REGULAR ARTICLE Anticoagulant therapy for splanchnic vein thrombosis: an individual patient data meta-analysis Matteo Candeloro,1,2 Emanuele Valeriani,3 Manuel Monreal,4-6 Walter Ageno,7 Nicoletta Riva,8 Raquel Lopez-Reyes,9 Maria Luisa Peris,10 Jan Beyer Westendorf,11 Sam Schulman,2,12 Vladimir Rosa,13 Juan Jose Lopez-N un~ez,14-16 17,18 17,18 Juan-Carlos Garcia-Pagan, Marta Magaz, Marco Senzolo, Andrea De Gottardi, and Marcello Di Nisio21 19 20 1 Department of Innovative Technologies in Medicine and Dentistry, “G. D’Annunzio” University, Chieti-Pescara, Italy; 2Department of Medicine, Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, ON, Canada; 3Diagnostic and Therapeutic Medicine Department, University Campus Bio-Medico of Rome, Rome, Italy; 4 Department of Internal Medicine, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; 5Faculty of Health Sciences, Universidad Catolica San Antonio de Murcia (UCAM), Murcia, Spain; 6Universidad Aut onoma de Barcelona, Barcelona, Spain; 7University of Insubria and Ospedale di Circolo Fondazione Macchi, Varese, Italy; 8Department of Pathology, Faculty of Medicine and Surgery, University of Malta, Msida, Malta; 9Department of Pneumonology, Hospital Universitari i Polit ecnic La Fe, Valencia, Spain; 10 Thrombosis Unit, Internal Medicine Service, Consorcio Hospitalario Provincial de Castell on, Universidad CEU Cardenal Herrera, Castell on, Spain; 11Department of Medicine, Division of Hematology, Dresden University Hospital, Dresden, Germany; 12Department of Obstetrics and Gynecology, I.M. Sechenov First Moscow State Medical University, Moscow, Russia; 13Thrombosis Unit, Internal Medicine Service, Hospital Clinico Universitario Virgen de la Arrixaca, Murcia, Spain; 14Department of Internal Medicine, Hospital Germans Trias i Pujol, Badalona, Spain; 15Department of Medicine, Universitat Aut onoma de Barcelona, Barcelona, Spain; 16Institut de Recerca Germans Trias i Pujol, Badalona, Spain; 17Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, Institut D’Investigacions Biomediques August Pi i Sunyer (IDIBAPS) and Centro de Investigaci on Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain; 18Health Care Provider of the European Reference Network on Rare Liver Disorders; 19Gastroenterology, Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, University Hospital of Padua, Padua, Italy; 20Gastroenterology and Hepatology, Ente Ospedaliero Cantonale, Universita della Svizzera Italiana, Lugano, Switzerland; and 21Department of Medicine and Ageing Sciences, “G. D’Annunzio” University, Chieti-Pescara, Italy Robust evidence on the optimal management of splanchnic vein thrombosis (SVT) is Key Points lacking. We conducted an individual-patient meta-analysis to evaluate the effectiveness  Robust evidence on and safety of anticoagulation for SVT. Medline, Embase, and clincaltrials.gov were the optimal searched up to June 2021 for prospective cohorts or randomized clinical trials including management of patients with SVT. Data from individual datasets were merged, and any discrepancy with splanchnic vein published data was resolved by contacting study authors. Three studies of a total of 1635 thrombosis is lacking. patients were included. Eighty-five percent of patients received anticoagulation for a  In this meta-analysis median duration of 316 days (range, 1-730 days). Overall, incidence rates for recurrent of individual patient venous thromboembolism (VTE), major bleeding, and mortality were 5.3 per 100 data, anticoagulant patient-years (p-y; 95% confidence interval [CI], 5.1-5.5), 4.4 per 100 p-y (95% CI, therapy reduced the 4.2-4.6), and 13.0 per 100 p-y (95% CI, 12.4-13.6), respectively. The incidence risks of thrombosis, rates of all outcomes were lower during anticoagulation and higher after treatment major bleeding, and mortality. discontinuation or when anticoagulation was not administered. In multivariable analysis, anticoagulant treatment appeared to be associated with a lower risk of recurrent VTE (hazard ratio [HR], 0.42; 95% CI, 0.27-0.64), major bleeding (HR, 0.47; 95% CI, 0.30-0.74), and mortality (HR, 0.23; 95% CI, 0.17-0.31). Results were consistent in patients with cirrhosis, solid cancers, myeloproliferative neoplasms, unprovoked SVT, and SVT associated with transient or persistent nonmalignant risk factors. In patients with SVT, the risk of recurrent VTE and major bleeding is substantial. Anticoagulant treatment is associated with reduced risk of both outcomes. Submitted 28 April 2022; accepted 10 May 2022; prepublished online on Blood Advances The full-text version of this article contains a data supplement. First Edition 25 May 2022; final version published online 4 August 2022. DOI 10.1182/ © 2022 by The American Society of Hematology. Licensed under Creative bloodadvances.2022007961. Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC- Data will be made available upon reasonable request: matteo.candeloro@unich.it. ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved. 4516 9 AUGUST 2022 • VOLUME 6, NUMBER 15 Introduction registries, data also were requested for patients included after the publication of the main study identified by the search. Splanchnic vein thrombosis (SVT) includes portal, mesenteric, or The following individual patient data were collected: demographic splenic vein thrombosis and Budd-Chiari syndrome.1 SVT is fre- factors (eg, age and sex), clinical presentation (ie, symptomatic or quently associated with liver cirrhosis, solid cancers, and myelopro- incidentally detected SVT), site and extension of thrombosis, risk liferative neoplasms and less often with oral contraceptive agents, factors for SVT (eg, solid and hematological cancer, liver cirrhosis, pregnancy, abdominal infections, pancreatitis, or surgery.2-4 myeloproliferative neoplasm, pregnancy, oral contraceptive agents, hormonal therapy, recent surgery, pancreatitis, abdominal infections, Despite several observational studies and a few relatively small ran- and inflammatory bowel disease), laboratory parameters, type and domized controlled trials (RCTs) evaluating the efficacy and safety duration of anticoagulant therapy, use of antiplatelet agents or of anticoagulant treatment for SVT, robust evidence on SVT man- thrombolysis, and outcomes of interest. Data from individual data- agement is lacking. Recommendations from international societies bases were verified and merged into a single electronic database. or expert panels remain highly variable, and, in routine clinical prac- Any discrepancy with published data were resolved by contacting tice, physicians have to decide empirically about the type, dose, and the corresponding or first author. duration of anticoagulant therapy.1,5-11 A recent study-level meta- analysis including 7969 patients with SVT suggested a potential Patients were excluded from the analysis if they were aged ,18 benefit of anticoagulant treatment in terms of improved vein reca- years, had follow-up ,7 days, or were missing relevant information nalization and reduced thrombosis progression, recurrent venous th- (ie, start or end date of anticoagulation, type of anticoagulant agent, romboembolism (VTE), major bleeding, and all-cause mortality end of follow-up, and date of study outcome). compared with no anticoagulation.5 Conclusions were limited by the Study outcomes inherent heterogeneity of included populations, the potential for immortal bias, and residual confounding. The effectiveness outcomes were recurrent VTE (ie, recurrent SVT, deep vein thrombosis [DVT] of the lower or upper extremities, and To fill these knowledge gaps, we undertook a meta-analysis of indi- pulmonary embolism) and all-cause mortality. The safety outcome vidual patient data to evaluate the effectiveness and safety of an- was major bleeding as defined by the International Society on ticoagulant therapy in patients with SVT and obtain a better Thrombosis and Haemostasis.14 All outcomes were evaluated to understanding of the incidence of clinically relevant outcomes in the longest follow-up available and to a maximum of 2 years. Recur- subgroups at higher risk of thrombotic and bleeding complications. rent VTE or major bleeding were considered fatal events if the patient died within 24 hours of the event. Methods Statistical analysis This meta-analysis of individual patient data was performed accord- ing to the Preferred Reporting Items for Systematic Reviews and Differences between groups were tested with the Mann-Whitney U Meta-analysis guideline.12 test or x2 test as appropriate. In the primary analysis, follow-up dura- tion was calculated from SVT diagnosis to the occurrence of one of Database search and study selection the outcomes, last follow-up available, or end of the 2-year follow- Medline and Embase were searched from inception up to June up, whichever came first. Cumulative incidence curves of recurrent 2021 for prospective studies and RCTs including patients with SVT VTE and major bleeding were built considering death as competing (supplemental Table 1). Furthermore, we searched clincaltrials.gov risk. Subgroup analysis was performed for patients with liver cirrho- for ongoing or completed studies and screened the reference lists sis, solid cancers, myeloproliferative neoplasms, unprovoked SVT, of relevant studies to retrieve additional records. No language and SVT secondary to transient or persistent nonmalignant risk fac- restrictions were applied. tors. The latter included any of the following: pregnancy, contracep- tive agent use, hormonal therapy, recent surgery, inflammatory Two authors independently reviewed titles and abstracts identified bowel disease, pancreatitis, or abdominal infections.15 SVT was from the search to select studies that met the following inclusion cri- considered unprovoked in patients without apparent risk factors. teria: (1) prospective study or RCT including $50 patients with Incidence rates for the main outcomes were expressed as the num- SVT, (2) reporting of the outcomes of interest (ie, recurrent VTE, ber of events per 100 patient-years (p-y) with relative 95% confi- major bleeding, and all-cause mortality), and (3) anticoagulant treat- dence intervals (CIs) and calculated for the overall cohort during ment with low molecular weight heparin (LMWH), unfractionated anticoagulation and after treatment withdrawal and in patients who heparin, fondaparinux, vitamin K antagonists (VKAs), direct oral anti- received no anticoagulant treatment. Case fatality rates for major coagulants (DOACs), or no anticoagulant therapy. We excluded ret- bleeding and recurrent VTE were calculated as the number of rospective cohorts, case series, and case reports. patients with fatal bleeding or VTE divided by the total number of The risk of bias was assessed by 2 independent authors using the patients who experienced that outcome. Risk Of Bias In Non-randomized Studies of Interventions-I tool.13 Hazard ratios (HRs) were estimated with Cox’s proportional models Any disagreement was resolved through discussion or involving a considering anticoagulant treatment as a time-varying variable.16 third author. The association between each outcome of interest and anticoagu- lant treatment, age, sex, liver cirrhosis, solid cancer, myeloprolifera- Individual patient data extraction tive neoplasm, and transient or persistent nonmalignant risk factors Authors of included studies were asked to provide individual patient was first evaluated in univariable analysis. All variables with a signifi- data from their published study, and, in case of ongoing cohorts or cant association were subsequently entered in multivariable models. 9 AUGUST 2022 • VOLUME 6, NUMBER 15 ANTICOAGULANTS FOR SPLANCHNIC VEIN THROMBOSIS 4517 Proportional hazard assumptions were checked through visual Table 1. Baseline patient characteristics inspection of residual graphs and Schoenfeld test. In sensitivity anal- Variable Overall (N 5 1635) ysis using univariable Cox’s models, we evaluated the association Mean age 6 SD 56.17 6 16.16 between study outcomes and anticoagulant treatment as time- Male sex 986 (60.3) varying covariate, age, and sex within the subgroups of patients indi- cated above. A 2-sided P value ,0.05 was considered to indicate Symptomatic patients 950 (58.1) statistical significance. All analyses were performed using R soft- Involved vein ware (version 4.0.4 and Rstudio version 1.1.423, 2009-2018; R Portal vein 562 (34.4) Foundation for Statistical Computing, Vienna, Austria).17 Mesenteric vein 217 (13.3) Budd-Chiari syndrome 201 (12.3) Results Splenic vein 107 (6.5) A total of 5037 records were identified from the search, along with Multiple veins 548 (33.5) 3 from clinicaltrials.gov (supplemental Figure 1). After removing 708 Risk factors duplicates and excluding 4320 records by title and abstract screen- Unprovoked 462 (28.3) ing, 12 studies (in 2525 patients) met the inclusion criteria.3,4,18-27 Solid cancer 523 (32.0) After direct contact with the authors, individual patient data from 5 studies (1871 patients) were made available, merged in a pooled Liver cirrhosis 287 (17.6) database, checked for completeness, and evaluated for inclusion in Myeloproliferative neoplasm 118 (7.2) the analysis. Recent surgery 155 (9.5) Hormonal therapy 57 (3.5) Characteristics of included studies Inflammatory bowel disease 24 (1.5) None of the included studies was an RCT. Four studies were inter- Pregnancy or puerperium 15 (0.9) national prospective multicenter registries,3,4,26,27 and 1 study included patients from a single center.21 Sample sizes ranged Pancreatitis/abdominal infection 155 (7.0) between 57 and 975 patients. After data cleaning, 236 patients, Leukemia, lymphoma, myeloma 20 (1.2) including the whole populations of 2 eligible studies,21,26 were Thrombophilia excluded because of patient age ,18 years (n 5 10), follow-up Tested negative 186 (11.4) duration ,7 days (n 5 33), or missing relevant information Tested positive 281 (17.2) (n 5 193). A total of 1635 patients from 3 studies (64.8% of the potentially eligible patients) were included in the final analysis.3,4,27 Laboratory test results Risk of bias across domains was moderate in 2 studies and serious Hemoglobin #10 g/dL* 284 (17.4) in 1 (supplemental Table 2). Platelets* #100 3 103/mm3 255 (15.6) Characteristics of the included population #50 3 10 /mm 3 3 60 (3.7) Baseline patient characteristics are reported in Table 1. The mean Anticoagulant therapy patient age was 56 6 16 years, and 60.3% of patients were male. None 325 (19.8) SVT was incidentally detected in 41.9% of patients. The most com- mon risk factors for SVT were solid cancers (32.0%) and liver cir- LMWH alone 521 (31.9) rhosis (17.6%); SVT was unprovoked in 31.7% of patients. VKAs alone 416 (25.4) Laboratory tests for thrombophilia were available in 28.6% of DOACs alone 27 (1.7) patients and showed the presence of $1 thrombophilia in 17.2% UFH alone 8 (0.5) (supplemental Table 3). The median follow-up duration was 442 Fondaparinux alone 17 (1.0) days (range, 7-730 days). Multiple agents 321 (19.6) Eighty-five percent of patients received anticoagulant therapy, Values in parentheses are percentages. including parenteral treatment alone (mostly LMWH) in 33.4%, SD, standard deviation; UFH, unfractionated heparin. VKAs alone in 25.4%, DOACs alone in 1.7%, and $1 anticoagu- *Measurements in 104 patients were missing. lant agent in 19.6% (Table 1; supplemental Table 4). Overall, 75 patients (5.7%) received a DOAC as single drug (n 5 27) or after switching to or from another anticoagulant drug (n 5 48). DOACs (supplemental Table 5). Concomitant antiplatelet therapy was used prescribed were rivaroxaban in 56 patients (4.2%), apixaban in 13 in 49 of 1310 patients (3.0%) and was the only treatment for SVT (1.0%), and edoxaban and dabigatran in 3 (0.2%) each. Information in 8 patients (0.5%). Thrombolysis was used in 27 of 1635 patients on the dose of DOACs was not available. (1.7%). The overall median duration of anticoagulant treatment was 316 Recurrent VTE days (range, 1-730 days), with 263 patients (16.1%) treated for ,3 months, 338 (20.7%) for 3 to 6 months, and 706 (43.2%) for .6 A total of 104 patients had recurrent VTE during follow-up, for an months. Solid cancer, liver cirrhosis, male sex, and sympto- incidence rate of 5.3 per 100 p-y (95% CI, 5.1-5.5; Table 2). matic presentation of SVT were less common in patients who Cumulative incidences of recurrent VTE in the overall population received anticoagulation therapy compared with untreated patients and patient subgroups are shown in Figures 1 and 2, respectively. 4518 CANDELORO et al 9 AUGUST 2022 • VOLUME 6, NUMBER 15 Table 2. Incidence rates for recurrent VTE, major bleeding, and all-cause mortality Event Overall cohort Never treated Treated, on treatment Treated, off treatment Total p-y 1975 376 1132 467* Recurrent VTE Events per 100 p-y 104 35 38 31 Relative 95% CI 5.3 (5.1-5.5) 9.3 (8.4-10.3) 3.4 (3.2-3.6) 6.6 (6.0-7.2) Major bleeding Events per 100 p-y 86 24 35 27 Relative 95% CI 4.4 (4.2-4.6) 6.4 (5.8-7.1) 3.1 (2.9-3.3) 5.8 (5.3-6.4) All-cause mortality Events per 100 p-y 136 82 65 109 Relative 95% CI 13.0 (12.4-13.6) 21.8 (19.7-24.1) 5.7 (5.4-6.0) 23.3 (21.3-25.3) Values are expressed as number of events per 100 p-y with relative 95% CIs. *p-y includes time before treatment initiation and time after treatment withdrawal. Recurrent VTE included recurrent SVT in 40 patients (38.5%), VKAs (2.0 per 100 p-y; 95% CI, 1.9-2.1), 1 patient receiving unfrac- usual-site VTE (DVT of the lower extremities or pulmonary embolism tionated heparin (25.0 per 100 p-y; 95% CI, 9.4-66.6), and none of with or without DVT) in 46 patients (44.2%), and thrombosis in those receiving DOACs. other sites in 18 patients (17.3%). Fifty percent of recurrent SVTs occurred in patients with cirrhosis, and 54.3% of usual-site re- Major bleeding current VTE and 66.7% of other-site DVT developed in patients with solid cancers. None of the recurrent VTE events were fatal. Major bleeding occurred in 86 patients, for an incidence rate of 4.4 Median time from index SVT to recurrent VTE was 253 days (range, per 100 p-y (95% CI, 4.2-4.6; Table 2). The site of major bleeding 9-719). was gastrointestinal in 69 patients (4.2%), intracranial in 7 (0.4%), and other in 10 (0.6%). The cumulative incidences of major bleed- The incidence rate of recurrent VTE was lower during anticoagulant ing in the overall population and patient subgroups are shown in treatment (3.4 per 100 p-y; 95% CI, 3.2-3.6) than after treatment Figures 1 and 2, respectively. In total, there were 5 fatal major discontinuation (6.6 per 100 p-y; 95% CI, 6.0-7.2) or in patients bleeding events (overall case fatality rate, 5.8%), of which 4 who received no anticoagulation (9.3 per 100 p-y; 95% CI, 8.4- occurred in patients who received no anticoagulation (case fatality 10.3; Table 2). The incidence rates of recurrent VTE in patient sub- rate in untreated patients, 16.6%) and 1 in a patient after unfractio- groups are reported in supplemental Table 6. nated heparin withdrawal. Sites of fatal bleeding were gastro- On-treatment recurrent VTE occurred in 21 patients treated with esophageal varices in 2 cases, nonvariceal gastrointestinal site in LMWH (7.9 per 100 p-y; 95% CI, 7.0-8.9), 16 patients receiving 1 case (postcolectomy hemorrhage), and not reported for the other 2 events. Median time to major bleeding was 197 days (range, 8-685). Overall cohort The incidence rate of major bleeding was lower during anticoagulant 0.20 Major bleeding treatment (3.1 per 100 p-y; 95% CI, 2.9-3.3) than after treatment Recurrent VTE discontinuation (5.8 per 100 p-y; 95% CI, 5.3-6.4) or compared with patients who did not undergo anticoagulation (6.4 per 100 p-y; 0.15 95% CI, 5.8-7.1; Table 2). The incidence rates of major bleeding in Cumulative incidence patient subgroups are reported in supplemental Table 7. On-treatment major bleeding occurred in 23 patients treated with 0.10 LMWH (8.6 per 100 p-y; 95% CI, 7.6-9.7), 11 patients receiving VKAs (1.3 per 100 p-y; 95% CI, 1.2-1.4), and 1 patient treated with DOACs (3.0 per 100 p-y; 95% CI, 2.1-4.2). 0.05 All-cause mortality A total of 256 patients died during follow-up, for an incidence rate 0.00 of 13 per 100 p-y (95% CI, 12.4-13.6; Table 2). Causes of death 0 200 400 600 were cancer progression (62.9%), sepsis (8.6%), liver failure Days (7.4%), cardiovascular disease (3.5%), multi-organ failure (1.6%), respiratory failure (1.6%), bowel obstruction (1.2%), kidney failure Figure 1. Cumulative incidence for recurrent VTE and major bleeding with (0.8%), suicide (0.4%), and fatal bleeding (2.0%). In the remaining death as competing risk in the overall study population. 10.0% of cases, the cause of death was unknown. 9 AUGUST 2022 • VOLUME 6, NUMBER 15 ANTICOAGULANTS FOR SPLANCHNIC VEIN THROMBOSIS 4519 Cirrhosis Solid cancer Myeloproliferative neoplasm 0.20 0.20 0.20 0.15 0.15 0.15 Cumulative incidence Cumulative incidence Cumulative incidence 0.10 0.10 0.10 0.05 0.05 0.05 0.00 0.00 0.00 0 200 400 600 0 200 400 600 0 200 400 600 Days Days Days Transient or non-malignant Unprovoked risk factors 0.20 0.20 0.15 0.15 Cumulative incidence Cumulative incidence 0.10 0.10 0.05 0.05 0.00 0.00 0 200 400 600 0 200 400 600 Days Days Major bleeding Recurrent VTE Figure 2. Cumulative incidence of recurrent VTE and major bleeding with death as competing risk in several patient subgroups. The incidence rate of all-cause mortality was lower during anticoag- Discussion ulant treatment (5.7 per 100 p-y; 95% CI, 5.4-6.0) than after treat- The present work provides prospective data on the management ment discontinuation (23.3 per 100 p-y; 95% CI, 21.3-25.3) or and clinical outcomes of SVT in a large study population with long- compared with patients who received no anticoagulation (21.8 per term follow-up. The risk of recurrent VTE, major bleeding, and all- 100 p-y; 95% CI, 19.7-24.1; Table 2). The incidence rates of all- cause mortality in patient subgroups are reported in supplemental cause mortality was lower during anticoagulant treatment after Table 6. adjustment for potentially relevant patient characteristics and across high-risk patient subgroups. The incidence rates of all outcomes Time-varying analysis increased after anticoagulant treatment discontinuation and were Table 3 shows the results of univariable and multivariable time-varying high in patients who did not receive any anticoagulation. analyses. Anticoagulant therapy appeared to be associated with lower In agreement with previous observations, the present data confirm risks of recurrent VTE (HR, 0.42; 95% CI, 0.27-0.64), major bleeding that a nonnegligible proportion of patients with SVT remained (HR, 0.47; 95% CI, 0.30-0.74), and all-cause mortality (HR, 0.23; untreated (15%), and an additional 16% received treatment for ,3 95% CI, 0.17-0.31) after adjusting for age, sex, liver cirrhosis, solid months. Although the risk of recurrent VTE in patients with SVT is cancer, myeloproliferative neoplasms, and transient or persistent non- relevant, concerns for bleeding complications remain major drivers malignant risk factors. The risks of recurrent VTE (HR, 2.02; 95% CI, of the decision whether to use anticoagulation.6 Several studies 1.35-3.04) and all-cause mortality (HR, 8.68; 95% CI, 6.24-12.07) suggested that anticoagulant therapy may actually lower bleeding appeared to be increased in patients with solid cancer, whereas the risk in these patients, presumably by promoting vein recanalization risk of major bleeding was higher in patients with liver cirrhosis (HR, with decreased intravascular pressure in the splanchnic circulation 1.92; 95% CI, 1.21-3.05). and gastrointestinal varices.28-31 A recent study-level meta-analysis In sensitivity analysis, the effects of anticoagulant treatment on recur- seemed to support this concept, showing increased rates of vein rent VTE, major bleeding, and all-cause mortality appeared to be recanalization, lower rates of thrombosis progression, and reduced consistent in all patient subgroups (supplemental Table 6). risk of bleeding complications in anticoagulated patients with SVT.5 4520 CANDELORO et al 9 AUGUST 2022 • VOLUME 6, NUMBER 15 Table 3. Time-varying analysis for recurrent VTE, major bleeding, and all-cause mortality in the overall study population Recurrent VTE Major bleeding All-cause mortality Variable Univariable Multivariable Univariable Multivariable Univariable Multivariable Anticoagulant treatment 0.35 (0.23-0.52) 0.42 (0.27-0.64) 0.38 (0.24-0.58) 0.47 (0.30-0.74) 0.17 (0.13-0.23) 0.23 (0.17-0.31) Age, 1-y increase 1.03 (1.01-1.04) 1.02 (1.00-1.03) 1.03 (1.02-1.05) 1.03 (1.01-1.04) 1.04 (1.03-1.05) 1.02 (1.01-1.03) Sex, male 1.78 (1.16-2.74) 1.54 (1.00-2.37) 1.16 (0.75-1.79) – 1.15 (0.89-1.49) – Cirrhosis 1.62 (1.04-2.52) 1.10 (0.70-1.73) 2.87 (1.85-4.45) 1.92 (1.21-3.05) 1.57 (1.18-2.09) 0.95 (0.71-1.27) Solid cancer 2.78 (1.88-4.12) 2.02 (1.35-3.04) 1.70 (1.09-2.67) 1.22 (0.77-1.92) 12.92 (9.46-17.65) 8.68 (6.24-12.07) Myeloproliferative neoplasm 0.31 (0.10-1.00) – 0.86 (0.38-1.98) – 0.19 (0.07-0.51) 0.96 (0.34-2.69) Transient or persistent nonmalignant 0.70 (0.42-1.16) – 0.45 (0.23-0.87) 0.63 (0.35-1.25) 0.34 (0.22-0.52) 0.50 (0.32-0.77) risk factor* Values are expressed as HR (95% CI). Only covariates that were associated on univariable analysis were tested in multivariable analysis. *Risk factors included any of the following: pregnancy, contraceptive, hormonal therapy, recent surgery, and inflammatory bowel disease. Our results strengthen and extend these earlier observations, con- observations and suggest that DOACs may represent an alternative firming the lower risks of recurrent VTE and major bleeding with to standard anticoagulation with LMWH and VKAs for SVT. anticoagulant treatment after adjustment for relevant confounders. The major strength of our study is the inclusion of a large population We also explored the effectiveness and safety of anticoagulant ther- that was prospectively followed for as long as 2 years. The use of apy in high-risk subgroups such as those with liver cirrhosis, solid time-varying and multivariable analyses allowed a more precise esti- cancers, or myeloproliferative neoplasms.24,28,32,33 Our findings mation of the effects of anticoagulant treatment while accounting for seem reassuring and suggest a lower risk of recurrent VTE, major potential confounders. bleeding, and all-cause mortality during anticoagulant therapy com- pared with off-treatment periods. These results support the recom- The present work has also some limitations that warrant discussion. mendations of recent guidelines to promptly start anticoagulation for First, some of the risk factors (eg, prior VTE, prior bleeding, or acute SVT irrespective of underlying risk factors in the absence of severe thrombocytopenia) were poorly represented, precluding the major contraindications.3,6,32 Sixty-one percent of recurrent VTEs evaluation of their impact on study outcomes. Second, variables occurred outside the splanchnic venous circulation, most often in such as stage of thrombosis (ie, acute or chronic), presence of patients with persistent risk factors. The latter have a chronic pro- thrombophilia, JAK-2 mutation, and use of concomitant antiplatelet coagulant state and, as for usual-site VTE, may warrant long-term agents were missing in a significant proportion of patients and could anticoagulation. Interestingly, even though none of the recurrent not be accounted for in the analysis. Third, the use of a specific anti- VTEs resulted in death, the case-fatality rate of major bleeding was coagulant regimen as well as the decision to withhold anticoagula- approximately 6%, largely accounted for by the number of fatal tion were not randomized or protocol-mandated and could be bleeding episodes (80% of total) occurring among untreated influenced by patients’ characteristics and prognoses. In this regard, patients. In this latter group, the case-fatality rate was as high as the reduction of all-cause mortality observed in anticoagulated 17%, which seems to support the physician decision not to provide patients may be the result of selection bias, as physicians could be anticoagulant therapy. Further studies are needed to identify patient more reluctant to administer anticoagulation to sicker patients with subgroups with a very high risk of life-threatening bleeding in whom poor prognoses. For these reasons, the comparison between differ- an individualized approach would be advisable. It is worth noting ent types of anticoagulant agents remains exploratory. Most of the that we could not evaluate the safety of anticoagulation in patients included patients (81.3%) had a persistent risk factor or unprovoked SVT, potentially limiting the generalizability of our findings to patients with prior major bleeding, hematological malignancy, or severe with SVT associated with transient risk factors. However, subgroup thrombocytopenia as a result of the low number of patients with analysis suggested consistent results in this latter group of patients. these risk factors. Finally, the heterogeneity of anticoagulant treatment did not allow a There is scant information about the optimal type, dose, and dura- more granular analysis of effectiveness and safety according to spe- tion of anticoagulant therapy for SVT, and most evidence stems cific agents or doses. from observational studies in which the decision to use or withhold In conclusion, patients with SVT have a substantial risk of recurrent anticoagulation was at the discretion of the treating physician. Fur- VTE and major bleeding that appears to be reduced during antico- thermore, most of these studies included patients with liver cirrhosis agulant treatment. These benefits are consistent in high-risk who received LMWH or VKAs, limiting generalizability to other subgroups. patient groups or types of anticoagulant agents. Data on the effec- tiveness and safety of DOACs for the treatment of SVT are limited. In a recently completed prospective study of 100 noncirrhotic Acknowledgments patients with acute SVT who were treated with rivaroxaban for 3 The authors thank all investigators of the included studies for months, the incidence of both recurrent VTE and major bleeding their contribution on data collection in the original reports. A full was 2.1%.34 Despite only 75 patients having received a DOAC in list of investigators that participated to the included studies is the present study, our findings seem consistent with earlier provided in the supplemental Appendix. 9 AUGUST 2022 • VOLUME 6, NUMBER 15 ANTICOAGULANTS FOR SPLANCHNIC VEIN THROMBOSIS 4521 Authorship institutional research support from Bayer AG, Boehringer Ingel- heim, Bristol Myers Squibb/Pfizer, Daiichi Sankyo, DOASENSE, Contribution: M.D.N. conceived and designed the study; M.C. and Norgine, Sanofi, and Alexion. S.S. has received research funding M.D.N. performed data acquisition; M.C. performed statistical analy- from Boehringer Ingelheim and Octapharma and honoraria from sis; all authors interpreted the data; and M.C., E.V., and M.D.N. Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi- drafted the manuscript, which was critically revised for important Sankyo, Pfizer, and Sanofi. J.J.L.-N. has received honoraria for intellectual content and approved as a final manuscript by all authors. lectures from Bayer, Pfizer, and Rovi; educational events from Conflict-of-interest disclosure: M.D.N. received honoraria for Leo Pharma and Pfizer; support for attending meetings and travel participation at advisory boards from Bayer, Daiichi Sankyo, from Bayer, BMS, Pfizer, Leo Pharma, Rovi, and Sanofi; and advi- Pfizer, Leo Pharma, Sanofi, and Viatris, outside the submitted sory board participation from Pfizer. The remaining authors work. W.A. has received a research grant from Bayer to support declare no competing financial interests. a clinical study in patients with SVT, received honoraria for partic- ORCID profiles: M.C., 0000-0001-9673-4073; E.V., 0000- ipation at advisory boards from Bayer, BMS/Pfizer, Sanofi, Leo 0001-9729-3214; M.M., 0000-0002-0494-0767; W.A., 0000- Pharma, and Portola, and reports grants and personal fees from 0002-1922-8879; N.R., 0000-0002-8922-8823; V.R.-S., 0000- Bayer, and personal fees from BMS/Pfizer, Daiichi Sankyo, 0001-5039-6638; J.J.L.-N., 0000-0002-1226-2353; M.M., 0000- Sanofi, Aspen, Janssen, and Portola, Werfen, outside the submit- 0002-9787-1739; A.D.G., 0000-0002-4401-2340. ted work. M.B.M. is a recipient of a Rıo Hortega grant from Insti- tuto de Salud Carlos III, Spain. J.-C.G.-P. is a consulting for Correspondence: Matteo Candeloro, Department of Innova- Cook Medical, Shionogi, W.L. Gore y Asociados, Vifor Pharma, tive Technologies in Medicine and Dentistry, “G. 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