Elsevier

The Lancet

Volume 386, Issue 9990, 18–24 July 2015, Pages 303-310
The Lancet

Series
Oral anticoagulants for stroke prevention in atrial fibrillation: current status, special situations, and unmet needs

https://doi.org/10.1016/S0140-6736(15)60245-8Get rights and content

Summary

In patients with non-valvular atrial fibrillation, oral anticoagulation with vitamin K antagonists reduces the risk of stroke by more than 60%. But vitamin K antagonists have limitations, including causing serious bleeding such as intracranial haemorrhage and the need for anticoagulation monitoring. In part related to these limitations, they are used in only about half of patients who should be treated according to guideline recommendations. In the past decade, oral agents have been developed that directly block the activity of thrombin (factor IIa), as well as drugs that directly inhibit activated factor X (Xa), which is the first protein in the final common pathway to the activation of thrombin. These novel non-vitamin K antagonist oral anticoagulants (NOACs) have been shown to be at least as good as warfarin for stroke prevention in atrial fibrillation and they have proved to have better safety profiles. Their net advantage is underscored by significantly lower all-cause mortality compared with warfarin in large clinical trials. Because of these features and their ease of use, they are recommended for stroke prevention in atrial fibrillation. They have also a fast onset and offset of action, but they currently lack specific antidotes. This paper addresses the role of anticoagulation for stroke prevention in atrial fibrillation in the era of NOACs, with a focus on special situations including management in the event of bleeding and around the time of procedures including cardioversion, catheter ablation, and device implantation. Also their use in patients with concomitant coronary artery disease, with advanced age, with chronic kidney disease, or with valvular heart disease will be discussed as well as the interaction of NOACs with other cardiac medication, and switching between anticoagulants.

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

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