Assessing Safety of Direct Thrombin Inhibitors, Direct Factor Xa Inhibitors and Vitamin K Antagonists in Patients with Atrial Fibrillation: A Nation-Wide Propensity Score Matched Cohort from Sweden

Figures & data

Figure 1 Flow chart of the study population. All patients were 60 years of age or older and with a diagnosis of atrial fibrillation within 6 months before start of treatment with dabigatran, direct factor Xa inhibitors or with warfarin.

Notes:¹Individuals could fulfil more than one exclusion criteria. ²To include only non-valvular atrial fibrillation, excluding valvular atrial fibrillation. ³To exclude thrombosis prophylaxis after elective knee/hip joint replacements, look-back period is 5 weeks. ⁴To exclude patients at altered risk for the outcomes, look-back period is 6 months.

Table 1 Baseline Characteristics for All Included, Matched Individuals by Propensity Score Matched Cohorts and Index Drug. All Patients Were 60 Years of Age or Older and with a Diagnosis of Atrial Fibrillation Within 6 Months Before Start of Treatment with Direct Thrombin Inhibitors, Direct Factor Xa Inhibitors or with Vitamin K Antagonists

Characteristics	Direct Thrombin Inhibitors vs Vitamin K Antagonists		Direct Factor Xa Inhibitors vs Direct Thrombin Inhibitors		Direct Factor Xa Inhibitors vs Vitamin K Antagonists
	DTI	VKA	XAB	DTI	XAB	VKA
Total, n	3632	3632	3303	3303	6283	6283
Age, mean (SD)	72.8 (7.7)	73.1 (7.8)	73.0 (7.7)	72.7 (7.7)	75.6 (8.5)	75.6 (8.3)
Female, n (%)	1705 (46.9%)	1714 (47.2%)	1545 (46.8%)	1557 (47.1%)	3120 (49.7%)	3125 (49.7%)
CHA2DS2VASc,^a mean (SD)	3.0 (1.5)	3.0 (1.5)	2.9 (1.5)	2.9 (1.5)	3.4 (1.6)	3.4 (1.6)
Modified HAS-BLED,^b mean (SD)	2.2 (1.0)	2.2 (1.0)	2.1 (1.0)	2.1 (1.0)	2.4 (1.1)	2.4 (1.1)
Hospitalization (days), mean (SD)	0.9 (3.1)	0.9 (3.3)	0.9 (2.9)	0.9 (3.1)	1.4 (4.0)	1.4 (4.0)
Municipal services (hours), mean (SD)	1.3 (10.2)	1.1 (9.2)	1.1 (8.6)	1.4 (10.1)	2.6 (14.5)	2.7 (14.9)
Number of simultaneous drugs, mean (SD)	5.3 (2.9)	5.4 (3.0)	5.2 (2.9)	5.3 (2.9)	5.9 (3.1)	6.0 (3.2)
Number of visits in specialized care, mean (SD)	1.3 (2.0)	1.3 (2.0)	1.1 (1.9)	1.1 (1.9)	1.0 (1.9)	1.0 (1.9)
Private clinic, n (%)	100 (2.8%)	93 (2.6%)	131 (4.0%)	126 (3.8%)	64 (1.0%)	58 (0.9%)
Urban living, n (%)	1818 (50.1%)	1819 (50.1%)	1602 (48.5%)	1620 (49.0%)	2906 (46.3%)	2830 (45.0%)
Education
9-year compulsory, n (%)	1134 (31.2%)	1121 (30.9%)	967 (29.3%)	996 (30.2%)	2379 (37.9%)	2362 (37.6%)
High school, n (%)	1361 (37.5%)	1393 (38.4%)	1272 (38.5%)	1255 (38.0%)	2492 (39.7%)	2440 (38.8%)
Tertiary education, n (%)	1092 (30.1%)	1067 (29.4%)	1019 (30.9%)	1015 (30.7%)	1341 (21.3%)	1396 (22.2%)
Missing, n (%)	45 (1.2%)	51 (1.4%)	45 (1.4%)	37 (1.1%)	71 (1.1%)	85 (1.4%)
Comorbidities
Abnormal renal function, n (%)	68 (1.9%)	63 (1.7%)	45 (1.4%)	55 (1.7%)	344 (5.5%)	328 (5.2%)
Abnormal hepatic function, n (%)	6 (0.2%)	7 (0.2%)	7 (0.2%)	6 (0.2%)	23 (0.4%)	16 (0.3%)
Alcohol intake, n (%)	121 (3.3%)	125 (3.4%)	105 (3.2%)	104 (3.1%)	170 (2.7%)	158 (2.5%)
Bleedings, n (%)	446 (12.3%)	451 (12.4%)	434 (13.1%)	418 (12.7%)	938 (14.9%)	948 (15.1%)
Congestive heart failure, n (%)	755 (20.8%)	763 (21.0%)	629 (19.0%)	638 (19.3%)	1697 (27.0%)	1667 (26.5%)
Diabetes, n (%)	496 (13.7%)	485 (13.4%)	423 (12.8%)	427 (12.9%)	1023 (16.3%)	1015 (16.2%)
Disorders of thyroid gland, n (%)	330 (9.1%)	330 (9.1%)	288 (8.7%)	299 (9.1%)	597 (9.5%)	590 (9.4%)
Embolism, n (%)	27 (0.7%)	32 (0.9%)	23 (0.7%)	25 (0.8%)	64 (1.0%)	61 (1.0%)
Hepatic disease, n (%)	61 (1.7%)	61 (1.7%)	50 (1.5%)	51 (1.5%)	124 (2.0%)	107 (1.7%)
Hypertension, n (%)	2409 (66.3%)	2428 (66.9%)	2108 (63.8%)	2132 (64.5%)	4483 (71.4%)	4498 (71.6%)
Ischemic stroke, n (%)	151 (4.2%)	137 (3.8%)	129 (3.9%)	133 (4.0%)	328 (5.2%)	317 (5.0%)
Peripheral arterial disease, n (%)	132 (3.6%)	141 (3.9%)	126 (3.8%)	110 (3.3%)	328 (5.2%)	324 (5.2%)
Renal disease, n (%)	64 (1.8%)	56 (1.5%)	40 (1.2%)	49 (1.5%)	328 (5.2%)	313 (5.0%)
Transient ischemic attack, n (%)	160 (4.4%)	163 (4.5%)	137 (4.1%)	142 (4.3%)	335 (5.3%)	343 (5.5%)
Vascular disease, n (%)	317 (8.7%)	323 (8.9%)	289 (8.7%)	282 (8.5%)	817 (13.0%)	810 (12.9%)
Comedication
Antiarrhythmics, n (%)	84 (2.3%)	87 (2.4%)	64 (1.9%)	59 (1.8%)	189 (3.0%)	212 (3.4%)
Antibiotics, n (%)	1 (0.0%)	2 (0.1%)	0 (0.0%)	1 (0.0%)	1 (0.0%)	2 (0.0%)
Antidepressants, n (%)	194 (5.3%)	204 (5.6%)	186 (5.6%)	180 (5.4%)	396 (6.3%)	385 (6.1%)
Antimycotics, n (%)	1 (0.0%)	0 (0.0%)	0 (0.0%)	1 (0.0%)	1 (0.0%)	0 (0.0%)
Low dose acetylsalicylic acid, n (%)	1243 (34.2%)	1257 (34.6%)	1005 (30.4%)	998 (30.2%)	2232 (35.5%)	2223 (35.4%)
Clopidogrel, n (%)	110 (3.0%)	103 (2.8%)	95 (2.9%)	89 (2.7%)	281 (4.5%)	287 (4.6%)
NSAIDs,^c n (%)	204 (5.6%)	194 (5.3%)	180 (5.4%)	185 (5.6%)	302 (4.8%)	301 (4.8%)
Other previous anticoagulants, n (%)	1725 (47.5%)	1749 (48.2%)	1470 (44.5%)	1444 (43.7%)	3252 (51.8%)	3283 (52.3%)
Steroids, n (%)	142 (3.9%)	144 (4.0%)	141 (4.3%)	124 (3.8%)	304 (4.8%)	311 (4.9%)

Notes: ^aScore based on congestive heart failure, hypertension, age, diabetes, stroke, vascular disease and sex. ^bScore based on hypertension, abnormal renal function, abnormal hepatic function, stroke, bleedings, age, medicines and alcohol intake. ^cAnti-inflammatory and antirheumatic products, non-steroids.

Abbreviations: DTI, direct thrombin inhibitors; VKA, vitamin K antagonists; XAB, direct factor Xa inhibitors.

Table 2 Hazard Ratios with 95% Confidence Intervals, for Each Outcome and Comparison, by Sex and Age. All Patients Were 60 Years of Age or Older and with a Diagnosis of Atrial Fibrillation Within 6 Months Before Start of Treatment with Direct Thrombin Inhibitors, Direct Factor Xa Inhibitors or with Vitamin K Antagonists

Outcome	Comparison	Men				Women
		60–74	75–79	80–84	85+	60–74	75–79	80–84	85+
Bleedings	DTI vs VKA	0.76 (0.53, 1.09)	0.62 (0.37, 1.05)	2.90* (1.01, 10.41)	2.42 (0.72, 10.94)	0.88 (0.52, 1.50)	1.45 (0.72, 3.05)	1.13 (0.47, 2.73)	0.84 (0.33, 2.10)
	XAB vs VKA	0.75 (0.53, 1.04)	0.89 (0.57, 1.38)	1.40 (0.79, 2.56)	1.28 (0.74, 2.25)	0.85 (0.55, 1.33)	1.62 (0.90, 3.02)	1.89* (1.03, 3.65)	0.99 (0.63, 1.56)
	XAB vs DTI	1.03 (0.68, 1.57)	1.27 (0.66, 2.49)	1.31 (0.56, 3.22)	1.68 (0.64, 4.80)	1.25 (0.64, 2.48)	1.24 (0.66, 2.39)	1.17 (0.54, 2.62)	1.70 (0.64, 4.97)
Gastro-intestinal bleeding	DTI vs VKA	0.80 (0.35, 1.79)	0.55 (0.17, 1.70)	0.95 (0.11, 7.93)	1.60 (0.15, 34.46)	1.97 (0.90, 4.60)	2.29 (0.67, 10.40)	6.00* (1.02, 113.47)	1.52 (0.25, 11.58)
	XAB vs VKA	0.65 (0.31, 1.30)	0.72 (0.31, 1.65)	1.96 (0.65, 7.20)	0.89 (0.32, 2.55)	0.67 (0.27, 1.63)	3.19* (1.01, 14.02)	1.30 (0.48, 3.86)	1.34 (0.65, 2.93)
	XAB vs DTI	0.90 (0.40, 2.02)	1.04 (0.29, 3.74)	1.61 (0.28, 12.30)	0.59 (0.03, 6.18)	0.39 (0.11, 1.18)	0.98 (0.36, 2.69)	0.54 (0.14, 1.90)	2.16 (0.60, 10.05)
Intracranial bleeding	DTI vs VKA	0.65 (0.24, 1.71)	0.14* (0.01, 0.84)	NE	NE	0.47 (0.02, 4.91)	1.22 (0.29, 6.09)	0.76 (0.03, 19.45)	0.37 (0.02, 3.97)
	XAB vs VKA	0.47 (0.20, 1.03)	0.95 (0.31, 2.97)	1.04 (0.23, 5.33)	0.86 (0.22, 3.50)	1.01 (0.37, 2.84)	1.22 (0.37, 4.71)	2.70 (0.65, 18.19)	0.68 (0.23, 2.01)
	XAB vs DTI	0.92 (0.17, 5.00)	3.03 (0.39, 61.27)	0.84 (0.03, 21.23)	0.96 (0.04, 24.33)	NE	1.18 (0.20, 9.02)	1.53 (0.14, 33.05)	NE
Death	DTI vs VKA	2.85* (1.20, 7.83)	0.57 (0.23, 1.37)	1.36 (0.22, 10.39)	1.37 (0.45, 4.55)	6.71* (1.20, 125.51)	2.55 (0.73, 11.74)	6.24* (1.03, 119.90)	2.05 (0.66, 7.57)
	XAB vs VKA	1.99* (1.11, 3.76)	1.51 (0.75, 3.24)	1.21 (0.64, 2.33)	2.91* (1.55, 5.96)	1.70 (0.76, 4.17)	1.15 (0.47, 2.95)	1.84 (0.85, 4.41)	2.03* (1.31, 3.26)
	XAB vs DTI	0.83 (0.41, 1.65)	1.10 (0.39, 3.16)	4.57* (1.16, 30.31)	1.10 (0.40, 3.15)	1.60 (0.53, 5.31)	0.88 (0.28, 2.71)	1.41 (0.49, 4.62)	1.81 (0.81, 4.42)

Note: *Statistically significant at the 5% significance level.

Abbreviations: DTI, direct thrombin inhibitors; VKA, vitamin K antagonists; XAB, direct factor Xa inhibitors; NE, not estimable.