Protecting Patients at Risk of VTE Recurrence
This section introduces secondary prevention of VTE, the risk factors for recurrent VTE and extended antithrombotic strategies
In this section:
Epidemiolgy
Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), is a serious cardiovascular condition that poses a significant danger to patients due to chronic complications and mortality.1,2 Anticoagulant therapy with non-vitamin K antagonist oral anticoagulants (NOACs) or vitamin K anticoagulants (VKAs) are recommended for the treatment of VTE;3 however, recurrence occurs in approximately 40% of patients within 10 years after treatment discontinuation.4
An initial episode of VTE may be classified as provoked or unprovoked (idiopathic) depending on whether it is possible to identify specific patient risk factors associated with the formation of the clot.1 Provoking risk factors can be further divided into major and minor subgroups depending on the extent to which the risk factor increases the risk of recurrence.2,5 The aetiology of the initial episode of VTE affects the risk of recurrence and is, therefore an important consideration when deciding the duration of anticoagulant treatment.2,4-6
Risk of VTE recurrence by stratified factors at 1-year in patients not treated with extended anticoagulation therapy, and examples of provoking risk factors.2
Unprovoked VTE accounts for approximately 40–50% of all venous thromboembolic events and has an estimated recurrence rate of up to 10% at 1 year and 30% at 5 years after stopping anticoagulation.2,5,7 As such, extended anticoagulant treatment beyond 3 months is recommended for patients with unprovoked VTE to protect these patients from a dangerous recurrence.3 In contrast, the risk of recurrence in patients with VTE provoked by a risk factor such as surgery is approximately 1% after stopping anticoagulation therapy.5 Therefore, extended anticoagulation is not recommended and should be limited to 3 months in these patients.3
Importantly, not all provoking factors are associated with the same risk. As a provoking factor, surgery is characterized by the major risk of recurrent VTE it presents for patients and the transient nature of this risk. However, other risk factors may present a different degree of risk or risk that persists for a different length of time.5,6 It is, therefore, necessary to further classify provoking risk factors based on whether they pose a major or minor risk of VTE for patients and whether they are transient or persistent.
The risk of recurrence in patients with VTE provoked by minor transient or persistent risk factors is uncertain, and there is limited guidance on the use of extended anticoagulation in these patients.2,3 However, recent findings suggest that recurrent VTE occurs at a similar rate in patients provoked by minor transient or persistent risk factors compared with patients with unprovoked VTE.2 In this regard, patients with VTE provoked by minor persistent and minor transient risk factors may also benefit from extended protection with anticoagulant therapy and be able to live a life without fear of a life-threatening event.2
Trial data
Extended Protection against Recurrent VTE
Protect your patients from VTE by considering their individual risk factors and providing appropriate extended anticoagulation
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Several phase III studies have investigated the benefit of extended anticoagulation with NOACs compared with placebo in patients who received prior anticoagulation therapy for DVT/PE (EINSTEIN EXT for rivaroxaban, AMPLIFY-EXT for apixaban and RE-SONATE for dabigatran) in order to reduce recurrence and prevent a potentially life-threatening event.8-10
Compared with placebo, NOACs – rivaroxaban, apixaban and dabigatran – were associated with a reduction in the rate of VTE recurrence without significantly increasing the incidence of major bleeding events.8-10
Furthermore, the effects of dabigatran and edoxaban for extended treatment have been compared with warfarin in post-hoc analyses of the RE-MEDY10 and Hokusai-VTE trials,11 respectively. In both active-comparator studies, dabigatran and edoxaban demonstrated non-inferiority compared with warfarin in preventing VTE recurrence.10,11
Recently, the EINSTEIN CHOICE study evaluated the efficacy and safety of extended treatment with rivaroxaban at a standard dose of 20 mg once daily (od) or a reduced dose of 10 mg od compared with acetylsalicylic acid (ASA) 100 mg od in patients who had completed 6–12 months of VTE anticoagulation therapy and for whom there was uncertainty about the need for extended anticoagulation.12 Rivaroxaban 20 mg od and rivaroxaban 10 mg od were associated with a significant reduction of approximately 70% in the risk of recurrent VTE compared with ASA.12 Importantly, the rate of major bleeding was <1% across all treatment groups. These data highlight possible extended treatment protection with a patient-tailored dosing strategy that will not underdose or compromise on efficacy.12
Rate of VTE recurrence (A) and major bleeding (B) with rivaroxaban compared with ASA in the EINSTEIN CHOICE study.12
In EINSTEIN CHOICE, a similar considerable risk of VTE recurrence was identified in patients who received ASA for provoked VTE (3.6%) and unprovoked VTE (5.6%).12 By looking at the risk of recurrence in patients receiving ASA, these data identify the high risk of VTE recurrence in patients with provoked and unprovoked VTE who did not receive anticoagulation therapy. In contrast, rivaroxaban 20 mg od and rivaroxaban 10 mg od were both associated with a reduction in the risk of VTE recurrence in patients with both provoked and unprovoked initial VTE, demonstrating that patients with provoked VTE can benefit from extended anticoagulation to prevent a potentially dangerous venous thromboembolic event. Furthermore, the rate of major bleeding was <1% across all treatment groups regardless of the initial index VTE.10
Based on the EINSTEIN CHOICE study data, rivaroxaban 10 mg od was approved in Europe for patients indicated for extended treatment of recurrent VTE following ≥6 months of anticoagulation therapy. Rivaroxaban 20 mg od should be considered for patients at high risk of VTE recurrence due to complicated co-morbidities, or recurrent DVT/PE during extended treatment with rivaroxaban 10 mg od.13 Rivaroxaban is currently the only NOAC with two dosing options indicated for extended treatment of recurrent VTE, allowing physicians flexibility to tailor the dose of rivaroxaban following assessment of individual patient risk at 6 months providing patients with a more certain future.13
The pooled population of EINSTEIN EXT and EINSTEIN CHOICE generates a dataset with a large number of patients with provoked VTE and, therefore, provides valuable information about the benefits of extended anticoagulation in this population.12
In a pooled analysis of the EINSTEIN EXT and EINSTEIN CHOICE studies, VTE associated with minor persistent or transient provoking risk factors were shown to have a similar risk of recurrence at 1 year compared with unprovoked VTE and further supports the potential benefit of extended anticoagulation in protecting these patients from potentially life-threatening events.2 This is important because the benefit of extended anticoagulation in patients with VTE provoked by minor transient or persistent risk factors is less certain; however, EINSTEIN EXT and EINSTEIN CHOICE have provided valuable data in these patients where there was previous ambiguity.
Reduction in recurrent VTE in patients with unprovoked VTE and VTE provoked by transient or persistent risk factors with extended rivaroxaban treatment in EINSTEIN EXT and EINSTEIN CHOICE.2
Evidence supporting data from the EINSTEIN CHOICE and EINSTEIN EXT studies in the real world is provided by a recent analysis of US healthcare claims data.14 The study, which included a total of 7469 patients, compared the incidence of VTE recurrence in patients who continued and discontinued treatment with rivaroxaban.14 Overall, extended treatment with rivaroxaban after the initial 3- or 6-month treatment period was associated with a significant reduction in the risk of VTE recurrence compared with patients who discontinued therapy. Furthermore, as shown previously in the EINSTEIN EXT and EINSTEIN CHOICE studies, major bleeding was low among study groups. These data demonstrate the potential real-world benefits of NOAC treatment in protecting patients from future venous thromboembolic events.14
Guidelines
The American College of Chest Physicians (ACCP) and the European Society of Cardiology (ESC) guidelines recommend treatment with NOACs for at least 3 months in all patients with VTE (without an associated cancer diagnosis) over the use of VKAs.3,15
Long-term anticoagulation is associated with an increased risk of bleeding, therefore, the use of anticoagulant therapy beyond
3 months is dependent on an individual patient’s risk of recurrence – i.e. whether the VTE is provoked (low risk) or unprovoked (high risk).3,7,15 According to the ACCP and ESC guidelines, anticoagulation therapy should be limited to 3 months in patients with VTE secondary to a major transient or reversible risk factor, or those patients with unprovoked VTE who are at a high risk of bleeding. Extended oral anticoagulation should also be considered for patients with a first episode of PE associated with VTE provoked by minor transient or persistent risk factors.15 Recent data from the EINSTEIN CHOICE study suggest that these patients have a similar risk of recurrence to those with unprovoked VTE and may, therefore, benefit from the protection of extended anticoagulation.12 Extended therapy is only recommended in patients with unprovoked VTE with a low-to-moderate risk of bleeding.3,15 The ACCP and ESC guidelines also recommend that the benefit–risk ratio of continuing anticoagulation treatment should be re-assessed at regular intervals.3,15
References
- Martinez C, Cohen AT, Bamber L, Rietbrock S. Epidemiology of first and recurrent venous thromboembolism: a population-based cohort study in patients without active cancer. Thromb Haemost 2014;112:255–263. Return to content
- Prins MH et al. Risk of recurrent venous thromboembolism according to baseline risk factor profiles. Blood Adv 2018;2:788–796. Prins MH et al. Risk of recurrent venous thromboembolism according to baseline risk factor profiles. Blood Adv 2018;2:788–796. Return to content
- Kearon C., Akl E.A., Ornelas J. et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 2016;149(2):315-52. Return to content
- Prandoni, P. et al., The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients. Haematologica 2007; 92(2):199-205 Return to content
- Kearon C, Ageno W, Cannegieter SC et al. Categorization of patients as having provoked or unprovoked venous thromboembolism: guidance from the SSC of ISTH. J Thromb Haemost 2016;14:1480–1483. Return to content
- Khan F, Rahman A, Carrier M et al. Long-term risk of recurrence after discontinuing anticoagulants for a first unprovoked venous thromboembolism: protocol for a systematic review and meta-analysis. BMJ Open 2017;7:016950. Return to content
- Kearon C and Akl EA. Duration of anticoagulant therapy for deep vein thrombosis and pulmonary embolism. Blood 2014;123:1794–1801. Kearon C and Akl EA. Duration of anticoagulant therapy for deep vein thrombosis and pulmonary embolism. Blood 2014;123:1794–1801. Return to content
- The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:2499–2510. Return to content
- Agnelli G, Buller HR, Cohen A et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013;368:699–708. Return to content
- Schulman S, Kearon C, Kakkar AK et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 2013;368:709–718. Return to content
- Raskob G, Ageno W, Cohen AT et al. Extended duration of anticoagulation with edoxaban in patients with venous thromboembolism: a post-hoc analysis of the Hokusai-VTE study. Lancet Haematol 2016;3:e228–236. Return to content
- Weitz JI, et al. N Engl J Med. 2017;376:1211–1222. Weitz JI, et al. N Engl J Med. 2017;376:1211–1222. Return to content
- Bayer AG. Xarelto® (rivaroxaban) Summary of Product Characteristics. 2019. Available at: https://www.ema.europa.eu/documents/product-information/xarelto-epar-product-information_en.pdf [accessed 14 November 2019]. Return to content
- Khorana AA, Berger JS, Wells PS et al. Risk for venous thromboembolism recurrence among rivaroxaban-treated patients who continued versus discontinued therapy: analyses among patients with VTE. Clin Ther 2017;39:1396–1408. Return to content
- Konstantinides SV, et al. Eur Heart J. 2020;41:543–603. Konstantinides SV, et al. Eur Heart J. 2020;41:543–603. Return to content
See Also
Peripheral Artery Disease: causes and consequences
See Also
Coronary Artery Disease: causes and consequences
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Updated date 10/10/2022
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