Clinical trial

Apixaban for the Treatment of Venous Thromboembolism Associated with Cancer

N Engl J Med · 20201155 patients in the primary outcome analysis (576 apixaban, 579 dalteparin)

Agnelli G, Becattini C, Meyer G, Muñoz A, Huisman MV, Connors JM, et al. N Engl J Med. 2020. 382:1599-1607

Study type: Clinical trial
Study name: Caravaggio
Design: Multinational, investigator-initiated, open-label randomised non-inferiority trial with blinded central adjudication of outcomes
Sample size: 1155 patients in the primary outcome analysis (576 apixaban, 579 dalteparin)
Source: N Engl J Med · 2020
Trial registration: NCT03045406

In plain words

This international study in more than 1100 people with cancer and a blood clot compared apixaban tablets with daily dalteparin injections for 6 months. Apixaban tablets were no worse than dalteparin injections at preventing clots from coming back (clots returned in 5.6% versus 7.9%). Although some blood-thinning tablets had caused more bleeding in earlier studies, apixaban did not increase serious bleeding in this study (3.8% versus 4.0%). The drug should be chosen with your doctor, taking into account your type of cancer, your kidney function and your other medicines.

Key results

5.6% vs 7.9%

Recurrent venous thromboembolism (primary outcome)

32 of 576 patients with apixaban vs 46 of 579 with dalteparin; HR 0.63 (95% CI 0.37–1.07); P<0.001 for non-inferiority

3.8% vs 4.0%

Major bleeding (principal safety outcome)

22 patients with apixaban vs 23 with dalteparin; HR 0.82 (95% CI 0.40–1.69); P=0.60

Dose and schedule cards

Therapeutic apixaban (Caravaggio)

Symptomatic or incidental cancer-associated VTE (proximal DVT or pulmonary embolism)Cycle length: DailyOn the page “Venous thromboembolism in cancer: risk assessment, prevention and treatment” · Treatment of cancer-associated VTE

Symptomatic or incidental cancer-associated VTE (proximal DVT or pulmonary embolism)

Drug	Dose	Route	Schedule
Days 1 to 7
Apixaban	10 mg twice a day	Oral	First 7 days
From day 8
Apixaban	5 mg twice a day	Oral	Continuous

Cycle length: Daily
Duration: 6 months in Caravaggio; after that based on cancer activity (extended phase in the next table)

Reduce the dose by 50% with combined strong P-gp and CYP3A4 inhibitors; do not use with combined strong inducers. For DVT/PE treatment, the label does not recommend dose adjustment for renal impairment (even dialysis patients), because the recommendation is based on pharmacokinetic data and the trials did not enrol patients on dialysis or with CrCl below 15. In Caravaggio, recurrence was 5.6% vs 7.9% with dalteparin and major bleeding 3.8% vs 4.0%.

On the page “Venous thromboembolism in cancer: risk assessment, prevention and treatment” · Treatment of cancer-associated VTE

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Apixaban

Apixaban 10 mg orally twice daily for the first 7 days, then 5 mg twice daily; treatment duration 6 months.

FDA label for apixaban (ELIQUIS), DVT/PE treatment: 10 mg orally twice daily for 7 days, then 5 mg twice daily (the same regimen as in this trial).

2Dalteparin (comparator)

Dalteparin subcutaneously 200 IU per kg of body weight once daily for the first month, then 150 IU per kg once daily; treatment duration 6 months.

FDA label for dalteparin (FRAGMIN), venous thromboembolism in patients with cancer: the total daily dose should not exceed 18,000 IU.

Source of the regimen details: Abstract of the paper (N Engl J Med 2020); DVT/PE treatment dose from the FDA label for apixaban (ELIQUIS, DailyMed); maximum daily dose from the FDA label for dalteparin (FRAGMIN, DailyMed, section 2.3)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Consecutive patients with cancer and acute symptomatic or incidental proximal deep-vein thrombosis (DVT) or pulmonary embolism (PE). Other inclusion criteria are not given in the abstract.

Endpoints

Primary outcome (non-inferiority): objectively confirmed recurrent venous thromboembolism during the trial period.

Principal safety outcome: major bleeding.

Safety and side effects

Major bleeding occurred in 22 patients (3.8%) in the apixaban group and 23 patients (4.0%) in the dalteparin group (hazard ratio 0.82; 95% CI 0.40–1.69; P=0.60). Other adverse events, including clinically relevant non-major bleeding, are not reported in the abstract.

Clinical significance and place in guidelines

Caravaggio showed that oral apixaban is non-inferior to dalteparin for the treatment of cancer-associated venous thromboembolism, without an increased risk of major bleeding. The 2023 update of the ASCO guideline added apixaban to the treatment options for venous thromboembolism with a strong recommendation and high-quality evidence (Key NS et al., J Clin Oncol 2023). The 2022 international ITAC guideline recommends direct oral anticoagulants (rivaroxaban, apixaban, edoxaban) for cancer-associated thrombosis in patients with creatinine clearance ≥30 mL/min who are not at high risk of gastrointestinal or genitourinary bleeding and have no strong drug interactions (grade 1A), and advises caution in gastrointestinal cancers, especially of the upper gastrointestinal tract (Farge D et al., Lancet Oncol 2022). The apixaban dose in this trial is the same as the DVT/PE treatment dose in the FDA label for apixaban (ELIQUIS).

Limitations

According to the abstract: the trial was open-label, although outcomes were adjudicated centrally and blinded. The confidence interval of the hazard ratio for recurrence (0.37–1.07) includes 1, so only non-inferiority was shown and superiority of apixaban was not proven. Treatment lasted 6 months. Clinically relevant non-major bleeding, mortality and cancer types are not reported in the abstract.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.