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. Epub 2020-03-29:.
PubMedFull textClinicalTrials.gov

Clinical Question

Is apixaban non-inferior to dalteparin (LMWH) for the treatment of venous thromboembolism (VTE) in cancer patients?

Bottom Line

In patients with cancer, apixaban is as effective as dalteparin for the prevention of VTE recurrence without increasing the risk of bleeding.

Major Points

Patients with cancer are at increased risk for thrombosis as well as bleeding [1]. Low molecular weight heparin (LMWH) has been the mainstay treatment of VTE for patients with cancer [2]. This is due in part to the results of the CLOT trial which provided evidence that dalteparin was superior to warfarin [3]. Patients with the diagnosis of cancer tend to have complex drug regimens, and subcutaneous LMWH utilization adds another layer of drug-burden, complexity and decreases in quality of life (QOL). Converting an injectable anticoagulant to an oral option could improve QOL and reduce patients' therapeutic burden. Direct Oral Anticoagulants (DOACs) are a nascent class of medications approved for VTE treatment; however, they have not been approved in the setting of secondary VTE prevention in patients with cancer [4]. Previous studies in drugs of this class have shown promising evidence, specifically edoxaban (Hokusai VTE) and rivaroxaban (SELECT-D), which leads to the clinical question of whether apixaban could also yield a potential benefit in this setting [5][6]. The results of the CARAVAGGIO trial reveal that apixaban is non-inferior to dalteparin for the secondary prevention of VTE in patients with cancer.

Guidelines

As of August 2020, there are no guidelines published that reflect the results of this trial. The following are examples of guidelines that have issued recommendations on the use of apixaban in patients with cancer.

  • The American College of Chest Physicians (CHEST) guidelines from 2016 still recommend LMWH for the treatment of VTE in cancer patients over vitamin K antagonists (VKA), apixaban, dabigatran, rivaroxaban, and edoxaban.
  • In 2019, the American Society of Clinical Oncology (ASCO) issued an update recommending apixaban for thromboprophylaxis in cancer patients, but not for treatment. Conversely, edoxaban and rivaroxaban are recommended for long-term anticoagulation by ASCO.
  • The National Comprehensive Cancer Network (NCCN) issued an update to its guidelines in 2018, recommending apixaban for the treatment of cancer associated VTE only in patients who refuse or otherwise cannot receive a LMWH.
  • According to The International Initiative on Thrombosis and Cancer (ITAC) 2019 guidelines, edoxaban and rivaroxaban are the preferred DOACs to treat VTE in patients with cancer.

Based on the current states of these guidelines and their recommendations on the use of edoxaban (HOKUSAI VTE) and rivaroxaban (SELECT-D), it is reasonable to suggest that apixaban will achieve similar recommendations after the consideration of the results of CARAVAGGIO.

Design

  • Multinational, Randomized, Controlled, Investigator-Initiated, Open Label, Non-inferiority trial with blinded adjudication of the outcomes.
  • N= 1170
    • Group 1: Assigned to receive Apixaban (n=576)
    • Group 2: Assigned to receive Dalteparin (n=579)
  • Setting: Nine European countries, Israel, and the United States.
  • Enrollment: April 2017 through June 2019
  • Median duration of assigned treatment: 178 days (IQ range, 106 to 183) in the Apixaban group and 175 days (IQ range, 79 to 183) in the Dalteparin group.
  • Analysis: Modified Intention-to-treat
  • Primary outcome: Recurrent Venous Thromboembolism.

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. Cohen AT et al. Epidemiology of first and recurrent venous thromboembolism in patients with active cancer. A population-based cohort study. Thromb. Haemost. 2017. 117:57-65.
  2. Kearon C et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest 2016. 149:315-52.
  3. 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.
  4. Kearon C et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest 2016. 149:315-52.
  5. Büller HR et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N. Engl. J. Med. 2013. 369:1406-15.
  6. Young AM et al. Comparison of an Oral Factor Xa Inhibitor With Low Molecular Weight Heparin in Patients With Cancer With Venous Thromboembolism: Results of a Randomized Trial (SELECT-D). J. Clin. Oncol. 2018. 36:2017-2023.