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 Characteristics^7-13

	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

1. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001;285:2370-5.
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.
3. Feigin VL, Lawes CM, Bennett DA, Barker-Collo SL, Parag V. Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Lancet Neurol 2009;8:355-69.
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;146:857-67.
5. Van der Meer FJ, Rosendaal FR, Vandenbroucke JP, Briët E. Bleeding complications in oral anticoagulant therapy. An analysis of risk factors. Arch Intern Med 1993;153:1557-62.
6. Tulner LR, Van Campen JPCM, Kuper IMJA, et al. Reasons for undertreatment with oral anticoagulants in frail geriatric outpatients with atrial fibrillation: a prospective, descriptive study. Drugs Aging 2010;27:39-50.
7. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014;383:955-62.
8. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093-104.
9. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-1151.
10. Halperin JL, Hankey GJ, Wojdyla DM, et al. Efficacy and safety of rivaroxaban compared with warfarin among elderly patients with nonvalvular atrial fibrillation in 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).. Circulation 2014:138-46.
11. Granger CB, Alexander JH, McMurray JJ V, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-92.
12. Eikelboom JW1, Wallentin L, Connolly SJ, et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial. Circulation 2011;123:2363-72.
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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