Natural history of bleeding and characteristics of early bleeders among warfarin initiators – a cohort study in Finland

Figures & data

Figure 1 Measurement of indications, comorbidities, medications, and exposure to interacting drugs.

Notes: ^aA hospital admission within a 1-year period before or at the warfarin initiation date, or a valid entitlement to special reimbursement at the warfarin initiation date, or within a 3-month period after the warfarin initiation date. ^bA hospital admission within a 7-year period before or at the warfarin initiation date, or a valid entitlement to special reimbursement at the warfarin initiation date, or a prescription dispensed within a 1-year period before or at the warfarin initiation date. ^cA prescription dispensed within a 1-year period before or at the warfarin initiation date. ^dA prescription overlapped with the warfarin initiation date, or a prescription dispensed at the warfarin initiation date.

Figure 2 Rate of bleedings requiring hospitalization during the entire follow-up for each month starting from warfarin initiation (n=101,588).

Abbreviation: PY, person-year.

Table 1 Rate of bleedings requiring hospitalization (% per PY) among warfarin initiators during the first 30 days after initiation and during the entire follow-up (n=101,588)

Bleeding site	First 30 days		Entire follow-up
	Number of bleeders	Rate, % per PY (95% CI)	Number of bleeders	Rate, % per PY (95% CI)
Any bleeding	539	6.5 (6.0–7.1)	5,354	2.6 (2.5–2.7)
Intracranial bleeding	83	1.0 (0.8–1.2)	920	0.4 (0.4–0.5)
Gastrointestinal bleeding	192	2.3 (2.0–2.7)	1,874	0.9 (0.9–0.9)
Other bleeding	267	3.2 (2.8–3.6)	2,721	1.3 (1.3–1.4)

Abbreviations: CI, confidence interval; PY, person-year.

Table 2 Characteristics of early bleeders (n=539) and nonearly bleeders (n=101,049) at the warfarin initiation date

Characteristics	Early bleeders	Nonearly bleeders	Unadjusted HR (95 % CI)
Demographics
Men	56.4 (304)	51.5 (52,018)	1.22 (1.03–1.45)
Age, years, median (IQR)	73 (64–81)	72 (62–80)	1.10 (1.03–1.17)a
≤64	26.0 (140)	30.8 (31,081)	1.00 (reference)
65–74	27.5 (148)	26.5 (26,799)	1.23 (0.97–1.54)
≥75	46.6 (251)	42.7 (43,169)	1.29 (1.05–1.59)
Indications
Atrial fibrillation	37.9 (204)	40.1 (40,560)	0.91 (0.76–1.08)
Venous thrombosis	17.6 (95)	11.2 (11,272)	1.70 (1.36–2.12)
Mechanical heart valve	12.1 (65)	12.0 (12,144)	1.00 (0.78–1.30)
Pulmonary embolism	12.2 (66)	7.3 (7,357)	1.78 (1.37–2.30)
Ischemic stroke or transient ischemic attack	11.5 (62)	8.9 (8,985)	1.33 (1.02–1.73)
History of bleeding
Any bleeding	31.0 (167)	7.4 (7,523)	5.53 (4.61–6.64)
1 day–<180 days before warfarin initiation	20.0 (108)	1.3 (1,345)	17.9 (14.5–22.2)
180 days–7 years before warfarin initiation	14.3 (77)	6.4 (6,490)	2.42 (1.90–3.08)
Intracranial bleeding	6.7 (36)	0.7 (663)	10.6 (7.57–14.9)
Gastrointestinal bleeding	8.9 (48)	2.9 (2,933)	3.25 (2.42–4.38)
Other bleeding	17.1 (92)	4.2 (4,207)	4.70 (3.75–5.88)
Comorbidities
Coronary artery disease	45.8 (247)	43.0 (43,445)	1.12 (0.95–1.33)
Heart failure	19.3 (104)	17.0 (17,179)	1.17 (0.95–1.45)
Ischemic stroke or transient ischemic attack	17.3 (93)	14.1 (14,260)	1.27 (1.01–1.59)
Hypertension	51.6 (278)	46.3 (46,782)	1.24 (1.04–1.46)
Peripheral arterial disease	6.3 (34)	4.6 (4,657)	1.40 (0.99–1.98)
Thrombosis in cerebral arteries or in intracranial veins	1.1 (6)	1.2 (1,190)	0.95 (0.42–2.11)
Diabetes	18.6 (100)	18.2 (18,431)	1.02 (0.82–1.27)
Renal impairment	4.6 (25)	2.5 (2,497)	1.92 (1.29–2.87)
Liver disease	2.2 (12)	1.0 (1,047)	2.17 (1.23–3.85)
Dementia	4.8 (26)	4.6 (4,691)	1.05 (0.71–1.55)
Malignancy	17.4 (94)	13.6 (13,742)	1.34 (1.08–1.68)
Alcohol abuse	5.8 (31)	3.0 (3,009)	1.98 (1.38–2.85)
Pulmonary disease	18.9 (102)	16.0 (16,121)	1.23 (0.99–1.53)
Rheumatic disease	11.7 (63)	7.1 (7,122)	1.74 (1.34–2.27)
Gastrointestinal disease	42.3 (228)	31.3 (31,612)	1.61 (1.36–1.91)
Charlson comorbidity index, median (IQR)	1 (0–2)	0 (0–1)	1.27 (1.19–1.36)
Medications
Number of drugs, median (IQR)	10 (7–14)	9 (6–12)	1.82 (1.55–2.13)b
Any cardiovascular drug	86.3 (465)	85.0 (85,908)	1.11 (0.87–1.42)
Antithrombotic drugs	40.5 (218)	26.9 (27,180)	1.84 (1.55–2.19)
Lipid-modifying drugs	44.5 (240)	43.2 (43,697)	1.05 (0.89–1.25)
Bleeding risk scorec
0	11.3 (61)	13.4 (13,497)	1.00 (reference)
1.3–1.6	40.3 (217)	38.5 (38,865)	1.24 (0.93–1.64)
2.2–2.9	32.1 (173)	35.1 (35,503)	1.08 (0.81–1.45)
≥3.5	16.3 (88)	13.0 (13,184)	1.48 (1.07–2.05)
CHADS2 score^d (among those with atrial fibrillation, n=40,764)
0	11.8 (24)	18.9 (7,662)	1.00 (reference)
1	26.0 (53)	27.6 (11,191)	1.51 (0.93–2.45)
2	30.4 (62)	26.1 (10,577)	1.87 (1.17–3.00)
≥3	31.9 (65)	27.4 (11,130)	1.87 (1.17–2.98)

Notes: Data shown as percentage (n), median (IQR), or unadjusted HR (95 % CI). HRs reported for presence versus absence of a characteristic unless otherwise stated.

a Per 10 years.

b Per one unit increase in the number of drugs measured on a logarithmic scale.

c Bleeding risk score defined based on age, sex, and malignancy, and ranges from 0 to 5.1.^{32 d}CHADS₂ score reflects the risk of stroke in persons with atrial fibrillation, defined based on heart failure, hypertension, age ≥75 years, diabetes, stroke/transient ischemic attack, and ranges from 0 to 6.³³

Abbreviations: CHADS₂, congestive heart failure, hypertension, age ≥75, diabetes and stroke; CI, confidence interval; HR, hazard ratio; IQR, interquartile range.

Table 3 Exposure to interacting drugs at the warfarin initiation date among early bleeders (n=539) and nonearly bleeders (n=101,049)

Interacting drugs	Early bleeders, % (n)	Nonearly bleeders, % (n)
Any interacting drug	67.5 (364)	57.1 (57,731)
One interacting drug	37.9 (204)	35.5 (35,902)
Two interacting drugs	21.0 (113)	15.8 (15,958)
Three or more interacting drugs	8.7 (47)	5.8 (5,871)
Any drug with dynamic mechanism of interaction	53.3 (287)	41.1 (41,493)
Paracetamol	26.2 (141)	19.4 (19,574)
Prednisolone	9.1 (49)	5.9 (5,907)
Levothyroxine	7.6 (41)	6.8 (6,863)
Clopidogrel	5.8 (31)	3.2 (3,278)
Ibuprofen	5.6 (30)	5.3 (5,310)
Citalopram	3.5 (19)	2.5 (2,546)
Etoricoxib	3.0 (16)	1.5 (1,497)
Escitalopram	2.6 (14)	1.6 (1,627)
Tramadol	2.4 (13)	2.1 (2,166)
Diclofenac	1.3 (7)	1.3 (1,348)
Naproxen	0.7 (4)	1.0 (1,023)
Dexamethasone	1.3 (7)	0.4 (356)
Methylprednisolone	1.5 (8)	0.5 (503)
Meloxicam	0.9 (5)	0.8 (837)
Venlafaxine	0.6 (3)	0.6 (610)
Any drug with kinetic mechanism of interaction	3.3 (18)	3.3 (3,299)
Amiodarone	0.9 (5)	1.0 (1,014)
Fluvastatin	0.7 (4)	1.4 (1,377)
Any drug with unclear mechanism of interaction	27.1 (146)	24.8 (25,055)
Simvastatin	24.5 (132)	22.9 (23,180)
Rosuvastatin	2.2 (12)	2.0 (2,003)
Ciprofloxacin	0.9 (5)	0.6 (586)
Levofloxacin	1.3 (7)	0.6 (607)
Doxycycline	0.6 (3)	0.7 (652)

Notes: Persons were considered as exposed if interacting drug prescription overlapped with the warfarin initiation date. Individual drugs with a prevalence of <0.5% in both early and nonearly bleeders are excluded.

Table 4 Factors associated with early bleeding among warfarin initiators (n=101,588)

Factors	Age-adjusted HR (95% CI)	Multivariable-adjusted HR (95% CI)a	Multivariable-adjusted HR (95% CI)b
Sex
Men	1.30 (1.09–1.55)	1.32 (1.10–1.57)	1.34 (1.11–1.60)
Age
Per 10 years	NA	1.13 (1.04–1.22)	1.12 (1.04–1.21)
Indications
Atrial fibrillation	0.87 (0.73–1.03)	1.00 (0.83–1.21)	0.98 (0.81–1.19)
Venous thrombosis	1.94 (1.54–2.44)	1.83 (1.44–2.34)	1.80 (1.41–2.92)
Mechanical heart valve	1.04 (0.80–1.34)	0.99 (0.76–1.30)	0.95 (0.73–1.24)
Pulmonary embolism	1.85 (1.43–2.40)	1.46 (1.11–1.91)	1.42 (1.09–1.87)
Ischemic stroke or transient ischemic attack	1.31 (1.01–1.71)	1.22 (0.93–1.61)	1.04 (0.77–1.39)
History of bleeding
During 1 day–<180 days before warfarin initiation	17.7 (14.3–21.9)	NA	NA
During 180 days–7 years before warfarin initiation	2.35 (1.84–2.99)	1.48 (1.15–1.90)	1.46 (1.14–1.88)
Comorbidities
Coronary artery disease	1.04 (0.87–1.24)	1.00 (0.82–1.21)	0.95 (0.78–1.15)
Heart failure	1.10 (0.88–1.37)	1.04 (0.83–1.31)	0.93 (0.73–1.18)
Hypertension	1.17 (0.98–1.39)	1.13 (0.94–1.35)	1.07 (0.89–1.29)
Peripheral arterial disease	1.34 (0.94–1.90)	1.11 (0.78–1.59)	1.04 (0.73–1.49)
Thrombosis in cerebral arteries or in intracranial veins	0.97 (0.43–2.16)	0.75 (0.33–1.68)	0.72 (0.32–1.62)
Diabetes	0.99 (0.80–1.24)	0.88 (0.70–1.10)	0.79 (0.63–1.01)
Renal impairment	1.87 (1.25–2.79)	1.22 (0.81–1.85)	1.09 (0.71–1.67)
Liver disease	2.27 (1.28–4.02)	1.40 (0.77–2.56)	1.29 (0.71–2.36)
Dementia	0.92 (0.62–1.38)	0.89 (0.60–1.34)	0.82 (0.55–1.23)
Malignancy	1.28 (1.02–1.60)	1.06 (0.85–1.34)	0.94 (0.74–1.20)
Alcohol abuse	2.18 (1.51–3.15)	1.59 (1.08–2.35)	1.55 (1.05–2.28)
Pulmonary disease	1.21 (0.97–1.50)	1.05 (0.84–1.31)	0.95 (0.75–1.19)
Rheumatic disease	1.70 (1.31–2.21)	1.40 (1.07–1.83)	1.30 (0.99–1.71)
Gastrointestinal disease	1.58 (1.33–1.87)	1.10 (0.92–1.33)	1.02 (0.84–1.24)
Charlson comorbidity index
0	1.00	NA	1.00
1–3	1.74 (1.46–2.07)	NA	1.32 (1.06–1.65)
4–9	3.14 (2.08–4.74)	NA	1.66 (0.99–2.76)
Number of drugs
1–4	1.00	NA	1.00
5–9	1.82 (1.30–2.55)	NA	1.56 (1.10–2.20)
10–14	2.16 (1.53–3.06)	NA	1.57 (1.06–2.31)
≥15	3.14 (2.20–4.50)	NA	1.88 (1.20–2.93)
Exposure to interacting drugs
Drugs with dynamic mechanism of interaction	1.63 (1.38–1.93)	1.43 (1.20–1.71)	1.32 (1.10–1.59)
Drugs with kinetic mechanism of interaction	1.01 (0.63–1.61)	0.94 (0.59–1.52)	0.90 (0.56–1.44)
Drugs with unclear mechanism of interaction	1.10 (0.91–1.34)	1.10 (0.90–1.33)	1.05 (1.05–2.28)

Notes: History of bleeding during 1 day<180 days before warfarin initiation treated as a stratifying variable.

a Mutually adjusted for all variables except for Charlson comorbidity index and number of drugs;

b mutually adjusted for all variables.

Abbreviations: CI, confidence interval; HR, hazard ratio; NA, not applicable.

Figure S1 Rate of bleedings requiring hospitalization for each month of the first warfarin episode when the episode was assumed to continue until the gap between consecutive dispensations exceeded 111 days (A) or 180 days (B).

Table S1 Identification of bleeding events, indications, comorbidities, and medications

Bleeding events, indications, comorbidities and medications	ICD-10 codes/procedure codes	Reimbursement codes	ATC codes
Bleedingsa
Intracranial	I60*, I61*, I62*
Gastrointestinal	K920, K921, K922, I850, K221, K250, K252, K254, K256, K260, K262, K264, K266, K270, K272, K274, K276, K280, K282, K284, K286, K290, K625
Other	N02*, K661, N938, N939, N950, R041, R042, R048, R049, R31, R58, D683, H356, H431, H450, M250
Indications
Atrial fibrillation	I48*, FPD*, TFP46, TFP20	207 (based on I48)
Venous thrombosis	I80*, I81*, I82* (not I801)
Mechanical heart valve	Z952*, FJ*, FK*, FM*, FG*
Pulmonary embolism	I26*
Ischemic stroke/TIA	I63*, G45*
Comorbidities
Coronary artery disease	I20*–I25*/FNA*, FNB*, FNC*, FND*, FNE*, FN1AT, FN1BT, FN1YT, TFN40, TFN50	206	C01
Heart failure	I50*	201
Ischemic stroke/TIA	I63*–I66*, G45*
Hypertension	I10*–I15*	205
Peripheral arterial disease	I70*, I74*/PFH*, PDQ*, PEQ*, PFQ*, PF1AT, PF1BT, PE1AT, PE1BT	211
Thrombosis in cerebral arteries or in intracranial veins	I65*, I66*, I676
Diabetes	E10*–E14*	103	A10
Renal impairment	N04*, N17*–N19*, N258, Z491, Z492	123, 137, 138, 190, 320
Liver disease	K70*–K77*, B15*–B19*, B942
Dementia	F00*, F01*, F03*, G30*	307	N06D
Malignancy	C00*–C99*, D00*–D09*	115–117, 128, 130	L01*, L02B* (not L01BA01)
Alcohol abuse	E244, F10*, G312, G4051, G621, G721, I426, K292, K70*, K852, K860, R780, T510, Y911, Y912, Y913, Y919, Z502, Z714		N07BB
Pulmonary disease	J44*–J46*	203	R03
Rheumatic disease	M05*–M09*, M13*, M31*–M36*, M45*, M46*	202, 281, 313
Gastrointestinal disease	K21*, K223, K251, K253, K255, K257, K259, K261, K263, K265, K267, K269, K271, K273, K275, K277, K279, K281, K283, K285, K287, K289, K633		A02B
Medications
Number of drugs			Number of different ATC-codes
Any cardiovascular drug			C01–C04, C07–C09
Antithrombotic drugs			B01 (not B01AA03)
Lipid-modifying drugs			C10

Notes:

a Data adapted from Gomes T, Mamdani MM, Holbrook AM, et al. Rates of hemorrhage during warfarin therapy for atrial fibrillation. CMAJ. 2013;185(2):E121–E127.¹ Codes I9820, I983, K6380, and K3180 were excluded as they do not appear in the Finnish ICD-10 codes.

* Includes all the diagnoses from the given ICD-10 code.

Abbreviations: ATC, Anatomical Therapeutic Chemical; ICD, International Classification of Diseases; TIA, transient ischemic attack.

HallinenTSoiniEJAsseburgCWarfarin treatment among Finnish patients with atrial fibrillation: retrospective registry study based on primary healthcare dataBMJ Open201442e004071

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GomesTMamdaniMMHolbrookAMRates of hemorrhage during warfarin therapy for atrial fibrillationCMAJ20131852E121E12723184840

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