Evidence-based Appraisal of the CARAVAGGIO Trial

Abstract

Patient Population: The study population included adult patients with cancer and symptomatic or incidental proximal lower-limb deep-vein thrombosis (DVT) or pulmonary embolism (PE). Key exclusion criteria were as follows: age <18 years old, an Eastern Cooperative Oncology Group (ECOG) status of III or IV, life expectancy of less than 6 months, basal-cell or squamous-cell carcinoma of the skin, primary brain tumor, known intracerebral metastases, acute leukemia, indication for anticoagulation therapy other than the trial inclusion criteria, creatinine clearance <30 mL/min, and severe liver dysfunction. Intervention: 576 patients received apixaban 10 mg orally twice daily for the first 7 days, then 5 mg twice daily for a total of six months. Comparison: 579 patients received dalteparin 200 International Units/kg subcutaneously once daily for 1 month, then 150 International Units/kg daily (maximum daily dose of 18,000 International Units) for a total of six months. Outcome: The primary outcome included recurrent venous thromboembolism (VTE) over a six-month period, while the primary safety outcome was major bleeding. Citation: Apixaban for the Treatment of Venous Thromboembolism Associated with Cancer. N Engl J Med. 2020;382(17):1599-1607. doi: 10.1056/NEJMoa1915103. The CARAVAGGIO trial evaluated the efficacy and safety of apixaban compared to dalteparin for the treatment of cancer-associated venous thromboembolism. It was a multi-national, randomized, controlled, open-label, noninferiority trial, with a low percentage of patients who were lost to follow up. The trial applies to patients who are older than 18 years of age with active cancer or a history of cancer with a new diagnosis of symptomatic or incidental proximal lower-limb DVT or PE. The statistical analysis of a non-inferiority study should consist of an intention-to-treat analysis and per-protocol analysis. However, in this study, the primary efficacy data was analyzed with a modified intention to treat principle and consisted of all patients who had undergone randomization and received at least one dose of trial drug. The absolute risk reduction of the primary outcome was found to be 2.3%, with a relative risk reduction of 29%. Apixaban was found to be noninferior to injectable dalteparin for the treatment of cancer-associated VTE, with no significant difference in major bleeding. Oral apixaban may serve as an alternative to LMWH in patients with cancer for the treatment of venous thromboembolism who prefer oral therapy over subcutaneous injections, though clinicians should be aware that apixaban is a P-glycoprotein and CYP3A4 substrate and may interact with other drugs. Patients with gastrointestinal and genitourinary cancers may be at higher risk of bleeding with the use of the DOACs. Gastrointestinal bleeding was not a prespecified trial outcome for this trial, and the sample size was not large enough to make a definitive conclusion on bleeding. For patients with gastrointestinal or genitourinary cancers, the bleeding risk must be weighed against benefits when deciding on the appropriate anticoagulant to prescribe. Additional limitations of the study include the open-label trial design and the short duration of six months.