cost, which appears to be justified from a cost-effectiveness perspective.15 Whether any of these drugs will have a routine role after acute coronary syndromes remains uncertain, and the combination of oral anticoagulants and antiplatelet therapy for patients with an indication for both is a challenge.
Section snippets
NOACs for stroke prevention in atrial fibrillation
NOACs have been extensively tested for stroke prevention in patients with atrial fibrillation eligible for oral anticoagulation with VKA. More than 72 000 such patients have been tested in four large randomised trials5, 6, 7, 8 that have undergone meta-analysis.12 The NOACs are at least as effective as warfarin at preventing stroke (figure 1) with advantages of less serious bleeding (figure 2) except for gastrointestinal bleeding, which occurs 25% more often than with warfarin. Also, a relative
Management of bleeding
Although large clinical trials have provided clear evidence of the effects of NOACs versus warfarin in the atrial fibrillation population, there are several practical clinical issues that have not been fully addressed by those trials. To use the NOACs safely, there are special situations with which clinicians should be familiar.28
One of the advantages of the NOACs includes the lack of the need for anticoagulation monitoring. However, in case of serious or life-threatening bleeding the ability
Conclusion
For patients with atrial fibrillation and risk of stroke, oral anticoagulation is highly effective at preventing stroke, but a substantial proportion of eligible patients are treated either suboptimally or not at all. The oral direct inhibitors of factors IIa or Xa provide important new approaches, since they are at least as effective as warfarin for stroke prevention in atrial fibrillation with a more favourable safety profile, especially concerning intracranial bleeding. Safe use of these
References (51)
- et al.
Improving the quality of anticoagulation of patients with atrial fibrillation in managed care organizations: results of the managing anticoagulation services trial
Am J Med
(2002) - et al.
SAMe-TT2R2 score, time in therapeutic range, and outcomes in anticoagulated patients with atrial fibrillation
Am J Med
(2014) - et al.
Adherence to dabigatran therapy and longitudinal patient outcomes: insights from the veterans health administration
Am Heart J
(2014) - et al.
Treatment discontinuations with new oral agents for long-term anticoagulation: insights from a meta-analysis of 18 randomized trials including 101 801 patients
Mayo Clin Proc
(2014) - et al.
Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials
Lancet
(2014) - et al.
Laboratory measurement of the anticoagulant activity of the non-vitamin K oral anticoagulants
J Am Coll Cardiol
(2014) - et al.
The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy)
J Am Coll Cardiol
(2014) - et al.
A specific antidote for dabigatran: functional and structural characterization
Blood
(2013) - et al.
Outcomes after cardioversion and atrial fibrillation ablation in patients treated with rivaroxaban and warfarin in the ROCKET AF trial
J Am Coll Cardiol
(2013) - et al.
Efficacy and safety of apixaban in patients after cardioversion for atrial fibrillation: insights from the ARISTOTLE Trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation)
J Am Coll Cardiol
(2014)