Highlights
The age-adjusted D-dimer cutoff (age × 10 µg/L for patients 50 years or older) has been prospectively validated to safely rule out deep vein thrombosis (DVT) in outpatients. In the multicenter ADJUST-DVT study, no symptomatic venous thromboembolic events were identified during a 3-month follow-up in patients ruled out using the adjusted threshold. This diagnostic strategy significantly increases the proportion of elderly patients in whom DVT can be ruled out without the need for leg compression ultrasonography, tripling the diagnostic yield in those aged 75 and older.
Introduction: The Diagnostic Dilemma of D-Dimer and Aging
In the diagnostic workup of suspected venous thromboembolism (VTE), the D-dimer test serves as a cornerstone for ruling out disease in patients with a low or moderate clinical pretest probability. However, the conventional fixed cutoff of 500 µg/L faces a significant physiological challenge: D-dimer levels naturally increase with age, even in the absence of thrombosis. This age-related rise in fibrin degradation products leads to a high frequency of false-positive results in elderly populations, necessitating expensive and time-consuming imaging such as leg compression ultrasonography.
The Evolution of Age-Adjusted Thresholds
To address this limitation, researchers previously developed and validated an age-adjusted D-dimer cutoff for patients suspected of pulmonary embolism (PE). By using the formula of age multiplied by 10 µg/L for patients aged 50 and older, clinicians were able to maintain high sensitivity while improving specificity. However, until recently, this strategy had not been rigorously validated in a prospective management study specifically for deep vein thrombosis. The ADJUST-DVT trial was designed to fill this gap in evidence, providing clinicians with the data needed to apply this approach to suspected leg DVT.
Study Design and Methodology
The ADJUST-DVT study was a multicenter, multinational prospective management outcome study conducted across 27 centers in Belgium, Canada, France, and Switzerland. Between January 2015 and October 2022, researchers enrolled outpatients presenting to emergency departments with symptoms suggestive of DVT.
Diagnostic Algorithm
The study utilized a sequential diagnostic strategy. First, patients were assessed for clinical pretest probability using the Wells score. Patients were categorized as having a high probability or a non-high (unlikely) probability. Second, all patients underwent a highly sensitive D-dimer test. If a patient had a non-high clinical probability and a D-dimer level below the age-adjusted cutoff (age × 10 µg/L for those ≥50 years; 500 µg/L for those <50 years), DVT was ruled out, and no further imaging was performed. Patients with D-dimer levels above the cutoff or a high clinical probability proceeded to leg compression ultrasonography.
Follow-up and Primary Outcome
The primary safety outcome was the rate of adjudicated symptomatic VTE (either DVT or PE) during a 3-month follow-up period in patients in whom DVT was initially ruled out based on a D-dimer level between the conventional 500 µg/L cutoff and the age-adjusted cutoff. This group represents the cohort that would have undergone imaging under traditional guidelines but was spared imaging under the new protocol.
Key Findings: Safety and Efficiency
A total of 3205 patients were included in the final analysis, with a median age of 59 years. The prevalence of DVT in the study population was 14%. Among the 2169 patients with a non-high or unlikely clinical probability, 531 (24.5%) had a D-dimer level below the traditional 500 µg/L cutoff. An additional 161 patients (7.4%) had a D-dimer level between 500 µg/L and their specific age-adjusted cutoff.
Safety Outcomes
The most critical finding of the study was the safety of the adjusted cutoff. Among the 161 patients who were ruled out solely because of the age-adjusted threshold, there were zero symptomatic VTE events during the 3-month follow-up (0%; 95% CI, 0%-2.3%). This confirms that the age-adjusted strategy does not compromise patient safety compared to the traditional fixed cutoff.
Diagnostic Yield in the Elderly
The impact of this strategy was most pronounced in the elderly population. For patients aged 75 years or older, the proportion of negative D-dimer results increased dramatically. Under the conventional 500 µg/L cutoff, only 8.7% (33 of 379) of these patients would have been ruled out without imaging. By applying the age-adjusted cutoff, this figure rose to 26.1% (99 of 379), effectively tripling the number of elderly patients who could safely avoid ultrasound examination.
Expert Commentary: Clinical Integration and Practical Implications
The results of the ADJUST-DVT trial provide high-level evidence that the age-adjusted D-dimer strategy is as safe for DVT as it is for PE. For clinicians in the emergency department and primary care settings, this finding simplifies the diagnostic workup of VTE by allowing a unified age-adjustment rule across both DVT and PE suspected cases.
Biological Plausibility and Specificity
The success of age-adjustment lies in its ability to account for the subclinical activation of the coagulation system and the decrease in renal clearance of fibrin fragments that occurs with advancing age. By shifting the threshold upward in older adults, the test regains the specificity it loses when a rigid 500 µg/L limit is applied to all adults regardless of age.
Limitations and Generalizability
While the study is robust, it is important to note that it focused on outpatients in emergency settings. The generalizability to hospitalized patients, who often have comorbid conditions that independently elevate D-dimer levels (such as malignancy or recent surgery), remains to be fully established. Furthermore, the strategy relies on the use of highly sensitive D-dimer assays; clinicians must ensure that the laboratory tests used in their specific institutions meet these sensitivity standards before implementing age-adjustment.
Conclusion
The ADJUST-DVT study represents a significant step forward in evidence-based VTE management. By demonstrating that an age-adjusted D-dimer cutoff is safe and effective for ruling out DVT, the researchers have provided a tool that reduces unnecessary healthcare utilization and minimizes the burden of diagnostic imaging on elderly patients. As healthcare systems continue to strive for high-value care, the adoption of age-adjusted D-dimer thresholds stands as a prime example of optimizing diagnostic pathways without sacrificing clinical safety.
Funding and Trial Registration
The study was supported by various national research grants from the participating countries. Trial Registration: ClinicalTrials.gov Identifier: NCT02384135.
References
Le Gal G, Robert-Ebadi H, Thiruganasambandamoorthy V, et al. Age-Adjusted D-Dimer Cutoff Levels to Rule Out Deep Vein Thrombosis. JAMA. Published online January 5, 2026. doi:10.1001/jama.2025.21561.
