The AVERT and CASSINI trials evaluated the efficacy and safety of apixaban and rivaroxaban for preventing venous thromboembolism in ambulatory cancer patients at high risk. The trials found that both apixaban and rivaroxaban significantly reduced the risk of VTE compared to placebo, with acceptable rates of major bleeding. However, a large percentage of patients discontinued the anticoagulant therapy. While the results support the use of DOACs for VTE prevention in selected high-risk ambulatory cancer patients, more research is needed focusing on specific cancer types and chemotherapy regimens. Currently, low molecular weight heparin remains the standard for acute medically ill or surgical cancer patients, while

1. CASSINI & AVERT
trials
Fotios Barkas MD
Resident Physician in Internal Medicine
2nd Department of Internal Medicine
University Hospital of Ioannina, Ioannina, Greece

2. Cancer & VTE risk
• 10% of patients with cancer develop VTE
• Tumor-specific factors (increased thrombin generation & procoagulant activity)
• Anatomic factors (infiltration or compression of proximal veins)
• Patient-specific factors (prior VTE, advanced age, obesity & inherited thrombophilia)
• Therapy-associated factors (chemotherapy agents, surgeries)
Risk in hospitalized patients (28-41%)
BUT
80% of VTE events occur in outpatients (Incidence rates: 1.6-3.1%)
Toft Sørensen, et al. N Engl J Med 2000;343:1846-50
Blom, et al. J Thromb Haemost 2006;4:529-35

3. Primary prevention of VTE in outpatients
LMW heparins
50% VTE risk
BUT
Too low difference in absolute risk
• International guidelines propose antithrombotic therapy in high-
risk ambulatory patients with cancer
• Various predictive scores have been developed for VTE risk assessment
(Khorana)
PROTECT
SAVE-ONCO
Cohrane meta-analysis of 5 RCTs
Agnelli , et al. Lancet Oncol 2009;10:943-9
Agnelli G, et al. N Engl J Med 2012;366:601-9
Akl,et al. Cochrane Database Syst Rev 2017; 9:CD006652

5. AVERT & CASSINI trials
Inclusion criteria
• Adult patients with newly diagnosed cancer or progression of known
cancer
• Khorana score ≥2
Exclusion criteria
• Severe renal and liver disease
• Short life expectancy (<6 months)
• Patients with preexisting proximal VTE at baseline (CASSINI trial)
Carrier et al. N Engl J Med. 2019 Feb 21;380(8):711-719
Khorana et al. N Engl J Med 2019;380:720-8

6. AVERT & CASSINI trials
Primary efficacy outcome
• Venous thromboembolism (symptomatic or accidental)
• Pulmonary embolism (symptomatic or accidental)
• Pulmonary embolism related death
Safety outcome
• Overt bleeding
• Decrease in Hb of 2 gr/dL
• Transfusion with ≥2 packed red cells
• Occurred in critical site
• Contributed to death Carrier et al. N Engl J Med. 2019 Feb 21;380(8):711-719
Khorana et al. N Engl J Med 2019;380:720-8

7. Baselinecharacteristics
AVERT CASSINI
Randomized patients 574 841
Assigned anticoagulant therapy (dose) Apixaban (2.5 mg bid) Rivaroxaban (10 mg qd)
Incompliance 240 (41.8%) 395 (47%)
Median duration of treatment period,
months
5.2 4.3
Age, yrs 61.4 63
Male sex, % 42 51
Tumor type
Gynecologic 26 N/A
Lymphoma 25 7
Pancreatic 13 33
Lung 10 16
Gastric 8 21
Khorana score ≥3 (%) 34 31

8. PRIMARY EFFICACY & SAFETY OUTCOMES
HR (95% CI) AVERT CASSINI
Primary efficacy outcome
ITT analysis 0.41 (0.26-0.65) 0.66 (0.40-1.09)
Analysis during treatment period 0.14 (0.05-0.42) 0.40 (0.20-0.80)
Major bleeding
ITT analysis 2 (1.01-3.95) 1.96 (0.59-6.49)
Analysis during treatment period 1.89 (0.39-9.24) N/A
Death from any cause 1.29 (0.98-1.71) 0.83 (0.62-1.11)
Carrier et al. N Engl J Med. 2019 Feb 21;380(8):711-719
Khorana et al. N Engl J Med 2019;380:720-8

9. AVERT trial
• Major bleeding rates: gastrointestinal bleeding, hematuria and
gynecologic bleeding
• No difference was found regarding severe major bleeding rates
CASSINI trial
• 39% of all the primary end-point events occurred in patients who
discontinued the trial regimen
Carrier et al. N Engl J Med. 2019 Feb 21;380(8):711-719
Khorana et al. N Engl J Med 2019;380:720-8

10. Giancarlo et al. N Engl J Med. 2019 Feb 21;380(8):781-783

11. Limitations
• Common cancers, such as colorectal, breast and prostate cancers,
were underrepresented
• Khorana score has a low predictive role in some cancer types (ie.
Lung)
• No data on chemotherapy regiments
• A high percentage of patients discontinued anticoagulant therapy
Carrier et al. N Engl J Med. 2019 Feb 21;380(8):711-719
Khorana et al. N Engl J Med 2019;380:720-8
Giancarlo et al. N Engl J Med. 2019 Feb 21;380(8):781-783

12. Take home messages
• Apixaban and rivaroxaban seem to be effective and safe in
ambulatory patients with cancer at high VTE risk
• Need for future studies involving patients with individual types
of cancer
UNTIL THEN….
• LMWH is strongly suggested in
• acute medically ill patients
• patients undergoing surgery
• LMWH or DOACs could be considered in
• ambulatory patients at increased VTE risk