Age-Adjusted D-Dimer Cut-off Levels to Rule out Pulmonary Embolism: A Prospective Outcome Study
Authors: Righini Marc , Exter Paul den , van ES Josien , Verschuren Franck , Ghuisen Alexandre , Rutschman Olivier , Schotté Thibault , Sanchez Olivier , Jaffrelot Morgan , Karre Meissa , Peudepiece Pascal , Schmidt Jeannot , Principe Alessandra , van Houten Anja A , Wolde Marije Ten , Douma Renée A , Hazelaar Germa , Erkens Petra MG , Van Kralingen Klaas , Grootenboers Marco , Durian Marc F , Cheung Whitney , Bounameaux Henri , Huisman Menno V. , Kamphuisen Pieter W. , Le Gal Gregoire 
Published: October 2019

Abstract

Introduction
D-dimer testing allows to safely rule out pulmonary embolism (PE) without imaging test in approximately one third of outpatients. However, D-Dimer test is less useful as age increases because of a lower specificity. We recently derived an age-adjusted D-dimer cut-off value (age-adjusted cut-off = patient’s age x 10 in patients aged > 50 years, in μg/L), which allowed to significantly increase the proportion of patients in whom PE could be non-invasively excluded, without compromising safety. However, before being implemented in clinical practice, the safety of the age-adjusted cut-off should be verified in a management outcome study.

Methods
We designed a multicentre multinational prospective management outcome study. All consecutive outpatients seen in the emergency room of 22 centres in 4 countries with clinically suspected PE were assessed by a sequential diagnostic strategy based on the assessment of clinical probability, D-dimer measurement and computed tomography pulmonary angiography (CTPA). Patients with a D-dimer value between the usual threshold of 500 μg/L and their age-adjusted cut-off did not undergo CTPA and were left untreated and formally followed for a three-month period.

Results
Between January 1, 2010 and February 28, 2013, we included 3,377 patients. Mean age was 62 years, and 57% were females. Overall, the proportion of confirmed PE was 18%. Among the 2,927 patients with a non-high clinical probability, 832 (28.4%) had a D-Dimer < 500 μg/L, and 345 additional patients (11.8%) had a D-Dimer comprised between 500 μg/L and their age-adjusted cut-off. During the 3-month follow-up period, out of the 345 patients with a D-Dimer between 500 μg/L and their age-adjusted cut-off, 18 patients received anticoagulation for another indication than PE. Of the remaining 327 patients, 7 died, and 7 underwent testing for suspected venous thromboembolism (VTE), of which one was confirmed. Therefore, the failure rate of the age-adjusted cut-off was 1/327: 0.3%, (95% CI 0.1 to 1.7%).
Overall, 789 patients were aged 75 years or more, of them 697 had a non-high clinical probability. The proportion of patients with D-Dimer < 500 μg/L was 50/697 (7.2%). Another 161 patients had a D-Dimer above 500 μg/L and under their age-adjusted cut-off. Therefore, the proportion of patients > 75 with a negative D-Dimer using the age-adjusted cut-off was 211/697 (30.3%), of them none had a confirmed VTE during follow-up: 0.0%, (95%CI: 0.0 to 1.9%).

Conclusions
Our study demonstrates that the age-adjusted D-Dimer cut-off may now be used in clinical practice in emergency room patients with suspected PE. Combined with clinical probability, it increases the number of patients in whom PE can be excluded without imaging test, and this is particularly true among elderly patients, with a four-fold increased yield of D-dimer. A D-Dimer above 500 μg/L but under the age-adjusted cut-off safely excludes the diagnosis of PE, with a 3-month risk of VTE in line with that observed in patients with a D-Dimer under 500 μg/L or after a negative pulmonary angiography, the gold-standard test for PE.

Disclosures:
No relevant conflicts of interest to declare.