Managing older people with atrial fibrillation and preventing stroke: a review of anticoagulation approaches

Figures & data

Table 1. Secondary analyses of phase III trials comparing non-vitamin K antagonist oral anticoagulants vs. warfarin in people aged ≥75 years.

Drug name, trial name	Participant characteristics*	Clinical efficacy and safety outcomes (effect measure, 95% CI)
	^a Sample size ^b Proportion of females, n (%) ^c Age (mean [SD] or median [IQR]) ^d NOAC dose	Stroke/systemic embolism		Major bleeding		Gastrointestinal bleeding
Dabigatran RE-LY¥ [23,35,36]	^a 7,258 ^b 3,062 (42.2) ^c ≥75 to <80 years: 76.8 [1.4]/≥80 to <85 years: 81.7 [1.4]/≥85 years: 86.8 [2.2] ^d 110mg/150mg bid (random allocation)	150mg bid	110mg bid	150mg bid	110mg bid	150mg bid	110mg bid
		≥75 years RR 0.67 (0.49–0.90)	≥75 years RR 0.88 (0.66–1.17)	≥75 years RR 1.18 (0.98–1.42)	≥75 years RR 1.01 (0.83–1.23)	≥75 years RR 1.79 (1.35–2.37)	≥75 years RR 1.39 (1.03–1.98)
		≥75 to <80 years HR 0.65 (0.42–1.01)	≥75 to <80 years HR 1.08 (0.73–1.60)	≥75 to <80 years HR 1.04 (0.81–1.35)	≥75 to <80 years HR 0.93 (0.71–1.21)
		≥80 to <85 years HR 0.67 (0.41–1.10)	≥80 to <85 years HR 0.75 (0.46–1.23)	≥80 to <85 years HR 1.41 (1.02–1.94)	≥80 to <85 years HR 1.18 (0.84–1.65)
		≥85 years HR 0.70 (0.31–1.57)	≥85 years HR 0.52 (0.21–1.29)	≥85 years HR 1.22 (0.74 to 2.02)	≥85 years HR 1.01 (0.59–1.73)
Rivaroxaban ROCKET-AF [26,32]	^a 3,120/3,109 ^b 1,446 (46.4)/1432 (46.1) ^c 79.0 [76.0–82.0]/79.0 [76.0–82.0] ^d 20mg qd (15mg qd if CrCl <50ml/min)	HR 0.80 (0.63–1.02)		HR 1.11 (0.92–1.34)		Event rate per 100 person-years (rivaroxaban 2.81 vs. warfarin 1.66, p=0.0002)
Apixaban ARISTOTLE [25,33]	^a 5,678 ^b 2,396 (42.2) ^c ∞ ^d 5mg bid (2.5mg bid if two or more of: age ≥80 years, bodyweight ≤60 kg, serum creatinine ≥133 μmol/L)	HR 0.71 (0.53–0.95)		HR 0.64 (0.52–0.79)		∞
Edoxaban ENGAGE AF-TIMI 48 [24,34]	^a 8,474 ^b 3,777 (45.0%) ^c 79.0 [76.0–82.0] ^d 60mg qd (30mg qd if CrCl ≤50ml/min, weight ≤60 kg, or concomitant use of potent P‐glycoprotein inhibitor)	HR 0.83 (0.66–1.04)		HR 0.83 (0.70–0.99)		HR 1.32 (1.01–1.72)

ARISTOTLE, apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation trial; bid, twice daily; CI, confidence interval; CrCl, creatinine clearance; ENGAGE-TIMI 48, effective anticoagulation with factor Xa next generation in atrial fibrillation – thrombolysis in myocardial infarction 48 trial; HR, hazard ratio; IQR, interquartile range; RE-LY, the randomized evaluation of long-term anticoagulation trial; ROCKET-AF, the rivaroxaban once daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation; RR, risk ratio; SD, standard deviation; qd, once daily.

Significant results highlighted in bold.

*reported for NOAC and warfarin groups separately where data is available, otherwise reported for entire study cohort or relevant specified subgroups.

¥results from two sub-analyses of RE-LY reported for dabigatran 110/150mg bid in different age categories (≥75 years [36] and ≥75 to <80 years, ≥80 to <85 years and ≥85 years [35]).

∞not reported.

Table 2. Non-vitamin K antagonist oral anticoagulant prescribing aid for older people and high-risk subgroups, based on product licensing and available randomized and observational data.

Clinical scenarios	Apixaban	Edoxaban	Rivaroxaban	Dabigatran
Required dispensing into blister pack [44]	✓	✓	✓	X
Dietary intake unpredictable (unlikely to take medication with food) [45–48]	✓	✓	X	✓
Preference for once daily preparation [45–48]	X	✓	✓	X
Required crushing for oral/enteral tube administration [49,50]	✓ Licensed	✓ Licensed	✓ Licensed	X
Severe chronic kidney disease (creatinine clearance 15-29ml/min) [45–48]	✓ Reduced dose	✓ Reduced dose	✓ Reduced dose	X
Evidence presented below to guide NOAC choice in high-risk older subpopulations should be interpreted cautiously Prescribing decisions should consider a person’s preference and local prescribing guidelines
High risk of major bleeding - consider NOAC(s) with evidence of lowest major bleeding risk in older people (≥75 years) compared to VKA^π	✓ [25,33,39,42,43]	✓ [24,34]
High risk of gastrointestinal bleeding - consider NOAC(s) with evidence of lowest gastrointestinal bleeding risk in older people compared to VKA∞	✓ [37,38,40]
High risk of stroke/systemic embolism - consider NOAC(s) with evidence of highest risk reduction in older people (≥75 years) compared to VKA^Ϯ	✓ [25,33,42]			✓ [36,42] 150mg twice daily, if person qualifies for lower dose dabigatran, consider another NOAC
High risk of dementia/cognitive impairment* - consider NOAC(s) with evidence of highest risk reduction compared to VKA	✓ [51]		✓ [51]
Frailty - consider NOAC(s) with evidence of equivalent/higher risk reduction of stroke/systemic embolism and bleeding compared to VKA	✓ [37,38]
Low body weight (≤60kg) – consider NOAC(s) with RCT evidence of safety and efficacy compared to VKA	✓ [52]	✓ [53]
High falls risk – consider NOAC(s) with RCT evidence of safety and efficacy compared to VKA	✓ [37,54]	✓ [37,55]

NOAC, non-vitamin K antagonist oral anticoagulant; RCT, randomized controlled trial; VKA, vitamin K antagonist. Images taken from flaticon.com.

Table key: ✓[supporting references] = NOAC with most evidence to support prescribing in high-risk sub-group.

Πevidence from secondary analyses of phase III NOAC randomized controlled trials in favor of apixaban and edoxaban [24,25,34,35], additional evidence from real world studies in favor of apixaban [39,42,43].

∞observational data only.

Ϯevidence from secondary analyses of phase III NOAC randomized controlled trials and real-world studies in favor of apixaban and dabigatran 150mg [25,33,36,42].

*people with risk factors according to stage of life: early life (age <18 years) - less education; mid-life (age 45–65 years) - hearing loss, hypertension, obesity; and later life (age >65 years) - smoking, depression, physical inactivity, social isolation and diabetes [62].

Table 3. Key findings from meta-analyses investigating the effect of oral anticoagulant use (vs. nonuse) and choice of oral anticoagulant (NOAC vs. VKA) on dementia or cognitive impairment in AF.

Author (Year)	Number of studies included in meta-analysis (study design)	Population, n	Average age (mean/median) range (years) of participants in included studies (where reported)	Prior history of dementia or stroke specified as exclusion criteria	Main findings (p value reported if provided)
OAC vs. No OAC
Wang [79]	8 (retrospective observational [84–91])	217, 767	60.0–76.4	Studies including individuals with prior events of moderate to severe cognitive impairment or dementia were excluded	OAC use associated with reduced dementia risk vs. no OAC use (HR 0.68, 95% CI 0.55–0.82, p=0.005, I^2=87.7%) Protective effects of OAC use on dementia risk persisted when people with prior history of stroke were excluded (HR 0.60, 95% CI 0.54–0.66, I^2=44.9%, n=4 studies 59,533 participants)
Mongkhon [80]	4 (n=2 retrospective observational [84,85], n=2 prospective observational [92,93])	448, 418	71.0–75.7	Studies including individuals with a prior history of dementia were excluded	OAC use associated with reduced dementia risk vs. no OAC use (risk ratio 0.79, 95% CI 0.67–0.93, p=0.005, I^2=59.7%) Protective effects of OAC use on dementia risk persisted in subgroup analysis including people with and without history of prior stroke (risk ratio 0.77, 95% CI 0.64–0.93, I^2=58.2%)
Cheng [77]	5 (n=3 retrospective observational [84,85,94], n=2 prospective observational [92,95])	452, 661	71.0–74.8	Studies including individuals with dementia history excluded	OAC use associated with reduced risk of dementia vs. no OAC use (HR 0.71, 95% CI 0.69–0.74, p <0.00001, I^2=0%)
Moffit [78]	3 (prospective observational [92,95,96])	5, 899	Not reported for individual studies	No	No significant difference between OAC vs. no OAC on incident cognitive syndromes (OR 0.89, 95% CI 0.47–1.69, p=0.73, I^2=66%) Planned subgroup analysis to explore the effect of stroke history but unable to perform with available data
NOAC vs. VKA
Wang [79]	9 (retrospective observational [85,86,89,90,97–101])	809, 467	60.0–73.9	Studies including individuals with prior events of moderate to severe cognitive impairment or dementia excluded	NOAC use associated with reduced dementia risk vs. VKA (HR 0.87, 95% CI 0.79–0.95, I^2=72%) No statistically significant difference between NOAC vs. VKA when people with prior history of stroke excluded (HR 0.90, 95% CI 0.71–1.15, I^2=76.6%, n=6 studies 96,534 participants)
Lee [51]	9 (n=5 retrospective observational [81,85,86,98,102], n=4 randomized controlled trials [23–26])	611, 069	Not reported for individual studies	No	NOAC use associated with reduced risk of composite dementia outcomes vs. VKA (OR 0.56, 95% CI 0.34–0.94, p=0.03, I^2=97%) When individual NOACs were considered, there was no statistically significant difference between dabigatran vs. VKA and composite dementia outcomes (OR 0.97, 95% CI 0.88–1.08, p=0.61, I^2=29%), whereas apixaban (OR 0.58, 95% CI 0.50–0.67, p=0.00001, I^2=0%) and rivaroxaban (OR 0.67, 95% CI 0.61–0.75, p=0.00001, I^2=44%) had a significantly lower risk compared to VKA
Cheng [77]	2 (retrospective observational [85,102])	208, 740	72.4–74.8	Studies including individuals with dementia history excluded	NOAC use associated with reduced risk of dementia vs. VKA (HR 0.51, 95% CI 0.37–0.71, p < 0.00001, I^2=0%)

CI, confidence interval; HR, hazard ratio; NOAC, non-vitamin K antagonist oral anticoagulant; OAC, oral anticoagulant; OR, odds ratio; VKA, vitamin K antagonist.

Figure 1. Practical considerations when prescribing oral anticoagulant therapy for stroke prevention in AF in older people.

CrCl, creatinine clearance; FBC, full blood count; INR, international normalized ratio; LFT, liver function tests; NOAC, non-vitamin K antagonist oral anticoagulant; TTR, time in therapeutic range; VKA, vitamin K antagonist. Images taken from flaticon.com.

Table 4. Summary characteristics and outcomes of individual studies included in a systematic review and meta-analysis by Guo et al [112] comparing non-vitamin K antagonist oral anticoagulant vs. vitamin K antagonist therapy in people with AF and prior history of stroke, transient ischemic attack and intracranial hemorrhage.

				Main outcomes aHR (95% CI) reported for all outcomes unless otherwise stated
Author (Year)	^a Sample size, n ^b Mean [SD]/median [IQR] age (years) ^c Proportion (%) female	NOACs	VKAs	Stroke	Bleeding	Other
NOAC vs. VKA in people with AF and prior history of stroke/transient ischemic attack
Yang [118]	^a Apix 494/Dab 247/Riva 1,104/Warf 3,082 ^b Apix 80.3 [8.3]/Dab 78.3 [8.4]/Riva 78.8 [8.6]/Warf 77.9 [10.0] ^c Apix 65.0/Dab 56.3/Riva 62.7/Warf 60.7	Dab, Riva, Apix	Warfarin	Analysis included a mixture of people on low-dose (Dab 110mg, Riva 15mg, Apix 2.5mg) and regular dose NOACs
				Ischaemic stroke Apixaban vs. Warfarin 1.04 (0.86–1.27) Dabigatran vs. Warfarin 0.64 (0.48–0.85) Rivaroxaban vs. Warfarin 0.73 (0.63–0.85) Dabigatran vs. Apixaban 0.61 (0.44–0.85) Rivaroxaban vs. Apixaban 0.70 (0.56–0.87) Rivaroxaban vs. Dabigatran 1.14 (0.85–1.54)	Major bleeding Apixaban vs. Warfarin 0.78 (0.60–1.01) Dabigatran vs. Warfarin 1.03 (0.78–1.36) Rivaroxaban vs. Warfarin 0.98 (0.84–1.15) Dabigatran vs. Apixaban 1.32 (0.92–1.89) Rivaroxaban vs. Apixaban 1.25 (0.95–1.67) Rivaroxaban vs. Dabigatran 0.95 (0.71–1.28) Gastrointestinal bleeding Apixaban vs. Warfarin 0.71 (0.44–1.14) Dabigatran vs. Warfarin 1.41 (0.92–2.15) Rivaroxaban vs. Warfarin 1.21 (0.94–1.56) Dabigatran vs. Apixaban 2.00 (1.09–3.57) Rivaroxaban vs. Apixaban 1.70 (1.04–2.78) Rivaroxaban vs. Dabigatran 0.86 (0.55–1.35)	Thromboembolism Apixaban vs. Warfarin 0.62 (0.43–0.90) Dabigatran vs. Warfarin 0.62 (0.39–0.99) Rivaroxaban vs. Warfarin 0.73 (0.58–0.93) Dabigatran vs. Apixaban 1.00 (0.57–1.75) Rivaroxaban vs. Apixaban 1.18 (0.79–1.75) Rivaroxaban vs. Dabigatran 1.18 (0.72–1.92)
Coleman [119]	^a Apix vs. Warf 2,514/Dab vs. Warf 1,962/Riva vs. Warf 5,208* ^b Apix vs. Warf 74 [9,63–81], 74 [9,63–81]/Dab vs. Warf 73 [9,63–79], 73 [9,64–81]/Riva vs. Warf 72 [9,63–80], 72 [9,63–81]* ^c Apix vs. Warf 46.00, 44.2/Dab vs. Warf 48.2, 47.7/Riva vs. Warf 46.9, 46.3	Dab, Riva, Apix	Warfarin	Analysis included people on regular dose NOACs only HR (95% CI) reported for each propensity score matched NOAC vs. warfarin comparison
				Ischemic stroke/intracranial hemorrhage Apixaban vs. Warfarin 0.70 (0.33–1.48) Dabigatran vs. Warfarin 0.53 (0.26–1.07) Rivaroxaban vs. Warfarin 0.45 (0.29–0.72)	Major bleeding Apixaban vs. Warfarin 0.79 (0.38–1.64) Dabigatran vs. Warfarin 0.58 (0.26–1.27) Rivaroxaban vs. Warfarin 1.07 (0.71–1.61)
Larsen [114]	No prior warfarin therapy ^a Warf 1,825/Dab 110mg 793/Dab 150mg 646 ^b Warf 76 [68–81]/Dab 110mg 83 [77–84,103,104]/Dab 150mg 69 [9,64–73] ^c Warf 44.0/Dab 110mg 56.2/Dab 150mg 35.9 Prior Warfarin therapy ^a Warf 1,918/Dab 110mg 547/Dab 150mg 412 ^b Warf 75 [68–81]/Dab 110mg 82 [77–83,103,104]/Dab 150mg 70 [9,65–73] ^c Warf 38.7/Dab 110mg 55.0/Dab 150mg 38.0	Dab	Warfarin	No prior VKA therapy: Stroke Dabigatran 110mg vs. Warfarin 0.74 (0.56–0.97) Dabigatran 150mg vs. Warfarin 1.10 (0.83–1.44) Transient ischemic attack Dabigatran 110mg vs. Warfarin 0.48 (0.28–0.83) Dabigatran 150mg vs. Warfarin 0.79 (0.49–1.28) Prior VKA therapy: Stroke Dabigatran 110mg vs. Warfarin 1.73 (1.21–2.47) Dabigatran 150mg vs. Warfarin 1.79 (1.18–2.72) Transient ischemic attack Dabigatran 110mg vs. Warfarin 1.30 (0.68–2.50) Dabigatran 150mg vs. Warfarin 1.72 (0.92–3.22)
Seiffge [116]	^a Warf 2,256/NOAC 2,656 ^b Warf 78.00 [70–83]/NOAC 77 [70–83] ^c Warf 47.00/NOAC 48.00	NOACs (all)	Warfarin, phenprocoumon			Composite of ischemic stroke, intracerebral hemorrhage and mortality NOACs vs. VKA 0.82 (0.66–1.00) No significant interactions between treatment effects in subgroup analysis comparing people NOAC vs. VKA in people aged ≥80 vs. <80 years
NOAC vs. VKA in people with AF and prior history of ischemic stroke
Xian [115]	^a Warf 7,621/NOAC 4,041 ^b Warf 80 [73–83,103,104]/NOAC 80 [73–83,103,104] ^c Warf 56.3/NOAC 56.3	NOACs (Dab, Riva, Apix)	Warfarin			Number of days at home in first year post-discharge NOACs vs. warfarin: mean 287.2 [SD 114.7] vs. 263.0 [127.3] days; adjusted difference, 15.6 [99% CI 9.0–22.1] days Major adverse cardiovascular events NOACs vs. Warfarin 0.89 (99% CI 0.83–0.96)
Komen [113]	^a Warf 1,229/NOAC 454 ^b Warf 80.62 [8.45]/NOAC 79.25 [9.35] ^c Warf 46.9/NOAC 52.2	NOACs (all)	Warfarin			Mortality NOACs vs. Warfarin 0.84 (0.63–1.12)
Park [121]	^a Warf 28,839/NOAC 32.729 ^b Warf 73.1 [9.4]/NOAC 75.2 [9.1] ^c Warf 46.8/NOAC 49.0	NOACs (all)	Warfarin	HR reported after inverse probability of treatment weighting Analysis included people on regular dose NOACs only
				Recurrent stroke NOACs vs. Warfarin 0.67 (0.62–0.72) Rivaroxaban 20mg vs. Warfarin 0.63 (0.57–0.70) Dabigatran 150mg vs. Warfarin 0.71 (0.62–0.80) Apixaban 5mg vs. Warfarin 0.70 (0.63–0.79) Edoxaban 60mg vs. Warfarin 0.65 (0.55–0.76) Fatal recurrent stroke NOACs vs. Warfarin 0.69 (0.59–0.79) Rivaroxaban 20mg vs. Warfarin 0.77 (0.63–0.93) Dabigatran 150mg vs. Warfarin 0.78 (0.60–0.99) Apixaban 5mg vs. Warfarin 0.64 (0.50–0.81) Edoxaban 60mg vs. Warfarin 0.43 (0.29–0.62)	Major bleeding NOACs vs. Warfarin 0.73 (0.66–0.80) Rivaroxaban 20mg vs. Warfarin 0.80 (0.70–0.92) Dabigatran 150mg vs. Warfarin 0.87 (0.73–1.02) Apixaban 5mg vs. Warfarin 0.59 (0.49–0.70) Edoxaban 60mg vs. Warfarin 0.54 (0.42–0.70) Fatal major bleeding NOACs vs. Warfarin 0.50 (0.37–0.68) Rivaroxaban 20mg vs. Warfarin 0.67 (0.45–0.97) Dabigatran 150mg vs. Warfarin 0.30 (0.13–0.58) Apixaban 5mg vs. Warfarin 0.44 (0.25–0.74) Edoxaban 60mg vs. Warfarin 0.45 (0.19–0.90)	Composite outcome (recurrent stroke and major bleeding) NOACs vs. Warfarin 0.69 (0.65–0.73) Rivaroxaban 20mg vs. Warfarin 0.69 (0.64–0.75) Dabigatran 150mg vs. Warfarin 0.75 (0.67–0.83) Apixaban 5mg vs. Warfarin 0.67 (0.61–0.74) Edoxaban 60mg vs. Warfarin 0.62 (0.54–0.71) Fatal composite outcome NOACs vs. Warfarin 0.65 (0.57–0.74) Rivaroxaban 20mg vs. Warfarin 0.74 (0.62–0.88) Dabigatran 150mg vs. Warfarin 0.68 (0.53–0.86) Apixaban 5mg vs. Warfarin 0.60 (0.48–0.75) Edoxaban 60mg vs. Warfarin 0.44 (0.31–0.60) All-cause mortality NOACs vs. Warfarin 0.84 (0.80–0.89) Rivaroxaban 20mg vs. Warfarin 0.93 (0.86–0.99) Dabigatran 150mg vs. Warfarin 0.78 (0.70–0.86) Apixaban 5mg vs. Warfarin 0.85 (0.77–0.93) Edoxaban 60mg vs. Warfarin 0.71 (0.63–0.81)
NOAC vs. VKA in people with AF and prior history of intracranial hemorrhage
Tsai [117]	^a 4,540 ^b 76.00 [10.50] ^c 41.6	NOACs (Dab, Riva, Apix)	Warfarin	Intracranial hemorrhage NOACs vs. Warfarin 0.56 (0.39–0.80) Ischemic stroke NOACs vs. Warfarin 0.88 (0.68–1.14)	Major bleeding NOACs vs. Warfarin 0.65 (0.53–0.79)	All-cause mortality NOACs vs. Warfarin 0.52 (0.46–0.59)
Lee [122]	^a 5,712 ^b 72.40 [10.00] ^c 43.10	NOACs (all)	Warfarin	HR reported after inverse probability of treatment weighting
				Ischemic stroke NOACs vs. Warfarin 0.77 (0.61–0.97) Intracranial hemorrhage NOACs vs. Warfarin 0.66 (0.47–0.92)		Composite (ischemic stroke and intracranial hemorrhage) NOACs vs. Warfarin 0.73 (0.60–0.88)
Nielsen [120]	^a 622 ^b 76.10 [9.20] ^c 39.10	NOACs (Dab, Riva, Apix)	Warfarin	Weighted risk ratio (95% CI) reported
				Ischemic stroke at 1 year NOACs vs. Warfarin 0.52 (0.27–1.00) Ischemic stroke at 3 years NOACs vs. Warfarin 0.72 (0.44–1.17) Intracerebral hemorrhage at 1 year NOACs vs. Warfarin 0.72 (0.38–1.38) Intracerebral hemorrhage at 3 years NOACs vs. Warfarin 0.94 (0.53–1.64)
Komen [113]	^a Warf 1,028/NOAC 311 ^b Warf 79.62 [8.75]/NOAC 80.02 [9.12] ^c Warf 40.4/NOAC 42.40	NOACs (all)	Warfarin			Mortality NOACs vs. Warfarin 1.36 (1.04–1.78)

aHR, adjusted hazard ratio; CI, confidence interval; IQR, interquartile range; NOAC, non-vitamin K antagonist oral anticoagulant; SD, standard deviation; VKA, vitamin K antagonist.

Significant results highlighted in bold.

*numbers reported in article as 1:1 propensity score–matched cohorts.

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