Novel Oral Anticoagulant Agents in Atrial Fibrillation: New Indications and Approvals

Noel G. Boyle, MD, of the University of California, Los Angeles (UCLA), Cardiac Arrhythmia Center, and Ronald Reagan UCLA Medical Center discussed effective anticoagulation strategies for stroke prevention in patients with atrial fibrillation at the Fall Managed Care Forum 2015 in Las Vegas, Nevada. Dr Boyle discussed recent FDA approvals for the prevention of stroke, including the novel oral anticoagulants (NOACs) and medical devices, as well as the appropriate use of these therapies for treatment in a manner consistent with guidelines.

Recent FDA approvals in the anticoagulant treatment arena include dabigatran (Pradaxa, October 19, 2010), rivaroxaban (Xarelto, July 1, 2011), apixaban (Eliquis, December 28, 2012, and for use in dialysis patients, January 30, 2014), edoxaban (Savaysa, January 8, 2010), and the reversal agent idarucizumab (Praxbind, October 16, 2015). Medical devices intended to reduce stroke risk included the Watchman device (approved March 13, 2015), and the Lariat device (approved in 2006 as a class II medical device).

With the Lariat atrial appendage occlusion device, the procedure was successful in 96% of 89 patients, with access-related and postoperative adverse events, including severe pericarditis, late pericardial effusion, unexplained sudden death, and nonembolic stroke. An estimated 15% of all strokes are attributable to atrial fibrillation, with that proportion approaching one-third (30%) of patients in elderly individuals. In more than three-fourths (80%) of patients, these emboli originate in the left atrial appendage (LAA). Although LAA closure devices may be used in some patients, these devices have certain technical limitations and are associated with intraprocedural and postprocedural complications.

In terms of pharmacologic therapy, improving adherence with warfarin therapy and INR monitoring remains an important priority. However, direct thrombin inhibitors and factor Xa inhibitors have been demonstrated equivalent to warfarin with fewer side effects and drug interactions. In large phase III clinical trials, treatment with NOACs for prevention of stroke has proven at least as effective, and as safe as warfarin. Importantly, the cost of these agents and the lack of reversal agents (with 1 exception) are important considerations in therapeutic choice.

In general, NOACs have a rapid onset of action of 2 to 4 hours, with effects dissipating rapidly 12 to 24 hours after administration of a dose. Because of this rapid dissipation of the anticoagulant effects of NOACs, warfarin may be preferable clinically in patients who have difficulty maintaining adequate adherence.

In terms of administration characteristics and drug interactions, there are several important differences between agents. For instance, whereas rivaroxaban (Xarelto) must be taken with food, all other NOACs may be taken without regard to meals. Drug interaction considerations with these agents must also be taken into account, including potential interactions with dronedarone, statins, cyclosporine, and grapefruit juice.

Use or nonuse of NOACs also affects patient eligibility for certain medical procedures. In patients who have received more than 3 weeks of therapy with Pradaxa or Xarelto, cardioversion may be performed, but NOAC treatment should be stopped for 48 hours or more prior to undergoing surgery if the patients have a major bleeding risk, and for 24 hour or more prior to undergoing survey if the patients have a minor bleeding risk.

Because NOACs are generally excreted through the kidneys, but to varying degrees, renal function should be assessed regularly with all agents, and dose reductions should be performed if renal function is compromised. Until recently, none of the NOACs were indicated for use in patients with a creatinine clearance lower than 15 mL/min or in patients undergoing hemodialysis. Previously, only warfarin was indicated for use in these patient populations, but this has changed with the approval of apixaban in patients undergoing hemodialysis.

NOACs have a growing range of indications as oral anticoagulants, but warfarin remains the only anticoagulant indicated for use in patients with mechanical heart valves. However, pending the results of ongoing postmarketing registries and studies, more information on the safety and efficacy of NOACs in certain high-risk populations will become available.

In 2014, the American Heart Association/ American College of Cardiology/Heart Rhythm Society (AHA/ACC/HRS) jointly published guidelines for the management of atrial fibrillation, and in 2015, the European Heart Rhythm Association (EHRA) released practical guidance for the use of NOACs. These guidelines emphasize the importance of the CHA₂DS₂-VASc score as a useful assessment tool for estimating stroke risk in patients with AF, and emphasize the importance of shared decision making between the patient and physician with regard to the use of NOACs.

Ongoing controversies with NOACs include selection of patients for therapy based on comorbidities and the severity of atrial fibrillation. In the ASSERT study, patients with asymptomatic AF who had experienced a prior stroke and had been implanted with a pacemaker were assessed for the hazard ratio of stroke or systemic embolism in the 6 minutes following an episode of AF, as assessed by continuous monitoring equipment. Results indicated a 2.5-fold greater risk of stroke or systemic embolism in the 6 minutes following a new-onset episode of AF. Considering that the median duration of subclinical AF averages 4.2 hours, and that most strokes in the ASSERT study were not temporally related to an episode of AF, subclinical AF may simply function as a risk marker for stroke in most patients—no causal relationship between paroxysmal episodes of AF and stroke has been established.

Because nearly one-third (30%) of patients in the ASSERT trial who experienced a systemic embolism or stroke had AF that was detected only after the event, the ASSERT study showed that the relationship between AF episodes and stroke is not as strong as was once thought. This finding resulted in new concerns about performance of cardioversion in patients in patients with an AF episode of fewer than 18 hours' duration. Previously, in these patients, physicians believed anticoagulant therapy was unnecessary. However, because AF episodes are detected only after a stroke in 30% of cases, cardioversion of patients who are not receiving anticoagulation may place these patients at increased risk of stroke.

Other studies in the acute management of AF are ongoing. An important in-progress study, STROKE-STOP, will answer further unanswered questions about atrial fibrillation. In 25,000 patients with an average age of 75 to 76 years randomized in a 1:1 ratio to receive screening for AF or no screening, of the roughly 12,500 possible participants, approximately half of patients (n = 6496) opted to receive screening with a handheld electrocardiogram (ECG) device for 1 minute each day over 2 weeks. Of these patients, the ECG device identified AF in 11% of patients, of whom 3% had newly diagnosed AF. Results of this in-progress study are expected in 2018.

As answers to questions about the use of NOACs in certain populations of patients with AF are clarified through clinical trials, and the use of existing agents expands, it is important for managed care professionals to be aware of new populations who are eligible for NOAC therapy. Although warfarin remains an important treatment in the management of AF, the improved safety profile and superior efficacy of NOACs over warfarin is well documented in pivotal trials. Expanding indications for the use of these novel agents in new patient populations remains an important clinical development.