Selecting antithrombotic therapy for patients with atrial fibrillation

In nonvalvular atrial fibrillation

According to the 2014 guidelines,¹ oral anticoagulation is preferred in all patients with nonvalvular atrial fibrillation but those at lowest risk (CHA₂DS₂-VASc = 0).

Experience with TSOACs is lacking in patients with end-stage kidney disease (creatinine clearance < 15 mL/min), and warfarin is advised in this group.

TSOACs are recommended in patients with nonvalvular atrial fibrillation in whom therapeutic INR levels cannot be maintained with warfarin. For most patients with nonvalvular atrial fibrillation, TSOACs are an option equivalent to warfarin. Anticoagulant choice is largely driven by dosing convenience, out-of-pocket cost for treatment with a TSOAC, and ready availability of antidotes for warfarin in case of bleeding (Tables 5 and 6).

In patients with nonvalvular atrial fibrillation, TSOACs are as effective as warfarin in preventing systemic thromboembolism, and some of them have been shown to be superior in terms of lower rates of ischemic stroke (dabigatran), systemic embolism (apixaban), and mortality (apixaban; trend for dabigatran). All TSOACs demonstrate modestly favorable bleeding risk profiles compared with warfarin, with lower risk of intracranial hemorrhage. Potential differences in efficacy and safety among TSOACs are unknown since there have been no randomized direct comparisons between them. A summary of landmark trial results and assessment of the advantages and disadvantages of each are listed in Table 7.

Two groups of patients with nonvalvular atrial fibrillation warrant special consideration: 

Patients with hypertrophic cardiomyopathy. There are no randomized controlled trials of anticoagulation therapy in patients with hypertrophic cardiomyopathy; however, because of their high risk of thromboembolism, anticoagulation is indicated irrespective of the  CHA₂DS₂-VASc score. TSOACs are an option as an alternative to warfarin.

Patients with coronary artery disease and an indication for antiplatelet therapy. In this group the decision for concurrent anticoagulation is guided by the CHA₂DS₂-VASc score. For patients who have intracoronary stents, dual antiplatelet therapy is the standard of care for reducing risk of cardiovascular events after stent implantation.⁶³ When triple therapy (ie, two antiplatelet drugs and an anticoagulant) is indicated, such as after intracoronary stent placement, the guidelines suggest trying to minimize the duration of triple therapy. For instance, a bare-metal stent may be preferred. Alternatively, after coronary revascularization, it may be reasonable to use clopidogrel 75 mg daily with an oral anticoagulant and to omit aspirin.

Interrupting and bridging anticoagulation

Patients with atrial fibrillation often require suspension of anticoagulation, most commonly before an elective invasive procedure. The duration of interruption, timing of resumption, and need for bridging anticoagulation are guided by clinical judgment, which considers risk of thromboembolism and severity of procedure-related bleeding risk.

In general, if therapy needs to be interrupted, it should be restarted as soon as possible

In general, if therapy needs to be interrupted, it should be restarted as soon as possible. Short-term interruption does not seem to be associated with clinically significant risk of thromboembolic events, whereas postoperative heparin bridging therapy increases the risk of hematoma with implantation of a cardiac electronic device.^64,65

To date, evidence is lacking to advise upon periprocedure bridging anticoagulation. The Bridging Anticoagulation in Patients Who Require Temporary Interruption of Warfarin Therapy for an Elective Invasive Procedure or Surgery (BRIDGE) study (NCT00786474)— enrolling chronically anticoagulated patients undergoing an invasive procedure to randomly receive placebo or bridging low-molecular-weight heparin—may provide guidance.

Currently, it is common practice in low-risk patients undergoing an invasive procedure with significant bleeding risk to interrupt anticoagulation for up to 1 week without bridging. Warfarin is typically held 3 to 5 days, while TSOACs are held for 24 hours if renal function is preserved or up to 2 to 3 days if renal function is severely impaired (creatinine clearance 15–30 mL/min). If complete hemostasis is necessary, it could be confirmed by a normalized INR (for warfarin), activated partial thromboplastin time (dabigatran), or prothrombin time (apixaban or rivaroxaban).

For patients at high risk (valvular atrial fibrillation or CHA₂DS₂-VASc ≥ 2), bridging with unfractionated heparin or low-molecular-weight heparin during periods of subtherapeutic anticoagulation is common. Alternatively, it is becoming increasingly common to perform cardiac electronic device implantation, catheter ablation, and coronary angiography and intervention without interrupting anticoagulation.^66–72

Recently, concern has been raised over a possible increase in thromboembolism upon discontinuation of rivaroxaban and apixaban. ROCKET-AF reported a spike in thrombotic events in the rivaroxaban-treated group at the end of the trial (HR 1.50, 95% CI 1.05–2.15, P = .026). This raised concern for a possible “rebound” effect upon drug cessation. Yet a post hoc analysis of ROCKET-AF demonstrated that events clustered in the rivaroxaban-treated cohort who completed the study and were transitioning to open-label warfarin, and this alone accounted for the rise in stroke occurrence. In contrast, there was no increase in the cohort of patients treated with rivaroxaban who either temporarily interrupted or permanently discontinued the drug.⁷³ The authors concluded that increased stroke was the consequence of transiently interrupted anticoagulation, rather than a rebound prothrombotic effect. Similar results were reported in ARISTOTLE.

Another possibility is that, during the transition to warfarin therapy, transient hypercoagulability could be a function of warfarin. Azoulay et al⁷⁴ observed in a large cohort that warfarin was associated with a 71% increased risk of stroke in the first 30 days after initiation, compared with decreased risk thereafter. Nevertheless, there is now a black- box warning recommendation for all three TSOACs that if discontinuation is required for a reason other than pathological bleeding, bridging with another anticoagulant should  at least be considered.

The perioperative management of the TSOACs was recently reviewed in this journal by Anderson et al.⁷⁵

WEIGHING THE RISKS OF STROKE AND BLEEDING

Stroke is the most feared complication in patients with atrial fibrillation. Risk reduction is an important goal in management, yet decisions for individuals must take into account both stroke and bleeding risks related to antithrombotic therapy.

In deciding whether to start anticoagulation, weigh the risk of both stroke and bleeding

The 2014 guidelines¹ differ from past versions. First, they endorse the use of CHA₂DS₂-VASc for categorizing stroke risk in patients with nonvalvular atrial fibrillation. This in turn guides antithrombotic therapy. This scheme effectively identifies patients at very low risk of stroke (men with a score of 0, women with a score of 0 or 1), in whom it is reasonable to omit antithrombotic therapy. For all patients with valvular heart disease or hypertrophic cardiomyopathy, unless bleeding risk is prohibitive, anticoagulation is recommended irrespective of the CHA₂DS₂-VASc score. Second, they incorporate the TSOACs, which offer convenience and improved safety in select patients.

While the guidelines mention the potential relevance of subclinical atrial tachyarrhythmias as they pertain to stroke risk, there is no specific recommendation as to their management. We do take into consideration the finding of atrial high-rate events (≥ 180 bpm, ≥ 6 minutes in duration) diagnostically confirmed by cardiac implantable electronic devices or telemetric monitoring, particularly in patients with a clinical profile of high stroke risk. In addition, atriopathy with increased left atrial size and renal insufficiency, as discussed in this review, appear to correlate with greater risk of thromboembolism, yet neither is a component of the stroke risk scheme endorsed by the guidelines.

Other risk factors, some unknown to us, undoubtedly exist. Again, our empiric judgment is to at least consider these nontraditional risk factors while guided primarily by the CHA₂DS₂-VASc score when assessing stroke risk in patients with atrial fibrillation.

The goal in managing patients with atrial fibrillation is to balance thromboembolic risk reduction with the risk of bleeding associated with antithrombotic therapy.