CARAVAGGIO – Apixaban for Cancer VTE

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Apixaban for the Treatment of Venous Thromboembolism Associated with Cancer.

Agnelli G, Becattini C, Meyer G, et al.; for the Caravaggio Investigators.

N Engl J Med. 2020 Apr 23;382(17):1599-1607. [Full Text]

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Summary by Kaitlyn Dykes

Cancer patients are at high risk for recurrent thromboembolism as well as bleeding complications [1]. VTE is the second leading cause of mortality in cancer patients receiving chemotherapy [2] and the occurrence of VTE is associated of mortality within the first year after VTE diagnosis for all cancer types [3]. Therefore, cancer patients need to have access to anticoagulation options that are effective at VTE prevention and have a favorable side effect profile, not to mention that are convenient to take.

Prior to the CARAVAGGIO study, major guidelines recommended low-molecular-weight heparin as the gold standard in cancer-associated VTE [4-8]. The CLOT trial published in 2003 established dalteparin as superior to vitamin K antagonists in cancer associated VTE prevention, with similar bleeding adverse events [6, 9]. However, since CLOT the direct oral anticoagulants (DOACs) have been investigated as alternatives for cancer-associated VTE treatment and prevention, given their advantage of oral administration versus subcutaneous injection.  In the Hokusai VTE cancer study [10] and SELECT-D trials [11], oral edoxaban and rivaroxaban respectively were confirmed non-inferior to subcutaneous dalteparin with respect to recurrent VTE prevention; however, both found increased rates of major bleeding in the DOAC groups. Interestingly, neither study excluded patients with brain tumors or metastases.

The CARAVAGGIO study compared treatment of cancer-associated VTE with either oral apixaban or dalteparin in a large, multinational, open-label, randomized non-inferiority trial, and established non-inferiority of apixaban. Therefore this study established apixaban as a viable treatment option for select patients with cancer-associated VTE and is commonly prescribed in clinical practice today.

Patient Population

Adults with confirmed cancer and a new diagnosis of imaging documented symptomatic or incidental proximal lower-limb deep-vein thrombosis (DVT) or pulmonary embolism where eligible to participate in the trial. Incidental VTE was limited to 20%. Further history of cancer was limited to 20% of participants, with a preference for patients with active cancer, defined as a cancer diagnosis within 6 months, or on active anticancer treatment or therapy within the last 6 months of randomization. Patients with basal or squamous-cell skin cancer, primary brain tumors, acute leukemia and known intra-cerebral metastases were excluded. One-third of patients in the study had a gastrointestinal

Outcomes

The primary outcome was objectively confirmed recurrent venous thromboembolism (VTE) within 6 months of the incident VTE. The safety outcome was major bleeding. Bleeding was defined as a decrease in the hemoglobin level of at least 2g/dL, a transfusion of ≥ 2 units of packed red cells, bleeding at a critical site, bleeding leading to surgical intervention or fatal bleeding. Bleeding at a critical site included: intracranial, intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome or retroperitoneal.

Results

This study included 1155 patients with cancer and acute VTE between April 2017-June 2019. Twenty percent of the included patients had an incidental DVT or PE and 97% of the cases had active cancer. 576 patients were randomized to the apixaban group and 579 to the dalteparin group. Demographic and clinical baseline characteristics were similar between the two groups.

A modified intention-to-treat analysis of the primary outcome, found recurrent VTE occurred in similar frequency between groups: 32 of 576 patients (5.6%) in the apixaban treatment group and in 46 of 579 patients (7.9%) in the dalteparin group (HR 0.63; 95% CI 0.37-1.07; P-value=<0.001 for noninferiority).

The primary safety outcome, major bleeding, occurred in 22 patients (3.8%) in the apixaban group and in 23 patients (4.0%) in the dalteparin group (HR 0.82; 95% CI 0.40-1.69; P-value=0.6). Significant gastrointestinal bleeding occurred in 1.9% of patients in the apixaban group and 1.7% in the dalteparin group. There were no fatal bleeding events in the apixaban group and two fatal bleeding events in the dalteparin group. The rates of non-major bleeding were not significantly different, 9% in the apixaban group and 6% in the dalteparin group. Mortality incidence was not different between the groups: 23.4% of patients in the apixaban group and 26.4% in the dalteparin group died. The majority of deaths were related to cancer, 85.2% and 88.2% in the apixaban group and dalteparin groups, respectively.

Discussion

The CARAVAGGIO study was a landmark trial because it established apixaban as non-inferior to low molecular weight heparin, specifically dalteparin, with respect to recurrent VTE prevention and bleeding adverse events. The results of this study have changed clinical practice such that now anticoagulation options for patients with cancer-associated VTE have been expanded to include apixaban. This may have a quality of life impact as well, as many patients with active cancer may not want to receive daily injections, particularly in the setting of complex medical regimens and when potentially near end-of-life.

Not only has this study directly impacted the clinical practice of cancer-associated VTE, it has also provided a bases for subsequent studies. To date, 187 published articles have cited the CARAVAGGIO study. Many of these articles target limitations of the CARAVAGGIO study and are areas of ongoing research exploration. Specifically, the CARAVAGGIO study had exclusion criteria parameters that limited generalization of results. The study suggested apixaban was non-inferior to dalteparin in gastrointestinal cancers; however, given gastrointestinal cancers, especially of the pancreas and upper tract, represented only a minority of the CARAVAGGIO patients, apixaban use in this population may have more uncertainty.

Also, no conclusions can be made from CARAVAGGIO regarding cancer associated VTE treatment in patients with intracranial lesions and acute leukemia, as these patients were excluded. Treatment of cancer-associated VTE in these subset populations is an area of active research. Furthermore, few patients were on monoclonal antibodies (~8%) or specifically checkpoint inhibitors (~2%), which may not represent current oncology practice. Finally. apixaban is just one of the available DOACs; additional studies regarding other DOAC’s efficacy and safety profiles for cancer-associated VTE treatment are needed and are ongoing in order to fully expand treatment options for cancer patients.  

In conclusion, the CARAVAGGIO study expanded cancer-associated VTE treatment options to include apixaban in carefully selected patients, by showing it was non-inferior with respect to recurrent VTE and adverse bleeding events. The study has also provided foundational work for numerous studies that have since been published and that are currently ongoing.

F: Follow up7 mo (0, 4 wk, 3 mo, 7 mo visits)
R: RandomizationYes, stratified by symptomatic vs incidental VTE & active or historical cancer
I: Intention to treatYes
S: Similar at baselineYes
B: BlindingNO, open label but outcomes blinded
E: Equal treatmentYes
S: Source (funding)Bristol-Myers Squibb-Pfizer Alliance.        
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