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Agnelli G, Becattini C, Meyer G, et al. Apixaban for the Treatment of Venous Thromboembolism Associated with Cancer. N Engl J Med. 2020 Apr 23;382(17):1599-1607. doi: 10.1056/NEJMoa1915103. Epub 2020 Mar 29. (Original study)
Abstract

BACKGROUND: Recent guidelines recommend consideration of the use of oral edoxaban or rivaroxaban for the treatment of venous thromboembolism in patients with cancer. However, the benefit of these oral agents is limited by the increased risk of bleeding associated with their use.

METHODS: This was a multinational, randomized, investigator-initiated, open-label, noninferiority trial with blinded central outcome adjudication. We randomly assigned consecutive patients with cancer who had symptomatic or incidental acute proximal deep-vein thrombosis or pulmonary embolism to receive oral apixaban (at a dose of 10 mg twice daily for the first 7 days, followed by 5 mg twice daily) or subcutaneous dalteparin (at a dose of 200 IU per kilogram of body weight once daily for the first month, followed by 150 IU per kilogram once daily). The treatments were administered for 6 months. The primary outcome was objectively confirmed recurrent venous thromboembolism during the trial period. The principal safety outcome was major bleeding.

RESULTS: Recurrent venous thromboembolism occurred in 32 of 576 patients (5.6%) in the apixaban group and in 46 of 579 patients (7.9%) in the dalteparin group (hazard ratio, 0.63; 95% confidence interval [CI], 0.37 to 1.07; P<0.001 for noninferiority). Major bleeding occurred in 22 patients (3.8%) in the apixaban group and in 23 patients (4.0%) in the dalteparin group (hazard ratio, 0.82; 95% CI, 0.40 to 1.69; P = 0.60).

CONCLUSIONS: Oral apixaban was noninferior to subcutaneous dalteparin for the treatment of cancer-associated venous thromboembolism without an increased risk of major bleeding. (Funded by the Bristol-Myers Squibb-Pfizer Alliance; Caravaggio ClinicalTrials.gov number, NCT03045406.).

Ratings
Discipline Area Score
Internal Medicine 7 / 7
Hematology 7 / 7
Oncology - General 7 / 7
Hemostasis and Thrombosis 6 / 7
Comments from MORE raters

Hematology rater

Confirms the efficacy of direct factor Xa inhibitors in cancer patients.

Hematology rater

This is a really interesting article, much anticipated since the approval of edoxaban and rivaroxaban for the same indication. What is more, it proves once again the relevant safety of apixaban among patients with even advanced disease and under various chemotherapeutic regimens.

Hemostasis and Thrombosis rater

Important study that demonstrates the efficacy and safety of apixaban for cancer-associated thrombosis, including the GI malignancy population that has been a subset of concern given prior studies (Hokusai VTE Cancer).

Internal Medicine rater

This is something primary care physicians don't deal with very often, but often enough that they should know this because they will be the ones managing these patients.

Internal Medicine rater

Extremely important and suggests this may be the safest agent in this population.

Internal Medicine rater

A highly relevant article for hospitalists who are are at the front line of admitting and managing these patients. The results from this article provide us with another oral option that may be easily available. The results from this study are very encouraging.

Internal Medicine rater

Apixaban is noninferior to dalteparin for preventing recurrent VTE in patients with malignancy. The P-value for non-inferiority, <.0001; the P-value near significant (0.09) for superiority. Table 1 shows that the apixaban group had less PE (57% vs 52%) at enrollment and more DVT. This was not noted as statistically significant, but given the results that these were driven largely by reduction in recurrent PE, it warrants consideration. The authors note that KM curves diverge at 30 days, which is after a dose reduction of dalteparin in the trial protocol. Continuing the higher dose of dalteparin may prevent more events, but the net risk/benefit with likely higher bleeding is unknown.

Oncology - General rater

Why was the trial named after Caravaggio?

Oncology - General rater

Adds to the accumulating evidence supporting NOACs as an option for treating VTE in patients with cancer.

Oncology - General rater

It is important to know that the use of an oral agent in the outpatient setting is non-inferior to a difficult-to-administer parenteral LMWH, the current standard (CLOT study). Safety is acceptable. There were some numerical differences in CRNM and major bleeding, but the study was truly powered for the main endpoint and not for these secondary endpoints. However, the point for clinicians is that they should know that if they are going to use a DOAC (apixaban in this case), there is some risk for bleeding, in particular from GI and GU luminal lesions.
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