Frail and Elderly Patients with VTE
This section looks at the epidemiology of venous thromboembolism (VTE) in frail, elderly patients and discusses the clinical evidence available for the optimal treatment of these patients with non-vitamin K antagonist oral anticoagulants (NOACs)
In this section:
Epidemiology
The incidence of VTE increases with advancing age andapproximately six out of ten patients with VTE are aged ≥70 years.1-3 Conventional risk factors for thrombosis, such as co-morbidities, immobility or malignancy are well understood. Studies have found these risk factors to be more prevalent in the elderly.2 However, risk factors such as frailty are less well understood, and these are important to consider when identifying those at high risk of VTE.2,4
The majority of VTE events are in patients aged ≥70 years2
There is no one definition of a frail patient, but it is often associated with characteristics such as older age, lower body weight and renal impairment.4 According to a large, real-world, international registry study RIETE, 42% of patients with acute VTE were frail (defined as those with creatinine clearance (CrCl) levels ≤50 mL/min, aged ≥75 years or body weight ≤50 kg).5
As the prevalence of VTE is likely to increase with a growing, ageing population, understanding appropriate treatment options for people who are frail will become ever more important in protecting the future health of these patients.6
Almost half of patients with acute VTE are considered to be frail in the real world5
Clinical evidence
Anticoagulants are the mainstay of VTE treatment, with clinical data showing that, overall, the NOACs have similar efficacy and improved safety compared with vitamin K antagonists (VKAs) in both young and elderly patients.7,8
Subanalyses of the NOAC phase III data have been published for rivaroxaban and edoxaban and suggest that these treatments offer at least as much benefit to frail patients as they do to those who are not frail.9,10
In the EINSTEIN DVT and PE phase III pooled analysis, rivaroxaban demonstrated similar efficacy based on the primary endpoint of VTE recurrence and similar safety in terms of the principal safety endpoint of major or clinically relevant non-major bleeding, compared with enoxaparin plus VKA. Rates of major bleeding were significantly lower with rivaroxaban.9 In a prespecified subgroup analysis of frail patients (defined as one or more of the following: aged >75 years old, CrCl levels <50 mL/min or low body weight ≤50 kg), comparable efficacy was achieved respective of frailty. Rates of major bleeding were also significantly reduced, with rivaroxaban associated with a 73% relative risk reduction (3.2% absolute risk reduction) versus enoxaparin and VKA in frail patients.9
Combining the risk of recurrent VTE and the risk of bleeding into a composite endpoint, rivaroxaban was found to have a significantly improved net clinical benefit compared with enoxaparin and VKA in frail patients. This suggests that rivaroxaban is suitable in subgroups of patients considered to be frail.9
Rates of recurrence and major bleeding in a pooled subgroup-analysis of frail patients with VTE in EINSTEIN DVT and EINSTEIN PE9
In the Hokusai-VTE study, edoxaban was found to have similar efficacy compared with warfarin and was associated with significantly lower rates of major or clinically relevant non-major bleeding. No significant differences were seen in major bleeding events versus warfarin in the overall population. These effects were consistent in patients with or without frailty.10
There is no published clinical study available for frail patients with VTE treated with the NOACs apixaban or dabigatran.
Rivaroxaban is the only NOAC to have a specific real-world outcomes study in frail patients with VTE. A retrospective claims database analysis using US Truven MarketScan® was conducted in 6869 VTE patients classified as frail by the John Hopkins Claims-based Frailty Indicator and treated with rivaroxaban or warfarin. The analysis demonstrated that the composite of recurrent VTE and major bleeding was significantly reduced with rivaroxaban compared with warfarin and suggests that rivaroxaban might be preferable in patients with frailty.11 Real-world data such as these provide reassurance that a particular treatment has been studied in similar conditions to those seen in routine clinical practice.
There is compelling evidence showing that NOACs provide clinicians with an effective treatment option in some of their most vulnerable patients with VTE.
Treatment guidelines
There is no specific guidance available for frail patients; however, they are covered by the same guidelines as patients without frailty. The 2016 guidelines from the American College of Chest Physicians recommend long-term anticoagulant therapy with the NOACs apixaban, dabigatran, edoxaban and rivaroxaban over VKAs and low molecular weight heparins (LMWH) in patients with VTE and without active cancer. These recommendations are based on phase III trials that demonstrated the safety and efficacy of NOACs for the treatment of VTE.12
The 2019 European Society of Cardiology mention the improved safety of NOACs compared with VKAs and the ongoing evaluation of extended anticoagulation based on the lower bleeding rates associated with NOACs.13
An important consideration for the use of NOACs is the potential for dose reductions that may apply to patients who are frail. Apixaban, dabigatran, edoxaban and rivaroxaban all have label guidance for reduction in some patients with VTE and renal impairment.14-17 Furthermore, edoxaban routinely requires a dose reduction in patients with body weight ≤60 kg, and a reduced dose may be required for patients receiving dabigatran if aged ≥75 years.15,16 More information on dose reductions in patients with VTE and renal impairment can be found here.
Always ensure patients get the right dose at the right time for the right reason.
References
- Spencer FA Gore JM, Lessard D et al. Venous thromboembolism in the elderly. A community-based perspective. Thromb Haemost 2008;100:780–788. Return to content
- Engbers MJ, van Hylckama Vlieg A, Rosendaal FR. Venous thrombosis in the elderly: incidence, risk factors and risk groups. J Thromb Haemost 2010;8:2105–2112. Return to content
- Bauersachs RM. Managing venous thromboembolism with novel oral anticoagulants in the elderly and other high-risk patient groups. Eur J Intern Med 2014;25:600-606. Return to content
- Brenner B, Arya R, Beyer-Westendorf J et al. Evaluation of unmet clinical needs in prophylaxis and treatment of venous thromboembolism in at-risk patient groups: pregnancy, elderly and obese patients. Thromb J 2019;17:24. Return to content
- Moustafa F, Giorgi Pierfranceschi M, Di Micco P et al. Clinical outcomes during anticoagulant therapy in fragile patients with venous thromboembolism. Res Pract Thromb Haemost 2017;1:172–179. Return to content
- Yayan J and Bals R. Relative risk of deep vein thrombosis in very elderly patients compared with elderly patients. Clin Appl Thromb Hemost 2016;22:77–84. Return to content
- Klok FA, Kooiman J, Huisman MV et al. Predicting anticoagulant-related bleeding in patients with venous thromboembolism: a clinically oriented review. Eur Respir J 2015;45:201–210. Return to content
- Geldhof V, Vandenbriele C, Verhamme P, Vanassche T. Venous thromboembolism in the elderly: efficacy and safety of non-VKA oral anticoagulants. Thromb J 2014;12:21. Return to content
- Prins MH, et al. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thrombosis J. 2013;11(1):21. Return to content
- Hokusai-VTE Investigators, Büller H.R., Décousus H. et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369(15):1406–15. Return to content
- Coleman CI, Turpie AGG, Bunz TJ, Beyer-Westendorf J. Effectiveness and Safety of Rivaroxaban Versus Warfarin in Frail Patients with Venous Thromboembolism. Am J Med 2018;131:933–938. Coleman CI, Turpie AGG, Bunz TJ, Beyer-Westendorf J. Effectiveness and Safety of Rivaroxaban Versus Warfarin in Frail Patients with Venous Thromboembolism. Am J Med 2018;131:933–938. 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
- Konstantinides SV, Meyer G, Becattini C et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J 2020;41:543–603. 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 February 2020]. 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 February 2020]. Return to content
- Daiichi Sankyo Europe GmbH. Lixiana® (edoxaban) Summary of Product Characteristics. 2019. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002629/WC500189045.pdf [accessed February 2020]. Daiichi Sankyo Europe GmbH. Lixiana® (edoxaban) Summary of Product Characteristics. 2019. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002629/WC500189045.pdf [accessed February 2020]. Return to content
- Boehringer Ingelheim International GmbH. Pradaxa® (dabigatran etexilate) Summary of Product Characteristics. 2019. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000829/WC500041059.pdf [accessed February 2020]. Boehringer Ingelheim International GmbH. Pradaxa® (dabigatran etexilate) Summary of Product Characteristics. 2019. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000829/WC500041059.pdf [accessed February 2020]. Return to content
- Bristol-Myers Squibb, Pfizer. Eliquis® (apixaban) Summary of Product Characteristics. 2019. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002148/WC500107728.pdf [accessed [accessed February 2020]. Bristol-Myers Squibb, Pfizer. Eliquis® (apixaban) Summary of Product Characteristics. 2019. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002148/WC500107728.pdf [accessed [accessed February 2020]. 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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