Long‐term risk of recurrent venous thromboembolism among patients receiving extended oral anticoagulant therapy for first unprovoked venous thromboembolism: A systematic review and meta‐analysis

Khan, Faizan; Tritschler, Tobias; Kimpton, Miriam; Wells, Philip S.; Kearon, Clive; Weitz, Jeffrey I.; Büller, Harry R.; Raskob, Gary E.; Ageno, Walter; Couturaud, Francis; Prandoni, Paolo; Palareti, Gualtiero; Legnani, Cristina; Kyrle, Paul A.; Eichinger, Sabine; Eischer, Lisbeth; Becattini, Cecilia; Agnelli, Giancarlo; Vedovati, Maria Cristina; Geersing, Geert‐Jan; Takada, Toshihiko; Cosmi, Benilde; Aujesky, Drahomir; Marconi, Letizia; Palla, Antonio; Siragusa, Sergio; Bradbury, Charlotte; Parpia, Sameer; Mallick, Ranjeeta; Lensing, Anthonie W. A.; Gebel, Martin; Grosso, Michael; Shi, Minggao; Thavorn, Kednapa; Hutton, Brian; Gal, Grégoire Le; Rodger, Marc; Fergusson, Dean

doi:10.1111/jth.15491

Cited by 25 publications

(12 citation statements)

References 65 publications

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“…On-treatment recurrence occurred with a similar rate to that reported in a recent metanalysis (IR 1.7 vs. 1.5 per 100 person-years, respectively) [ 16 , 17 ], aligning with registered randomized trials (Einstein DVT, PE, and Ext). Extended-phase treatment with rivaroxaban was associated with a statistically significant reduction in recurrent events.…”

Section: Discussionsupporting

confidence: 83%

Safety and Efficacy of Rivaroxaban for Extended-Phase Anticoagulation of Patients with Unprovoked or Recurrent Venous Thromboembolism: Real-Life Data from the MAC Project

Bortoluzzi

Bernardi²,

Camporese³

et al. 2022

Life

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Venous thromboembolism (VTE) is a major cause of death in the world. After the acute-phase treatment, the optimal duration of anticoagulation is still debatable. The latest guidelines suggest maintaining long-term anticoagulation in patients with cancer-associated thrombosis (CAT) or with unprovoked VTE and a low bleeding risk. Methods: The MAC Project is an ongoing prospective-cohort, multi-center, observational study in Italy. The project aims to collect real-life clinical information in unselected patients given oral anticoagulants for VTE over a 5-year follow-up period. There were no exclusion criteria, except for life expectancy <6 months and refusal to sign the informed consent form or to attend the planned follow-up visit. All patients were followed-up prospectively with clinical controls scheduled at 3, 6, and 12 months after the index event, and then annually for up to 5 years. The primary efficacy and safety outcomes were symptomatic recurrent VTE and major bleeding. Results: We analyzed 450 consecutive patients treated with rivaroxaban and referred them to the MAC Project database for unprovoked or recurrent VTE. Of these, 267 (55%) were unprovoked VTE, and 377 (87%) were symptomatic. We followed up with the patients for a mean of 22 months (Q1 10.7; Q3 37.4 months). Recurrent VTE occurred in 12 patients on rivaroxaban treatment (IR 1.7 per 100 person-years). Males had more recurrence than women. During the follow-up period, we recorded 13 (2.9%) major bleeding, 12 (2.7%) clinically relevant non-major bleeding, 8 minor bleeding, and no fatal bleeding events. Overall, bleeding events occurred in 33 (7.3%) patients, most occurring within the first 2 years of treatment. In addition, we observed a statistically significant higher incidence of bleeding in patients with a baseline HAS-BLED score of 3 to 4 compared with those with a score of 0 to 2, with most events occurring during the first 3 months of treatment (RR 5.9). Discussion: Rivaroxaban appears to be safe and effective for the long-term treatment of patients with recurrent or unprovoked VTE. Our results match previously published data, and we are confident that the continuation of the follow-up for up to 5 years will confirm these outcomes.

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Section: Discussionsupporting

confidence: 83%

Safety and Efficacy of Rivaroxaban for Extended-Phase Anticoagulation of Patients with Unprovoked or Recurrent Venous Thromboembolism: Real-Life Data from the MAC Project

Bortoluzzi

Bernardi²,

Camporese³

et al. 2022

Life

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“…17 The risk of recurrent thromboembolic events on anticoagulation in our two groups was similar to the low risk reported in a meta-analysis of 26 studies that included patients with first unprovoked VTE and with extended oral anticoagulant treatment, namely, 1.41 per 100 patient-years. 18 Furthermore, the risk of recurrent events after discontinuation of anticoagulation was of the same magnitude as the 10.3 events per 100 patient-years (during the first year) in another meta-analysis of 18 studies with patients treated after first unprovoked VTE. 19 The guidelines of American Society of Hematology on VTE suggest indefinite duration of anticoagulation after unprovoked VTE, as well as after VTE "provoked by a chronic persistent risk factor," 20 which include both IBD and elevated FVIII.…”

Section: Discussionmentioning

confidence: 88%

High Factor VIII Levels and Recurrent Thromboembolism in Patients with and without Inflammatory Bowel Disease: A Retrospective Comparative Study

Eagle

Schulman

2022

TH Open

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Background The natural course of elevated factor VIII (FVIII) in patients with venous thromboembolism (VTE) and with or without inflammatory bowel disease (IBD) is not well described. Furthermore, the data on effectiveness and safety of extended anticoagulation in these patients are limited. Methods We performed a retrospective chart review of all patients with VTE, who had an elevated FVIII level (>1.5 IU/mL) during a period of 16 years. FVIII levels, duration of anticoagulation, recurrent thromboembolic events and bleeding requiring hospitalization were captured and compared between patients with and without IBD. Results Fourteen patients with IBD and 66 without IBD were followed for 8.0 years (standard deviation [SD] ±3.5) and 5.6 years (SD ±5.1), respectively. Among the 41 patients with repeat levels, FVIII remained elevated in most patients. None of the IBD patients had thromboembolic events or major bleeding during a mean of 5.6 years (SD ±5.1) of anticoagulation. Three of 5 IBD patients that stopped anticoagulation had thromboembolic events at a median of 9 months after stopping – observed event rate 12 per 100 patient-years. For the 66 non-IBD patients the event rates of thromboembolism on and off anticoagulation were 1.6 and 7.2 per 100 patient-years, respectively, and of major bleeding on anticoagulation 0.8 per 100 patient-years. Conclusion Elevated FVIII in patients with VTE is often a persistent risk factor. The cohort with VTE and elevated FVIII that we analyzed appeared to have a favorable benefit/risk ratio of extended anticoagulation.

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“…4 Using the overall incidence for major bleeding of 0.35 events (95% CI: 0.20-0.54) in patients with first unprovoked or weakly provoked VTE not receiving extended anticoagulation, determined in this meta-analysis, the incremental risk (per patient-year) of major bleeding during extended anticoagulant therapy would be estimated at 1.39% (95% CI: 0.99-1.85; number needed to harm: 72) with VKAs and 0.77% (95% CI: 0.37-1.27; number needed to harm: 130) with DOACs. When combined with incidences for recurrent VTE of 1.55 events per 100 person-years (95% CI: 1.01-2.20) with VKAs, 5 1.08 events per 100 person-years (95% CI: 0.77-1.44) with DOACs, 5 and 10.3 events per 100 person-years (95% CI: 8.6-12.1) without extended anticoagulation, 6 estimates from this meta-analysis could be used to balance the absolute VTE reduction benefits of extended anticoagulant therapy in shared decision making regarding long-term management of patients with a first unprovoked or weakly provoked VTE.…”

Section: Discussionmentioning

confidence: 99%

Long-Term Risk of Major Bleeding after Discontinuing Anticoagulation for Unprovoked Venous Thromboembolism: A Systematic Review and Meta-analysis

et al. 2021

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Background: The long-term risk of major bleeding after discontinuing anticoagulant therapy for a first unprovoked venous thromboembolism (VTE) is uncertain. Objectives: To determine the incidence of major bleeding up to 5 years after discontinuing anticoagulation for a first unprovoked VTE. Methods: We searched MEDLINE, EMBASE, and Cochrane CENTRAL (from inception to January 2021) to identify relevant randomized controlled trials (RCTs) and prospective cohort studies reporting major bleeding after discontinuing anticoagulation in patients with a first unprovoked VTE who had completed ≥3 months of initial treatment. Unpublished data on major bleeding events and person-years were obtained from authors of included studies to calculate study-level incidence rates. Random-effects meta-analysis was used to pool results across studies. Results: Of 1123 records identified by the search, 20 studies (17 RCTs) and 8740 patients were included in the analysis. During 13 011 person-years of follow-up after discontinuing anticoagulation, the pooled incidence of major bleeding (n=41) and fatal bleeding (n=7) per 100 person-years was 0.35 (95% confidence interval [CI], 0.20-0.54) and 0.09 (95% CI, 0.05-0.15). The 5-year cumulative incidence of major bleeding was of 1.0% (95% CI, 0.4%-2.4%). The case-fatality rate of major bleeding after discontinuing anticoagulation was 19.9% (95% CI, 10.6%-31.1%). Conclusions: Patients with a first unprovoked VTE have a non-trivial risk of major bleeding once anticoagulants are discontinued. Estimates from this study can help clinicians counsel patients about the incremental risk of major bleeding with extended anticoagulation to guide decision making about treatment duration for unprovoked VTE.

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Long‐term risk of recurrent venous thromboembolism among patients receiving extended oral anticoagulant therapy for first unprovoked venous thromboembolism: A systematic review and meta‐analysis

Cited by 25 publications

References 65 publications

Safety and Efficacy of Rivaroxaban for Extended-Phase Anticoagulation of Patients with Unprovoked or Recurrent Venous Thromboembolism: Real-Life Data from the MAC Project

Safety and Efficacy of Rivaroxaban for Extended-Phase Anticoagulation of Patients with Unprovoked or Recurrent Venous Thromboembolism: Real-Life Data from the MAC Project

High Factor VIII Levels and Recurrent Thromboembolism in Patients with and without Inflammatory Bowel Disease: A Retrospective Comparative Study

Long-Term Risk of Major Bleeding after Discontinuing Anticoagulation for Unprovoked Venous Thromboembolism: A Systematic Review and Meta-analysis

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