For Patients with Cancer and VTE, Apixaban Associated with Similar Outcomes, Less Bleeding Than Enoxaparin

Patients with cancer are predisposed to developing venous thromboembolism (VTE). While a standard treatment for VTE is the vitamin K antagonist warfarin, high rates of recurrence and bleeding complications have been observed in this patient population.

Using data from the randomized, double-blind AMPLIFY study that compared apixaban and enoxaparin followed by warfarin in patients with cancer and VTE, Giancarlo Agnelli, MD, from the University of Perugia in Italy, and colleagues conducted a subgroup analysis in patients with active cancer or a history of cancer at study inclusion.

Patients were included in the AMPLIFY study if they were age 18 years or older and had objectively confirmed symptomatic proximal deep-vein thrombosis, pulmonary embolism, or both. Patients were excluded from the study if they:

  • had active bleeding or a high risk of bleeding
  • were receiving treatment with dual antiplatelet therapy, aspirin, or potent inhibitors of cytochrome P450 3A4
  • were treated for longer than 48 hours with low-molecular-weight heparin (LMWH), unfractionated heparin, or fondaparinux
  • received treatment of the index VTE with thrombectomy, vena cava filter, or thrombolytic therapy
  • had creatinine clearance of <25 mL/min, hemoglobin level of <9 g/dL, or platelet count of <100,000 mm3

Patients with symptomatic VTE were randomized to a six-month course of either:

  • Apixaban 10 mg twice daily for seven days, followed by 5 mg twice daily
  • Enoxaparin 1 mg/kg-1 twice daily for at least five days, followed by dose-adjusted warfarin

The study’s primary outcomes were objectively confirmed symptomatic VTE or VTE-related death and major bleeding up to two days after stopping the study drug.

A total of 5,395 patients were included: 169 (3.1%) had active cancer at baseline, 365 (6.8%) had a history of cancer without active cancer at baseline, and 4,861 (90.1%) had neither a history of cancer nor active cancer.

Dr. Agnelli and researchers found that apixaban was non-inferior to enoxaparin for recurrent symptomatic VTE or VTE-related death: 2.3 percent versus 2.7 percent, respectively (relative risk [RR] = 0.84; 95% CI 0.60-1.18; p<0.001). However, apixaban treatment produced significantly less bleeding (0.6% vs. 1.8%, respectively; RR=0.31; 95% CI 0.17-0.55; p<0.001).

Of the 159 evaluable patients with active cancer at baseline, recurrent VTE occurred in three of 81 patients (3.7%) receiving apixaban and in five of 78 patients (6.4%) receiving enoxaparin/warfarin (RR=0.56; 95 CI 0.13-2.37).

For the 354 evaluable patients with a history of cancer without active cancer at baseline, recurrent VTE was also lower in apixaban-treated patients (RR=0.17; 95% CI 0.04-0.78).

Similarly, for patients with either active cancer or history of cancer, recurrent VTE occurred less frequently in apixaban-treated patients (RR=0.30; 9% CI 0.11-0.82). The rates of recurrent VTE were similar for both treatment groups for patients without active cancer or a history of cancer (RR=0.99; 95% CI 0.69-1.44). See the TABLE for a report of study outcomes related in different patient cohorts.

Overall, apixaban was non-inferior to enoxaparin/warfarin in preventing bleeding events in the AMPLIFY population. Among the 167 patients with active cancer at baseline who were evaluable for bleeding analysis, major bleeding (defined as a decrease in hemoglobin level of ≥2 g dL-1, transfusion of ≥2 units of packed red blood cells, bleeding that occurred in a critical site, or fatal bleeding) occurred in 2.3 percent (2/87 patients) and five percent (4/80 patients) in the apixaban cohort and the enoxaparin/warfarin cohort, respectively (RR=0.45; 95% CI 0.08-2.46). Apixaban treatment also led to lower incidence of major bleeding in patients with a history of cancer (TABLE).

Limitations of the study include the small sample size and that the VTE recurrence rate in the enoxaparin/warfarin group was lower than other studies performed in this patient population, the authors noted. Due to certain exclusion criteria, the participant pool in the AMPLIFY study may have had less aggressive or extensive cancer than other studies of this patient population, and thus results may not be generalizable to the entire population of cancer patients with VTE.

“In clinical practice, approximately 10 to 20 percent of patients with VTE have active cancer or a history of cancer at baseline, and some patients with unprovoked VTE develop cancer during treatment,” Dr. Agnelli and colleagues explained. And, though current guidelines recommend a six-month course of LMWH over treatment with warfarin for cancer patients with VTE, “it is inconvenient, because it requires daily subcutaneous injections.”

The results from the current study suggest that apixaban may be a more convenient option for cancer patients requiring treatment for longer periods of time, but additional studies are needed to confirm this concept and to compare apixaban with LMWH in cancer patients with VTE, the authors concluded.


Reference

Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of venous thromboembolism in cancer patients: results from the AMPLIFY trial. J Thromb Haemost. 2015;13:2187-91.

TABLE. Safety and Efficacy Comparison of Apixaban Versus Enoxaparin/Warfarin
VTE or VTE-Related Death Major Bleeding MB/CRNMB
Apixaban Enoxaparin/
warfarin
Apixaban Enoxaparin/
warfarin
Apixaban Enoxaparin/
warfarin
Active cancer n=3/81 (3.7%) n=5/78 (6.4%) n=2/87 (2.3%) n=4/80
(5%)
n=11/87 (12.6%) n=18/80 (22.5%)
Cancer history (without active cancer) n=2/179

(1.1%)

n=11/175

(6.3%)

n=1/184

(0.5%)

n=5/179

(2.8%)

n=11/184

(6%)

n=27/179

(15.1%)

Active cancer and cancer history n=5/260

(1.9%)

n=16/253

(6.3%)

n=3/271

(1.1%)

n=9/259

(3.5%)

n=22/271

(8.1%)

n=45/279

(17.4%)

No cancer history/no active cancer n=54/2,349

(2.3%)

n=55/2,382

(2.3%)

n=12/2,405

(0.5%)

n=40/2,430

(1.7%)

n=93/2,405

(3.9%)

n=216/2,430

(8.9%)

p Value p=0.07 p=0.83 p=0.84
MB/CRNMB = major bleeding/clinically relevant non-major bleeding

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