TRACK
Low-Dose Rivaroxaban and Cardiovascular Events in Advanced Kidney Disease: The TRACK Randomized Clinical Trial
Clinical Question
Does low-dose rivaroxaban (2.5 mg twice daily) reduce major adverse cardiovascular events compared with placebo in patients with advanced chronic kidney disease?
Bottom Line
In patients with advanced CKD (stage 4/5 or dialysis-dependent) at high cardiovascular risk, low-dose rivaroxaban did NOT reduce cardiovascular events and significantly increased major bleeding. Low-dose rivaroxaban monotherapy should not be used for cardiovascular event prevention in this population.
Major Points
- First large RCT of low-dose rivaroxaban in advanced CKD (stage 4/5 including dialysis)
- No cardiovascular benefit: primary composite outcome 22.6% vs 20.7% (HR 1.09, P=.46)
- Significant harm: major bleeding 8.8% vs 6.0% (HR 1.51, 95% CI 1.02-2.22, P=.04)
- Trial stopped early on August 7, 2025 for lack of efficacy on DSMB recommendation
- TRACK tested rivaroxaban monotherapy, not the COMPASS-style rivaroxaban + aspirin regimen; whether the combination with aspirin is effective in advanced CKD remains untested
Design
Study Type: Randomized, double-blind, placebo-controlled clinical trial
Randomization: 1
Blinding: Double-blind (participants, investigators, study coordinators, site pharmacists, treating physicians, outcome assessors all blinded)
Allocation: 1:1 via password-protected web-based system using covariate-balancing adaptive allocation algorithm minimizing imbalances by study site, aspirin use at randomization, CKD stage, and diabetes status
Enrollment Period: January 18, 2021 to July 31, 2025
Follow-up Duration: Median 1.7 years; final follow-up October 30, 2025
Centers: 90
Countries: Australia, Belgium, Canada, France, Germany, India, Malaysia, Nepal, Saudi Arabia, Singapore, Taiwan, Tunisia
Sample Size: 1458
Analyzed: 1458
Analysis: Intention-to-treat; shared-frailty Cox model with random site effect, including 3 stratification variables (baseline aspirin use, CKD stage, diabetes) as fixed covariates. Final significance level set at 2-sided 4.86% accounting for 1 interim analysis. Holm-Sidak step-down for 5 secondary outcomes.
Power Calculation: Original plan: 1900 participants to detect 25% risk reduction (HR 0.75), assuming placebo event rate 10/100 person-years, 90% power, 2-sided alpha 5%; required 515 primary events (also 80% power for 22% reduction, HR 0.78). Trial stopped early at 1458 patients for lack of efficacy.
Registration: ClinicalTrials.gov NCT03969953
Inclusion Criteria
- Adults ≥18 years
- Dialysis-dependent kidney failure OR CKD stage 4/5 not on kidney replacement therapy (eGFR ≤29 mL/min/1.73 m²)
- Increased cardiovascular risk defined by ≥1 of: coronary artery disease, nonhemorrhagic/nonlacunar stroke, peripheral artery disease, diabetes, or age ≥65 years
- Successful completion of run-in phase (≥80% adherence to placebo over 21 days [range 14-30])
Exclusion Criteria
- Mechanical or prosthetic heart valve (other than bioprosthetic)
- Indication for or contraindication to anticoagulant therapy
- High bleeding risk per treating clinician
- Lesion/condition significantly associated with major bleeding risk
- Major bleeding within past 30 days or active major bleeding
- History of hemorrhagic or lacunar stroke; any stroke within past month
- Treatment with P2Y12 inhibitor or phosphodiesterase inhibitor that cannot be discontinued
- Concurrent strong inhibitors of combined CYP3A4 and P-glycoprotein or strong CYP3A4 inducers
- Severe heart failure (LVEF <30% or NYHA class III/IV)
- Uncontrolled hypertension at screening (SBP >180 or DBP >110 mm Hg)
- Hemoglobin <90 g/L, platelet count <100 × 10⁹/L
- Significant liver disease (Child-Pugh B or C), ALT >3× ULN
- Kidney transplant with functioning allograft or scheduled living-donor transplant
- Pregnancy or intention to become pregnant or breastfeed (premenopausal women excluded in Europe)
- Inability to understand or comply with study requirements
- Atrial fibrillation (unless therapeutic anticoagulation not indicated)
Arms
| Field | Low-dose rivaroxaban | Control |
|---|---|---|
| N | 727 | 731 |
| Intervention | Rivaroxaban 2.5 mg twice daily | Matching placebo twice daily |
| Duration | Median 1.7 years (trial stopped early) | Median 1.7 years (trial stopped early) |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or nonfatal peripheral artery disease event | Primary | 151/731 (20.7%); 11.8 events per 100 person-years | 164/727 (22.6%); 13.0 events per 100 person-years | 1.09 | 0.46 |
| All-cause mortality | Secondary | 186/727 (25.6%) rivaroxaban vs 168/731 (23.0%) placebo; 13.9 vs 12.4 events per 100 person-years; HR 1.14 (95% CI 0.92-1.40); Holm-Šídák P=.66 | |||
| Cardiovascular death (component of primary composite) | Secondary | 112/727 (15.4%) vs 97/731 (13.3%); 8.4 vs 7.1 per 100 person-years; HR 1.18 (95% CI 0.89-1.55); P=.68 | |||
| Nonfatal myocardial infarction (component of primary composite) | Secondary | 39/727 (5.4%) vs 41/731 (5.6%); 3.0 vs 3.1 per 100 person-years; HR 0.94 (95% CI 0.60-1.45); P=.77 | |||
| Nonfatal stroke (component of primary composite) | Secondary | 19/727 (2.6%) vs 16/731 (2.2%); 1.4 vs 1.2 per 100 person-years; HR 1.19 (95% CI 0.61-2.31); P=.85 (ischemic/uncertain 14 vs 14; hemorrhagic 5 vs 2) | |||
| Nonfatal peripheral artery disease event (component of primary composite) | Secondary | 15/727 (2.1%) vs 22/731 (3.0%); 1.1 vs 1.6 per 100 person-years; HR 0.69 (95% CI 0.36-1.34); P=.62 | |||
| Composite of CV death, nonfatal MI, or stroke | Secondary | 154/727 (21.1%) vs 137/731 (18.7%); 12.0 vs 10.5 per 100 person-years; HR 1.14 (95% CI 0.90-1.44) | |||
| Composite of all-cause mortality, nonfatal MI, or stroke | Secondary | 220/727 (30.3%) vs 201/731 (27.4%); 17.2 vs 15.4 per 100 person-years; HR 1.12 (95% CI 0.92-1.35) | |||
| Composite of all-cause mortality, nonfatal MI, stroke, or PAD event | Secondary | 228/727 (31.4%) vs 212/731 (29.0%); 18.0 vs 16.6 per 100 person-years; HR 1.08 (95% CI 0.90-1.31) | |||
| Venous thromboembolism | Secondary | 4/727 (0.6%) vs 14/731 (1.9%); 0.3 vs 1.0 per 100 person-years; HR 0.29 (95% CI 0.09-0.87) | |||
| Major bleeding (composite of fatal bleeding, symptomatic bleeding into critical area/organ, bleeding into surgical site requiring reoperation, or bleeding leading to hospitalization) | Safety | 44/731 (6.0%); 3.4 events per 100 person-years | 64/727 (8.8%); 5.1 events per 100 person-years | 1.51 | 0.04 |
| Gastrointestinal bleeding | Safety | 17/731 (2.3%); 1.3 events per 100 person-years | 29/727 (4.0%); 2.2 events per 100 person-years | 1.76 | 0.07 |
| Adverse | 335 patients (45.8%); 936 events | 367 patients (50.5%); 934 events | |||
| Adverse | 3 patients | 6 patients | |||
| Adverse | 17 patients (2.3%); 27 events | 29 patients (4.0%); 33 events | |||
Subgroup Analysis
Primary outcome consistent across prespecified subgroups (age, sex, country/region, aspirin use, diabetes, CKD stage, smoking). Bleeding risk was higher in patients ≥65 years (rivaroxaban 10%, placebo 5.6%) vs <65 years (rivaroxaban 7.3%, placebo 6.4%); interaction P=.03.
Criticisms
- Trial stopped early for lack of efficacy at 1458 of planned 1900 patients, which may limit precision for secondary and subgroup analyses
- Median follow-up of only 1.7 years may be insufficient to detect long-term cardiovascular benefits
- Aspirin use at baseline was a stratification variable but the combination effect (vs COMPASS regimen of rivaroxaban + aspirin) is not clearly separable in this abstract
- Broad inclusion criteria (age ≥65 alone qualifies) may dilute treatment effect in truly high-risk patients
- High rate of permanent study drug discontinuation (28.2%) may have reduced the ability to detect benefit
- Very few Black participants enrolled (0 rivaroxaban, 5 [0.7%] placebo) and no US sites participated, limiting generalizability to these populations
Funding
NHMRC of Australia (2018/GNT1162375), French Ministry of Health Programme Hospitalier de Recherche Clinique (PHRC-19-0112), and Deutsche Forschungsgemeinschaft (506165771). Rivaroxaban 2.5 mg and placebo tablets provided free by Bayer AG through Investigator-Initiated Research Support Scheme. Funders had no role in design, analysis, or manuscript preparation.
Based on: TRACK (JAMA, 2026)
Authors: Badve SV, Perkovic V, Jha V, ..., Gallagher M; for the TRACK Trial Investigators
Citation: JAMA. 2026;336(4):296-305. doi:10.1001/jama.2026.9379
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