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Raj Patel, MD
Venous thromboembolism (VTE) is a common cardiovascular disorder associated with substantial morbidity and mortality. Anticoagulation is highly effective in reducing the risk of recurrent VTE; however, treatment may be more complicated in frail patients.
Although there is no universally accepted definition of frailty, one international consensus group has defined it as a “medical syndrome characterized by diminished strength, endurance and reduced physiological function that increases an individual’s vulnerability for developing increased dependency and/or death”. This definition of frailty includes characteristics such as older age (age >70 years) and weight loss (≥5%) due to chronic disease; and individuals with these characteristics may be physically frail.
Old age is one of the most important patient characteristics to consider because VTE becomes more common with increasing age. In addition, elderly patients may have multiple co-morbidities, which further complicate VTE treatment. For example, age >75 years and low body mass, which may be age related, are risk factors for impaired renal function, a complication that is in turn associated with an increased risk of both recurrent VTE and bleeding events.
The 2016 guidelines from the American College of Chest physicians recommend that VTE should be treated with non-vitamin K antagonist oral anticoagulants (NOACs; e.g. apixaban, dabigatran, edoxaban and rivaroxaban) over vitamin K antagonists and low molecular weight heparins in patients without active cancer. These recommendations are based on phase III trials that demonstrated the safety and efficacy of NOACs for the treatment of VTE (AMPLIFY [apixaban]; RE-COVER and RE-COVER II [dabigatran]; Hokusai-VTE [edoxaban]; and EINSTEIN DVT and EINSTEIN PE [rivaroxaban]). However, these trials included different patient populations, and, as such, the degree of their applicability to frail patient populations may not be the same.
All the above trials demonstrated non-inferiority for NOAC therapy compared with standard therapy, with similar treatment effects observed in the renally impaired, low body weight and elderly patient subgroups compared with the overall trial populations. On closer inspection of the frail patient populations included in these phase III VTE trials, it is apparent that the EINSTEIN DVT/PE trials included the greatest proportion of patients with moderate renal impairment (30% of patients with creatinine clearance [CrCl] 30–50 ml/min, compared with less than 10% in the RE-COVER, AMPLIFY and Hokusai-VTE trials). The RE-COVER and EINSTEIN DVT/PE studies included the highest proportions of elderly patients, whereas the Hokusai-VTE study included the highest proportion of patients with a low body weight (Figure).
Further analyses of the EINSTEIN DVT/PE and Hokusai-VTE trials investigated the efficacy and safety of a NOAC in specific subgroups of frail patients. A subgroup analysis of the EINSTEIN DVT/PE trials pooled all frail patients (defined as those aged >75 years, with body weight ≤50 kg or moderate renal impairment [CrCl <50 ml/min]), with consistent efficacy observed with rivaroxaban irrespective of frailty. Furthermore, a 73% reduction in the risk of major bleeding events was observed for rivaroxaban compared with enoxaparin/VKA in patients who were frail, with a significantly more favourable net clinical benefit observed in this patient subgroup (hazard ratio 0.51; 95% confidence interval 0.34–0.77). In the Hokusai-VTE study, the use of edoxaban in frail patients (defined as aged ≥75 years, body weight ≤50 kg, or CrCl 30–50 ml/min) was found to be non-inferior to warfarin, with the relative efficacy of edoxaban versus warfarin significantly higher in frail patients as compared with non-frail patients. Furthermore, occurrence of clinically relevant bleeding (defined as composite of major or clinically relevant nonmajor bleeding) was similar in frail and non-frail populations. Major bleeding was reported in 1.4% of patients in the edoxaban group and 1.6% of patents in the warfarin group (hazard ratio 0.84; 95% confidence interval 0.59–1.21).
An important consideration for the treatment of VTE in frail patients using NOACs is the requirement for dose reductions. Although frailty in itself is not an indication for reduced NOAC dosing, dose reductions are recommended for the use of edoxaban in patients with moderate-to-severe renal impairment (CrCl 15–50 ml/min), low body weight (<60 kg) or concomitant use of the P-glycoprotein inhibitors ciclosporin, dronedarone, erythromycin, or ketoconazole. Recommendations for dose reduction are also included in the prescribing information for apixaban (where ≥2 of the following apply: age ≥80 years; body weight ≤60 kg; or serum creatinine ≥1.5 mg/dL), dabigatran (where ≥1 of the following apply: CrCl 30‒50 ml/min; aged ≥75; or on concomitant verapamil, amiodarone or quinidine medication) and rivaroxaban (dose reductions from 20 mg od to 15 mg od should be considered only when the risk of bleeding outweighs the risk for recurrent DVT and PE). Consideration of the patient characteristics in clinical practice is essential to translating trial data into improved outcomes for challenging patients. Reassuring trial data for the NOACs present favourable options to the clinician in the treatment of VTE within these special populations.