Predictors of Major Bleeding in Patients with First Venous Thromboembolism Treated with Vitamin K Antagonists in Clinical Practice in the United Kingdom

Introduction: The management of venous thromboembolism (VTE) and the prevention of recurrent VTE consists of anticoagulation primarily with Vitamin K Antagonists (VKA). The main adverse effect of anticoagulation is bleeding. This study aimed to investigate the predictors of major bleeding in patients with first VTE treated with VKA.

Methods: A cohort study was undertaken using the United Kingdom's Clinical Practice Research Datalink with additional data from hospitalizations and causes of death. Patients with incident first VTE between 2008-2013 treated with VKA, i.e. starting VKA treatment within 60 days after first VTE, were included in the cohort. Major bleeding was defined in accordance with the International Society of Thrombosis and Haemostasis recommendations comprising fatal bleeds, bleeds at a critical site, and bleeding events in association with anemia or blood transfusions. Patients were followed until the end of the first VKA treatment episode. Hazard ratios of potential predictors for major bleeding during the first VKA treatment episode were estimated from Cox regression models which included recognized predictors for major bleeding before the diagnosis of VTE, and a list of potential predictors during VKA treatment.

Results: Among 10,118 VKA-treated VTE patients the incidence rate of major bleeding was 2.6 (95% confidence interval (CI), 2.2-3.1) per 100 person-years (145 major bleeds during 5,548 person-years of VKA use). Among baseline characteristics, predictors for major bleeding (Table) included increasing age, and history of a major bleeding and of a non-major clinically relevant bleeding. Furthermore the following events after the first VTE (80 of 145 cases) were also associated with an increased risk of major bleeding: non-major clinically relevant bleeding, HR 2.88 (95% CI, 1.85 – 4.46), active cancer 4.13 (2.48-6.89), trauma 14.05 (7.96-24.82), surgery 3.27 (1.29-8.28), and medical illness 3.03 (1.87-4.90). Additional predictors for major bleeding were new onset or history of moderate/severe liver disease, 7.44 (2.93-18.92), or renal disease, 1.73 (1.19-2.52).

Conclusions: Assessment for and awareness of these predictors prior to and during VKA treatment is needed to prevent major bleeding events. Caution is warranted in patients with these independent risk factors.

Table: Association between factors at first VTE and during VKA treatment and major bleeding

	Incident major bleeding after first VTE n (%)	Crude hazard ratio (95%-CI)	Adjusted hazard ratio (95%-CI)
Total	145 (100)
Age1
<60	26 (17.93)	1	1
60-69	31 (21.38)	2.03 (1.21 - 3.42)	1.83 (1.07 - 3.14)
70-79	39 (26.90)	2.56 (1.56 - 4.21)	2.19 (1.27 - 3.76)
80+	49 (33.79)	4.52 (2.81 - 7.28)	3.28 (1.90 - 5.68)
Gender
Female	72 (49.66)	0.98 (0.71 - 1.35)	0.89 (0.63 - 1.25)
Type of first VTE
DVT	82 (56.55)	1	1
PE	63 (43.45)	0.91 (0.65 - 1.27)	0.78 (0.56 - 1.09)
History of bleeding prior to first VTE
Non-major clinically relevant	56 (38.62)	2.09 (1.48 - 2.95)	1.75 (1.23 - 2.49)
Major bleeding	13 (8.97)	4.47 (2.48 - 8.05)	3.17 (1.73 - 5.80)
Prevalence of prior events at the day of the first VTE (duration of exposure)
Active cancer (90 days)	14 (9.66)	2.07 (1.20 - 3.60)	0.75 (0.37 - 1.50)
Non-active cancer	14 (9.66)	1.40 (0.81 - 2.43)	0.75 (0.42 - 1.37)
Trauma (90 days)	11 (7.59)	1.01 (0.54 - 1.86)	1.09 (0.58 - 2.04)
Inpatient surgery (90 days)	13 (8.97)	1.00 (0.57 - 1.77)	0.90 (0.48 - 1.68)
Medical illness (90 days)	11 (7.59)	1.14 (0.62 - 2.11)	0.71 (0.35 - 1.42)
Liver disease
Mild	4 (2.76)	1.62 (0.60 - 4.38)	1.15 (0.42 - 3.17)
Moderate/severe	5 (3.45)	6.80 (2.78 - 16.64)	7.44 (2.93 - 18.92)
Renal disease	50 (34.48)	2.60 (1.84 - 3.66)	1.73 (1.19 - 2.52)
Bleeding after first VTE
Non-major clinically relevant	27 (18.62)	3.91 (2.55 - 5.99)	2.88 (1.85 - 4.46)
Events after first VTE (duration of exposure)
Active cancer (90 days)	32 (22.07)	4.76 (3.19 - 7.10)	4.13 (2.48 - 6.89)
Trauma (14 days)	14 (9.66)	16.63 (9.49 - 29.12)	14.05 (7.96 - 24.82)
Inpatient surgery (14 days)	5 (3.45)	5.79 (2.33 - 14.37)	3.27 (1.29 - 8.28)
Medical illness (90 days)	24 (16.55)	3.24 (2.06 - 5.10)	3.03 (1.87 - 4.90)