Poor adherence to oral anticoagulation impacts outcomes of high-risk patients

Yao X, Abraham NS, Caleb Alexander G, et al.
J Am Heart Assoc. 2016; published online ahead of print

Background

The prescription rate of oral anticoagulants for stroke prevention in patients with atrial fibrillation (AF) has been suboptimal in the past, but during the past decades, physician adherence to the relevant guidelines has improved [1,2]. However, studies show that patients with a prescription of warfarin have difficulties to adhere to their therapy in the long term [3].
The introduction of NOACs was expected to lead to better patient adherence, since they decrease the need of routine monitoring, are easy to dose, and have less drug interactions [4]. However, on the other hand, they are associated to higher out-of-pocket costs compared with warfarin, which also impacts on adherence [5]. Some data confirm the hypothesis of better patient adherence to NOACs, however, there are no studies comparing the relative adherence of NOACs in every day clinical practice. Neither have the impact of nonadherence on safety and effectiveness outcomes among NOACs has not been evaluated.
In this retrospective cohort analysis of 64,661 patients with AF, it was evaluated whether 3 NOACs (dabigatran, rivaroxaban, and apixaban) are associated with improved adherence compared with warfarin, and whether adherence is associated with improved outcomes, during a median of 1.1 year of follow-up. Risk of patients was assessed with the CHA2DS2-VASc risk score.

Main results

• Fewer than half (47.5%) of the NOAC patients had ≥80% days covered by oral anticoagulants, compared with 40.2% in warfarin patients (P<0.001). Unadjusted percentages of adherent patients were 61.9% for apixaban, 50.5% for rivaroxaban, and  38.5% for dabigatran.
• Warfarin was associated with a lower probability of adhering to anticoagulation therapy compared with those initiating NOACs in all risk categories (38.7% vs 52.1% with apixaban, 47.6% with rivaroxaban, 45.9% with dabigatran, P<0.001 for all comparisons).
• Adherence was higher in high-risk patients than in those with a low stroke risk:

- CHA2DS2-VASc score 0 or 1: 30.5%
- CHA2DS2-VASc score 2 or 3: 43.4%
- CHA2DS2-VASc score ≥4: 45.3%

• Patients with CHA2DS2-VASc score ≥4 were at increased risk of stroke when they were not taking anticoagulation ≥1 month versus <1 week (P<0.001 for all comparisons):

- 1–3 months: HR: 1.96; CI 95%: 1.48–2.60
- 3–6 months: HR: 2.64; CI 95%: 1.93–3.61
- ≥6 months: HR: 3.66; CI 95%: 2.68–5.01

• Patients with CHA2DS2-VASc score 2 or 3 were at increased risk of stroke when they were not taking anticoagulation ≥6 months compared with not taking oral anticoagulants for <1 week (adjusted HR: 2.73; CI 95%: 1.76–4.23; P<0.001)
• In patients with CHA2DS2-VASc score ≥2, nonadherence was not associated with intracranial hemorrhage.
• In patients with CHA2DS2-VASc score 0 or 1, time not taking anticoagulation was not associated with stroke, but not taking anticoagulation ≥3 months was associated with a significant reduction of bleeding.  

Conclusion

In patients with AF, adherence to oral anticoagulation for stroke prevention was suboptimal, and only modestly improved by the use of NOACs as compared with warfarin. Adherence to therapy is most important in patients with CHA2DS2-VASc score ≥2, whereas the benefit/harm ratio for this intervention is not so favourable for patients with a lower risk for stroke. These data suggest that clinicians may need to follow-up their AF patients at elevated risk of stroke regularly, in order to stimulate patient adherence to oral anticoagulation therapy.

Editorial comment [6]

In their editorial, Ayabe et al highlight the two most important findings of the Yao et al paper:

• These data confirm the low adherence to warfarin in everyday clinical practice, and reveal a somewhat better adherence to NOACs, which is still suboptimal. Since the latter finding might be associated to higher costs of therapy with no obvious and immediate therapeutic effect, the need of health economic data on this topic is highlighted.
• These data show that adherence to OACs is of particular importance for high-risk patients, since the discontinuation of therapy in these patients was associated with an increased incidence of stroke. Whether this observation is due to ‘rebound increase in thrombogenicity’, or rather an indication of a longer ‘non-protection period’ is debated.

“It is most likely that the prevention effects of OACs revealed in clinical trial results can be expected only when the discontinuation rates of OACs in actual “clinical settings” become similar to the rates revealed in clinical trials.” (...) ”If patients discontinue the ‘evidence-based therapy’, event rates become similar to that of the ‘natural course’. Although the increased event rate after discontinuing ‘evidence-based therapy’ mimics ‘rebound’,it may simply reflect the return of the event rate observed in the ‘natural course’.To avoid returning to the ‘natural course’,it is important to adhere to evidence-based therapy once the physician/patient has decided to undergo that therapy. We have to keep in mind that the effects of the therapy demonstrated by clinical trials can be achieved only by its long enough persistence.”

Find this article online at JAHA

References

1. Fang MC, Stafford RS, Ruskin JN, et al. National trends in antiarrhythmic and antithrombotic medication use in atrial fibrillation. Arch Intern Med.2004;164:55–60
2. Holt TA, Hunter TD, Gunnarsson C, et al. Risk of stroke and oral anticoagulant use in atrial fibrillation: a cross-sectional survey. Br J GenPract. 2012;62:e710–e717
3. Fang MC, Go AS, Chang Y, et al. Warfarin discontinuation after starting warfarin for atrial fibrillation. Circ Cardiovasc Qual Outcomes. 2010;3:624–631
4. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007;146:857–867
5. Go AS, Hylek EM, Chang Y, et al. Anticoagulation therapy for stroke prevention in atrial fibrillation: how well do randomized trials translate into clinical practice? JAMA.2003;290:2685–2692
6. Ayabe K, Goto S, Goto S. Persistence and Discontinuation of Oral Anticoagulant: Remaining Issues Not Addressed by Phase III Clinical Trials. J Am Heart Assoc. 2016; published online ahead of print