CARAVAGGIO

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Agnelli G, et al. "Apixaban for the Treatment of Venous Thromboembolism Associated with Cancer". The New England Journal of Medicine. 2020. 382:1599-607.
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Clinical Question

Is apixaban noninferior to dalteparin (LMWH) for the treatment of cancer-associated venous thromboembolism (VTE)?

Bottom Line

Apixaban is noninferior to dalteparin in treating cancer-associated VTE.

Major Points

Low molecular weight heparins (LMWHs) have been the mainstay treatment of VTE for patients with cancer[1] based in large part on the CLOT trial which demonstrated the superiority of LMWH to warfarin.[2] The advent of direct acting oral anticoagulants (DOACs) made them an attractive alternative in an effort to reduce patients' injection burden. Previous studies demonstrated favorable outcomes with edoxaban in Hokusai-VTE and rivaroxaban in SELECT-D, but randomized data with apixaban were lacking.

CARAVAGGIO enrolled 1,170 patients with cancer-associated VTE, randomizing to either apixaban or dalteparin for 6 months. Chief eligibility criteria included symptomatic or incidental VTE, active or recent malignancy, and absence of brain lesions. The primary outcome was objectively confirmed recurrent VTE at 6 months from randomization, and the principal safety outcome was major bleeding; both types of events were centrally adjudicated. The primary analysis tested whether apixaban would be noninferior to dalteparin for the primary outcome, with a noninferiority margin of 2.00 for the upper limit of the two-sided 95% CI of the hazard ratio. The primary outcome occurred in 5.6% of patients in the apixaban group and 7.9% in the dalteparin group (HR 0.63; 95% CI 0.37-1.07), which met the prespecified noninferiority margin. Major bleeding was observed in 3.8% of patients in the apixaban group and 4.0% in the dalteparin group (HR 0.82; 95% CI 0.4-1.69).

The main takeaways are that, like other DOACs, apixaban yields similar outcomes to dalteparin in patients with cancer-associated VTE.

Guidelines

NCCN Guidelines on Cancer-Associated Venous Thromboembolic Disease (2020, adapted)[3]

  • DOACs are preferred for patients with cancer-associated VTE who do not have gastric or gastroesophageal lesions (Category 1).
  • LMWHs are preferred for patients with cancer-associated VTE who have gastric or gastroesophageal lesions (Category 1).

Design

  • Multinational, randomized, controlled, investigator-initiated, open label, noninferiority trial with blinded adjudication of outcomes
  • N=1,170 patients with cancer-associated VTE
    • Apixaban (n=576)
    • Dalteparin (n=579)
  • Setting: Europe, Israel, and US.
  • Enrollment: 2017-2019
  • Analysis: Modified intention-to-treat
  • Primary outcome: Recurrent VTE

Population

Inclusion Criteria

  • Consecutive patients with a newly diagnosed, objectively confirmed:
    • Symptomatic or unsuspected, proximal lower-limb DVT or,
    • Symptomatic PE or
    • Unsuspected PE in a segmental or more proximal pulmonary artery
  • Any type of cancer (other than basal-cell or squamous-cell carcinoma of the skin, primary brain tumor or known intracerebral metastases and acute leukemia) that met at least one of the following:
    • Active cancer defined as diagnosis of cancer within six months before the study inclusion, or receiving treatment for cancer at the time of inclusion or any treatment for cancer during 6 months prior to randomization, or recurrent locally advanced or metastatic cancer.
    • Cancer diagnosed within 2 years before study inclusion (Hx of CA)

Exclusion Criteria

  • Age <18
  • ECOG Performance Status III or IV
  • Life expectancy < 6 months

The following are related to Anticoagulation:

  • Administration of therapeutic doses of LMWH, Fondaparinux, or unfractionated Heparin (UFH) for more than 72 hours before randomization
  • 3 or more doses of Vitamin K Antagonist (Warfarin) before randomization
  • Thrombectomy, Vena Cava filter insertion, or thrombolysis used to manage the index episode
  • Indication for anticoagulation treatment for a disease other than the index VTE episode
  • Concomitant use of strong inhibitors or inducers of both cytochromc P-450 3A4 and P-Glycoprotein.

The following are related to bleeding risk:

  • Concomitant thienopyridine therapy (Clopidogrel, Prasugrel, Ticagrelor) or aspirin over 165mg daily or DAPT
  • Active bleeding or high-risk bleeding contraindicating anticoagulant treatment
  • Recent (In the last month prior to randomization) brain, spinal, or ophthalmic surgery
  • Hemoglobin level < 8 mg/dL or platelet count <75x109/L or hx of Heparin-induced thrombocytopenia
  • Creatinine clearance < 30 mL/min based on Cockcroft Gault equation
  • Acute Hepatitis, Chronic active Hepatitis, Cirrhosis, or an ALT level x3 and/or bilirbin level x2 the upper limit of normal range
  • Uncontrolled HTN (Systolic BP >180 mm Hg or Diastolic BP > 100 mm Hg despite antihypertensive treatment)

The following relate to standard criteria:

  • Bacterial endocarditis
  • Hypersensitivity to the study drugs or to any of their excipients
  • Women of childbearing potential (WOCBP) who do not practice a medically accepted highly effective contraception during the trial and one month beyond (Combined hormonal contraception associated with inhibition of ovulation, Progesterone-only hormonal contraception, IUD, ISU, Bilateral tubal occlusion, Vasectomized partner, Sexual abstinence)
  • Pregnancy or breast feeding
  • Any condition that, as judged by the investigator, would place the subject at increased risk of harm if he/she participated in the trial

Baseline Characteristics

From the Apixban group (n=576)

  • Demographics: Aged 67 YO (Mean) both groups, 49% males
  • Weight - kg: 75.7 +/- 16.1
  • Platelet count <100 000 per mm 3 - no. (%): 21 (3.6)
  • Creatinine clearance <= 50 mL per min - no. (%): 51 (8.9)
  • Qualifying diagnosis of VTE - no. (%)
    • Pulmonary embolism with or without DVT: 304 (52.8)
    • DVT only: 272 (47.2)
    • Symptomatic DVT or PE: 460 (79.9)
    • Incidental DVT or PE: 116 (20.1)
  • Hx of VTE before index event - no. (%): 45 (7.8)
  • Active Cancer - no. (%): 559 (97%)
  • Undergoing Cancer treatment - no. (%)
  • At enrollment: 350 (60.8)
  • During trial period: 344 (59.7)

Interventions

  • Eligible patients assigned randomly in 1:1 ratio to monotherapy for 6 months of either:
    • Apixaban PO 10mg BID x 7 days then 5mg BID thereafter
    • Dalteparin SQ 200 IU/Kg Q Daily for 1 month then 150 IU/Kg Q Daily thereafter (with a max dose of 18,000 IU)
  • Trial drugs were held for platelet count lower than 50 000 per cubic millimeter or any condition with increased risk of bleeding
  • Trial visits were scheduled at enrollment, and at 4 weeks, 3 months, 6 months and 7 months after randomization
  • Evaluation of the primary outcome was done by considering time from randomization until the first recurrent event of VTE or until the occurrence of death unrelated to VTE (Time to last follow-up visit was used if neither occurred)
  • Fine and Gray regression model was used to compute the hazard ratio and two sided 95% confidence intervals for the comparison between Apixaban and Dalteparin after adjustment for competing risk of death unrelated to VTE

Outcomes

Comparisons are Apxiban group vs. Dalteparin group.

Primary Outcomes

Recurrent Venous thromboembolism (Including Proximal DVT of the LE (symptomatic or incidental), Symptomatic DVT of the UE, and PE (symptomatic, incidental or fatal) during the 6 month trial period
32 of 576 (5.6%) vs. 46 of 579 (7.9%) (Hazard ratio 0.63; 95% CI 0.37 - 1.07; p<0.001 for non-inferiority, p =0.09 for superiority)

Secondary Outcomes

Combined cumulative incidence of recurrent VTE or Major Bleeding
8.9% vs 11.4% (Hazard ratio 0.70; 95% CI 0.45 to 1.07)
Clinically relevant non-major bleeding
52 (9.0%) vs. 35 (6.0%) (Hazard ratio 1.42; 95% CI 0.88 to 2.30)
Major Bleeding
22 (3.8%) vs. 23 (3.8%) (Hazard ratio, 0.82; 95% CI 0.40 - 1.69, p=0.60)
Major gastrointestinal bleeding
11 (1.9%) vs. 10 (1.7%)
Major non-gastrointestinal bleeding
11 (1.9%) vs. 13 (2.2%)
Major or clinically relevant non-major bleeding
70 (12.2%) vs. 56 (9.7%) (Hazard ratio 1.16; 95% CI 0.77 to 1.75)
Fatal bleeding episodes
0 vs. 2
Death from any cause
135 (23.4%) vs. 153 (26.4%)

Subgroup Analysis

Via subgroup analysis a significant difference between the use of Apixban and Dalteparin was found in the age group < 65 YO favoring Apixaban use and treatment for recurrent venous thromboembolism.

Adverse Events

From the Apixaban group

  • Most common adverse event was progression of cancer - 72 (12.5%) patients
  • Hemoptysis and thrombocytopenia occurred in 15 (2.6%) and 14 (2.4%) of patients

Criticisms

  • Excluded patient with primary and metastatic brain lesions and included only few patients with cancer of the upper gastrointestinal tract as well as hematological cancers (which were included in the Hokusai VTE Cancer trial and SELECT-D trial).
  • Patients who were receiving strong inducers or inhibitors of P-glycoprotein or CYP3A4 were excluded, a common therapy for patients with cancer, therefore excluding its relatability and creating concern for drug-drug interactions.

Funding

The trial was sponsored by FADOI (Federazione delle Associazioni dei Dirigenti Ospedalieri Internisti) and funded by an unrestricted grant from the Bristol-Myers Squibb-Pfizer Alliance (Per documentation played no role in the design or conduct of the trial, the collection or analysis of the data or the review or editing of the manuscript).

Further Reading

  1. Kearon C et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest 2016. 149:315-52.
  2. Lee AY et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N. Engl. J. Med. 2003. 349:146-53.
  3. NCCN Guidelines on Cancer-Associated Venous Thromboembolic Disease 1.2020