Editorials
How to Avoid Adverse Events During Apixaban Therapy in Patients With Atrial Fibrillation
2015 Volume 79 Issue 12 Pages 2539-2540
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2015 Volume 79 Issue 12 Pages 2539-2540
Apixaban, a non-vitamin K antagonist oral anticoagulant (NOAC), was approved worldwide for prevention of stroke in patients with non-valvular atrial fibrillation (NVAF).1,2 Randomized, double-blind clinical trials have shown that apixaban has improved efficacy and safety without biological monitoring, because its pharmacokinetics and pharmacodynamics are predictable.1,3 In addition, it has been reported that most conventional coagulation assays, such as prothrombin time (PT) or activated partial thromboplastin time, are not sensitive enough to monitor apixaban plasma concentrations because of several limitations.4 However, in the clinical setting, including the recurrence of stroke, bleeding, and urgent surgery, it would be important to monitor apixaban-associated anticoagulant activity. We reported that the PT value calculated using the specific regents (Triniclot PT Excel S and Coagpia PT-N) is closely associated with apixaban anticoagulant activity in Japanese NVAF patients.5 In this regard, measurement of chromogenic Xa activity is more accurate for estimating apixaban plasma concentration.4 In this issue of the Journal, Osanai et al analyze the distribution of anti-Xa activity in Japanese NVAF patients taking apixaban in daily clinical practice.6
Article p 2584
When Should We Measure Anti-Xa Activity?Fixed-dosage apixaban therapy significantly reduces adverse bleeding events compared with adjusted-dosage warfarin with PT monitoring.1 However, it is still possible that adverse events under apixaban therapy may occur in AF patients with a high risk of bleeding. To reduce bleeding events, it might be reasonable to monitor apixaban plasma concentration in such circumstances. Baglin et al reported that the following situations may be appropriate for monitoring anti-Xa activity: bleeding incidents, perioperative management, and suspicion of overdose because of worsening of renal function. In addition, patients’ non-adherence to anticoagulant NOAC therapy is associated with thromboembolic events. When the thrombotic event occurs, measuring anti-Xa activity may be useful to monitor whether patients are regularly taking NOACs.7 The cost of measuring anti-Xa activity is another issue to be solved in the future, because it is not covered by insurance.
Does the Therapeutic Range Matter for NOACs?In the era of anticoagulant therapy with warfarin, the concept of the time in the therapeutic range (TTR) was used to monitor effectiveness of anticoagulant activity. However, titrating the dose of warfarin to maintain a higher TTR was challenging and often unsatisfactory. In fact, clinical trials of NOACs (RE-LY, ROCKET-AF and ARISTOTLE) revealed that NOACs were superior or at least non-inferior for preventing stroke compared with warfarin, the TTR of which was only 55–65% in patients with NVAF. The ARISTOTLE study demonstrated safety and efficacy profiles of apixaban without monitoring anticoagulant activity compared with dose-adjusted warfarin.1 These results led to the conclusion that the concept of therapeutic range does not matter when we use NOACs, even if the plasma concentration may vary according to individual metabolism, unless the patients meet the criteria of recommended dose reduction. However, the RE-LY trial revealed that major bleeding risk, mainly from the intestine, was associated with the trough value of dabigatran plasma concentration.8 Taken together these results suggest that we still should be careful with patients with a high bleeding risk, although the concept of therapeutic range is no longer practical with NOACs.
In this regard, Osanai et al report no significant differences in trough and peak anti-Xa activity in patients with bleeding events compared with those without events, raising the question that measuring anti-Xa activity does not identify high-risk patients. However, it may be associated with the small number of bleeding events in their study and the fact that anti-Xa activity was measured in the steady state, but not when adverse events occurred. Further assessment of anti-Xa activity in patients at high risk of bleeding because of worsening of renal function or age-associated poor drug metabolism is required.
Measurement of Anti-Xa Activity: Peak or Trough?Apixaban has multiple metabolic pathways, a small volume distribution, a plasma half-life of almost 12 h, and is taken twice daily.9 In contrast, rivaroxaban, another Xa inhibitor, is taken once daily with a similar plasma half-life to apixaban. Median time to peak plasma concentration (Tmax) is 2 h (min 1 h, max 3 h) for both drugs. The Mean peak-to-trough plasma concentration ratio is 3.6-fold greater for rivaroxaban (16.9) than for apixaban (4.7).10 It has also been reported that there are individual differences in the time to reach peak plasma concentration of each drug. Indeed, variation in the peak values appears to be larger than with the trough, as reported in the present study (see Figure 2).6 Therefore, measuring steady-state trough plasma concentration appears to be feasible for monitoring apixaban-associated anticoagulant activity in the outpatient clinic.
Is the Recommended Dose Reduction Appropriate?The recommended dose reduction of apixaban is 2.5 mg b.i.d. in NVAF patients with at least 2 of the following characteristics: >80 years of age, body weight <60 kg, or serum creatinine level >1.5 mg/dl. Osanai et al report that the 2.5 mg b.i.d. group had significantly lower peak anti-Xa activity than the 5-mg b.i.d. group, whereas trough anti-Xa activity did not differ between groups.6 These results suggest that the recommended dose reduction strategy for apixaban is appropriate in Japanese NVAF patients.
How to Avoid Adverse EventsPhase III clinical trials of other NOACs, including dabigatran (RE-LY) and rivaroxaban (ROCKET-AF), resulted in increased gastrointestinal bleeding compared with warfarin therapy. Apixaban has been reported to be a safe drug compared with warfarin and other NOACs.1 In the present study, Osanai et al point that high dose, age, and serum creatinine were significantly associated with high anti-Xa activity at both the trough and peak level.6 In fact, elderly people have various comorbidities, renal dysfunction, malnutrition, and take many concomitant drugs, including antibiotics, aspirin and non-steroidal anti-inflammatory drugs (NSAIDs).11,12 Preexisting malignancies also should not be forgotten in the elderly.13
In summary, to avoid adverse events, it is important to administrate the recommended dose of NOACs, to monitor renal function as appropriate, to avoid concomitant use of aspirin and/or NSAIDs, and to exclude malignancy (Figure).
Schematic of the ranking of measurement of anti-Xa activity under apixaban therapy. DM, diabetes mellitus: BP, blood pressure: NSAIDs, non-steroidal anti-inflammatory drugs.
None declared.
