Risk and Determinants of Provoked Recurrent Venous Thromboembolism: A Prospective Cohort Study

Scientific Research Question: Venous thromboembolism (VTE) is a chronic disease, as it tends to recur. Patients are treated with anticoagulants to prevent recurrence. Once anticoagulation is stopped, the recurrence risk is high, particularly among patients with unprovoked VTE. During temporary risk situations including surgery, trauma or immobilization, short-term thromboprophylaxis is required. Data on the risk of recurrent VTE among patients exposed to a transient risk factor are scarce. We evaluated the occurrence of provoked VTE in patients with unprovoked VTE.

Methodology: Patients with first unprovoked VTE were followed after anticoagulation withdrawal. Patients with VTE secondary to surgery, trauma, immobilization, pregnancy, cancer, and those with major thrombophilia or requirement for indefinite anticoagulation were excluded. The study endpoint was symptomatic recurrent VTE. Provoked recurrence was defined according to SSC/ISTH guidance criteria, i.e., VTE within 3 months after a triggering factor or during female hormone use.

Findings: During a mean follow-up of 7 (± 5.7) years, 312 of 1188 patients with unprovoked VTE (46% men, mean age 49 years) had recurrence, which was provoked in 42 and unprovoked in 270 patients. The mean duration of anticoagulation in patients with provoked and unprovoked recurrence was 7.9 (± 2.9) and 7.3 (± 2.6) months, respectively. Provoked and unprovoked VTE occurred 58.9 (± 58.6) and 54.4 (± 51.0) months after the incident VTE, respectively. Twenty-four recurrences were secondary to surgical interventions, 9 after trauma, 4 during hospitalization, 1 during immobilization, 1 was associated with cancer diagnosis, and 3 occurred in women using hormonal contraceptives ([Table 1]). The risk of provoked recurrence did not differ between men and women (HR 1.2, 95% CI 0.6–2.2). The mean time interval between the provoking factor and recurrent VTE was shorter after trauma than after surgery (13 versus 24 days). Four patients with provoked recurrent VTE received anticoagulants at the time of VTE.

Table 1 Characteristics of patients with provoked recurrent VTE

Provoking factor	n	Sex (m/f)	Age (years) Mean ± SD	Anticoagulation (yes/no)	Interval (days) Mean, median
Surgery	24	9/15	50 ± 12	3/21	24, 17
Trauma	9	8/1	54 ± 16	1/8	13, 7
Hormonal contraceptives	3	0/3	34 ± 12	0/3	Not applicable
Other	6	5/1	51 ± 6	0/6	Not applicable

Conclusions: Patients with first unprovoked VTE are at risk of recurrence secondary to a provoking risk factor. The risk of recurrent provoked VTE is not different between men and women. Most importantly, the majority of patients did not receive anticoagulant thromboprophylaxis at the time of recurrence. In patients with a first unprovoked VTE, thromboprophylaxis during high-risk situations needs to be optimized.

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