Trial updates In thromboprophylaxis of cancer-related venous thromboembolism

 

The past decade has seen a large number of studies focusing on identifying cancer patients at high risk for venous thromboembolism (VTE). This interest peaked after large trials focused on identifying patients simply based on site of cancer for thromboprophylaxis did not report high enough rates of VTE to alter clinical practice. Current trials are adopting a risk-stratified approach to finding high-risk patients for prophylaxis. Proof-of-concept of this approach was obtained from results of the PHACS trial and a pooled analysis of this study, along with subgroup analyses of the PROTECHT and SAVE-ONCO trials, which were published in 2017 [pooled relative risk for VTE with thromboprophylaxis was 0.41 (95% CI: 0.22 to 0.78; p = 0.006)][1]. A recent individual patient-level meta-analysis of multiple randomized trials similarly evaluated the efficacy and safety of LMWH among patients with a high-risk score[2]. Among high-risk patients, LMWH decreased the risk of VTE by 64% compared to placebo or observation (OR 0.36; 95%-CI, 0.22-0.58). Overall, therefore, these published data provide support for outpatient prophylaxis in patients with a score of 3 or higher.

Two ongoing studies are seeking to expand this by focusing on patients with a score of 2 or higher. CASSINI is a double-blind, randomized, parallel-group, multicenter trial of rivaroxaban versus placebo in adult ambulatory cancer patients initiating systemic cancer therapy and score ≥ 2[3]. Approximately 700 patients will be randomized 1:1 to rivaroxaban 10 mg daily or placebo for up to 6 months if there is no evidence of VTE from compression ultrasonography (CU) during screening or from routine care imaging within 30 days prior to randomization. Mandatory CU will also be performed at weeks 8 and 16 (±7 days), and at study end (±3 days). The primary efficacy hypothesis is that anticoagulation with rivaroxaban reduces the composite of objectively confirmed symptomatic or asymptomatic, lower-extremity, proximal deep-vein thrombosis (DVT); symptomatic, upper-extremity DVT; symptomatic or incidental pulmonary embolism; and VTE-related death compared with placebo. The primary safety objective is to assess major bleeding events. The study is currently enrolling and it is anticipated that results from CASSINI will be available by end-2018 or early 2019.

AVERT (NCT02048865) is a similar study, focusing on ambulatory solid tumor patients with a cut-off of 2 or higher but using apixaban 2.5 mg twice daily for 6 months as the prophylactic agent, with a planned study population of 574 patients. A major difference is that this study does not include CU screening either at baseline or while on study. This study is also currently actively enrolling, primarily in Canada, and results are anticipated in 2019 as well.

CAT IQ (NCT02195232) is an ongoing study to evaluate the benefit of an unconventional approach using isoquercetin, an oral flavonoid, in preventing VTE in three specific cancers: pancreas, lung and colorectal. This study has a lead-in phase II portion to identify the appropriate dose, and a phase III portion designed to reduce cumulative rates of VTE in these three malignancies when compared to placebo. This study is also actively enrolling.

Finally, the role of inpatient thromboprophylaxis in cancer patients has not been fully investigated, with a majority of data derived from studies in predominantly non-cancer populations. One pilot randomized study is addressing this knowledge gap by evaluating the benefit of two doses of enoxaparin: the standard 40 mg prophylactic dose versus a weight-based dose of 1 mg/kg to select the appropriate dose for a larger randomized trial in the future.

Together, these studies should report out in the next several months and hopefully these data will allow clinicians to appropriately select patients for targeted thromboprophylaxis with the important goal of reducing the burden and consequences of VTE for patients with cancer.


REFERENCES

  1. Khorana AA, Francis CW, Kuderer NM, Carrier M, Ortel TL, Wun T, et al. Dalteparin thromboprophylaxis in cancer patients at high risk for venous thromboembolism: A randomized trial. Thromb Res. 2017 Mar;151:89-95. PubMed PMID: 28139259.
  2. Van Es N, Ventresca M, Zhou Q, Noble S, Crowther M, Di Nisio M, et al. The Khorana Score for the Prediction of Venous Thromboembolism in Patients with Solid Cancer: An Individual Patient Data Meta-Analysis. Blood. 2017;627.
  3. Khorana A, Vadhan-Raj S, Kuderer NM, Wun T, Liebman H, Soff G, et al. Rivaroxaban for Preventing Venous Thromboembolism in High-Risk Ambulatory Patients with Cancer: Rationale and Design of the CASSINI Trial. Rationale and Design of the CASSINI Trial. Thromb Haemost. 2017 Sep 21;117(11). PubMed PMID: 28933799.

 

  • Alok Khorana

    Alok Khorana

    Professor of Medicine, Cleveland Clinic Lerner College of Medicine, Director of the Gastrointestinal Malignancies Program at the Cleveland Clinic, Cleveland, Ohio
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