The Hematologist

January-February 2020, Volume 17, Issue 1

Direct Oral Anticoagulant Thromboprophylaxis Trials for Ambulatory Cancer Patients: Guideline Changing, but Are They Practice Changing?

Lori-Ann Linkins, MD, MSc(Clin Epi), FRCPC Associate Professor
McMaster University, Hamilton, ON, Canada

Published on: January 02, 2020

Recommendations for thromboprophylaxis for cancer patients who are hospitalized or undergoing surgery have been around for decades. So why don’t we routinely offer thromboprophylaxis to ambulatory cancer patients? The answer lies in the risks-versus-benefits ratio.

For hospitalized and postoperative patients with cancer, the reduction in venous thromboembolism (VTE) clearly outweighs the increased risk of bleeding due to anticoagulant therapy. In contrast, the baseline risk of VTE in ambulatory patients with cancer is lower, which makes the risk of bleeding less acceptable. The key therefore is to select ambulatory patients who have a higher than average baseline risk for VTE, thereby tipping the ratio in favor of prophylaxis.

The year 2019 is notable for the publication of two large randomized controlled trials evaluating the use of direct oral anticoagulants (DOACs) for thromboprophylaxis for high-risk ambulatory cancer patients.1,2 In both trials, the Khorana score (leukocyte count, platelet count, hemoglobin or use of red-cell growth factors, body mass index, and tumor type)3 was used to select patients who were about to start or switch chemotherapy regimens in the setting of newly diagnosed or newly progressive cancer. The findings of these trials, an estimated 44 percent risk reduction for VTE, resulted in a change in 2019 cancer practice guidelines (ASH clinical practice guidelines pending).4

The main characteristics of AVERT and CASSINI are outlined in the Table (for a more detailed review of AVERT, see the Diffusion article by Stephan Moll, MD, in the March/April 2019 issue of The Hematologist). Some differences between these two trials are worthy of mention. First, the patient populations differed with respect to cancer types (additionally, CASSINI excluded patients with brain tumors or intracranial metastases). Second, CASSINI had double the number of patients with metastatic cancer than AVERT. Interestingly, despite these differences, the VTE rate in the placebo group of each study was similar. With respect to intervention, both studies included asymptomatic VTE in the primary outcome measure, which is appropriate given that the natural history of symptomatic and asymptomatic VTE in patients with cancer is reported to be similar.5 However, CASSINI used screening ultrasounds pre-randomization every eight weeks to actively search for incidental deep vein thrombosis, which is not part of standard clinical practice. Lastly, while AVERT showed a significant reduction in VTE and increased risk of major bleeding, neither outcome event reached significance in the intention-to-treat analysis of CASSINI.

The results of these two trials are changing cancer guidelines, but will they change clinical practice? Currently, there are several obstacles to wide uptake of prophylaxis for ambulatory cancer patients. First, less than half of the patients screened were enrolled in these studies, and nearly half discontinued the study drug (discontinuation rate did not differ between DOAC and placebo groups). Together, these observations suggest that only a fraction of ambulatory cancer patients will both be eligible and tolerate taking an additional drug. Second, the twofold increased risk of major bleeding is still a concern, especially gastrointestinal and genitourinary bleeding given the results of the DOAC for cancer-associated VTE treatment studies.6,7 Third, there is still potential for DOACs to interact with antineoplastic agents that share the same metabolic pathways. Lastly, but likely one of the largest obstacles, is the cost.

The bottom-line is that ambulatory cancer patients may benefit from receiving thromboprophylaxis with a DOAC, however, they must be carefully selected, motivated, and have a way to cover the cost.

Comparison of AVERT and CASSINI Trials
 AVERT (n=574)CASSINI (n=841)
InterventionApixaban 2.5 mg twice daily vs. placebo for 180 daysRivaroxaban 10 mg once daily vs. placebo for 180 days
Baseline patient characteristicsMean age, 61 years; 58% female; gynecologic, lymphoma, pancreatic*; metastatic, 24%Mean age 63; 49% female; pancreatic, gastrointestinal, lung*; metastatic, 54%
Efficacy outcome measureSymptomatic or incidental proximal DVT of the lower or upper limbs, symptomatic or incidental pulmonary embolism, and pulmonary embolism-related deathSymptomatic or incidental lower limb DVT, symptomatic upper limb DVT, symptomatic distal lower limb DVT, symptomatic or incidental PE or death due to VTE
Venous thromboembolism rate4.2% vs. 10.2%; HR, 0.41 (95% CI, 0.26-0.65)†; p<.001)6.0% and 8.8%; HR, 0.66 (95% CI, 0.40-1.09); p=.10
Major bleeding rate3.5% vs. 1.8%†; HR, 2.00 (95% CI, 1.01 to 3.95); p=.0462.0% vs. 1.0%; HR, 1.96 (95% CI, 0.59 to 6.49); p=.26

Abbreviations: DVT, deep-vein thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism.
*Top three tumor types
†Modified intention-to-treat


  1. Carrier M, Abou-Nassar K, Mallick R, et al. Apixaban to prevent venous thromboembolism in patients with cancer. N Engl J Med. 2019;380:711-719.
  2. Khorana AA, Soff GA, Kakkar AK, et al. Rivaroxaban for thromboprophylaxis in high-risk ambulatory patients with cancer. N Engl J Med. 2019;380:720-728.
  3. Khorana AA, Kuderer NM, Culakova E, et al. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood. 2008;111:4902-4907.
  4. Key NS, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO Clinical Practice Guideline Update. J Clin Oncol. 2019;JCO1901461.
  5. O'Connell C, Razavi P, Ghalichi M, et al. Unsuspected pulmonary emboli adversely impact survival in patients with cancer undergoing routine staging multi-row detector computed tomography scanning. J Thromb Haemost. 2011;9:305-311.
  6. Raskob GE, van Es N, Verhamme P, et al. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018;378:615-624.
  7. Young AM, Marshall A, Thirlwall J, 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.

Conflict of Interests

Dr. Linkins was a data adjudicator for MARINER (rivaroxaban prophylaxis for medical patients). back to top