Stroke Incidence and Death in Atrial Fibrillation Patients Newly Treated with Direct Oral Anticoagulants

Figures & data

Table 1 Characteristics of the Study Population and Incidence of Stroke and Death in 2015 (N=76,795)

	Men (N=41,429)	Women (N=35,366)	Chi2 p-value for Sex	Total (N=76,795)	Adherent (PDC>80%) N=51,167	Non-Adherent (PDC≤80%) N=25,628	Chi 2 p-value for Adherence
Median age, years	72	78	<0.0001	75	76	72	<0.0001
Age group, %			<0.0001				<0.0001
20–64	27.2	13.4		20.8	15.0	31.8
65–74	31.8	24.6		28.5	29.8	25.4
75–84	30.1	37.9		33.7	37.2	26.8
≥85	11.0	24.1		17.0	18.0	16.0
Women, %	–	–	–	46.0	47.7	42.8	<0.0001
Social deprivation, %			<0.0001				<0.0001
Quintile 1 (least deprived)	19.8	18.4		19.1	18.2	20.8
Quintile 2	20.0	19.6		19.8	19.5	20.4
Quintile 3	19.8	19.9		19.8	19.9	19.7
Quintile 4	20.1	20.3		20.2	20.6	19.4
Quintile 5 (most deprived)	20.3	21.9		21.0	21.8	19.7
Direct AF identification^a, %	49.7	54.4	<0.0001	51.9	54.6	47.7	<0.0001
AF-related medical procedure, %	3.8	2.2	<0.0001	3.1	2.5	4.2	<0.0001
Comorbidities in the 2 years preceding inclusion
Stroke	5.8	7.2	<0.0001	6.4	7.9	3.4	<0.0001
Heart failure	12.3	13.6	<0.0001	12.9	15.3	12.2	0.235
Acute coronary syndrome	3.3	2.2	<0.0001	2.8	2.9	3.1	0.081
Haemorrhage	1.4	1.1	0.001	1.3	1.3	1.7	0.983
Acute kidney disease	0.2	0.3	0.018	0.2	0.2	0.3
Medication reimbursement (at least 3) in the year preceding inclusion
Antihypertensive	71.3	75.8	<0.0001	73.4	78.3	64.1	<0.0001
Antidiabetic	21.1	16.3	<0.0001	18.9	20.8	15.6	<0.0001
Lipid-lowering	43.7	36.8	<0.0001	40.5	45.0	31.8	<0.0001
Antiplatelets	47.1	39.8	<0.0001	43.8	47.6	36.7	<0.0001
DOAC adherence (PDC>80%)	64.7	68.9	<0.0001	66.6	100	0	-
Only one DOAC delivery, %	7.5	7.8	<0.0001	7.7	0	22.9	<0.0001
Dosage^b of the first DOAC (standard dose as reference), %			<0.0001				<0.0001
Standard dose	67.1	51.3		59.8	60.1	59.3
Low dose	32.9	48.7		40.2	39.9	40.7
Incidence per 1000 py with 95% CI of
Stroke	9.5 [8.8–10.3]	10.7 [9.9–11.6]	–	10.1 [9.6–10.6]	9.5 [8.8–10.1]	11.3 [10.3–12.3]	–
Ischemic stroke	6.6 [6.1–7.3]	7.9 [7.2–8.6]	–	7.2 [6.8–7.7]	6.2 [5.7–6.8]	9.1 [8.2–10.0]	–
Stroke/SE	13.5 [12.7–14.4]	12.9 [12.0–13.9]	–	13.2 [12.6–13.9]	12.8 [12.1–13.6]	14.0 [12.9–15.2]	–
Death	38.5 [37.1–40.0]	41.0 [39.4–42.7]	–	39.7 [38.6–40.8]	37.4 [36.2–38.7]	44.1 [42.2–46.1]	–
Median follow-up, days	700	700	–	700	700	700	–

Notes: ^adiagnosed AF versus attributed AF. ^bFor Dabigatran, rivaroxaban, and apixaban, standard dosages were 150mg, 20mg, and 5mg, respectively; low doses were 75–110mg, 10–15mg, and 2.5mg, respectively.

Abbreviations: AF, atrial fibrillation; CI, confidence interval; DOAC, direct oral anticoagulant; PDC, percentage of days covered; py, person-year; SE, systemic embolism.

Figure 1 Kaplan–Meier curves for (A) all events of interest (stroke and death), (B) stroke, and (C) death.

Abbreviation: PDC, percentage of days covered by direct oral anticoagulant treatment.

Table 2 Subdistribution Hazard Ratios (SHR) for Stroke from Fine and Gray Models^† and Cause-Specific Hazard Ratios (CHR) for Stroke and Death from Cox Models^†, 2012–2015 (N=238,261)

	Univariate Analyses			Multivariate Analyses
	SHR for Stroke [95% CI]	CHR for Stroke [95% CI]	CHR for Death [95% CI]	SHR for Stroke [95% CI]	CHR for Stroke [95% CI]	CHR for Death [95% CI]
Women vs men	1.20 [1.13–1.28]	1.20 [1.13–1.28]	1.04 [1.01–1.07]	0.95 [0.90–1.02]	0.94 [0.88–1.00]	0.68 [0.66–0.70]
Social deprivation quintile with quintile 1 (least deprived) as reference
Quintile 2	0.96 [0.87–1.06]	0.97 [0.88–1.06]	1.04 [0.99–1.10]	0.99 [0.90–1.09]	1.00 [0.90–1.10]	1.09 [1.03–1.14]
Quintile 3	0.97 [0.88–1.07]	0.98 [0.89–1.07]	1.08 [1.03–1.14]	1.01 [0.92–1.11]	1.02 [0.92–1.12]	1.13 [1.07–1.19]
Quintile 4	1.00 [0.91–1.10]	1.00 [0.91–1.10]	1.07 [1.02–1.13]	1.03 [0.93–1.13]	1.03 [0.94–1.14]	1.11 [1.06–1.17]
Quintile 5 (most deprived)	1.01 [0.92–1.12]	1.02 [0.93–1.12]	1.17 [1.11–1.23]	1.03 [0.94–1.14]	1.04 [0.95–1.14]	1.18 [1.12–1.24]
Direct AF identification	1.15 [1.08–1.22]	1.16 [1.10–1.24]	1.31 [1.27–1.35]	1.12 [1.05–1.19]	1.13 [1.06–1.20]	1.18 [1.14–1.22]
AF-related medical procedure	0.49 [0.38–0.63]	0.49 [0.38–0.63]	0.68 [0.61–0.76]	0.62 [0.48–0.80]	0.61 [0.47–0.78]	0.77 [0.69–0.86]
Comorbidities in the 2 years preceding inclusion
Stroke	2.80 [2.57–3.05]	2.82 [2.60–3.07]	1.24 [1.17–1.32]	2.60 [2.38–2.84]	2.61 [2.39–2.85]	1.10 [1.04–1.17]
Heart failure	1.22 [1.12–1.33]	1.30 [1.19–1.41]	2.97 [2.86–3.07]	1.03 [0.94–1.13]	1.09 [0.99–1.20]	2.09 [2.01–2.18]
Acute coronary syndrome	1.30 [1.10–1.54]	1.32 [1.11–1.56]	1.26 [1.16–1.38]	1.23 [1.03–1.46]	1.23 [1.03–1.46]	0.99 [0.90–1.08]
Haemorrhage	1.27 [0.99–1.63]	1.32 [1.03–1.71]	2.14 [1.93–2.38]	0.89 [0.69–1.15]	0.92 [0.71–1.18]	1.53 [1.37–1.70]
Acute kidney disease	1.71 [0.99–2.94]	1.78 [1.03–3.06]	2.00 [1.53–2.61]	1.29 [0.75–2.23]	1.33 [0.77–2.29]	1.13 [0.86–1.48]
Medication reimbursement (at least 3) in the year preceding inclusion
Antihypertensive	1.21 [1.12–1.30]	1.22 [1.13–1.32]	1.37 [1.32–1.42]	1.04 [0.96–1.12]	1.04 [0.96–1.13]	1.09 [1.04–1.14]
Antidiabetic	1.08 [1.02–1.15]	1.08 [1.01–1.15]	0.93 [0.90–0.96]	1.21 [1.12–1.31]	1.23 [1.14–1.33]	1.40 [1.35–1.45]
Lipid-lowering	1.38 [1.30–1.46]	1.40 [1.32–1.49]	1.64 [1.59–1.70]	0.95 [0.88–1.01]	0.93 [0.87–1.00]	0.80 [0.77–0.82]
Antiplatelets	1.18 [1.11–1.25]	1.18 [1.11–1.26]	1.20 [1.16–1.24]	1.14 [1.06–1.21]	1.15 [1.07–1.23]	1.25 [1.20–1.29]
DOAC non-adherence (PDC≤80%) vs adherence	1.21 [1.12–1.30]	1.22 [1.13–1.32]	1.37 [1.32–1.42]	1.42 [1.33–1.51]	1.44 [1.35–1.53]	1.38 [1.33–1.43]
Dosage* of the first DOAC (standard dose as reference)
Low dose	1.67 [1.57–1.77]	1.72 [1.62–1.83]	2.63 [2.55–2.73]	1.10 [1.02–1.18]	1.10 [1.03–1.18]	1.31 [1.26–1.36]

Notes: ^†Multivariate models adjusted for age, year of DOAC initiation, and all covariates. *For Dabigatran, rivaroxaban, and apixaban, the standard dosages were 150mg, 20mg, and 5mg, respectively. In bold: hazard ratios statistically different from 1 (p<0.05).

Abbreviations: AF, atrial fibrillation; CI, confidence interval; DOAC, direct oral anticoagulant; PDC, percentage of days covered.