Henrike J. Schouten

Diagnostic accuracy of conventional or age adjusted D-dimer cut-off values in older patients with suspected venous thromboembolism: systematic review and meta-analysis

Objective To review the diagnostic accuracy of D-dimer testing in older patients (>50 years) with suspected venous thromboembolism, using conventional or age adjusted D-dimer cut-off values. Design Systematic review and bivariate random effects meta-analysis. Data sources We searched Medline and Embase for studies published before 21 June 2012 and we contacted the authors of primary studies. Study selection Primary studies that enrolled older patients with suspected venous thromboembolism in whom D-dimer testing, using both conventional (500 µg/L) and age adjusted (age×10 µg/L) cut-off values, and reference testing were performed. For patients with a non-high clinical probability, 2×2 tables were reconstructed and stratified by age category and applied D-dimer cut-off level. Results 13 cohorts including 12 497 patients with a non-high clinical probability were included in the meta-analysis. The specificity of the conventional cut-off value decreased with increasing age, from 57.6% (95% confidence interval 51.4% to 63.6%) in patients aged 51-60 years to 39.4% (33.5% to 45.6%) in those aged 61-70, 24.5% (20.0% to 29.7% in those aged 71-80, and 14.7% (11.3% to 18.6%) in those aged >80. Age adjusted cut-off values revealed higher specificities over all age categories: 62.3% (56.2% to 68.0%), 49.5% (43.2% to 55.8%), 44.2% (38.0% to 50.5%), and 35.2% (29.4% to 41.5%), respectively. Sensitivities of the age adjusted cut-off remained above 97% in all age categories. Conclusions The application of age adjusted cut-off values for D-dimer tests substantially increases specificity without modifying sensitivity, thereby improving the clinical utility of D-dimer testing in patients aged 50 or more with a non-high clinical probability.

Validation of two age dependent D-dimer cut-off values for exclusion of deep vein thrombosis in suspected elderly patients in primary care: retrospective, cross sectional, diagnostic analysis

Objective To determine whether the use of age adapted D-dimer cut-off values can be translated to primary care patients who are suspected of deep vein thrombosis. Design Retrospective, cross sectional diagnostic study. Setting 110 primary care doctors affiliated with three hospitals in the Netherlands. Participants 1374 consecutive patients (936 (68.1%) aged >50 years) with clinically suspected deep vein thrombosis. Main outcome measures Proportion of patients with D-dimer values below two proposed age adapted cut-off levels (age in years×10 μg/L in patients aged >50 years, or 750 μg/L in patients aged ≥60 years), in whom deep vein thrombosis could be excluded; and the number of false negative results. Results Using the Wells score, 647 patients had an unlikely clinical probability of deep vein thrombosis. In these patients (at all ages), deep vein thrombosis could be excluded in 309 (47.8%) using the age dependent cut-off value compared with 272 (42.0%) using the conventional cut-off value of 500 μg/L (increase 5.7%, 95% confidence interval 4.1% to 7.8%). This exclusion rate resulted in 0.5% and 0.3% false negative cases, respectively (increase 0.2%, 0.004% to 8.6%).The increase in exclusion rate by using the age dependent cut-off value was highest in the oldest patients. In patients older than 80 years, deep vein thrombosis could be safely excluded in 22 (35.5%) patients using the age dependent cut-off value compared with 13 (21.0%) using the conventional cut-off value (increase 14.5%, 6.8% to 25.8%). Compared with the age dependent cut-off value, the cut-off value of 750 μg/L had a similar exclusion rate (307 (47.4%) patients) and false negative rate (0.3%). Conclusions Combined with a low clinical probability of deep vein thrombosis, use of the age dependent D-dimer cut-off value for patients older than 50 years or the cut-off value of 750 μg/L for patients aged 60 years and older resulted in a considerable increase in the proportion of patients in primary care in whom deep vein thrombosis could be safely excluded, compared with the conventional cut-off value of 500 μg/L.

Accuracy of the Wells Clinical Prediction Rule for Pulmonary Embolism in Older Ambulatory Adults

To determine whether the Wells clinical prediction rule for pulmonary embolism (PE), which produces a point score based on clinical features and the likelihood of diagnoses other than PE, combined with normal D‐dimer testing can be used to exclude PE in older unhospitalized adults.

Need for tailored strategies to diagnose venous thrombo-embolism in older primary care patients. Extension of a keynote presentation at the 2012 Wonca Europe conference

Abstract Venous thrombo-embolism (VTE, pulmonary embolism and deep vein thrombosis) is common in the elderly and short-term mortality risk increases with age. Hence, notably in older patients, accurately diagnosing VTE can be lifesaving. However, most clinically suspected individuals turn out to have no VTE after imaging examination. Therefore, many physicians would feel reluctant to refer older patients as this can be very burdensome for these patients. Consequently, it is possible that elderly patients are often not referred for diagnostic work-up (risk of under diagnosis), or that treatment for VTE is initiated without confirmation by further testing (risk of overtreatment). Moreover, anticoagulation treatment of VTE is associated with a higher bleeding risk in the elderly. This bleeding risk might even outweigh the potential benefits in some of these patients. Therefore, availability of an accurate diagnostic strategy to safely exclude, and timely diagnose VTE without the need of burdening referrals in many patients might better serve the needs of older patients. Such strategies have been derived and validated in both primary and secondary care patients suspected of VTE. However, the generalizability of these strategies to older patients may be hampered, and their accuracy has never been tested in elderly populations; this in spite of the high prevalence of VTE and the potential for misdiagnosis and thus mistreatment in these patients. Therefore, we advocate validation and adaptation of current diagnostic strategies for VTE for application in elderly patients.

Response to Richard Schreiber: Diagnosing Pulmonary Embolism in Frail Older Adults Out of the Hospital

dimer tests, there would have been at least five more participants with confirmed PE. Recalculating the total number of participants with PE with a low score but an abnormal D-dimer brings the total to 25 of 98 (24.5%). The newly recalculated false-negative rate is 0, and the sensitivity of a Wells score of 4 or less combined with a negative bedside D-dimer rises from 92.2% to 100%. The specificity of an unlikely Wells score but with a positive D-dimer does not change, although the negative predictive value rises from 94.1% to 100%, and the positive predictive value rises from 50.8% to 52.9%. The study protocol called for clinicians to “refrain from referral in all other individuals (unlikely risk: ≤4 points).” Why then did these five individuals have further tests? Furthermore, we do not know whether there were more individuals with low scores and high D-dimers who had PE, nor do we know if all individuals with high scores had PEs. (Only 62% were tested, contrary to the study protocol.) These are not so much “irregularities” as they are protocol violations. All studies suffer from some deviations, but when as many as 40% of participants are not followed per protocol, it is difficult to draw reliable conclusions. Based on these deficiencies in the methodology and follow-up, the only valid conclusions are that the selection of a bedside D-dimer test must be based on vigorous evaluation of its testing characteristics in the individuals on whom it will be used, one must follow a rigorous testing algorithm to ensure that individuals with this potentially fatal disease are detected and that those who do not have the disease are not treated with potentially life-threatening treatment, and clinicians must make vigorous efforts to follow up with these individuals. The authors assert that theirs is the first study that focuses on older adults, but there was one study on elderly adults seen in emergency departments and inpatients in 2012 and another in outpatients in March 2014.