AVERT – Apixaban to Prevent Cancer VTE
Apixaban to Prevent Venous Thromboembolism in Patients with Cancer.
Carrier M, Abou-Nassar K, Mallick R, et al.; AVERT Investigators.
N Engl J Med. 2019 Feb 21;380(8):711-719. [Full text]
Summary by Austin Kordic
Cancer is a pro-thrombotic state and increases the risk for venous thromboembolism (VTE). Ever since the CLOT trial demonstrated that low molecular weight heparin (LMWH) prevented more VTEs than vitamin K antagonists, LMWH (i.e. dalteparin or enoxaparin) had been standard for cancer related VTE and secondary prophylaxis. Subsequently, direct oral anticoagulants (DOACs) have also been shown efficacious in cancer related VTE, such as in the CARAVAGGIO trial.
Given that cancer is a risk for VTE, LMWH has been evaluated for primary prophylaxis of VTE in this population. There has been some benefit but at the expense of bleeding [1, 2]. LMWH has the additional drawbacks in that it is associated with decreased quality of life and lower adherence.
The AVERT trial sought to determine whether the use of a low DOAC, apixaban, is both efficacious in primary VTE prophylaxis in cancer patients and has an acceptable risk profile for major bleeding events. This remains a critical question that warrants further investigation in order to optimize care for cancer patients using a more holistic approach.
Patient population and Design
The population for the study comprised 574 patients across 13 Canadian medical centers with newly diagnosed cancer or progression of known cancer after complete or partial remission who were initiating a new course of chemotherapy, with a minimum treatment intent of 3 months. This was a double-blind, placebo-controlled study with an intention-to-treat analysis. Patients were randomized into two groups, to receive either apixaban 2.5 mg PO twice daily or placebo twice daily. The treatment period was 180 days with a follow up period of 210 days (or death).
The mean age was 61 years-old, with a slight female predominance (58.2%) and similar ratios of metastatic disease, obesity, and ECOG status. The most represented types of cancer were gynecologic, lymphoma, and pancreatic malignancies. Inclusion criteria were age ≥ 18 yo, ability to consent, and a Khorana score ≥ 2 (intermediate-high 2.5-month risk for VTE). Notable exclusion criteria were GFR ≤ 30, Plt ≤ 50k, < 40 kg, increased risk for clinically significant bleeding, life expectancy < 6 months, and pregnancy.
Outcomes
The primary efficacy outcome was the first objectively documented episode of major VTE (DVT or PE) within the first 180 days after randomization. These episodes encompassed both symptomatic and incidentally detected VTE; however, routine U/S screening for asymptomatic DVT was not performed. The major safety outcome was major bleeding, as defined by overt bleeding associated with a Hgb drop of ≥ 2g/dL, transfusion of ≥2 units pRBC, occurring in a critical site, or that contributed to death. The secondary outcomes were overall survival and clinically relevant nonmajor bleeding events.
Results
VTE occurred in 12/288 (4.2%) of the apixaban group vs 28/275 (10.2%) in the placebo with a Hazard Ratio of 0.41 (95% CI 0.26-0.65; P < 0.001), NNT = 17. Major bleeding occurred in 10/288 (3.5%) patients in the apixaban group vs 5/275 (1.8%) patients in the placebo group with a Hazard Ratio of 2.0 (95% CI 1.01-3.95; P = 0.046), NNH was 59.
All-cause mortality occurred in 35/288 (12.2%) of patients in the apixaban group vs 27/275 (9.8%) in the placebo (HR 1.29, 95% CI 0.98-1.71). Clinically relevant nonmajor bleeding occurred in 21/288 (7.3%) in the apixaban group vs 15/275 (5.5%) in the placebo group (HR 1.28, 95% CI 0.8-3.8). The competing-risk analysis that accounted for deaths from causes other than VTE or bleeding was consistent with the primary analysis (hazard ratio, 0.42; 95% CI, 0.27 to 0.65).
Discussion
AVERT demonstrated that taking apixaban 2.5 mg PO twice daily resulted in significantly lower risk of VTE versus placebo in ambulatory patients with cancer who are initiating chemotherapy and have an intermediate-high risk of VTE as assessed by the Khorana score. This finding is not surprising.
To implement in practice, the risks need to be well understood. Bleeding was more frequent in the apixiban group, but the benefits (VTE prevention, NNT 17) may outweigh the bleeding risk (NNH 59). What was particularly interesting was that while that major bleeding was significantly higher during the defined follow-up period (P = 0.046, HR 1.01-3.95, NNH = 59), it was not significant during the actual treatment period (HR 1.89; 95% CI, 0.39 to 9.24; NNH = 100).
Secondary analysis also found that the difference between groups was mainly due to higher rates of GI bleeding, hematuria, and gynecologic bleeding in patients with a diagnosed GI or GU malignancy. Amongst the major bleeding events, the most severe (Category 3 or 4) represented ~ 20% of events and were evenly distributed between the groups with no documented cases of fatal bleeding or bleeding into critical organs. Furthermore, the authors found no significant association of apixaban use with increased rates of nonmajor bleeding events (HR 0.8-3.8), which was lower at 6 months of treatment (7.3%) than in prior studies amongst patients with cancer with a Khorana score ≥ 3. In addition, it was interesting to find that despite their increased risk for VTE, the study found no significant difference in all-cause mortality though was not powered for this outcome (many patients in the study had advanced cancer with the most common cause of death being progression of disease, thus a larger study population may be required to better address this association).
Some of the limitations of this study relate to contraindications to apixaban use, including patients with elevated risk of bleeding (cytopenia, coagulopathy, history of major bleeding) and renal dysfunction, as only 5.9% of the study population had a creatinine clearance < 50. In addition, the limited patient population in this study precluded a proper analysis of VTE and bleeding risk stratified by type of cancer or chemotherapy regimens. Further studies could shed additional light on the appropriateness of DOAC use for VTE prophylaxis in various subtypes of malignancy and with certain chemotherapy and immunotherapy regimens.
These results suggest that apixaban may be considered a relatively safe, effective, and more patient-centered alternative for primary prophylaxis of VTE in certain patients with cancer who are initiating chemotherapy. Particular caution might be taken with GI or GU malignancies as they had increased bleeding risk, which has been seen previously (see CARAVAGGIO). For now it remains an individualized intervention, but risk stratification, for example with the Khorana score should be incorporated to identify the highest risk patients.
| F: Follow up | Treatment period of 180 days, follow up 210 days or death |
| R: Randomization | Yes, stratified by age, sex, participating center |
| I: Intention to treat | Yes |
| S: Similar at baseline | Yes |
| B: Blinding | Yes |
| E: Equal treatment | Yes |
| S: Source (funding) | Canadian Institutes of Health Research and Bristol-Myers Squibb-Pfizer alliance |
- Khorana AA, Francis CW, Kuderer NM, et al. Dalteparin thromboprophylaxis in cancer patients at high risk for venous thromboembolism: a randomized trial. Thromb Res 2017;151:89-95.
- Di Nisio M, Porreca E, Candeloro M, et al. Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy. Cochrane Database Syst Rev. 2016 Dec 1;12(12):CD008500.
- Lyman GH, Culakova E, Poniewierski MS, Kuderer NM. Morbidity, mortality and costs associated with venous thromboembolism in hospitalized patients with cancer. Thromb Res 2018;164:Suppl 1:S112-S118.
