The diagnostic value of D-dimer with simplified Geneva score (SGS) pre-test in the diagnosis of pulmonary embolism (PE)

Pulmonary embolism (PE) is a fatal condition which is induced by thromboembolus occluding the main pulmonary artery or its branches [1]. It is the third most common acute cardiovascular syndrome after myocardial infarction and stroke [2]. In American, it is estimated that venous thromboembolism, including PE and deep-vein thrombosis (DVT), may induce300 000 deaths every year using a modeling method [3]. Owing to using of more effective interventions and better adherence to guidelines, the mortality rate of acute PE has been reducing in many areas of the world [4‐7]. However, it is also reported that there is an over-diagnosis in the diagnosis of PE in the current [8], this may in turn induce a fake decline of mortality rate to a certain extent. We consider that improving efficiency of PE detection methods and optimizing the detection process would be great benefit for the clinical outcomes of acute PE.

dimerA highly sensitive D-dimer test is available for venous thromboembolism diagnosis by exclusion without further testing [9]. Less sensitive, but more specific D-dimer detection exhibits advantages in identifying the patients with low thromboembolism risk [10]. Recent research has indicated that patients with the levels of D-dimer higher than 2.15 mg/L have a notable increased risk of PE [11]. It is hinted that the role of D-dimer on PE diagnosis test should be expanded, except for exclusion diagnosis of PE. According to the ESC guidelines, CTPA is the clinical “gold standard” for the diagnosis of PE [12].

The Geneva score is a clinical prediction rule to assess PE pre-test probability [12]. The original Geneva score was developed by Jacques Wicki et al. in 2001 [13]. To enhance clinical applicability and practicability, it has been simplified [14, 15]. Due to the limited sensitivity in the diagnosis of PE [16], the Geneva score is suggested to use in early assessment of PE clinical (pre-test) probability [12]. In present study, a retrospective analysis of 1035 cases of patients with suspected PE was carried out, and all the patients were performed with simplified Geneva score (SGS) assessment, D-dimer levels evaluation, and CTPA detection. We aimed to determine the D-dimer cutoff point for PE risk in patients with pre-test of SGS, and the patients with a D-dimer levels higher than that should be accepted further CTPA detection coercively.

It is well investigated that D-dimer test has a good performance in PE ruling-out diagnosis [9, 12, 17]. On the other hand, several studies based on ROC curves have illustrated that high levels of plasma D-dimer (1.96 mg/L in present study) in patients are associated with significant risk for PE incidence [11, 18‐20]. However, the best D-dimer cutoff point level for significant PE risk is quite different in these studies. In the first study (PE confirmed patients/study population = 134/370), it was reported that the best D-dimer cutoff level for significant PE risk = should be 2.152 mg/L (AUC, 0.69; 95% CI, 0.64–0.74; p < 0.05) [11]. In the second study (PE confirmed patients/study population = 48/544), the optimal D-dimer cutoff point for significant PE risk was determined to be 0.9 mg/L (AUC, 0.76; 95% CI, 0.69–0.82; p < 0.001) [18]. In the third study (PE confirmed patients/study population = 40/80), the authors have declared a best D-dimer cutoff point for significant PE risk of 0.83 mg/L (AUC, 0.762; 95% CI, 0.653–0.850; p < 0.05) [19]. In the aspect of confirmation of D-dimer cutoff point for significant PE risk, our finding is similar to the first study. Meanwhile, compared with previous studies, our study has the largest investigation population (n = 1035) in which the number of PE confirmed patients is 294(28.41%). In the last two studies [18, 19], it is limited in terms of both research population and PE confirmed patients. It was also reported that the age is an important factor while evaluating D-dimer levels for PE diagnosis [21, 22]. But considering that age is one of the SGS items, we did not discuss the age factor independently in our research.

The sensitivity of Geneva score in diagnosis of PE was previously reported as 0.208 in Japanese population [16], which is generally consistence with that in present study (SGS sensitivity, 0.241; data not shown). The specificity of Geneva score for PE diagnosis is relatively high as 0.731 in our study (Data not shown). Combination D-dimer testing and Geneva scores in the diagnosis of PE could improve the diagnostic accuracy and utility of the diagnostic criteria [17, 22]. In our study, the ROC curves were constructed to assess the diagnostic value of D-dimer testing in both PE-likely (SGS ≥ 3) and PE-unlikely (SGS ≤ 2) patients. Our results showed that in patients with SGS ≤ 2, the AUC of the ROC curve raise from 0.328 to 0.722 (comparison with commonly used cutoff point level of 0.5 mg/L). In patients with SGS ≥ 3, the D-dimer optimal cutoff point for significant PE risk moved to the level of 2.2 mg/L, and the PPV increased from 0.345 to 0.476 (comparison with commonly used cutoff point level of 0.5 mg/L).

According to the guidelines for diagnosis and management of acute pulmonary embolism (PE) in 2019, the PPV of D-dimer test is low and D-dimer test is not suggested to applicate in PE confirmation [12]. However, our results revealed that patients with D-dimer levels higher than 1.96 mg/L have a significant risk for PE, in other words, D-dimer may have potential prognostic value in the PE diagnosis. Moreover, lung cancer in patient plays a positive role in PE incidence and poor prognosis [23]. In our study population, there were 68 patients suffered from lung cancer, 28 (41.2%) of which were confirmed with PE. The incidence rate of PE in patients with lung cancer is much higher than 28.4% of the overall study population. Therefore, it is necessary to investigate the prognostic value of D-dimer test for PE diagnosis in patients with lung cancer if large sample size is collected.

In our study, when using the D-dimer commonly used cutoff point (0.5 mg/L) to rule-out PE, 11.6% patients with normal D-dimer levels and confirmed PE would not be excluded by D-dimer testing effectively. Meanwhile, in the patients with PE, 10.9% (32 of 294) had normal levels of D-dimer, which was slightly higher than those reported in most studies, 5.2% (7 of 134) (11), 3.6% (2 of 55) [24], 4% (29 of 725) [25], and 27% (8 of 30) [26]. In present study, we desire to establish optimized test process for PE confirmation through combination SGS pre-test and D-dimer detection in large sample size. CTPA should be our final measure for PE confirmation in patients with high PE risk in our ideal testing process.

There were some limitations in our study. This was a retrospective analysis, and most of the study individuals were hospitalized patient with complex conditions. Plasma D-dimer concentration could be promoted in patients with cancer [27], during pregnancy [28], and in hospitalized patients [29]. Moreover, due to limited sample size of patients with lung cancer, we cannot analyze the D-dimer cut-off point levels for PE diagnosis in this separated population.

In summary, D-dimer test in combination with SGS pre-test could improve the accuracy of PE diagnosis. Patients with D-dimer levels over 1.96 mg/L (4 times of the normal level) have a significant risk for PE. In addition, in patients with SGS ≥ 3, the D-dimer cutoff point concentration for PE risk moves to the level of 2.2 mg/L. CTPA should be a compulsive measure for PE confirmation in patients with a high level of D-dimer.