Optimizing the best pharmaceutical agent while minimizing adverse effects is paramount in patients with cancer-associated venous thromboembolism.
Venous thromboembolism (VTE) is the second-leading cause of death among patients with cancer.1 Estimates for mortality in patients with cancer-associated VTE are as high as 64.5% after 1 year and 88.1% at 10 years.2 Additionally, this patient population has a 2.2-fold increase in mortality compared with patients with non—cancer-associated VTE.3
Optimizing the best pharmaceutical agent while minimizing adverse effects is paramount in this patient population. Low molecular weight heparin (LMWH) agents have been the standard of practice because of their reduced risk of recurrent VTE compared with oral vitamin K antagonist (VKA).4 LMWH agents have limitations: cost, renal elimination, and subcutaneous (SQ)—only formulation that makes it less desirable. Factor Xa inhibitors, such as rivaroxaban (Xarelto), edoxaban (Savaysa), and apixaban (Eliquis), are indicated for the treatment of acute VTE and atrial fibrillation. Recent evidence supports the use of edoxaban and rivaroxaban in cancer-associated VTE; however, these 2 agents lead to more major bleeding than LMWH.5-8 Apixaban is the latest agent investigated that has a favorable safety and efficacy profile for this patient population.
Previously Studied Oral Agents
Until recently, LMWH agents (dalteparin [Fragmin] and enoxaparin [Lovenox]) were the treatment standard for cancer-associated VTE, based on results of the CLOT trial, a Canadian study for which results were published in 2003.4 In this study, dalteparin led to a significantly lower probability of recurrent VTE than VKA (9% vs 17%, respectively; HR, 0.48; 95% CI, 0.30-0.77; P = .002) but no statistical difference in major bleeding or any bleeding.4 Fifteen years after this landmark study, alternative oral anticoagulant therapeutic options began to emerge with factor Xa inhibitors. Results of recent studies for rivaroxaban and edoxaban have shown benefit for use in cancer-associated VTE. Because of rivaroxaban and edoxaban efficacy compared with LMWH in 2 randomized control trials, major guidelines recommend these agents as treatment options.7,8
SELECT-D was a randomized controlled trial comparing standard dosing of rivaroxaban with dalteparin for a primary outcome of VTE recurrence rate over 6 months in the United Kingdom. The primary outcome was more favorable with rivaroxaban compared with dalteparin (4% vs 11%; HR, 0.43; 95% CI, 0.19-0.99, respectively).6 Unfortunately, in the safety assessment, rivaroxaban had a higher incidence of major bleeding (4% vs 6%, respectively; HR, 1.83; 95% CI, 0.68-4.96) and a higher clinically relevant rate of nonmajor bleeding than dalteparin (13% vs 4%; HR, 3.76; 95% CI, 1.63-8.69).6 Gastrointestinal (GI) bleeding comprised most of the cases of major bleeding.
The Hokusai trial (NCT02073682) was a larger noninferiority randomized controlled trial that compared standard dosing of edoxaban with dalteparin for the primary outcome of the composite of recurrent cancer-associated VTE or major bleeding. Recurrent VTE occurred in 7.9% (n= 41) of patients in the edoxaban group compared with 11.3% (n = 59) of patients in the dalteparin group (HR, 0.97; 95% CI, —7.0 to 0.2).5 Similar to rivaroxaban, edoxaban was efficacious in preventing VTE reoccurrence but also had a higher rate of major bleeding than dalteparin, with most of the bleeds in the upper GI tract.5
Apixaban is another factor Xa inhibitor that has been used for the treatment of atrial fibrillation and acute VTE in patients without cancer. Results of the AMPLIFY study (NCT00643201) showed that apixaban led to a significant reduction in major bleeding compared with LMWH plus VKA.9 Results of other recent studies showed that apixaban offers the advantage of the lowest risk of major, intracranial, and GI bleeding among factor Xa inhibitors compared with VKA.10,11 Additionally, unlike LMWH and other factor Xa inhibitors, apixaban can be used for end-stage kidney disease and in patients requiring dialysis.12 To evaluate how these clinical advantages translate to patients with cancer-associated VTE, investigators conducted 2 clinical trials.
The ADAM VTE trial (NCT02585713) was the first study to evaluate apixaban for the treatment of cancer-associated VTE.13 This multicenter study consisted of 300 patients randomly assigned to either SQ dalteparin 200 IU/kg for 1 month and then SQ 150 IU/kg daily for 5 months (N = 150) or apixaban 10 mg twice daily for 7 days followed by 5 mg twice daily for 6 months (N = 150 ).13 The primary outcome was to evaluate major bleeding between the 2 groups. No bleeds were reported in the apixaban group, whereas 2 patients (1.4%) experienced a major bleed in the dalteparin group (P = .138; HR and CI not determined because of 0 bleeds in the apixaban group). Secondary outcomes included the rate of recurrent venous or arterial thromboembolism and a composite of major and clinically relevant nonmajor bleeding. VTE recurred in 1 patient (0.7%) in the apixaban group and 9 patients (6.3%) in the dalteparin group (HR, 0.099; 95% CI, 0.013-0.780; P = .0281). The composite of major and clinically relevant nonmajor bleeding occurred in 6% of patients (N = 9) for each treatment group (HR, 0.931; 95% CI, 0.43-202; P = .88). Although the results from this trial are promising for reducing bleeding rates, the authors noted limitations: a small sample size and fewer patients with upper GI cancer, potentially resulting in a decreased bleeding rate.
A larger randomized controlled trial (CARAVAGGIO; NCT03045406) also evaluated apixaban versus LMWH in cancer-associated VTE.14 This study was a multinational, open-label, noninferiority trial that included 1170 patients randomly assigned to receive either apixaban or dalteparin at the same dose and duration as in the ADAM VTE study. The primary outcome was recurrent VTE during the trial. This occurred in 5.6% (N = 32) of patients in the apixaban group and 7.9% (N = 46) in the dalteparin group (HR, 0.63; CI, 0.37-1.07; P < .001 for noninferiority). The safety outcomes evaluated major bleeding and found no increase in frequency with apixaban (3.8%; N = 22) versus dalteparin (4.0%; N = 23) (HR, 0.82; 95% CI, 0.40-1.69; P = .60). The authors concluded that apixaban was noninferior to dalteparin in efficacy and had no increased bleeding risk. A limitation of this trial was that it was not powered enough to determine a definitive conclusion on bleeding. Additionally, GI bleeding was not a prespecified secondary outcome at the onset of the trial.
Striking a balance between treating VTE and avoiding bleeding remains a challenge in the clinical setting because of the limitation of available pharmacological options. Additional considerations for drug choice are cost, adherence, and specific disease state. Apixaban is the latest factor Xa inhibitor to show benefit in efficacy compared with dalteparin for the treatment of cancer-associated VTE.
In contrast with other factor Xa inhibitors studied in this patient population, apixaban demonstrated no increase in the frequency of major bleeding. Further studies are needed to confirm an advantage of decreased bleeding risk with apixaban; however, this agent affords clinicians another treatment option in patients with a challenging medical condition.
SHYAM GELOT, PHARMD, BCPS, earned his PharmD from the University of North Carolina Eshelman School of Pharmacy and completed a PGY1 pharmacy practice residency at Tampa General Hospital in Florida. He has worked in various fields of pharmacy, including academia, community and hospital practice.