New Oral Anticoagulants in Elderly Patients With Atrial Fibrillation

Atrial fibrillation (AF) is a common arrhythmia, especially among the elderly,1,2 and is associated with an increased risk of mortality and disability.3 It is estimated that at least 10% of elderly people (≥75 years) have AF. The number of adults with AF is projected to increase to more than 5.6 million by the year 2050 in the U.S., with more than half of individuals aged 80 years or older.1

This presents difficult challenges as the elderly are at higher risk of both ischemic and bleeding events. Although oral anticoagulant therapy with vitamin K antagonists (e.g., warfarin) reduces the risk of stroke by 64%,4 the risk of major bleeding in patients treated with vitamin K antagonists is estimated to increase by 46% for every 10-year increase in age in comparison with age <40.5 This concern for increased risk of bleeding complication is associated with underuse of anticoagulants in the elderly.6

Recently, four new oral anticoagulants (NOACs), dabigatran, rivaroxaban, apixaban, and edoxaban, have been evaluated in large phase 3 trials as alternatives to vitamin K antagonists in patients with AF. Dabigatran is a direct thrombin inhibitor, while rivaroxaban, apixaban, and edoxaban directly inhibit factor Xa. Due to fewer food and drug interactions, the anticoagulant effects are more predictable with NOACs compared to VKAs, allowing them to be administered in fixed doses without routine anticoagulation monitoring.7 Each of these NOACs have shown to be at least as effective as dose-adjusted warfarin (INR 2.0-3.0) in reducing the risk of stroke while reducing serious bleeding.8,9,10,11

The summary of available pharmacological and patient characteristics for individual phase 3 randomized trials is shown in Table 1. The absolute rates of both bleeding and stroke increase with the increasing age, a finding that was observed in each of the four trials. Within each trial, the absolute rates of stroke or systemic embolic events for patients aged ≥75 years were lower with NOAC regimens when compared to warfarin except for the lower dose edoxaban regimen. The absolute rates of major bleeding were also lower with apixaban and edoxaban, but not with dabigatran or rivaroxaban. However, this needs to be interpreted with caution as the definitions of elderly as well as the trial populations differ significantly between individual trials (Table 1). For example, patients in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial were younger with shorter follow-up duration while the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial had patients with higher risk of stroke and lower median time in therapeutic range (TTR). The elderly often have multiple comorbidities and, without a randomized trial directly comparing these NOACs, careful considerations including pharmacological and patient characteristics are mandatory when applying to practice in the real world.

Table 1: Comparison of Pharmacological and Patient Characteristics7-13

 

RE-LY

ROCKET-AF

ARISTOTLE

ENGAGE AF

NOACs

dabigatran

rivaroxaban

apixaban

edoxaban

Target

direct thrombin inhibitor

direct factor Xa inhibitor

direct factor Xa inhibitor

direct factor Xa inhibitor

Oral bioavailability

6.5%

80%

50%

62%

Frequency

twice-daily

once-daily

twice-daily

once-daily

Half life (hours)

12-17

5-9

9-14

10-14

Renal excretion

80%

33%

25%

50%

Number of patients

18,113

14,264

18,201

21,105

Age (years)

72 (mean)

73 (median)

70 (median)

72 (median)

Age ≥75

41.6%

43.2%

31.2%

40.2%

Female

36%

40%

35%

38%

Mean CHADS2

2.2

3.5

2.1

2.8

Median follow-up
(years)

2.0

1.9

1.8

2.8

Median TTR

66

58

66

68

In the individual subgroup analyses on elderly patients, there were no interactions between patient age and major bleeding with rivaroxaban, apixaban, and edoxaban versus warfarin. However, in the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial, dabigatran was associated with an increased risk of major bleeding (dabigatran 150 mg vs. warfarin; HR 1.18, p-interaction <0.001, dabigatran 110 mg vs. warfarin; HR 1.01, p-interaction <0.001) and particularly extracranial bleeding (dabigatran 150 mg vs. warfarin; HR 1.39, p-interaction<0.05, dabigatran 110mg vs. warfarin HR 1.20, p-interaction <0.05) in patients ≥75 years.12 Reilly et al. reported that age is strongly correlated with a higher plasma concentration and higher bleeding risks in RE-LY, and concluded that the decreasing renal function in the elderly is likely the key factor.13 Dabigatran was the only NOAC without dose adjustment, and this most likely was the main driver for this heterogeneous result.

In a meta-analysis by Ruff et al., pooled NOACs significantly reduced the risk of stroke or systemic embolic events compared to warfarin in patients aged ≥75 years (hazard ratio [HR] 0.78, 95% confidence interval [CI] 0.68-0.88).7 The pooled NOACs also tended to have less major bleeding (HR 0.93, 95% CI 0.74-1.17).7

In summary, elderly patients with AF are at increased risk of stroke and bleeding compared with younger patients. The efficacy and safety of NOACs are largely preserved in elderly patients and, with fewer drug/food interactions and the absence of a need for routine monitoring, the elderly may benefit more from NOACs. However, treatment decisions should be based on individual potential risk and benefit of treatment.

Table 2: Primary Efficacy and Safety Endpoints in the Elderly (≥75 yr)7-13

 

RE-LY

ROCKET-AF

ARISTOTLE

EDOXABAN

Event rate (%/yr)

Dabi
110mg

Dabi
150mg

Warfarin

NNT/NNH

Rivaro

Warfarin

NNT/NNH

Apix

Warfarin

NNT/NNH

HD edox

LD edox

Warfarin

NNT/NNH

Dabi
110mg

Dabi
150mg

HD
edox

LD
edox

Stroke/ SEE

1.9

1.4

2.1

400

141

2.3

2.9

179

1.6

2.2

159

1.9

2.6

2.3

244

-417

Major bleeding

4.4

5.1

4.4

-1667

-137

4.9

4.4

-200

3.3

5.2

54

4.0

2.3

4.8

122

39


NNT = Number needed to treat (if a positive result).
NNH = Number needed to harm (if a negative result).
Dabi = dabigatran, Rivaro = rivaroxaban, Apix = apixaban, HD edox = higher dose edoxaban regimen, LD edox = lower dose edoxaban regimen.




References

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  2. Miyasaka Y, Barnes ME, Gersh BJ, et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation 2006;114:119-25.
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  13. Reilly PA, Lehr T, Haertter S, et al.. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients : The RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy) J Am Coll Cardiol 2014;63:321-8.

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