Risk-Directed Ambulatory Thromboprophylaxis in Lung and Gastrointestinal Cancers: The TARGET-TP Randomized Clinical Trial

Abstract

Importance: Thromboprophylaxis for individuals receiving systemic anticancer therapies has proven to be effective. Potential to maximize benefits relies on improved risk-directed strategies, but existing risk models underperform in cohorts with lung and gastrointestinal cancers.

Objective: To assess clinical benefits and safety of biomarker-driven thromboprophylaxis and to externally validate a biomarker thrombosis risk assessment model for individuals with lung and gastrointestinal cancers.

Design, setting, and participants: This open-label, phase 3 randomized clinical trial (Targeted Thromboprophylaxis in Ambulatory Patients Receiving Anticancer Therapies [TARGET-TP]) conducted from June 2018 to July 2021 (with 6-month primary follow-up) included adults aged 18 years or older commencing systemic anticancer therapies for lung or gastrointestinal cancers at 1 metropolitan and 4 regional hospitals in Australia. Thromboembolism risk assessment based on fibrinogen and d-dimer levels stratified individuals into low-risk (observation) and high-risk (randomized) cohorts.

Interventions: High-risk patients were randomized 1:1 to receive enoxaparin, 40 mg, subcutaneously daily for 90 days (extending up to 180 days according to ongoing risk) or no thromboprophylaxis (control).

Main outcomes and measures: The primary outcome was objectively confirmed thromboembolism at 180 days. Key secondary outcomes included bleeding, survival, and risk model validation.

Results: Of 782 eligible adults, 328 (42%) were enrolled in the trial (median age, 65 years [range, 30-88 years]; 176 male [54%]). Of these participants, 201 (61%) had gastrointestinal cancer, 127 (39%) had lung cancer, and 132 (40%) had metastatic disease; 200 (61%) were high risk (100 in each group), and 128 (39%) were low risk. In the high-risk cohort, thromboembolism occurred in 8 individuals randomized to enoxaparin (8%) and 23 control individuals (23%) (hazard ratio [HR], 0.31; 95% CI, 0.15-0.70; P = .005; number needed to treat, 6.7). Thromboembolism occurred in 10 low-risk individuals (8%) (high-risk control vs low risk: HR, 3.33; 95% CI, 1.58-6.99; P = .002). Risk model sensitivity was 70%, and specificity was 61%. The rate of major bleeding was low, occurring in 1 participant randomized to enoxaparin (1%), 2 in the high-risk control group (2%), and 3 in the low-risk group (2%) (P = .88). Six-month mortality was 13% in the enoxaparin group vs 26% in the high-risk control group (HR, 0.48; 95% CI, 0.24-0.93; P = .03) and 7% in the low-risk group (vs high-risk control: HR, 4.71; 95% CI, 2.13-10.42; P < .001).

Conclusions and relevance: In this randomized clinical trial of individuals with lung and gastrointestinal cancers who were stratified by risk score according to thrombosis risk, risk-directed thromboprophylaxis reduced thromboembolism with a desirable number needed to treat, without safety concerns, and with reduced mortality. Individuals at low risk avoided unnecessary intervention. The findings suggest that biomarker-driven, risk-directed primary thromboprophylaxis is an appropriate approach in this population.

Trial registration: ANZCTR Identifier: ACTRN12618000811202.

Figure 1.. CONSORT Diagram

Of the 270 participants who were ineligible, 5 were excluded after signing consent (before randomization) due to demonstrable indications for therapeutic anticoagulation, including detected thromboembolism (n = 3) or known cardiac conditions (n = 2). Of the 128 participants in the low-risk observational arm, 35 had lung cancer and 93 had gastrointestinal cancer. Of the 200 participants in the high-risk arm, 92 had lung cancer and 108 had gastrointestinal cancer. Of the 100 participants assigned to receive enoxaparin and the 100 in the control group, each arm included 46 participants with lung cancer and 54 with gastrointestinal cancer. CRNM indicates clinically relevant nonmajor.

Figure 2.. Cumulative Thromboembolism Incidence Within 180 Days According to Thromboembolism Risk Classification and Randomization

HR indicates hazard ratio.

Figure 3.. Thromboembolism, Bleeding, Cancer Progression, and All-Cause Mortality Within 180 Days in the Intention-to-Treat Randomized Population and Low-Risk Population According to Subgroup

The intention-to-treat population included all eligible participants classified as being at high risk of thromboembolism who underwent randomization and eligible participants classified as low risk. Markers indicate hazard ratios, and horizontal lines indicate 95% CIs. CRNM indicates clinically relevant nonmajor; GI, gastrointestinal; PY, person-years. ^aP = .10 for interaction (GI vs lung cancer). ^bP = .65 for interaction (GI vs lung cancer). ^cP = .52 for interaction (GI vs lung cancer). ^dP = .63 for interaction (GI vs lung cancer). ^eP = .29 for interaction (GI vs lung cancer). ^fP = .93 for interaction (GI vs lung cancer).

Figure 4.. Cumulative Incidence of All-Cause Mortality and Cancer Progression Within 180 Days According to Thromboembolism Risk Classification and Randomization

HR indicates hazard ratio.