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An overview of the treatment and prevention of cancer-associated thrombosis
Fast and effective anticoagulation is essential for preventing fatalities and mitigating the risk of venous thromboembolism (VTE) recurrence.1
Inadequate use of anticoagulants, in respect to dose or duration, may result in recurrent events that were otherwise avoidable.2
Relative increase in the rate of recurrent VTE and major bleeding events in patients with cancer compared with those without cancer
Several studies have demonstrated that mortality rates for recurrent VTE are higher than those for bleeding events.3
Case fatality rates from recurrent thrombosis and major bleeding in patients with cancer3
In the evolution of anticoagulant choice available for cancer-associated thrombosis (CAT), two major changes have taken place: 1) the move from vitamin K antagonists (VKAs) to low molecular weight heparins (LMWHs) as the guideline-preferred standard of care; 2) the endorsement of non-vitamin K antagonist oral anticoagulant (NOACs) as a treatment option in this setting.4-7
VKAs were the mainstay of treatment for VTE in patients with and without cancer for many years, but alternatives were warranted due to challenges unique to VKA therapy, including:
Over a decade ago, LMWHs replaced VKAs as the standard of care for the treatment of CAT based on:
However, there are challenges associated with the use of LMWHs, these include:
These factors may impact on persistence with therapy,10 as demonstrated by lower levels of persistence with LMWHs than with oral anticoagulants in various studies.11,12
More recently, the NOACs edoxaban and rivaroxaban13-16 (and in most recent updates apixaban)7 have been endorsed by several international clinical guidelines for the treatment of CAT based on head-to-head comparisons with the LMWH dalteparin in RCTs.12,17-19
To date there have been four RCTs comparing NOACs with dalteparin for the treatment of CAT: Hokusai-VTE-Cancer12 for edoxaban, SELECT-D17 for rivaroxaban, and ADAM-VTE and CARAVAGGIO for apixaban.18,19
A reduction in the risk of recurrent VTE with NOAC therapy compared with dalteparin was observed across all trials.12,17-19 This came at the cost of a significant increase in major bleeding with edoxaban and rivaroxaban in Hokusai-VTE-Cancer and SELECT-D, respectively.12,17 A high proportion of major bleeding events with NOAC therapy were gastrointestinal12,17,19 and occurred in patients with primary gastrointestinal tumours.12,17 The incidence of fatal bleeding events was similar between treatment arms across all trials.17-21
Meta-analysis of data from Hokusai-VTE-Cancer, SELECT-D, ADAM-VTE and CARRAVAGIO comparing the relative risks of VTE recurrence and major bleeding at 6 months with NOAC versus LMWH therapy for the treatment of CAT21
Results from an additional RCT, CASTA-DIVA, in which the efficacy and safety of rivaroxaban for the treatment of CAT in patients with a high risk of VTE recurrence were investigated, are awaiting publication.22,23
In addition to RCTs, there is accumulating real-world evidence on the use of NOACs for the treatment of CAT (specifically for rivaroxaban and apixaban), which provides some reassurance on the effectiveness and safety of NOACs in this clinical setting. For example:
Updated clinical guidelines on the treatment of CAT include NOACs as a recommend treatment option (specifically edoxaban and rivaroxaban in updates predating publication of the apixaban trials).7,13-16 When choosing between a NOAC and LMWH, careful consideration of tumour type, risk factors for bleeding, potential for drug–drug interactions, and patient preference are recommended.
In general, NOACs are the preferred option for patients with CAT at a low risk of bleeding, with LMWHs preferred for those at a high risk of bleeding (including patients with upper gastrointestinal cancer).7,13-16
In the absence of robust RCT data, current guideline recommendations regarding the duration of therapy for CAT are based on limited evidence.
Observations to date suggest that the risk of recurrent VTE remains higher than the risk of major bleeding beyond 6 months from the index event:
Of note, in the Hokusai-VTE-Cancer trial a similar trade-off between the benefits and risks of anticoagulation with edoxaban and dalteparin was observed in terms of outcomes between 6 and 12 months.30
Recent guidelines recommend that extended anticoagulation therapy (beyond the initial 6 months) should be considered for an ‘indefinite period’ in patients with active cancer,7,10,14 or until the cancer is cured.16 Termination of anticoagulation therapy should be determined based on individual patient evaluation of the risk of bleeding, cancer activity, life expectancy, quality of life and patient preference.5,7,10,14-16
Patient-centric decision-making is considering integral to anticoagulation management in international guidelines for the treatment of CAT.
The burdens and benefits of therapy, usually centred around convenience of medication (e.g. considering route of adminstration and dosing schedule) among other factors, may impact on patient satisfaction and compliance with therapy (i.e. adherence and persistance), which in turn can impact on clinical outcomes.31-33
Convenience of an anticoagulant has the potential to impact on clinical outcomes
Persistence with anticoagulant therapies for the treatment of CAT34
Results from patient-directed surveys designed to assess the percieved benefits and burdens of treatment options can be helpful to inform decision-making.
Patient-reported outcomes associated with anticoagulant use for the treatment of CAT have been evaluated in several studies: