Extended Reduced-Dose Apixaban for Cancer-Associated Venous Thromboembolism (API-CAT)

Authors, Journal, Affiliations, Type, DOI

• Authors: Isabelle Mahé, Marc Carrier, Didier Mayeur, et al. (API-CAT Investigators); 36 investigators across Europe, Canada, and Australia
• Journal: New England Journal of Medicine, Vol. 392:1363-73
• Affiliations: AP-HP (Paris), Ottawa Hospital Research Institute, and 121 centers across 11 countries
• Type: International prospective double-blind randomized noninferiority trial with blinded central outcome adjudication
• DOI: https://doi.org/10.1056/NEJMoa2416112
• Funding: Bristol-Myers Squibb–Pfizer Alliance (drug supply only; no role in design, analysis, or writing); ClinicalTrials.gov NCT03692065

Overview

The API-CAT trial randomized 1,766 patients with active cancer who had completed at least 6 months of anticoagulation for proximal DVT or PE to either reduced-dose apixaban (2.5 mg BID) or full-dose apixaban (5.0 mg BID) for 12 months. Reduced-dose apixaban was noninferior to full-dose for preventing recurrent VTE (2.1% vs 2.8%; SHR 0.76; 95% CI 0.41–1.41; P=0.001) and achieved significantly lower clinically relevant bleeding (12.1% vs 15.6%; SHR 0.75; P=0.03 superiority). This is the first RCT to establish that dose-reduced extended anticoagulation after the initial 6 months can maintain VTE protection while reducing bleeding in cancer patients.

Keywords

Cancer-associated thrombosis, apixaban, venous thromboembolism, extended anticoagulation, reduced dose, noninferiority, bleeding, pulmonary embolism, deep-vein thrombosis, active cancer

Key Takeaways

Background and Rationale

• Cancer patients remain at elevated risk for recurrent VTE after completing 6 months of anticoagulation; guidelines recommend continuing anticoagulation while cancer remains active or treatment is ongoing
• Balancing VTE recurrence prevention against ongoing bleeding risk during extended therapy is a key unresolved clinical challenge
• Dose-reduced apixaban (2.5 mg BID) is effective for extended VTE prophylaxis in non-cancer patients (AMPLIFY-EXT trial, 2013) but had not been prospectively tested specifically in the cancer setting

Study Design

• International, prospective, double-blind, noninferiority trial with blinded central adjudication
• N=1,766 patients randomized 1:1 at 121 centers in 11 countries (Oct 2018–Sep 2023)
• Eligibility: Active cancer + proximal DVT of lower limb (popliteal or above) or symptomatic/incidental PE in a segmental or larger artery; completed ≥6 months of anticoagulation (LMWH, DOAC, or VKA) without symptomatic recurrence
• Intervention: Reduced-dose apixaban 2.5 mg BID vs full-dose 5.0 mg BID × 12 months (double-dummy design)
• Stratification: Trial center, index event (PE ± DVT vs isolated proximal DVT), cancer site (breast/prostate/colorectal/lung/other)
• Noninferiority margin: Upper boundary of 95% CI of subhazard ratio ≤2.00 (based on AMPLIFY-EXT; preserving 50% of full-dose effect over placebo)
• Primary efficacy outcome: Fatal or nonfatal recurrent VTE at 12 months (centrally adjudicated)
• Key secondary outcome: Clinically relevant bleeding (major + clinically relevant nonmajor) — assessed for superiority if noninferiority met

Patient Characteristics

• Median age 69 years (IQR 61–75); 43.4% male
• Most frequent cancer sites: breast 22.7%, colorectal 15.2%, gynecologic 12.1%, lung 11.3%
• 75.5% had PE as index event (with or without DVT); 24.5% isolated proximal DVT
• Median time since index VTE: 8.0 months (IQR 6.5–12.6) — most enrolled slightly beyond 6-month window
• Pre-enrollment anticoagulation: LMWH 54.8%, DOAC 43.6%, VKA 1.2%, fondaparinux 0.4%
• 92.6% had ECOG performance score 0 or 1 (low disability)
• Median treatment duration: 11.9 months reduced-dose vs 11.8 months full-dose

Primary Efficacy Outcome — Recurrent VTE

• Reduced-dose group: 18 events, cumulative incidence 2.1%
• Full-dose group: 24 events, cumulative incidence 2.8%
• Adjusted SHR 0.76 (95% CI 0.41–1.41; P=0.001 for noninferiority; prespecified margin 2.00) ✓
• Per-protocol analysis consistent with intention-to-treat
• No fatal pulmonary embolism confirmed objectively in either group
• 5 unexplained sudden deaths (3 reduced-dose, 2 full-dose) for which PE could not be ruled out

Key Secondary Outcome — Clinically Relevant Bleeding

• Reduced-dose group: 102 events, cumulative incidence 12.1%
• Full-dose group: 136 events, cumulative incidence 15.6%
• Adjusted SHR 0.75 (95% CI 0.58–0.97; P=0.03 for superiority) ✓
• Major bleeding: 2.9% (reduced) vs 4.3% (full); SHR 0.66 (95% CI 0.40–1.10; NS but directionally consistent)
• Major GI bleeding: upper GI 6 vs 13 patients; lower GI 7 vs 13 patients
• Fatal bleeding: 2 in each group
• Clinically relevant nonmajor bleeding: 10.0% vs 12.3% (SHR 0.79; 95% CI 0.59–1.05; NS)
• Subgroup analyses consistent across all prespecified subgroups

Secondary Outcomes and Net Clinical Benefit

• Major VTE recurrence (PE or proximal DVT): 2.0% vs 2.4% (SHR 0.83; NS)
• 12-month all-cause mortality: 17.7% vs 19.6% (adjusted HR 0.96; 95% CI 0.86–1.06; NS); ~82–85% of deaths cancer-related
• Net clinical benefit composite (recurrent symptomatic VTE + major bleeding + death): 19.9% vs 22.1% (HR 0.96; 95% CI 0.87–1.07; NS)
• Serious adverse events: 39.8% (reduced) vs 43.8% (full) — numerically lower with reduced dose
• Mortality was lower than in first-6-month cancer VTE trials, reflecting selection for patients who survived index event

Discussion Points

• Recurrent VTE rates were lower than the anticipated 4% annual rate (used in power calculation), potentially due to inclusion of incidental VTE events and favorable tumor subtypes (breast cancer 22.7%)
• Results are consistent with EVE trial (McBane 2024) and Hokusai-VTE post-hoc edoxaban data showing low recurrence in extended-treatment phase
• High ongoing bleeding risk (>12% at 12 months) emphasizes the importance of dose optimization during extended therapy
• No ethnic group data due to legal constraints in France (data limitation)
• Trial only covers 12 months of extended treatment; optimal duration and efficacy/safety of >12 months of extended reduced-dose therapy remains unknown

Limitations of the Document

• No data on treatment effects by ethnic group (French legal constraints on race/ethnicity data collection)
• Only 12 months of extended anticoagulation data; longer-term outcomes beyond 24 months from index event unknown
• Recurrence rate (2.1–2.8%) lower than anticipated 4% — possible inclusion of lower-risk patients (incidental VTE, breast cancer); may affect generalizability to higher-risk populations
• No data on LVEF, echocardiography, or cardiac biomarkers (not a cardiac outcomes trial)
• Open-label choice of LMWH vs DOAC vs VKA during initial 6 months may introduce selection bias for patients enrolled
• Noninferiority design with wide margin (2.00) — upper CI 1.41 is reassuring but trial was not powered to exclude smaller differences in efficacy

Key Concepts Mentioned

• concepts/Cancer-Associated-VTE — primary topic: extended anticoagulation strategy beyond 6 months, efficacy/safety of reduced-dose apixaban
• Extended anticoagulation duration in cancer — guidelines recommend continuing while cancer is active; API-CAT provides first RCT data
• Noninferiority trial design — SHR framework with competing risk of death (Fine and Gray regression model)

Key Entities Mentioned

• Apixaban — direct oral factor Xa inhibitor; tested at 2.5 mg BID (reduced) vs 5.0 mg BID (full) in this trial

Wiki Pages Updated

• wiki/sources/reduced-apixaban-apicat-nejm-2025.md — created
• wiki/concepts/Cancer-Associated-VTE.md — updated with API-CAT extended anticoagulation data
• wiki/sourceindex.md — updated
• wiki/wikiindex.md — updated