Editorial theme | Meta-analysis of the effectiveness of anticoagulant therapy in patients with splanchnic vein thrombosis

Following on from our previous editorial theme article on the pathogenesis and management of splanchnic vein thrombosis (SVT) published on the MPN Hub here, we summarize an individual patient meta-analysis performed by Candeloro et al.¹ evaluating the effectiveness of anticoagulant therapy in relation to recurrent venous thromboembolism and all-cause mortality, as well as safety relating to major bleeding in patients with SVT. Datasets from several prospective cohorts and random clinical trials obtained from Medline, Embase, and clinicaltrials.gov were merged and assessed.

Results

A total of 1,635 patients from three eligible studies were included in the final analysis. The complete set of patient characteristics is shown in Table 1. The mean age of the patients was 56 years, with 41.9% of patients diagnosed with SVT. The median follow-up time was recorded at 442 days and median treatment duration was 316 days. Patients treated with anticoagulant therapy had a lower frequency of several factors, including:

• solid cancers;
• liver cirrhosis; and
• symptomatic presentation of SVT.

Table 1. Patient characteristics*

DOAC, direct oral anticoagulant; LMWH, low molecular weight heparin; SD, standard deviation; UFH, unfractionated heparin; VKA, vitamin K antagonist. *Adapted from Candeloro, et al.1
Variable, % (unless otherwise stated)	All patients (N = 1,635)
Mean age ± SD, years	56.17 ± 16.16
Male	60.3
Symptomatic patients	58.1
Involved vein
Portal vein	34.4
Mesenteric vein	13.3
Budd-Chiari syndrome	12.3
Splenic vein	6.5
Multiple veins	33.5
Risk factors
Unprovoked	28.3
Solid cancer	32.0
Liver cirrhosis	17.6
Myeloproliferative neoplasm	7.2
Recent surgery	9.5
Thrombophilia
Tested negative	11.4
Tested positive	17.2
Anticoagulant therapy
None	19.8
LMWH	31.9
VKA	25.4
DOAC	1.7
UFH	0.5
Fondaparinux	1.0
Multiple agents	19.6

Venous thromboembolism

At the time of follow-up, a total of 104 patients experienced a venous thromboembolism (VTE) at an incidence rate of 5.3 per 100 person-years. The cumulative incidence rates and types of VTE are shown in Figure 1 and Figure 2, respectively. The incidence rate of VTE was found to be lower during anticoagulant therapy compared with post-treatment discontinuation. The highest VTE incidence rate was recorded in patients who did not receive any anticoagulant therapy.

VTE, venous thromboembolism.
*Data from Candeloro, et al.¹

 

SVT, splanchnic vein thrombosis; VTE, venous thromboembolism.
*Data from Candeloro, et al.¹

The number of patients who experienced recurrent VTE while receiving treatment is shown in Table 2.

Table 2. Number of recurrent VTE events associated with each treatment type*

DOAC, direct oral anticoagulants; LMWH, low molecular weight heparin; VKA, vitamin K antagonist. *Data from Candeloro, et al.1
Type of treatment	Number of patients
LMWH	21
VKA	16
Unfractionated heparin	1
DOAC	0

Major bleeding

Major bleeding occurred in 86 patients, and the median time to an event was 197 days, at an incidence rate of 4.4 per 100 person-years (Figure 3).

*Data from Candeloro, et al.¹

A total of five fatal bleeding events were recorded (Table 3); four of these occurred in patients who were not treated with anticoagulant therapy and one occurred in a patient who withdrew from unfractionated heparin treatment.

Table 3. Causes of fatal bleeding events*

*Data from Candeloro, et al.1
Cause of bleeding	Number of patients
Gastroesophageal varices	2
Nonvariceal gastrointestinal bleeding	1
Unreported	2

There were 23 bleeding events among patients treated with LMWH, 11 events among patients treated with VKA, and only one event among patients receiving DOAC.

All-cause mortality

A total of 256 patients died during the follow-up period, at an incidence rate of 13 deaths per 100 person-years. The causes of death are shown in Figure 4.

CV, cardiovascular.
*Adapted from Candeloro, et al.¹

The incidence rate of deaths was lower for patients treated with anticoagulant therapy compared with patients who discontinued treatment, and highest in those who received no treatment (Figure 5).

CI, confidence interval.
*Data from Candeloro, et al.¹

 Univariable and multivariable analysis

Analysis found that patients on anticoagulant therapy had a lower risk of:

• recurrent VTE;
• major bleeding; and
• all-cause mortality.
  
  

All factors were adjusted for sex, age, liver cirrhosis, solid cancer, MPN, and transient or persistent nonmalignant risk factors. However, the risk of recurrent VTE and all-cause mortality increased in patients with solid cancer, while the risk of major bleeding increased in patients with liver cirrhosis.

Conclusion

The crucial strengths of the study were the large population size, as well as time-varying and multivariable analyses, which allowed for a more precise estimate of the therapeutic effects. In contrast, there were several limitations that should be noted. The first is that some risk factors, such as prior VTE and bleeding, were poorly represented among the patient population and therefore the effects were not shown in the reported outcomes. Other variables including stage of thrombosis and prevalence of thrombophilia were also missing and were omitted from the final analysis. Furthermore, specific anticoagulant therapy regimens and decisions were not randomized or directed by protocol. Finally, the diversity in treatments offered to patients did not allow full analysis of effectiveness and safety in relation to specific treatments or doses. However, crucially, the collective results from the analysis highlight patients with SVT have a significant risk of recurrent VTE and major bleeding events. This risk appears to be lowered upon the administration of anticoagulant therapy.